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HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
January 2005
Ministry of Health
Acknowledgments
The authors wish to thank the Ethiopian Ministry of Health. The authors would also
like to thank the International Training and Education Center on HIV (I-TECH), the
U.S. Centers for Disease Control and Prevention (CDC), and private practitioners for
their contributions in the development of the training curriculum.
Printing and distribution of training course materials has been made possible by
funding from the U.S. Centers for Disease Control’s Global AIDS Program (GAP),
with additional assistance from the International Training and Education Center on
HIV (I-TECH).
HIV Care & ART for Pharmacists
Reference Manual for Trainers
Introduction
ii
Table of Contents
Acknowledgements ...................................................................................................................ii
Table of Contents..................................................................................................................... iii
Section One: Introduction
Training Schedule ..................................................................................................... 1-1
Glossary of Terms ..................................................................................................... 1-2
Pre and Post Test Answer Key ................................................................................. 1-9
Section Two: About this Course
I.
II.
III.
IV.
V.
VI.
What will I teach in this course? .......................................................................... 2-2
How is this course organised? ............................................................................ 2-2
What ground rules are used during the training course? .................................... 2-3
How will this course be evaluated?..................................................................... 2-4
What are the course materials? .......................................................................... 2-4
How can I teach this course most effectively? .................................................... 2-5
Section Three: Course Units
Unit 1: HIV Epidemiology, ART in Ethiopia, and the Pharmacist’s Role .................. 1-1
Unit 2: Stages of HIV Disease and Initiation of Treatment ....................................... 2-1
Unit 3: Clinical Pharmacology of Antiretroviral Therapy ........................................... 3-1
Unit 4: Changing Therapy ........................................................................................ 4-1
Unit 5: Significant Drug Interactions with Antiretroviral Therapy .............................. 5-1
Unit 6: Women and HIV & ART in Pregnancy .......................................................... 6-1
Unit 7: Importance of Adherence for ART Success.................................................. 7-1
Unit 8: Prophylaxis and Treatment of Opportunistic Infections ................................ 8-1
Unit 9: TB and HIV Co-infection ............................................................................... 9-1
Unit 10: ART in Children.......................................................................................... 10-1
Unit 11: Communicating with Patients and Providers ............................................. 11-1
Unit 12: Universal Precautions and Post-Exposure Prophylaxis............................. 12-1
Refer to the Course Workbook for more handouts, references and worksheets,
including the Pre and Post Assessments and Course Evaluation
HIV Care & ART for Pharmacists
Reference Manual for Trainers
Introduction
iii
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Section One
Introduction
Training Schedule
HIV Care and ART:
A Course for Pharmacists
Day 1
Registration
Welcome,
Opening
Ceremony
Course Agenda,
Housekeeping,
Introductions
Pre-Test
Assessment
Day 2
Day 3
Day 4
Day 5
Review of Day 1
and Day 2
Agenda
Review of Day 2
and Day 3
Agenda
Review of Day 3
and Day 4
Agenda
Review of Day 4
and Day 5
Agenda
Clinical
Pharmacology of
Antiretroviral
Therapy
Significant Drug
Interactions with
Antiretroviral
Therapy
Prophylaxis and
Treatment of
Opportunistic
Infections
Communicating
with Patients and
Providers
Changing
Therapy
Women, HIV, &
ART in
Pregnancy
TB and HIV Coinfection
Universal
Precautions and
Post-Exposure
Prophylaxis
ART in Children
HIV
Epidemiology,
ART in Ethiopia,
and the
Pharmacist’s
Role
HIV: Stages of
Disease &
Initiation of
Treatment
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Importance of
Adherence for
ART Success
Jeopardy!
Review Game
Post-Test
Assessment
Course
Evaluation
Presentation of
Certificates
Introduction
Section 1-1
Glossary of Terms
The definitions in this glossary were taken from the “Glossary of HIV/AIDS-related Terms”
compiled by UNAIDS and available at:
http://www.unaids.org/Unaids/EN/Resources/Terminology/glossary+of+hiv_aidsrelated+terms.asp. Terms not found in this UNAIDS database were defined by present and
previous trainers of “Training on the Use of the Namibia Guidelines for Antiretroviral Therapy”
and are indicated with an asterisk (*).
Abacavir (ABC)
A nucleoside reverse transcriptase inhibitor antiretroviral
medicine used in HIV infection with at least two other
antiretroviral medicines.
Aciclovir
Antiviral medicine used to treat the symptoms of herpes
simplex virus infection, herpes zoster virus (shingles), and
disseminated varicella zoster virus (chicken pox) in
immunocompromised patients.
Adherence
The extent to which a patient takes his/her medication
according to the prescribed schedule (also referred to as
'compliance').
AIDS
Acquired Immune Deficiency Syndrome. The most
severe manifestation of infection with the human
immunodeficiency virus (HIV).
AIDS Defining Conditions
Numerous opportunistic infections and neoplasms
(cancers) that, in the presence of HIV infection, constitute
an AIDS diagnosis. Persons living with AIDS often have
infections of the lungs, brain, eyes and other organs, and
frequently suffer debilitating weight loss, diarrhoea, and a
type of cancer called Kaposi's sarcoma.
ARV
Antiretroviral. Drug used to fight infection by retroviruses,
such as HIV infection.
ART or ARVT
Antiretroviral Therapy. A treatment that uses antiretroviral
medicines to suppress viral replication and improve
symptoms.
Asymptomatic
Without symptoms. Usually used in the HIV/AIDS
literature to describe a person who has a positive reaction
to one of several tests for HIV antibodies but who shows
no clinical symptoms of the disease.
CD4 Cells
1. A type of T cell involved in protecting against viral,
fungal and protozoal infections. These cells normally
orchestrate the immune response, signaling other cells
in the immune system to perform their special
functions. Also known as T helper cells.
2. HIV's preferred targets are cells that have a docking
molecule called 'cluster designation 4' (CD4) on their
surfaces. Cells with this molecule are known as CD4positive (or CD4+) cells. Destruction of CD4+
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Introduction
Section 1-2
lymphocytes is the major cause of the
immunodeficiency observed in AIDS, and decreasing
CD4+ lymphocyte levels appear to be the best indicator
for developing opportunistic infections.
CD4 Receptors
The chemical on the surface of a CD4 lymphocyte to
which HIV attaches.*
CD4 Count
A way of measuring immuno-competency by counting the
lymphocytes that carry the CD4 molecule. Normal is well
over 1000/ml of blood. A count lower than 200 ml is an
indicator of AIDS.*
Combination Therapy
(For HIV infection or AIDS.) Two or more drugs or
treatments used together to achieve optimum results
against infection or disease. For treatment of HIV, a
minimum of three antiretrovirals is recommended.
Combination therapy may offer advantages over singledrug therapies by being more effective in decreasing viral
load. An example of combination therapy would be the
use of two nucleoside analogue drugs (such as
lamivudine and zidovudine) plus either a protease inhibitor
or a non-nucleoside reverse transcription inhibitor.
Combivir
A combined pill containing zidovudine and lamivudine that
was USFDA-approved in 1997 for the treatment of HIV
infection in adults and adolescents 12 years of age or
older.
Didanosine (ddI)
A nucleoside reverse transcriptase inhibitor antiretroviral
medicine used in HIV infection with at least two other
antiretroviral medicines.
DNA
Deoxyribonucleic acid. Except for a few viruses, all living
cells carry their genetic information in the form of DNA.*
Efavirenz (EFV or EFZ)
A non-nucleoside reverse transcriptase inhibitor for
combination use with at least two other antiretroviral drugs
for adults and children with HIV infection. Contraindicated
in pregnancy; substitute nevirapine for efavirenz in
pregnant women or women for whom effective
contraception cannot be assured.
Efficacy
(Of a drug or treatment). The maximum ability of a drug or
treatment to produce a result, regardless of dosage. A
drug passes efficacy trials if it is effective at the dose
tested and against the illness for which it is prescribed.
ELISA Test
Acronym for enzyme-linked immunosorbent assay. A type
of enzyme immunoassay (EIA) to determine the presence
of antibodies to HIV in the blood or oral fluids. Repeatedly
reactive (i.e. two or more), ELISA test results should be
validated with an independent supplemental test of high
specificity, such as the Western blot test.
Epidemiology
The branch of medical science that deals with the study of
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Introduction
Section 1-3
incidence, distribution and control of a disease in a
population.
Fusion
The stage of the HIV lifecycle in which the virus binds to
the CD4 receptor, activates other proteins on the surface
of the cell, then fuses with the T helper or macrophage
cell.*
Fusion Inhibitor (FI)
A category of ARV drugs that are designed to attack the
fusion stage of the HIV lifecycle. Drugs in this category
are not currently available in most resource-limited
settings.*
Generics
All drugs carry a generic name—an INN (International
Non-proprietary Name)—which is the official name given
to the molecule/medicine.
HAART
Highly Active AntiRetroviral Therapy. The name given to
treatment regimens recommended by leading HIV experts
to aggressively suppress viral replication and progress of
HIV disease. The usual HAART regimen combines three
or more different drugs such as two nucleoside reverse
transcriptase inhibitors and a protease inhibitor, two
NRTIs and a non-nucleoside reverse transcriptase
inhibitor or other combinations.
HIV
Human Immunodeficiency Virus. The virus that weakens
the immune system, ultimately leading to AIDS.
HIV-1
Human Immunodeficiency Virus Type 1. The retrovirus
isolated and recognized as the etiologic (i.e. causing or
contributing to the cause of a disease) agent of AIDS.
HIV-1 is classified as a lentivirus in a subgroup of
retroviruses. Most viruses and all bacteria, plants, and
animals have genetic codes made up of DNA, which uses
RNA to build specific proteins. The genetic material of a
retrovirus such as HIV is the RNA itself. HIV inserts its
own RNA into the host cell's DNA, preventing the host cell
from carrying out its natural functions and turning it into an
HIV factory.
HIV-2
Human Immunodeficiency Virus Type 2. A virus closely
related to HIV-1 that has also been found to cause AIDS.
It was first isolated in West Africa. Although HIV-1 and
HIV-2 are similar in their viral structure, modes of
transmission, and resulting opportunistic infections, they
have differed in their geographical patterns of infection.
HIV Antibody Test
If positive, the results of this test indicate that the person
has been exposed to HIV and has developed antibodies
to the virus after the window period of up to 12 weeks has
passed.
Immunodeficiency
Breakdown in immunocompetence (i.e. the ability of the
immune system to resist or fight off infections or tumors)
when certain parts of the immune system no longer
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Introduction
Section 1-4
function. This condition makes a person more susceptible
to certain diseases.
Immune Reconstitution
Syndrome
As the number of CD4 cells increases in a patient on
HAART, these cells recognize antigens to which the
patient has been previously exposed, leading to
symptoms of the diseases these antigens represent, e.g.
TB. Actual infection may or may not be present.*
Immunology
The study of the immune system.*
Incidence
The number of new cases within a specific period of time.*
Integrase
An enzyme used to integrate HIV DNA into the host cell’s
own DNA.*
Interferon
A protein that can inhibit the development of a virus in a
cell.
Lamivudine (3TC)
A nucleoside reverse transcriptase inhibitor antiretroviral
medicine used in HIV infection with at least two other
antiretroviral medicines.
Lopinavir
A protease inhibitor antiretroviral drug used in
combination with two other antiretroviral medicines.
Maternal Antibodies
Antibodies passed from mother to fetus during pregnancy.
Diagnosis of HIV through antibody testing for infants
under 18 months is complicated by maternal antibodies.
MTCT
Acronym for “mother-to-child transmission.”
Nelfinavir (NFV)
A protease inhibitor antiretroviral medicine used for the
treatment of HIV infection in combination with two other
antiretroviral medicines.
Nevirapine (NVP)
A non-nucleoside reverse transcriptase inhibitor used in
HIV infection in combination with at least two other
antiretroviral drugs; used in prevention of mother-to-child
transmission in HIV-infected patients.
NNRTI
Non-Nucleoside Reverse Transcriptase Inhibitors. A class
of drugs that inhibit an enzyme used by HIV called
“reverse transcriptase.” The non-nucleoside reverse
transcriptase inhibitors include efavirenz and nevirapine.
They interact with a number of drugs metabolized in the
liver; the dose of protease inhibitors may need to be
increase when they are given with efavirenz or nevirapine.
Nevirapine is associated with a high incidence of rash and
occasionally fatal hepatitis. Rash is also associated with
efavirenz but is usually milder. Efavirenz treatment has
also been associated with an increased plasma
cholesterol concentration.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Introduction
Section 1-5
NRTI
Nucleoside Reverse Transcriptase Inhibitors. A category
of ARV drugs that binds to the active site of the HIV
reverse transcriptase stopping the production of HIV DNA.
Drugs in this category include zidovudine (AZT),
didanosine (ddl), zalcitabine (ddC), stavudine (D4T),
lamivudine (3TC), and abacavir, zalctabine, tenofovir.*
Opportunistic Infections (OIs)
Illnesses caused by various organisms, some of which
usually do not cause disease in persons with healthy
immune systems. Opportunistic infections common in
persons diagnosed with AIDS include Pneumocystis
carinii pneumonia; Kaposi's sarcoma; cryptosporidiosis;
histoplasmosis; other parasitic, viral and fungal infections;
and some types of cancers.
PCR
Polymerase chain reaction. A laboratory method to find
and measure very small amounts of RNA or DNA. It is
used as the “viral load” test to diagnose HIV in infants and
to measure the level of HIV RNA in the blood of infected
persons.*
PEP
Post-Exposure Prophylaxis. The use of ARV therapy just
after a possible exposure to HIV has occurred.
Recommended after rape, an occupational exposure to
HIV (e.g. needlestick injury) or just after birth for infants
who are born to HIV infected mothers.*
PLWHA
Acronym for “person/people living with HIV/AIDS.”
PMTCT
Acronym for “prevention of mother-to-child transmission.”
Prevalence
The number of cases at any time during the study period,
divided by the population at risk.*
Protease
An enzyme used by HIV to process new copies of the
virus after it has reproduced; drugs specifically aimed at
this enzyme are called 'protease inhibitors' (see below).
Human cells also use protease enzymes, but they are
different from the HIV protease.
Protease Inhibitor (PI)
Antiviral drugs that act by inhibiting the virus protease
enzyme, thereby preventing viral replication. Specifically,
these drugs block the protease enzyme from breaking
apart long strands of viral proteins to make the smaller,
active HIV proteins that comprise the virion. If the larger
HIV proteins are not broken apart, they cannot assemble
themselves into new functional HIV particles. The
protease inhibitors include amprenavir, indinavir, lopinavir,
nelfinavir, ritonavir, and saquinavir.
RNA
Ribonucleic acid*
Rapid Test
Blood, saliva, urine, or vaginal secretions test for HIV that
yields same day results.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Introduction
Section 1-6
Resistance
The ability of an organism, such as HIV, to overcome the
inhibitory effect of a drug, such as AZT or a protease
inhibitor.
Retrovirus
A type of virus that, when not infecting a cell, stores its
genetic information on a single-stranded RNA molecule
instead of the more usual double-stranded DNA. HIV is an
example of a retrovirus. After a retrovirus penetrates a
cell, it constructs a DNA version of its genes using a
special enzyme called reverse transcriptase. This DNA
then becomes part of the cell's genetic material.
Reverse Transcriptase
This enzyme of HIV (and other retroviruses) converts the
single-stranded viral RNA into DNA, the form in which the
cell carries its genes. Some antiviral drugs approved by
the FDA for the treatment of HIV infection (e.g. AZT, ddI,
3TC, d4T, and ABC) work by interfering with this stage of
the viral life cycle. They are also referred to as reverse
transcriptase inhibitors (RTIs).
Ritonovir
A protease inhibitor antiretroviral medicine used in HIVinfection, as a booster to increase effect of indinavir,
lopinavir or saquinavir and in combination with two other
antiretroviral medicines.
Saquinavir (SQV)
A protease inhibitor antiretroviral medicine used in HIV
infection in combination with two other antiretroviral
medicines and usually with low-dose ritonavir booster.
Sentinel Surveys
This form of surveillance relates to a particular group
(such as men who have sex with men) or activity (such as
sex work) that acts as an indicator of the presence of a
disease.
Seroconversion
The development of antibodies to a particular antigen.
When people develop antibodies to HIV, they
'seroconvert' from antibody-negative to antibody-positive.
It may take from as little as one week to several months or
more after infection with HIV for antibodies to the virus to
develop. After antibodies to HIV appear in the blood, a
person should test positive on antibody tests. See
“Window Period”.
Side Effects
Medical problems that result from ARV rug toxicities.
Common side effects include: peripheral neuropathy,
lipodystrophy, hepatitis, pancreatitis, and lactic acidosis.*
STI
Also called venereal disease (VD), an older public health
term, or sexually transmitted disease (STD). Sexually
transmitted infections are spread by the transfer of
organisms from person to person during sexual contact.
Surveillance
The ongoing and systematic collection, analysis, and
interpretation of data about a disease or health condition.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Introduction
Section 1-7
Collecting blood samples for the purpose of surveillance is
called serosurveillance.
Symptomatic
Having evident signs of disease: weight loss, fever,
diarrhea, enlarged glands, oral candida, herpes, skin
problems.*
Transcription
The process of duplication or copying information from
DNA.*
Translation
The synthesis of proteins under the direction of RNA.*
VCT
Acronym for “voluntary counselling and testing.” Click
here for UNAIDS publications on VCT.
Viral Load
In relation to HIV: The quantity of HIV RNA in the blood.
Research indicates that viral load is a better predictor of
the risk of HIV disease progression than the CD4 count.
The lower the viral load the longer the time to AIDS
diagnosis and the longer the survival time.
WHO Staging System
A classification of the clinical stages of HIV disease
developed by the World Health Organization.*
Window Period
Time from infection with HIV until detectable
seroconversion.
During this time HIV antibody tests will be negative, even
though the person is infected. Ninety percent of infected
individuals will test positive within 3 months of exposure
and 10% will test positive within 3 to 6 months of
exposure.*
Zidovudine (ZVD or AZT)
HIV Care and ART for Pharmacists
Reference Manual for Trainers
A nucleoside reverse transcriptase inhibitor antiretroviral
medicine, zidovudine was the first antiretroviral drug to be
introduced. Used in HIV infection in combination with at
least two other antiretroviral drugs, and in monotherapy of
maternal-fetal HIV transmission.
Introduction
Section 1-8
Answer Key to Pre/Post-Test Assessment
The answers to the pre-test and post-test assessment are provided in detail in the
lecture slides. Multiple choice answers are listed below for grading purposes.
Copies of the pre-test assessment and post-test assessment are provided in the
Course Workbook.
1.
2.
3.
4.
5.
6.
7.
8.
9.
WHO staging: C
Pharmacology: D
Changing therapy: C
Drug interactions: C
Women and HIV: B
Adherence: C
OIs: A
TB: C
ART in children: A
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Introduction
Section 1-9
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Section Two
About This Course
I. What will I teach in this course?
The aim of the course is to equip pharmacists with sufficient knowledge of
antiretroviral medications available in Ethiopia to enable them to prescribe
appropriate treatment regimens, successfully manage treatment side effects, and
counsel patients effectively to increase treatment adherence.
At the end of the course, it is expected that participants will be able to:
•
Describe HIV epidemiology, the status of antiretroviral therapy in Ethiopia, and
the role of the pharmacist
Explain the WHO disease staging system and considerations when starting a
patient on ART
List the antiretroviral classes and common side effects of antiretrovirals
Understand the reasons for ART failure and for changing therapy
Explain drug interaction concepts and the management of interactions
Describe considerations when caring for HIV positive women and treating
pregnant HIV positive women
Understand the importance of adherence to care and adherence to ART
medications
Discuss the concept of resistance to antiretroviral drugs and how to proceed
when resistance arises
Determine prevention and treatment of opportunistic infections in HIV-infected
patients
Manage TB and HIV co-infected patients
Communicate effectively with providers and patients
Implement universal precautions and post exposure prophylaxis procedures
appropriately
•
•
•
•
•
•
•
•
•
•
•
II. How is this course organized?
The design of this course reflects the fact that participants are professional health
workers who are well-qualified and have experience in the field of HIV/AIDS. A
variety of approaches to teaching and learning will be adopted, with the underlying
assumption that participants are adult learners who will take considerable
responsibility for their own learning. The focus will be on experiential learning and
should emphasize the key knowledge and skills needed for pharmacists serving
individuals living with HIV/AIDS.
The course consists of a five-day facilitator-led program. It is comprised of 12 Units
and includes the following teaching/learning methods:
•
•
•
•
•
•
•
lecture
case studies
role plays
large and small group discussions
assignment work
individual work
small group work and discussions
HIV Care & ART for Pharmacists
Reference Manual for Trainers
About This Course
Section 2-2
Each session is approximately 2-3 hours. The sessions may be taught over the
course of several days or across several weeks. Participants should receive a
morning, lunch, and afternoon break if the training is all day. Be flexible in your
timing. The amount of time for each session will vary depending on participants’
experience with antiretroviral therapy and caring for HIV patients.
The knowledge and skills that participants bring to the course are important to the
learning process and participants are encouraged to share this knowledge and skills
and to raise issues that they find challenging in their practice.
III. What ground rules are used during the training
course?
To help ensure that time spent at the training is both productive and enjoyable, there
are some rules and procedures that we ask participants to follow. The following
information includes details on general procedures for the course and requirements for
completion of the course. These ground rules are not meant to constrain participants
but to contribute to a quality learning environment for everyone.
A.
Identifying Expectations
At the beginning of the course, ask participants what they expect to learn from the
course. Record this information on flip chart paper and keep it displayed for the
duration of the course. Identify which expectations are within the description of the
course and which fall outside. This will help participants understand what the course
will and will not cover.
B.
Determining Group Norms
It is important for course participants to establish and commit to their own group
norms on the first morning of the course. Lead a brief brainstorming exercise at the
beginning of the course to establish group norms. The following are examples of
group norms:
•
•
•
•
•
•
Respect each other’s confidentiality
Respect each other’s contributions, questions, and opinions
Be on time
Participate fully in discussions and exercises
If you must leave a session early, please inform the Course Director or
facilitator for that session before the session begins
Turn off mobile phones
HIV Care & ART for Pharmacists
Reference Manual for Trainers
About This Course
Section 2-3
IV.
How will this course be evaluated?
There are two methods used to assess and evaluate participant learning and the
usefulness of the course.
A.
Pre & Post-Test Assessment
An anonymous pre-test assessment and post-test assessment will enable course
coordinators to evaluate the transfer of knowledge. Provide participants 20 minutes
at the beginning of day one to complete the pre-assessment, and time at the end of
the last day to complete the same test again. Two copies of the pre-test assessment
are provided in the Course Workbook. Time permitting, review answers to the
assessment together as a group and/or distribute answers to participants as takehome materials. The answers to the pre/post tests are provided to trainers in
Section I of this Reference Manual.
B.
Course Evaluation Form
Ask participants at the end of each day to complete an anonymous Course
Evaluation Form to assess the content and delivery for each unit. Provide fifteenminutes at the end of the last day of training for participants to complete the form and
then collect them.
V. What are the course materials?
A.
Participant Handbook
Participants will receive a Participant Handbook, which serves as the primary
textbook for this course. This Handbook was developed to enhance learning and
participation in the course. The Participant Handbook contains the following
information to help participants succeed in the course:
Section I:
• Training Schedule
• Glossary of Terms
Section II:
•
Information About This Course
Section III:
• Unit Outlines
• Handouts to be used in the Unit
• Copies of PowerPoint Slides
• References
As you teach this course, refer participants as appropriate to the Participant
Handbook so that they can make use of the unit handouts and copies of PowerPoint
slides.
HIV Care & ART for Pharmacists
Reference Manual for Trainers
About This Course
Section 2-4
If the Participant Handbook is not available, facilitators can make copies of all
handouts and worksheets from their Reference Manual.
B.
Course Workbook
The Course Workbook is divided into two sections. The first section contains
reference materials that participants may refer to throughout the course. Section 2
contains worksheets that will be used during individual units. Participants should use
these as they work on group activities and case studies. Trainers should refer
participants to the Course Workbook as you teach each unit.
C.
Reference Manual for Trainers
This Reference Manual for Trainers was developed to enhance teaching and
effective facilitation of the 5-day ART course. The Reference Manual contains the
following information to help trainers succeed in teaching the course:
Section I:
• Training Schedule
• Glossary of Terms
• Answer Key to Pre and Post-Tests
Section II:
•
Information About this Course
Section III:
• Unit Outlines
• Handouts to be used in the Unit
• Copies of PowerPoint Slides with Facilitator Notes
• References
VI.
How can I teach this course most effectively?
There are six important things that you can do as a facilitator to help create an
effective learning atmosphere for yourself, faculty, and other facilitators.
A.
Master the content
Facilitators should thoroughly familiarize themselves with the curriculum. As a
facilitator, you should know: 1) Where issues raised in one presentation are
discussed at greater depth in a later presentation, 2) The issues that are and are not
covered in the five-day training, and 3) Where the curriculum offers trainers with
choices for presenting or not presenting, based on time and audience level of
knowledge. Finally, facilitators also need to know in advance of each day where
special preparation is required for that day.
HIV Care & ART for Pharmacists
Reference Manual for Trainers
About This Course
Section 2-5
B.
Prepare
There are a few specific tasks you must accomplish prior to implementing the course.
1. Customize the training schedule
A generic training schedule is included in Section One of the Reference
Manual. Customize this document with course dates and times.
2. Plan activities
Select methods for conducting introductions, reviewing expectations (See
III.A. above), and establishing group norms (See III.B. above). Identify
ice-breakers to use throughout the course to raise the energy level of the
group.
C.
Help to build an atmosphere of trust and support
One of the best ways to help build an atmosphere of trust and support is to listen
thoughtfully to the ideas of participants and provide constructive feedback that will
help improve the learning for everyone. Let someone know if they’ve said or done
something that you like. Learn and use people’s names. Look at individuals as they
are speaking, nod your head in understanding, or use facial expressions that indicate
“I’m listening.” Finally, assist participants if you see he or she is having a challenging
moment. The best learning takes place in a humane environment; help build one!
D.
Maintain a positive attitude
There will be times during the course when you might say to yourself, “I’m so tired!”
That’s okay to say because you will be working hard and expending a lot of energy
teaching new ideas to the participants. But try to stay positive and productive as you
participate in each session. Negativity does not support a quality learning
environment
E.
Involve others in the learning process
Participants are the most valuable resource in a training course. They help each
other learn through sharing relevant work experiences and providing different
perspectives. Ask participants questions, engage them in conversation, and ask
them to share relevant examples from their own work experience. Consider fellow
facilitators, faculty, and participants as resources, and the learning experience will be
enriched for all involved.
HIV Care & ART for Pharmacists
Reference Manual for Trainers
About This Course
Section 2-6
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Section Three
Course Units 1-12
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 1
HIV Epidemiology,
ART in Ethiopia, &
The Pharmacist’s Role
Unit 1: HIV Epi, ART in Ethiopia, & the Pharmacist’s Role
Aim: The aim of this unit is to provide participants with a background on HIV,
ART in Ethiopia, and the role of the pharmacist.
Learning Objectives: By the end of this unit, participants will be able to:
■ Explain local HIV epidemiology
■ Describe the current status of the ART program in Ethiopia
■ Define the role of the pharmacist in HIV care
■ Explain patient flow
■ Describe recordkeeping of HIV+ patients by physicians and
pharmacists
Unit Overview:
1 Hour
Activity/
Method
Content
Resources
Needed
Step
Time
1
30 minutes
Lecture
Epidemiology of HIV and ART
Status in Ethiopia (Slides 1.1 1.29)
Overhead or LCD
Projector
2
25 minutes
Lecture
Multidisciplinary Care (Slides 1.30
-1.49)
Overhead or LCD
Projector
3
5 minutes
Summary
Overview of Key Points (Slide
1.50)
Overhead or LCD
Projector
Resources Needed
•
Overhead or LCD Projector
•
One Handout: Patient Flow (Handout 1.1), located in the Participant
Handbook.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
HIV Epi, ART in Ethiopia, & Pharmacist’s Role
Unit 1-3
Key Points
1. AIDS impacts both the family and the national economy.
2. ART can reduce mortality due to AIDS in Ethiopia.
3. The success of ART depends on commitment at every level.
4. The pharmacist plays an important role as an ART educator for physicians,
nurses, and patients.
5. Careful recordkeeping is essential.
Step 1
Step 2
Step 3
Lecture (30 minutes)
•
This unit will to provide participants with a background on HIV,
ART in Ethiopia, and the role of the pharmacist.
•
Trainers should check and see if there is any more current
information available. For example, have demographics
changed? What about HIV prevalence in sub-Saharan Africa?
What is the current number of patients in Ethiopia on ART?
•
Begin by reviewing slides 1.3 - 1.29 of the PowerPoint
presentation, “HIV Epidemiology, ART Status in Ethiopia, and
the Pharmacist’s Role.” Ask the participants if they have any
questions about the objectives before continuing.
Lecture (25 minutes)
•
Present “Multidisciplinary Care of HIV-Positive Patients”
PowerPoint presentation (Slides 1.30 – 1.49).
•
Slide 32 - Refer to the “Patient Flow” Handout located in
Participant Handbook as necessary (Handout 1.1)
Summary (5 minutes)
•
Summarize the presentation, present Key Points in this Unit
(Slide 1.50), and answer any final questions.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
HIV Epi, ART in Ethiopia, & Pharmacist’s Role
Unit 1-4
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes
for reference during the planning and implementation of this course. The
facilitation notes and talking points are included in the “notes” section of the
accompanying PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
HIV Epi, ART in Ethiopia, & Pharmacist’s Role
Unit 1-5
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 1
HIV Epidemiology, ART Status,
& the Pharmacist’s Role
Unit 1
HIV Care and ART: A Course for Pharmacists
•
This unit should take approximately one hour to complete.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 2
Unit Learning Objectives
■ Explain local HIV epidemiology
■ Describe the current status of the ART program in
Ethiopia
■ Define the role of the pharmacist in HIV care
■ Explain patient flow
■ Describe recordkeeping of HIV+ patients by
physicians and pharmacists
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
2
•
We will begin this session by reviewing the local HIV epidemiology to better
understand the impact of the epidemic in Ethiopia
•
Next, we will be reviewing the current status of the ART program in Ethiopia
•
At the end of this session, you will be able to visualize the role of the pharmacist
in HIV care and better understand how the pharmacist fits into a team approach to
care.
•
Understanding how a patient flows through care will enable you to see where the
pharmacist can play a significant role in patient care.
•
Lastly, we will review the essential recordkeeping that is necessary to monitor
both adherence and response to therapy.
•
Does everyone understand what the objectives of this session are? Does anyone
have any questions about what will be covered?
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 3
Ethiopia’s Population
Demographics
■ Population
72.3 million
■ Female
50.2%
■ Household
5.9
■ Rural
85%
■ Age15 – 49
47%
■ GDP
$100
■ Literacy
36% (46%M, 25%F)
■ IMR
110 – 128/1000
■ MMR
560 – 850/100,000 lb
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
3
Ethiopia is a very young country. With a population of 72 million, nearly 50% are
aged 15-49. Half of the population are women. The majority of the population live
in rural areas.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 4
Ethiopia’s Population
Demographics (cont.)
■ Health Service Coverage
52%
■ EPI
42%
■ ANC
29%
■ Family Planning
6.5%
■ Hospitals
119
■ HC
365
■ Population:MD
50,273:1
■ Population:RPh
93,900:1
■ Per Capita Health Expenditure
$1.00
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
4
•
Only 50% of the population has health service coverage.
•
The ratio of patients to physician is extremely high. There are 50,000 people for
every 1 physician.
•
Many countries in sub-Saharan Africa do not meet he WHO’s minimum standards
for the number of physicians or nurses per 100,000 population. Shortages of
health professionals are exacerbated when doctors and nurses leave for better
positions and higher salaries in Western Nations.
•
There are only 70 pharmacists in Ethiopia to serve 72 million people.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 5
Global Health Crisis
It certainly did not spare Ethiopia
•
Significant progress has been made in the global response to AIDS, however the
response is inadequate. An estimated 1 million people throughout the world are
now using antiretroviral therapy- double the number who were receiving such
treatment two years ago.
•
As of June 2004, 440,000 people from low and middle income countries were
being treated. About 125,000 were from sub-Saharan Africa, where the burden is
the greatest, an increase of 100,000 in two years.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 6
HIV prevalence in adults
in SubSub-Saharan Africa, 19861986-2001
1986
1991
20 – 39%
10 – 20%
5 – 10%
1 – 5%
0 – 1%
trend data unavailable
1996
2001
outside region
01 July
2002 slide
number
SSA-5
Unit 1: HIV
Epi,
ART
Status,
& Pharmacist's Role
6
•
HIV prevalence is the amount of a population infected in a given time.
•
You can see that over time this number has increased, and as of 2001 the
prevalence remains 5-10%
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 7
Estimated HIV Prevalence and
Need for ART in Ethiopia
■ 1.5 million people living with HIV/AIDS at the end
of 2003
■ Prevalence is 4.4% among persons aged 15-49 at
the end of 2003
■ 200,000 in need of therapy in 2005
■ 4,500 adults receiving therapy as of June 2004
■ Antiretroviral therapy coverage 2.3%
NEJM Aug 19, 2004
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
7
•
This slide was not included in the participant’s manual
•
Recent data presented in the New England Journal of Medicine indicated that:
•
There are 1.5 million people in Ethiopia living with HIV/AIDS at the end of 2003
and 96,000 of them were children. The number of AIDS cases in 2003 was
estimated at 98,000 and 25,000 among adults and children, respectively.
•
The prevalence is 4.4% among persons aged 15-49 at the end of 2003
•
An estimated 200,000 will be in need of therapy in 2005
•
4,500 adults were receiving therapy as of June 2004
•
This demonstrates that current antiretroviral therapy coverage for those in need
to be 2.3%
•
Reference: The WHO estimates the needs for ART by calculating the number of
people who are expected to die from AIDS within two years and adding 80% of the
number currently receiving treatment.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 8
Historical Overview of
HIV/AIDS in Ethiopia
■ 1984
First evidence of HIV infection in Ethiopia
■ 1986
First two AIDS cases reported to Ministry
of Health
■ 1989
HIV/AIDS surveillance started
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
Reference Manual for Trainers
8
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 9
The HIV/AIDS Pyramid
in Ethiopia, 2001
15,202 Reported Cases
2001
Estimated 219,400
AIDS cases
Estimated 2.2
Million PLWHA
Number of Orphans
1.2 Million
•
Looking at the number of reported cases of HIV/AIDS in Ethiopia as of 2001, a
pyramid is an effective way of describing the problem.
•
15,000 cases were reported in 2001. However, the estimated AIDS cases
approach 220,000.
•
There are an estimated 2.2 million people living with HIV/AIDS
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 10
HIV Prevalence Estimates in
Ethiopia, 2003
■ National
4.4%
■ Urban
12.6%
■ Rural
2.6%
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
10
•
The prevalence of HIV in urban areas is higher than that in rural areas.
•
IN 2003, the national prevalence of HIV infection among adults was estimated at
4.4%. The range in prevalence in Ethiopia is between 2.6% in rural areas to
12.6% in urban areas.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 11
AIDS Projected Mortality
in Ethiopia
6
5
Millions
4
3
2
1
0
1984
1989
1994
1999
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
•
2004
2009
2014
11
Numbers of people infected by the virus and deaths from AIDS are expected to
increase over the years to come. The number of deaths due to AIDS is projected
to approach upwards of 5 million deaths 10 years from now. Scaling up of access
to treatment through a robust ART program is required to reverse the tide of the
epidemic.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 12
Projected Annual Mortality of
Age Group (15–49) in Ethiopia
500
Thousands
400
300
200
100
0
1984
1989
1994
1999
With AIDS Epidemic
2004
2009
2014
Without AIDS Epidemic
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
12
•
Compare the projected annual mortality of the young, aged 15-49 without the
AIDS epidemic to the projected mortality with the AIDS epidemic.
•
Projected deaths due to AIDS in the young is on the rise.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 13
Estimated & Projected AIDS
Orphans in Ethiopia
3
Millions
2
1
0
1984
1989
1994
1999
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
•
2004
2009
2014
13
Similarly, the estimated and projected AIDS orphans is expected to continue to
rise without effective interventions and therapy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 14
Impact on Rural Households
■ Loss of income (50% or more)
■ Loss of work force
■ Loss of management level skill & knowledge
■ Loss of land
■ Loss of remittances
■ Reduction in savings and investments
■ Expenses for treatment, funeral, teskar
■ Need to sell livestock to meet expenses
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
14
•
What is the impact of HIV/AIDS epidemic on families in rural areas?
•
Due to illness & lack of access to care, there is a dramatic impact on the work
force and loss of skill is the result.
•
When work is impacted it becomes more difficult to save money to support
families.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 15
Impact on Industry
■ Loss of workers
■ Expenses for recruiting/training replacements
■ Reduced productivity in cases of skilled workers or
managers
■ Lost days of work
■ Due to illness
■ 30 to 240 days per year
■ Due to funeral leave
■ Increased health care costs
■ 50% of illness due to AIDS
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
15
•
There is a larger impact on industry, loss of workers, reduced productivity of
available workers, lost days of work due to illness.
•
Also, increased health care costs.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 16
Access to Antiretroviral
Therapy
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
16
•
As you can see here, the percentage of adults who are receiving ART in Africa
is extremely low, only 2% are receiving treatment compared to 84% in the
Americas or compared to Europe, where nearly 20% of adults receive
treatment.
•
There are 28 million persons infected with HIV and an estimated 5 million who
have an AIDS diagnosis. The Ethiopia guidelines state that only 30,000
patients are estimated to be on ART in Africa.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 17
HIV/AIDS Deaths in 2001 and No. of
PLHAon ART by End 2001:
by Region
2,500
Thousands
2,000
HIV/AIDS Deaths
People using ARV drugs
1,500
1,000
500
0
SubSaharan
Africa
Asia
(excluding
Japan)
Latin
America &
Caribbean
Highly
Industrialized
Countries
Eastern
Europe &
Central Asia
North Africa
&
Middle East
Source: UNAIDS/WHO, 2002
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
17
•
This figure illustrates what we all know: the inverse relation between HIV/AIDSrelated deaths and the number of people using ARVs.
•
Compare the rates of death in sub-Saharan Africa to those in highly developed
countries and even in North Africa and the Middle East.
•
Note that in the past 2 years, 6 million people have died of AIDS and 10 million
have become infected.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 18
Status of ART in Ethiopia
■ ART Guidelines
■ ART Policy
■ ART Technical Work Group
■ ART training x 9 courses
■ August 2003 ARVs procured – AZT, d4T, 3TC,
NVP, EFV
■ For ~ 2,000 paying patients initially, then 8,000 paying
patients
■ Only < 2% of those who need it could afford to pay
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
18
•
Recent guidelines were published in August 2004 to assist practitioners,
including pharmacists in the care of the HIV infected patient
•
As of August 2003, 5 antiretroviral medications had been procured
•
•
There was enough medication available to treat 2000 paying patients
initially, then 8000 paying patients
However, less than 2% of those who need ART could afford to pay for it.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 19
Status of ART in
Ethiopia (cont.)
■ Currently ~ 5,000 patients are on ART
■ All regions except Afar, Benshangul & Somali
have started ART program
■ Some are NGO sponsored
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
19
•
As we saw earlier, it is estimated that 200,000 will be in need of therapy by 2005.
•
Currently 5000 are on ART
•
All regions except Afar, Benshangul & Somali have started ART program
•
Some are NGO sponsored
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 20
Concerns
■ Government
■ Competing demands
■ Famine, TB, Malaria
■ Sustainability
■ Technical experts
■ Inadequate access to trained HIV practitioners including
pharmacists
■ Unknown susceptibility profile
■ Inadequate capacity
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
•
20
What are some of the concerns with bringing ART to the country?
Government
•
Competing demands
• Famine, TB, Malaria
•
Sustainability- in order for the ART program to be successful, there must be a
certainty that the medications will continue to be made available, also, as more
patients are treated, the need for more expensive medication will need to be
made available to treat the patients who have become treatment experienced.
Technical experts
•
Inadequate access to trained HIV practitioners including pharmacists.
Pharmacists in the field are forced to learn about ART care during their practice
instead of learning in pharmacy school.
•
Unknown susceptibility profile it is unknown if the available regimens will be
effective without resistance testing to guide therapy.
•
Inadequate capacity to monitor laboratory parameters to detect either success
or failure of therapy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 21
Silver Lining
■ Global fund
■ Bush’s initiatives:
■ PMTCT
■ PEPFAR:
P 7,
T 2,
C 10 by 2008
■ WHO initiative:
■ 3x5
■ Overall: in FY ’04 there will be enough money from the US
and UN to start 30,000 patients on ART
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
21
•
There are substantial funding mechanisms, such as the global fund to fight
AIDS, TB and Malaria and from the US, the president's emergency plan for AIDS
relief.
•
The WHO has set a goal to treat 3 million persons in the developing world on
ART by the year 2005. This would be a 12 fold increase in less than 3 years.
•
Overall in the fiscal year 2004, there will be enough money from the US and UN
to start approximately 30,000 patients on ART.
•
At the 15th International AIDS Conference in Bangkok, it was said that the
worldwide response has entered a “new phase”…finally political, technical and
financial resources are starting to move. (Dr. Peter Piot, the executive director of
the Joint United Nations Program on HIV/AIDS (UNAIDS) . The world opinion
has shifted significantly in favor of providing access to ART in developing
countries.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 22
FY ’04 ART Roll Out Plan
■ National PMTCT program has been launched
■ First draft of National ART Implementation Plan will
be out end of this month
■ ITECH/CDC will roll out ART to 25 sites, and MOH
will add another 20 sites
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
22
•
National PMTCT program has been launched.
•
First draft of National ART Implementation Plan will be available soon.
•
ITECH/CDC will roll out ART to 25 sites, and MOH will add another 20 sites.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 23
Ethiopia’s ART Program
■ Enrollment of at least 35, 000 patients
■ 15,000 PEPFAR
■ 20,000 Global Fund
■ Nation-wide in all 11 regions
■ Will start with 52 hospitals (27 PEPFAR, 25 GF)
that will prescribe ART
■ 104 health centers (54 PEPFAR and 50 GF) may
follow stable patients on ART, including refilling
their Rx
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
23
•
Although ART is only one component of the response to AIDS, it is important as
any other. Medications not only treat the infection, but also prevent many of the
life-threatening complications of AIDS.
•
At the moment, we are integrating PEPFAR and GF programs into one national
ART rollout plan.
•
The goal is enrollment of at least 35,000 patients.
•
Nation-wide in all 11 regions.
•
Will start with 52 hospitals (27 PEPFAR, 25 GF) that will prescribe ART.
•
104 health centers (54 PEPFAR and 50 GF) may follow stable patients on ART,
including refilling their Rx.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 24
What Will be the
Pharmacist’s Role?
■ Train ART-specialty pharmacists
■ Become part of multidisciplinary ART team, first at your site,
then help train others in your region to establish the same
■ Establish the pharmacist’s role as an ART information
resource for physicians and nurses in your area
■ Establish the pharmacist’s role as an informational resource
for patients
■ Counsel patients about their medications
■ ITECH/CDC will provide technical and material assistance
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
24
•
The first step is to train pharmacists who specialize in HIV care.
•
These pharmacists will become integrated in the multidisciplinary ART team
along with physician and nurses.
•
•
They will establish a presence in their setting and will serve as an
information resource to MDs and RNs.
•
The next step will be to train others in your region to establish the same
role in their area of practice.
The pharmacist will then become more visible to patients as an informational
resource.
•
Pharmacists will be able to take a more active role in counseling of
patients
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 25
ART Care Model
(Adherence Protocol)
Multidisciplinary (Team) effort:
Social worker
Physician
Nursing
Patient
Nutritionist
Pharmacist
Minimum Team Members: MD, RN, RPh
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
Gabre-Kidan, T, MD, I-TECH, 2003
25
•
This is a depiction of how the multidisciplinary team interacts.
•
Does everyone know what is meant by a multidisciplinary team?
•
How do you envision that these individual team members could work together
to provide a more comprehensive care plan for a patient?
•
The minimum team members include a MD. RN and Rph. Each contributes from
their area of expertise to best address the needs of the patient. As the diagram
depicts, each discipline is connected to the other as information is shared.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 26
Assignment
■ Think about how you could change your current
practice setting to allow you to counsel patients
about ART and share your medication expertise
with physicians
■ Establish a network of communication with doctors
and pharmacists in your region
■ Let ITECH know if you need help
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
26
•
Think about how you could change your current practice setting to allow you to
counsel patients about ART and share your medication expertise with
physicians.
•
Establish a network of communication with doctors and pharmacists in your
region.
•
It is through sharing of information that we learn best from each other.
•
Let ITECH know if you need help.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 27
Continuum of Care Model
OI prophylaxis
OI treatment
ART
PMTCT &
PMTCT +
VCT
STI care &
prevention
Palliative Care
TB Care &
prevention
As committed providers, we
expect & plan to deliver no
less than comprehensive
care to our patients
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
Guidelines and Algorithms
Medication Purchasing, Storage,
Distribution and Control System
Clinical Training
Clinical and Laboratory
Monitoring
27
Adherence Support
•
Treatment of the patient involves many different levels of care and involves
each discipline at some step of the way.
•
Preventative services help to reduce the number of new infections, help to
prevent the number of opportunistic infections.
•
Ultimately the goal is to provide ART for those patients who require therapy to
prevent further immune function deterioration.
•
This step is only successful when it is combined with proper
distribution of medication (by pharmacists and doctors), effective
laboratory and clinical monitoring (by all disciplines), adherence
support (pharmacists).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 28
Successful Roll Out of ART
Program is a National Imperative
■ Assumptions:
■ There is individual commitment to fight HIV & not the
victims of HIV
■ There is total health professional commitment to treat
HIV/AIDS
■ There is national commitment to curb the raging
epidemic for the collective good
■ There is political will to commit resources & efforts
■ There is collective commitment to take care of people
with HIV/AIDS with sensitivity and dignity while
maintaining patient confidentiality
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
•
28
Assumptions must be set aside and facts must be presented.
i.e. how resistance is transmitted
•
There is individual commitment to fight HIV & not the victims of HIV.
•
There is total health professional commitment to treat HIV/AIDS.
•
There is national commitment to curb the raging epidemic for the collective
good.
•
There is political will to commit resources & efforts.
•
There is collective commitment to take care of people with HIV/AIDS with
sensitivity and dignity while maintaining patient confidentiality.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 29
ARVs
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
29
•
Evidence of success.
•
We know from past experiences that the use of ARVs prevents transmission of
the virus.
•
After the introduction of ARVs in Uganda in 1996, the trends in HIV prevalence
continued to decline.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 30
MULTIDISCIPLINARY CARE
OF HIV-POSITIVE
PATIENTS
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 31
Chronic Illness Care Provider Needs
5%
SP
35%
MD
Non-MD
60%
HO, MSW, RPh
Nut, RN
“Assign workload to the appropriate level when safe
and legal to do so” Gabre-Kidan, T., MD/PSHCS, Primary Care
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
31
•
HIV prevalence in Ethiopia is high and there aren’t enough physicians available
to meet all patient care needs if they are to shoulder the burden alone. To better
enable the needs of HIV-positive patients to be met, other health care
professionals must be utilized, creating a team approach for HIV care.
•
There are only 5% of specialized physicians to care for HIV infected patients.
•
The team would include: the physician or house officer, pharmacist and nurse
(and social worker and nutritionist when available).
•
Physicians will be responsible for assessment, diagnosis, and monitoring, and
pharmacists can help with ART regimen selection and initiation by sharing
their knowledge of the antiretrovirals including drug interaction information and
potential side effects with the provider.
•
Pharmacists can also assist providers and patients by counseling patients about
potential side effects related to their regimen and what methods they could use to
treat those side effects and the importance of medication adherence as well as
recommending methods to help patients with their adherence. Lastly,
pharmacists can maintain records of patient medication adherence over time by
tracking all medication refills that are dispensed.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 32
ART Care Model
(Adherence Protocol)
Multidisciplinary (Team) effort:
Social worker
Physician
Nursing
Patient
Nutritionist
Pharmacist
Minimum Team Members: MD, RN, RPh
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
TGK/ITECH/9.03
32
•
The physician, pharmacist, and nurse are intricately connected with the patient
and each other through the process of deciding to start a patient on ART.
•
Think about it this way, if a pharmacist has a visit with a patient to discuss the
ART regimen, before they start meds, based on their expertise regarding ART,
they can talk with the patient to determine the potential barriers to success on
the regimen.
•
For example, the patient may tell the pharmacist that they are planning on
sharing their medication with their family member to make their medicine “ last
longer”.
•
This is where the pharmacist can educate the patient about how resistance
develops, which we will talk about later in the curriculum. The pharmacist should
talk with the physician so that the physician has the discussion with the patient
so that they understand the importance of adherence in the success of ART.
•
This is just one example of how the pharmacist may play a role in helping the
patient to be successful with their therapy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 33
ART PATIENT FLOW
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 34
ID, age, gender, married, # children,
ART Patient Flow
Support (family, friend), Dx date, ART date
Intake Desk
First visit
Introduction to ARV
Life style, habits, family or friend support
Income, job
ABC/prevention, disclosure
RN visit
Awareness score, mental status, Karnofsky's Score, Wt.
HIV related Sx.
Nutritional status
MD visit
Complete H&P, baseline labs, CXR,
H&P, review past Tx, labs, CXR,
R/O or TX TB, order missing
R/O or TX TB (Reminder)
MC referred
Self or VCT referred
Eligible ?
NO
yes
Refer to enlarged image
at end of handout
ART protocol, TmSx
2nd visit
MD : Review lab, X-ray
Determine regimen
Discuss critical adverse effects
Emphasize adherence
Issue Rx
Schedule 4-week FU
TX OI, TmSx, FU
RPh : Regimen properties
Key side effects & monitoring
Adherence counseling
Invite & answer questions
Hand out written instructions
Hand out medications
schedule 2-week FU
Support Services
1. Emotional support
2. Counseling regarding ARVs &
adherence, transmission risk
reduction, general health
maintenance, status disclosure
3. Home-based Care
4. PMTCT
5. Family planning
6. Other services
RN : Adherence; review life style & counsel.
Explain access to emergent FU
Discuss nutrition & healthy living
Check mental competence & level of
understanding Hand out FU schedule
Refer to support services if indicated
Schedule 4-week FU
TGK/ITECH/12/03
•
The first screening will take place 2-4 weeks before starting therapy.
•
The patient will then meet with the multidisciplinary team for group and
individual information sessions.
•
At the second visit, when ARV therapy is to begin, the patient will again meet
with the pharmacist to gather a detailed review of the medication and repeat
adherence counseling.
•
Specifically, the pharmacist’s role in the multidisciplinary team is to:
•
Discuss regimen properties
•
Key side effect counseling and monitoring
•
Adherence counseling
•
Invite & answer patient or provider questions
•
Give patient written medication instructions
•
Hand out medications
•
Schedule 2-week FU appointment for refills and check to see how the
patient is doing.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 35
PRE-HAART ROUTING FLOW SHEET
(Completed by primary care provider)
Patient Name________________________________ID#_________________
Date Routing Slip Initiated: _______________ Patient Phone #_____________
Recent CD4 / (%)________ Date_________ Recent VL_______ Date________
All referring services VCT, HC, Private clinics, please circle any of the following
possible barriers to adherence that apply to your patient:
Active substance abuse
Untreated mental illness
Non-belief in antiretrovirals
Homelessness
Acute situational stressors
History of non-adherence
Fear of side effects
Limited funding to support continual ART
Lives far away
•
This is an example of what the documentation would look like when a provider
(physician, for example) refers a patient for ART.
•
At the first visit, for patients that meet criteria to start ART, the provider would
initiate the Pre-HAART Routing flow sheet (documenting info referenced on this
slide and next slide). Providers indicate to the nursing staff and pharmacists, what
the perceived barriers are to adherence.
•
This routing slip would then be given to the nursing staff so that an
appointment with pharmacy (and nursing, {and nutritionist and social worker if
available}) can be scheduled. These visits would all optimally happen before the
patient actually starts medicine.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 36
Primary Care Provider
Previous antiretrovirals used:
Proposed regimen:
Anticipated concerns/problems:
Potential for pregnancy: Yes / No
Zidovudine (Retrovir, AZT) [ ]
Stavudine (Zerit, d4T)
[]
Didanosine (videx, ddI)
[]
Lamuvidine (Epivir, 3TC)
[]
Abacavir (Ziagen, ABC)
[]
Tenofovir (Viread, TDF)
[]
Emtricitabine (Emtriva, FTC) [ ]
Efavirenz (Sustiva, EFV)
[]
Nevirapine (Viramune, NVP) [ ]
Indinavir (Crixivan, IDV)
[]
Lopinavir/ritonavir (Kaletra) [ ]
Nelfinavir (Viracept, NFV)
[]
Ritonavir (Norvir, RTV)
[]
Saquinavir (Fortovase, SQV) [ ]
Amprenavir (Agenerases, APV) [ ]
Combivir (AZT + 3TC)
[]
[]
Trizivir (AZT + 3TC + ABC)
Trimune (AZT + 3TC + NVP)
[]
Provider Signature:_________________ Date: ___________
Provider: please give form to nursing, so appointments can be scheduled
•
The provider also fills in the patient’s antiretroviral history and the proposed
ART regimen (or multiple regimens can be recommended and the pharmacist can
help narrow down the choices with the patient) they would like to propose for the
patient.
•
This alerts the pharmacist to what regimen the patient should be counseled
about and any problems they anticipate.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 37
Pharmacy
Education conducted:
Problems identified:
Comments/follow-up:
______ Suggest HAART
______ Suggest delay
Signature:___________________________________Date: __________________
•
The goal of the pharmacist appointment is to provide the patient with
education, assess for any potential barriers to adherence and correct those
barriers prior to initiation of ART.
•
During the pharmacist assessment, the pharmacist would review the following
information with the patient:
•
clarify the patient’s disease stage and make sure they understand what
that means, as well as their TLC, viral load and cd4 cell count if available;
•
review the regimen and its side effects
•
identify and correct any potential drug-drug or drug-food interactions
•
work with the patient to come up with a medication dosing schedule that
will fit into their life-style
•
review adherence and techniques to help the patient stay on schedule with
their regimen
•
provide the patient with written drug information, if problems are identified
with a certain regimen you can recommend and alternate regimen to the
provider
•
and lastly recommend to the provider whether you think the patient is
ready to begin therapy or if they need some time to address potential
adherence barriers (suggest delay) before starting therapy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 38
Patient Medication Daily
Dosing Record
AM
Midday
PM
Bedtime
AZT
.
3TC
EFV
•
Example of patient dosing schedule. For patients unable to read, use pictures
of the sun for morning, moon for bedtime, etc.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 39
Follow-up Tracking
Appointments Scheduled: Physician:_______________ / Pharmacy:______________ / Nurse:_________________
Outcome - completed, no-show or reschedule.
Date
Physician
Nurse
•
Outcome
Date
Outcome
_____________
_____________________
Pharmacy __________
____________________
_____________
_____________________
__________
____________________
_____________
_____________________
__________
____________________
_____________
_____________________
__________
____________________
Date
Outcome
Additional Comments:_________________
_______
_____________________
____________________________________
_______
_____________________
____________________________________
_______
_____________________
____________________________________
_______
_____________________
____________________________________________________
Use this form to track whether patients have kept their appointments and
where they are in the process.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 40
Clinical Evaluation and ART
Initiation Form
■ Date ______
■ Name: ___________________ Hospital # _________________
■ Sex: [ ] Male
■ Chest X-ray
[ ]Female
[ ] normal
Birth Date _______
[ ] abnormal
» suggestive of TB: [ ] yes
[ ] No
■ Wbc __________
Hb/Hct ______
Plt _____
■ TLC _________
CD4 ________
Viral load ________
■ ALT/AST ________ BUN/SrCr ______
MCV _____
Serum glucose_______
■ Pregnancy test [ ] positive [ ] negative [ ] not done
•
This form would be used by the provider for clinical evaluation and to identify
the baseline laboratory work, prior to starting ART
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 41
Lab Flow Chart
Name:______________________ Med Record # __________________
Date HIV Dx:____________ Date ART started: __________________
Date
Wt
CD4
TLC
WBC
Hgb
ALT
ARV
Note
Cr
•
For provider (pharmacists with access to the patient chart can review the
laboratory values).
•
We will talk more in depth about laboratory monitoring of ARVs. This is an
example of what a monitoring slip would look like, on the form you would be able
to track the ART regimen, and laboratory values that were a result of certain
regimens. This allows you to determine if a certain medication may be causing a
particular abnormality, for example anemia from the initiation of ZDV.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 42
Other Labs
Date
•
wt
Hb/
Hct
Lab Flow Chart (cont.)
Wbc/
ANC
Plt
gluc
ALT/
AST
T CHL
HDL
LDL
TGL
Stored in patient medical record as well.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 43
Assessment for Symptomatic HIV Disease
Check all
present
[ ]
[ ]
[ ]
[ ]
[ ]
[ ]
Does patient have:
tuberculosis needs to be ruled
Fever > 1 month
Night sweats > 1 month out or treated
Weight loss > 10%
Diarrhea > 1 month
Oral candidiasis
Current or Past CDC Stage 3 Opportunistic Illness If yes,
check all OI s in table below
Opportunistic illness, check all that apply (√)
Current
Past
Opportunistic Illness
Candidiasis, esophageal
Cryptococcosis (ex.
meningitis)
Herpes simplex: chronic
ulcer(s) (greater than 1
month's duration); or
bronchitis, pneumonitis,
or esophagitis
Kaposi's sarcoma
Encephalopathy, HIVrelated
Wasting syndrome due to
HIV
•
Current
Past
Opportunistic Illness
Mycobacterium tuberculosis
(pulmonary)
Mycobacterium tuberculosis
(extrapulmonary)
Pneumocystis carinii
pneumonia
Pneumonia, recurrent
Toxoplasmosis of brain
Other (specify)
______________
For Provider to complete a patient’s history of OIs and date of infection.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 44
Patient Medication Record
1
Date
Time
AZT
A
.
M
2
P
.
A
M
3
P
A M
4
P
A
M
P
.
3TC
EFV
In the past three days, how many days have
you missed doses?
Since last visit how has the patient
taken his/her ARVs?
[
[
[
[
[
[
[
[
] None
] One day
] Two days
]Three days
] About as prescribed
] Less often than prescribed
] More often than prescribed
] Not at all
•
Tracking adherence. The pharmacist should ask the patient the adherence
questions each time they pick up their refills (black circles represent missed
doses).
•
This information can be used for discussion on how to avoid missed doses in
the future, for example, if the evening dose is repeatedly being missed, the
pharmacist can work with the patient to devise a plan to avoid missing doses.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 45
Tracking ART Refill History
Med Name
Date
dispense
# Days
supply
given
Date due
for next
fill
# Days
late
Comment
3tc/d4t/nvp
1/1/04
30
2/1/04
15
Counseled about
adherence, referred
to nurse
3tc/d4t/nvp
2/15/04
30
3/15/04
Patient Name____________________ ID Number: __________
•
If the patient gets their medications filled at your pharmacy, you can also keep a
card for each patient and keep track of every refill they get and monitor their
adherence. Results can be reported back to the provider or nurse as needed.
•
Black ink = filled in on date of 1st fill, blue ink = filled in on date of 2nd fill.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 46
Clinical Tools
■ Standardize Documentation
■ Saves time
■ Facilitate continuity of care across disciplines
■ Helps facilitate record review
■ Foundation for clinical research
■ Helps with delegation of clinical workload
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
•
46
Implementing a standardized documentation system from the very beginning
will facilitate the whole process now and in the the future.
•
Saves time
•
Facilitate continuity of care across disciplines
•
Helps facilitate record review
•
Foundation for Clinical research
•
Helps with delegation of clinical workload
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 47
Clinical Tools-Documentation
■ Patient confidentiality should be taken very
seriously
■ All records should be stored in confidential space in
the pharmacy
■ Do not discuss patient cases with co-workers or your
family
■ Try to take patients to a confidential area to counsel
them
■ Never reveal private patient information to their family
members or others inquiring without the patient's
authorization
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
47
•
Patient confidentiality is incredibly important and should be taken very seriously. Communities
can be very small and sharing information with others can jeopardize a patient’s safety or wellbeing, result in loss of a job, or expose them to rejection from family or friends or numerous
other negative consequences stemming from HIV-related stigma.
•
All patient information should be handled in the following way:
•
All records should be stored in confidential space in the pharmacy that cannot be seen
by patients in line waiting for their prescriptions or non-pharmacy staff that are not
authorized to be involved in the patient’s care
•
All records should be locked up after hours when the pharmacy is closed
•
Information learned about patients should not be discussed with your family members,
friends, or work colleagues that are not involved in that patient’s care. Patient
information should only be discussed with the patient’s provider, nurse, or other
consultants involved in care for that patient.
•
Information about patients should not be discussed between co-workers in public
spaces such as hallways, waiting rooms, or any other place where other patients or staff
not involved in the care of the patient may overhear. It is not recommended to even
speak anonymously about patients in public spaces as details can convey a person’s
identity even if you don’t say their name.
•
Try to take patients to a confidential area to counsel them about their medications so
that other patients cannot hear.
•
Patient information should not be given to the patient’s family members or friends
unless the patient has authorized that you can share information.
•
If people call from outside asking questions about a patient, you should not reveal any
information that will divulge their HIV-positive diagnosis unless the conversation is
with a known care provider for that patient.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 48
Chronic Illness Care Provider Needs
5%
SP
35%
MD
Non-MD
60%
HO, MSW, RPh
Nut, RN
“Assign workload to the appropriate level when
safe and legal to do so” TGK/PSHCS, Primary Care
•
Resources are limited for patient care and pharmacists can play an integral
role in the care of HIV infected patients.
•
The role of the pharmacist should be seen as supportive to the other disciplines.
You are specialists in medication and can share your knowledge to both
providers and patients.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 49
Care Model & Optimization
■ How feasible do you think this model is?
■ What barriers could prevent this model from
working?
■ How could these barriers be overcome?
■ What are the insurmountable barriers?
■ Would you want any assistance to help facilitate
implementation of this model?
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
•
49
First of all, do you have an idea in your mind of what this model would look
like?
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Session 1: HIV Epi, ART Status, & the Phamacist’s Role
Slide 50
Key Points
■ AIDS impacts both the family and the national
economy.
■ ART can reduce mortality due to AIDS in Ethiopia.
■ The success of ART depends on commitment at
every level.
■ The pharmacist plays an important role as an ART
educator for physicians, nurses, and patients.
■ Careful recordkeeping is essential.
Unit 1: HIV Epi, ART Status, & Pharmacist's Role
Reference Manual for Trainers
50
HIV Care and ART: A Course for Pharmacists
Handout 1.1
Patient Flow
ART PHatient Flow
First visit
Intake Desk
Introduction to ARV
Life style, habits, family or friend
support, income, job
ABC/prevention, disclosure
RN visit
H&P, review past
Tx, labs, CXR, R/O
or TX TB, order
missing
ID, age, gender, married, # children,
Support (family, friend), Dx date, ART
date
Awareness score, mental status, Karnofsky's
Score, Wt. HIV related Sx. Nutritional status
MD visit
MC referred
Complete H&P, baseline labs, CXR,
R/O or TX TB (Reminder)
Self or VCT referred
Eligible ?
2nd visit
YES
NO
ART protocol, TmSx
TX OI,
TmSx, FU
MD : Review lab,
X-ray Determine
regimen
Discuss critical
adverse effects
Emphasize
adherence
Issue Rx
Schedule 4-week
FU
RPh : Regimen
properties
Key side effects &
monitoring
Adherence counseling
Invite & answer
questions
Hand out written
instructions
Hand out medications
Schedule 2-week FU
Support Services
1. Emotional support
2. Counseling regarding ARVs &
adherence, transmission risk
reduction, general health
maintenance, status disclosure
3. Home-based Care
4. PMTCT
5. Family planning
6. Other services
RN : Adherence; review life
style & counsel.
Explain access to emergent
FU
Discuss
nutrition & healthy living
Check mental competence
& level of understanding
Hand out FU schedule
Refer to support services if
indicated
Schedule 4-week FU
TGK/ITECH/12/03
HIV Care and ART for Pharmacists
Reference Manual for Trainers
HIV Epi, ART in Ethiopia, & Pharmacist’s Role
Unit 1-6
References
Frick, P. PharmD, MPH, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
Gabre-Kidan, T. MD, The Status of ART in Ethiopia - an Update, Physician
TOT, March 2004, Jimma, Ethiopia.
Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
Madison Clinic HAART Protocol (2004) Harborview Medical Center, University
of Washington, Seattle, WA, USA.
STD/AIDS Control Programme, Uganda (2001) HIV/AIDS Surveillance
Report.
UNAIDS/WHO (2002), HIV/AIDS Deaths in 2001 and Number of PLHA on
ART by end 2001: By Region.
Woldu, A. MD Ethiopian Ministry of Heath, Addis Ababa, Ethiopia 2003.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
HIV Epi, ART in Ethiopia, & Pharmacist’s Role
Unit 1-7
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
HIV Epi, ART in Ethiopia, & Pharmacist’s Role
Unit 1-8
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 2
HIV: Stages of Disease &
Initiation of Treatment
Unit 2: HIV: Stages of Disease & Initiation of Treatment
Aim: The aim of this unit is to introduce participants to the WHO disease staging
system and familiarize participants with considerations when starting a patient on
ART.
Learning Objectives: By the end of this unit, participants will be able to:
•
Understand natural history of HIV
•
Identify 4 interventions that delay the rate of HIV progression
•
Define W.H.O. disease staging system
•
Identify factors to consider before starting ART
•
Identify when it is appropriate to start ART
•
Identify goals of ART and tools for ART success
•
Recognize the role of the pharmacist in HIV care
Unit Overview:
2 Hours 40 minutes
Step
Time
Activity/
Method
Content
Resources
Needed
1
10 minutes
Question-Answer
Introductory Case Study and
Question Slides (2.2-2.3)
Overhead or LCD
Projector
2
70 minutes
Lecture
HIV: Stages of Disease & Initiation of
Treatment (Slides 2.4 - 2.74)
Overhead or LCD
Projector
3
70 minutes
Group Exercise
Case Studies (Slides 2.75 - 2.108)
Worksheets (2.1, 2.2,
2.3 & 2.4, in the
Workbook). Four flip
chart stands with
paper and markers.
4
10 minutes
Summary
Presentation of Key Points (Slide
2.109)
Overhead or LCD
Projector
HIV Care and ART for Pharmacists
Reference Manual for Trainers
WHO Staging and Starting Therapy
Unit 2-3
Resources Needed
•
Flip Chart and Paper
•
Markers
•
Overhead or LCD Projector
•
The following materials can be found in the Participant Handbook:
- Antiretroviral FDA Approval Dates (Handout 2.1)
- Algorithm for HAART in Adults & Adolescents (Handout 2.2)
•
Worksheets 2.1, 2.2, 2.3, and 2.4, which are located in the Course Workbook.
Key Points
1. HIV infection compromises the immune system and increases vulnerability to
infection.
2. ART is an important piece of the clinical care of the HIV patient but is not the
entire care spectrum and is NOT an emergency.
3. Initiate ART at appropriate WHO staging and when adherence can be
maximized.
4. Numerous factors must be considered before starting ART.
5. A multidisciplinary team approach is essential to patient adherence and
favorable patient outcomes.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
WHO Staging and Starting Therapy
Unit 2-4
Step 1
Step 2
Introductory Case Study (10 minutes)
•
Ask a participant to read the case study on Slide 2.2.
•
Ask participants to silently attempt to answer the question on
Slide 2.3.
•
Explain that the question will be answered and the case
discussed more fully as the unit progresses.
Lecture (70 minutes)
•
This unit will introduce participants to the WHO disease staging
system and familiarize them with considerations when starting a
patient on ART.
•
Begin by reviewing Slide 2.4 of the PowerPoint presentation,
“HIV: Stages of Disease and Initiation of Treatment.” Ask the
participants if they have any questions about the objectives
before continuing.
•
Present and discuss HIV epidemiology, WHO disease staging,
and starting ART in the PowerPoint presentation, “HIV: Stages
of Disease & Initiation of Treatment” (Slides 2.3-2.74).
•
Refer to “Antiretroviral FDA Approval Dates” (Handout 2.1)
located in the Participant Handbook as necessary.
•
Step 3
Step 4
Refer to “Algorithm for HAART in Adults and Adolescents”
(Handout 2.2) located in Participant Handbook as necessary.
Case Study Group Exercise (70 minutes)
•
Case Study Group Exercise: Divide participants into four work
groups. Provide each work group with one of the three Adult
ART Case Studies (Worksheets 2.1, 2.2, 2.3 in the workbook.)
Ask the groups to identify a recorder and a presenter, and then
spend twenty minutes discussing the case study together and
answering the related questions on flip-chart paper.
•
Ask each work group to share their decisions and answers.
Discuss each case thoroughly and use this time to answer
questions and clarify misinformation. Review the case studies in
the “HIV: Stages of Disease and Initiation of Treatment”
PowerPoint presentation (2.75 – 2.108). Spend 15 minutes
discussing each case.
•
An alternative way to discuss these case studies when time is
limited is to go through each one with all participants as a large
group. Ask individual participants to read the case studies and
ask for volunteers to answer the questions.
•
Use the answers to each question provided in the PowerPoint
slides to discuss the cases and questions with participants.
Summary (10 minutes)
•
Summarize the presentation, review the Key Points presented in
this Unit (Slides 2.109), and answer final questions.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
WHO Staging and Starting Therapy
Unit 2-5
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes
for reference during the planning and implementation of this course. The
facilitation notes and talking points are included in the “notes” section of the
accompanying PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
WHO Staging and Starting Therapy
Unit 2-6
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 1
HIV: Stages of Disease &
Initiation of Treatment
Unit 2
HIV Care and ART: A Course for Pharmacists
This unit should take approximately 2 hours, 40 minutes to complete.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 2
Introduction Case 1
■ A 32 year old Ethiopian woman recently diagnosed with
HIV comes to the clinic for her first evaluation
■ She was feeling well until one month ago when she
began losing weight and became too weak to do her
routine chores. She remained in bed 3 days out of the
week for the past month. She has no other HIV related
complications
■ At her last visit with her doctor she weighed 62 kg and
today her weight is 53 kg
■ CD4 count testing is unavailable. TLC = 1250/mm3
Session 2: HIV - Stages of Disease
•
2
Explain the following to participants:
•
This lecture and the subsequent lectures begin with an introductory case.
•
You will then be asked questions about these cases which help to answer
the objectives for the lecture.
•
Please answer these questions on your own in the pretest located in the
workbook before the lecture begins.
•
Other cases will be used similarly throughout the lecture to illustrate the
objectives of the lecture.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 3
Introduction Case 1 Question
■
According to the WHO Guidelines- criteria for initiating
antiretroviral therapy in adults, which of the following
statements is true?
A. ART therapy is not indicated for an individual with a TLC count >
1200/mm3
B. The occurrence of > 10% loss of body weight is categorized as clinical
stage I and is not an indication for ART therapy
C. > 10% loss of body weight and performance scale 3 (bedridden < 50% of
the day for the past month) are both considered clinical stage III, which
indicate that ART therapy would be appropriate
D. WHO stage IV disease is considered clinical AIDS and is the only
indication to begin ART therapy in resource limited settings
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
3
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 4
Unit Learning Objectives
■ Explain natural history of HIV
■ Identify 4 interventions that delay the rate of HIV
progression
■ Define W.H.O. disease staging system
■ Identify factors to consider before starting ART
■ Identify when it is appropriate to start ART
■ Identify goals of ART and tools for ART success
■ Recognize the role of the pharmacist in HIV care
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
4
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 5
Why Do We Need to Know This?
An understanding of the human
immunodeficiency virus (HIV) and its
actions in the body are essential to
providing care to persons living
with HIV infection
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
5
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 6
Characteristics of HIV
■ HIV is a chronic viral infection with no cure
■ HIV primarily affects the CD4 lymphocyte
■ CD4 cells are destroyed and impair a person’s
immunity
■ As immune function decreases, there is increase of
opportunistic infections
■ HIV progresses over time to death, if no prevention
measures or treatment are given
Session 2: HIV - Stages of Disease
•
6
HIV was discovered in 1983
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 7
Characteristics of HIV (cont.)
■ HIV is a retrovirus which targets T-helper cells (CD4
cells)
■ Uses reverse transcriptase to integrate into the host
cell’s genetic material
■ T-helper cells become “HIV factory” to reproduce HIV
■ T-helper cells destroyed in process with eventual rate of
destruction exceeding replacement
■ As T-helper count decreases, amount of virus in
bloodstream increases
Session 2: HIV - Stages of Disease
7
•
The primary targets for HIV are the CD4 cell, macrophages, and monocytes.
•
Once the virus enters the target cell, it crosses to regional lymph nodes and then
widespread dissemination through lymphatic system
•
Also, once in the cell, HIV combines with that cell’s genetic material. It
reproduces in the target cell and uses these cells to produce more virus
particles. This destroys the ability to fight illness. Left untreated, as HIV
progresses, immunity becomes more damaged and vulnerable to serious
infections and other conditions that characterize AIDS.
•
HIV reproduces at a rate of 100 billion new viruses per day. 1 billion CD4
cells are destroyed and re-built each day until the immune system is too weak
to do so
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 8
HIV Receptors
Session 2: HIV - Stages of Disease Levy JA, NEJM, 335(20); 1528-1530
8
•
Refer to copy of slide in the Participant Handout.
•
HIV normally binds gp120 to the CD4 receptor and co-receptors (CXCR4 or
CCR5) on the CD4 cell. Then gp120 shifts to expose gp41.
•
Once exposed, gp41 pierces the CD4 cell and pulls it in close enough to allow
viral-cell fusion.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 9
How Does HIV Cause AIDS?
HIV infects and destroys an important type of cell in the
body’s immune system known as the T-helper (TH) cell,
also known as the CD4 cell
Session 2: HIV - Stages of Disease
•
9
Refer to copy of the slide in Participant Handout.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 10
Modes of HIV Transmission
■ Sexual Contact with HIV-infected source
■ Exposure to HIV-infected body fluid
Intravenous drug use (IVDU)
Contaminated blood products
Occupational exposure – needle stick
Perinatal transmission – mother to fetus
Session 2: HIV - Stages of Disease
10
•
In the US, risk of infection from contaminated blood products is 1/90,000 units
of blood transfused. That risk would increase if blood from donors are not
screened effectively.
•
To place the risk in perspective, the risk of contracting Hepatitis B virus from
transfusion is 1 in 63,000 and for Hepatitis C virus is 1 in 100,000 (i.e., it is
easier to contract HBV than HIV from contaminated blood)
•
For perinatal transmission, the risk of infection from mother to fetus is 16%to
25%.
•
AZT is given in the 3rd trimester, IV during delivery and to the baby for 6 weeks
after, reduces the risk of transmission by 2/3 (results from ACTG 076 trial).
•
To further break down the 16% to 25% risk. The risk in-utero is 25% to 40%, intrapartum is 60% to 75% and through breast feeding is 14% to 29%.
•
COMMON MISCONCEPTIONS OF HIV TRANSMISSION THAT NEED TO BE
CORRECTED:
•
•
Share misconceptions common in Ethiopia.
•
OR ask participants for myths about HIV transmission.
HIV cannot be transmitted in the following ways:
•
By sitting on toilet seats
•
By sharing cups, silver ware, plates or bowls with an HIV-positive person
•
Kissing (as long as no visible blood is present or cuts in the mouth)
•
Mosquito bites
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 11
Risk of HIV Transmission with Single
Exposure from an HIV-infected Source
• Needle Sharing
0.67%
• Percutaneous (Occupational)
0.3%
• Receptive Anal Sex
0.1-0.3%
• Insertive Anal Sex
0.03%
• Receptive Vaginal Sex
0.08-0.2%
• Insertive Vaginal Sex
0.03-0.09%
• Oral Sex
Very low ~ 0%
Session 2: HIV - Stages of Disease
•
11
Occupational risk from a mucous exposure (e.g., blood splash into mouth or
eyes) is 0.09%
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 12
Stages of HIV Infection
■ Viral Transmission
■ Primary HIV Infection (Acute Retroviral Syndrome)
■ Seroconversion
■ Asymptomatic Chronic Infection
■ Symptomatic HIV Infection
■ AIDS
■ Advanced HIV Infection/AIDS (CD4 < 50/mm3)
Session 2: HIV - Stages of Disease
12
•
Asymptomatic – clinical latency: Immune system able to control virus.
Infection may be unknown but able to transmit to others
•
On average, asymptomatic chronic infection last 8 years.
•
Symptomatic: Some symptoms, some immune suppression
•
AIDS: Severe immunosuppression leads to opportunistic infections
•
Being HIV positive does not mean a person has AIDS. A person with a CD4
count above 200 or a TLC above 1200 that has never had an opportunistic
infection is considered to be HIV positive.
•
It is not until their CD4 count or their TLC drop below these thresholds or they
develop an OI that the person is considered to have AIDS. AIDS is the late stage
of HIV infection that is consistent with a compromised immune system.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 13
Stages of HIV Infection (cont.)
Primary
infection
1000
900
Opportunistic
diseases
Clinical latency
800
700
500
1:256
1:128
1:64
Constitutional
symptoms
600
1:512
1:32
1:16
400
1:8
300
Plasma Viremia
Acute HIV syndrome
Wide dissemination of virus
1100
CD4 Count
Death
{
1200
1:4
1:2
200
100
0 3 6 9 12
1
Weeks
2
3
4
5
6
7
8
9
10 11
Years
Refer to enlarged image at end of handout
•
Source: Fauci AS, Pantaleo G, Stanley, Weissman D. Immunopathogenic
mechanisms of HIV infection. Ann Intern Med 1996;124:654-63.
•
Galens Curriculum, Module 8, p. 17: “The initial event is the acute retroviral
syndrome, which is accompanied by a precipitous decline in CD4 cell counts
(green circles/gray line) and high plasma viremia (white circles/pink line).
Clinical recovery is accompanied by a reduction in plasma viremia, reflecting
development of cytotoxic T-cell (CTL) response.
•
The CD4 cell count gradually declines over several years, with a more
accelerated decline 1.5 to two years before an AIDS-defining diagnosis. HIV
RNA concentrations in plasma show an initial “burst” during acute infection
and then decline to a “set point” as a result of seroconversion and development
of an immune response.
•
The viral load correlates with the rate of CD4 decline (4 percent
decline/yr/log10/copies/ml). With continued infection, HIV RNA levels gradually
increase. Late-stage disease is characterized by a CD4 count <200 cells/mm3
and the development of opportunistic infections, selected tumors, wasting,
and neurologic complications.
•
In an untreated patient, the median survival after the CD4 count has fallen to
<200 cells/mm3 is 3.7 years; the median CD4 count at the time of the first AIDSdefining complication is 60-70 cells/mm3, the median survival after an AIDSdefining complication is 1.3 years.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 14
Primary HIV Infection
■ Acute Retroviral Syndrome (ARS)
■ Symptomatic in 80-90% of people
■ Only 20-30% seek health care
■ Occurs 2-4 weeks after exposure
■ Lasts 1-2 weeks
■ Signs and symptoms (next slide)
■ Increased likelihood of infecting others due to high viral load
Session 2: HIV - Stages of Disease
14
•
It is important to be aware of symptoms of primary infection so that if a person
does seek medical care or advice, an appropriate history can be taken and the
person can be referred for an HIV test.
•
Early diagnosis is beneficial for the health of the person themselves and can be
vital for preventing further transmission to others. Newly infected persons have
high viral loads and are at increased risk of infecting others.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 15
Acute Retroviral Syndrome
(ARS) Signs and Symptoms
■ Fever (96%)
■ Headache (32%)
■ Lymphadenopathy (74%)
■ Nausea and Vomiting (27%)
■ Pharyngitis (70%)
■ HSM (14%)
■ Rash (70%)
■ Weight Loss (13%)
■ Myalgia or Arthralgia (54%)
■ Thrush (12%)
■ Diarrhea (32%)
■ Neurologic symptoms (12%)
Session 2: HIV - Stages of Disease
15
•
Rash is typically erythematous, maculopapular with lesions on face/trunk and
sometimes palms or soles
•
HSM = hepatosplenomegaly
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 16
Seroconversion
■ HIV-antibody is detectable on average within 3 weeks
following transmission
■ Testing Strategies
■ Proviral DNA and Plasma HIV RNA (not generally used for
diagnosis)
■ HIV Antibody formation
■ Blood
(ELISA, Western Blot, Rapid Test, Home Access Express)
■ Saliva
(Orasure Test System)
■ Urine
(Calypte HIV-1)
■ Vaginal Secretions
(Wellcozyme HIV-1&2)
Session 2: HIV - Stages of Disease
16
•
HIV-antibody can take up to 3 months to be detectable. If a person has had a
potential HIV exposure and their antibody test is negative at 3 weeks, it should
be tested again at 3 to 6 months to ensure that the person is truly HIV negative.
During that window period, persons should use precautions to prevent potential
transmission to others.
•
Rapid HIV tests are very sensitive – 99.6%
•
Saliva tests identify the presence of HIV antibodies, not the virus itself. Unless
blood is present, HIV is not present in saliva (cannot transmit infection through
sharing cups or cooking supplies, etc.)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 17
ELISA Test
Enzyme Linked ImmunoSorbitant Assay
+ ELISA
- ELISA
Refer to enlarged image
Session 2: HIV - Stages of Disease
17
•
Routine procedures for HIV diagnosis are to perform 2 ELISA tests followed by a
Western Blot test (99.9% sensitive)
•
HIV antigen is added to the ELISA plate.
•
The patient’s serum is then added to the plate. If the patient’s serum contains
HIV antibodies, they will bind to the HIV antigens
•
Anti-human antibody with enzyme is next added to the plate. If the patient’s
serum contains HIV antibodies, this antibody with attached enzyme will bind to it.
•
Lastly Chromagen is added. Chromagen changes color when cleaved by the
enzyme attached to the second antibody.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 18
ELISA Test (cont.)
Refer to enlarged image at end of handout
•
Optical densities are tested
•
A positive test (dark green above), has an optical density of .500nm
•
An indeterminant test will be moderate green, has an optical
density of .3-.499nm
•
A negative test (light green) has an optical density of < .3nm
•
In most cases, a patient will be retested if the serum gives a positive result. If
the ELISA retests are positive, the patient will then be retested by Western Blot.
•
Which patient has a positive test? Negative test? Indeterminant test?
•
Patient A is negative
•
Patient B is indeterminant
•
Patient C is positive
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 19
Western Blot
No bands present
Bands at either p31 OR p24
AND bands present at either
gp160 OR gp120
Bands present, but pattern
does not meet criteria for
positivity
Session 2: HIV - Stages of Disease
Refer to enlarged image at end of handout
_
+
N/A
19
•
HIV antigens are blotted onto the gel. The gel is washed with the patient’s
serum. If HIV antibodies are present, they will bind to the specific viral
proteins.
•
Column 1 is a positive test
•
Column 2 is a control column
•
Which patient has a positive, negative, and indeterminant tests?
•
Patient A is negative
•
Patient B is indeterminant
•
Patient C is positive
•
Definitions:
•
Sensitivity: If have a person has HIV Æ It’s the % of time
that the test will actually be positive (higher sensitivity means
fewer false negatives)
•
Specificity: If a person does not have HIV Æ It’s the % of
time that the test will actually be negative (higher specificity
means fewer false positives).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 20
HIV Infection Basics
■ Viral Replication causes T-cell death
■ Loss of T-cells impairs immune system and
ultimately leads to AIDS
■ Viral replication is always harmful
■ It is impossible to completely inhibit replication of HIV
in the body
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
20
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 21
Measurements of HIV Infection
CD4 Count
- Measure of damage
already done
- Declines by about
30-90/year
- Marker for progression
of HIV and risk of OIs
Session 2: HIV - Stages of Disease
HIV RNA (viral load)
- Measure of potential for
damage
- Shows velocity of reproduction
- Only monitors HIV in the blood
- Lower viral load is best
indicator of slower progression
21
•
CD4 cell count is a measure of how much damage has already been done to
the immune system.
•
(The lower the CD4 cell count, the more immunocompromised the person is.
The higher the CD4 cell count, the more able a person can fight off infections
on their own.)
•
In areas where CD4 cell count is not available, use Total Lymphocyte Count
(TLC)
•
•
TLC = Total white blood cell count (WBC) X % Lymphocytes / 100
Viral load measures the rate at which HIV will progress (the higher the viral load,
the faster the rate of disease progression)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 22
Rate of HIV Progression
■ Low viral burden (HIV viral load) and high CD4 count
are highly predictive of improved survival
■ Symptomatic Primary Infection is indicative of poor
prognosis or more rapid progression to AIDS
■ Four interventions which prolong survival
■ Antiretroviral Therapy
■ PCP prophylaxis
■ MAC prophylaxis
■ Care by a physician specializing in HIV
Session 2: HIV - Stages of Disease
22
•
Prolonging Survival: Think of HIV infection like Diabetes - a chronic disease
with complications that is treated with multiple medications (prophylaxis and
treatment) for the patient’s lifetime to prolong survival.
•
We will get into opportunistic infection prophylaxis during another lecture
•
Research has shown that patients cared for by a practitioner that specializes in
HIV have better outcomes then those who don’t
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 23
Estimated Incidence of AIDS, Deaths, and Prevalence
by Quarter-Year of Diagnosis/Death,
United States, 1985-1999*
20,000
AIDS
Deaths
Prevalence
1993 definition
implementation
350,000
300,000
250,000
15,000
200,000
150,000
10,000
Prevalence
Number of Cases/Deaths
25,000
100,000
5,000
0
50,000
1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 19971998 1999
0
Quarter-Year
*Adjusted for reporting delays
•
Since the introduction of triple combination therapy in 1995, the widespread use
of ART in many well-resourced countries has led to a dramatic decline in the
number of AIDS-related deaths (blue line) and slowed patient progression from
HIV to AIDS (yellow line). Studies have shown that ART can improve health and
prolong life of people with HIV when used in resource-limited settings as well.
•
The prevalence of HIV/AIDS continues to rise (red line). Prevalence is a
measure of the amount of disease present at a point in time. People continue
to become newly infected with HIV and persons already infected are living
longer, consequently the prevalence continues to increase.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 24
HIV Disease Staging
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 25
W.H.O. Staging System for
HIV Infection
■ HIV disease stage provides reliable information about
prognosis
■ Disease stage is characterized by:
■ Current and prior complications of HIV
– evaluated by a medical history and physical exam
■ Degree of immune suppression
– evaluated by CD4 count or total lymphocyte count
Session 2: HIV - Stages of Disease
25
•
Reference: WHO Staging System for HIV Infection and Disease in Adults and
Adolescents (in Guidelines for Use of Antiretroviral Drugs in Ethiopia, Ministry of
Health, July 2004).
•
Pharmacists are not responsible for diagnosis of OIs or other HIV related
infections, but they should be able to recognize WHO stage of infection for
patients to determine if they ART candidates or not.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 26
Clinical Stage I
■ Asymptomatic OR
■ Persistent generalized lymphadenopathy (PGL)
■ Performance scale 1
■ Asymptomatic, normal activity
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
26
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 27
Swollen Posterior Cervical Lymph Nodes
•
Posterior cervical lymphadenopathy. Papular rash on neck as well.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 28
Introduction Case 1 Answers
■ B) The statement: The occurrence of > 10% loss of
body weight is considered clinical stage I and is not an
indication for ART therapy is false
■ The occurrence of > 10 % of body weight is categorized as
clinical stage III, which is an indication for ART therapy,
regardless of CD4 or TLC
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
28
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 29
Clinical Stage II
■ Weight loss < 10 % of body weight
■ Minor mucocutaneous manifestations (seborrheic dermatitis,
fungal nail infections, recurrent oral ulcerations, angular
chelitis)
■ Herpes zoster within the past 5 years
■ Recurrent upper respiratory tract infections
■ And/or performance scale 2
■ Symptomatic, normal activity
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
29
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 30
Seborrheic Dermatitis
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 31
Folliculitis
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 32
Oral Aphthous Ulcer and
Angular Chelitis
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 33
Dermatomal Herpes (Varicella) zoster
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 34
Dermatomal Herpes (Varicella) zoster
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 35
Zoster Sequence
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 36
Clinical Stage III
■ Weight loss >10% of body
weight
■ Unexplained chronic diarrhea
> 1 month
■ Unexplained prolonged fever
> 1 month
■ Persistent vulvovaginal
candidiasis
■ Oral candidiasis (thrush)
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
■ Oral hairy leukoplakia
■ Pulmonary tuberculosis
within the past year
■ Severe bacterial infection
(pneumonia, pyomyositis)
■ And/or Performance Scale 3
■ Bed-ridden < 50% of the day
during the past month
36
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 37
Introduction Case 1 Answers
■ C) The statement: > 10% loss of body weight and
performance scale 3 (bedridden < 50% of the day for
the past month) are both considered clinical stage III,
which indicate that ART therapy would be appropriate
is true.
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
37
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 38
Oral Candidiasis
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 39
Oral Candidiasis
Source: Salvatore Marra, http://members.xoom.it/Aidsimaging
•
Oral candidiasis
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 40
Oral Hairy Leukoplakia
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 41
Clinical Stage IV
■ HIV wasting syndrome*
■ Pneumocystis jirovecii pneumonia (PCP)
■ CNS toxoplasmosis
■ Cryptosporidiosis w/diarrhea > 1 month
■ Extrapulmonary cryptococcosis
■ Cytomegalovirus (CMV) disease of an organ other than liver,
spleen, or lymph nodes
■ Visceral HSV infection or mucocutaneous HSV infection > 1
month
■ Progressive multifocal leukoencephalopathy (PML)
Session 2: HIV - Stages of Disease
•
41
HIV Wasting syndrome; weight loss of > 10% of body weight plus either
unexplained chronic diarrhea (> 1 month) or chronic weakness and
unexplained prolonged fever (> 1 month)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 42
Clinical Stage IV (cont.)
■ Any disseminated endemic
mycosis
■ e.g. histoplasmosis,
coccidiodomycosis
■ Lymphoma
■ Candidiasis of the
esophagus, trachea, bronchi
or lungs
■ Kaposi’s sarcoma
■ Disseminated atypical
mycobacterium
■ And/or Performance Scale 4
■ Extrapulmonary tuberculosis
Session 2: HIV - Stages of Disease
•
■ Non-typhoid Salmonella
septicemia
■ HIV encephalopathy
■ Bed-ridden > 50% of the day
during the last month
42
HIV encephalopathy: clinical findings of disabling cognitive and/or motor
dysfunction interfering with activities of daily living, progressing over weeks to
months in absence of a concurrent illness or condition other than HIV infection
that could explain the findings
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 43
Cytomegalovirus Retinitis
Afebrile patient;
• reduced vision
in one or both
eyes;
• painless;
external eye
exam normal
Retinal exudate
and hemorrhage
follow retinal
vessels
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
43
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 44
Wasting Syndrome
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 45
Kaposi’s Sarcoma (KS)
■ Usually, multiple dark
raised lesions
■ Lesions themselves
are not itchy and
are rarely painful
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 46
Kaposi’s Sarcoma
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 47
Oral Kaposi’s Sarcoma
•
Implies involvement of internal organs such as gastrointestinal tract.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 48
Severe Chronic Herpes Simplex
Ulcers
Persistence for > 1 month is an AIDS-defining condition
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 49
Umbilicated papules of
Molluscum contagiosum
and
Cryptococcus
have the same
appearance
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 50
Esophageal Candidiasis
• HIV infected patient
with oral candidiasis
and chest (sub-sternal)
pain with swallowing
has presumed
Candida esophagitis.
• Endoscopy would
prove the diagnosis
but is unnecessary if
the patient responds to
antifungal therapy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 51
Esophageal Candidiasis
Linear ulcerations of the
esophagus as seen on
barium x-ray.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 52
USA CDC Classification System
Clinical Category
CD4 Cell Category
Asymp
Symp
OI
1. > 500/mm3
A1
B1
C1
2. 200-499 /mm3
A2
B2
C2
3. < 200 /mm3
A3
B3
C3
•
The system is used to stage HIV infection in the US. This system is not used to define when ART
should be started.
•
Based on the patients CD4 cell count, the patient would be assigned a number of 1 through 3.
Based on their clinical category (asymptomatic to symptomatic to ever presence of any
opportunistic infection) the patient would be assigned a letter A through C.
•
The diagnoses shaded in grey are considered an AIDS diagnosis (I.e., categorized as a C or a 3).
•
“A” Diagnosis Include: asymptomatic or persistent generalized lymphadenopathy (PGL), or acute
HIV infection
•
“B” Diagnosis Include: bacillary angiomatosis; thrush; vulvovaginal candiadiasis that is persistent,
frequent, or poorly responsive to therapy; cervical dysplasia (moderate or severe); cervical
carcinoma in situ; constitutional symptoms such as fever (38.5C) or diarrhea > 1 month; oral hairy
leukoplakia, herpes zoster involving 2 episodes or > 1 dermatome; idiopathic thrombocytopenic
purpura (ITP); listeriosis; pelvic inflammatory disease (PID) especially if complicated by a tuboovarian abscess; and peripheral neuropathy.
•
“C Diagnosis Include: Candidiasis of esophagus, trachea, bronchi, or lungs; invasive cervical
cancer; extrapulmonary coccidioidomycosis; cryptosporidiosis with diarrhea > 1 month; CMV of any
organ other than liver, spleen, or lymph nodes; CMV of eye; herpes simplex with mucocutaneous
ulcer > 1 month or bronchitis, pneumonitis, esophagitis; extrapulmonary histoplasmosis; HIVassociated dementia: disabling cognitive and/or other dysfunction interfering with occupation or
activities of daily living; HIV-associated wasting: involuntary weight loss > 10% of baseline plus
chronic diarrhea (>/= 2 loose stools per day for >/= 30 days) or chronic weakness and documented
enigmatic fever >/= 30 days; isoporosis with diarrhea > 1 month; Kaposi’s sarcoma in patient under
60 years (for over 60 years requires positive HIV serology); burkitt’s lymphoma; immunoblastic
lymphoma, primary CNS lymphoma; disseminated mycobacterium avium (MAC); pulmonary
mycobacterium tuberculosis; extrapulmonary tuberculosis; pneumocystis carinii pneumonia (PCP);
recurrent (>/= 2 episodes in 12 months) bacterial pneumonia; progressive multifocal
leukoencephalopathy (PML); recurrent salmonella septicemia (nontyphoid); and toxoplasmosis of
internal organ.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 53
When to Start ART
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 54
Important
Starting antiretrovirals is NOT an
emergency!!
Session 2: HIV - Stages of Disease
54
•
This can be a hard concept to accept, especially when a patient is demanding ART
because they’ve heard that without it they will die, but patients should not start
ART until they meet criteria.
•
If they do meet criteria, but they are not ready mentally or psychologically to start
medications either because it’s a new HIV diagnosis or they’re just not ready to
make the commitment to taking the medications as prescribed, they will be
nonadherent to the ART and will then fail therapy and they have gained nothing.
•
When we say ART is not an emergency, we mean that if you wait a month or 2
before starting therapy to allow time for the patient to be educated about ART and
for potential adherence barriers to be identified and corrected prior to starting
therapy, you increase that persons change of succeeding on therapy over the long
term.
•
HIV does not progress overnight from HIV to AIDS or from AIDS to death, there is
time to assess the situation completely and start therapy when appropriate.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 55
WHO Guidelines- Criteria for Initiating ARV
in Adults, Including Pregnant Women
If CD4 Cell Testing Is Available
WHO Guidelines
Clinical Category
Stage IV
(Symptomatic)
Stage III*
Stage I or II
CD4 Cell Count
Rec.
Any Value
Treat
CD4 cells < 350/mm3 to
assist in decision making
Treat
CD4 cells < 200/mm3
Treat
Session 2: HIV - Stages of Disease
55
•
Treat when Stage III with consideration of using CD4 cell counts <350/mm3 to
assist in decision making. CD4 count advisable to assist with determining need for
immediate therapy.
•
For example, pulmonary TB may occur at any CD4 level and other conditions may
be mimicked by non-HIV etiologies (chronic diarrhea, prolonged fever)
•
In areas where CD4 cell count is not available, use Total lymphocyte count (TLC)
•
TLC = Total white blood cell count (WBC) X % Lymphocytes / 100
•
A CD4 cell count of 200 is relatively equivalent to a TLC = 1200
•
This would be a good time to refer to handout 2.2 algorithm for
HAART in adults and adolescents. There is a typo on the sheet
regarding when treatment should be considered, can anyone point
this error out?
•
Treatment is indicated for those with WHO stage IV disease
irrespective of CD4 or TLC
•
WHO stage III with consideration of CD4 cell count < 350
•
WHO stage I or II if CD4 <200
•
And WHO stage II if CD4 unavailable and TLC < 1200
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 56
WHO Guidelines- Criteria for Initiating ARV
in Adults, Including Pregnant Women
If CD4 Testing is NOT Available
Clinical Category
WHO Stage IV
Irrespective of TLC
Rec.
Any Value
Treat
WHO Stage III
(Symptomatic)
Any Value
WHO Stage II
< 1200/mm3
Session 2: HIV - Stages of Disease
•
Total
Lymphocyte
Count (TLC)
Treat
Treat
56
In areas where CD4 cell count is not available, use Total lymphocyte count (TLC)
•
TLC = Total white blood cell count (WBC) X % Lymphocytes / 100
•
A total lymphocyte count of < 1200 can be substituted for the CD4 count
when the latter is unavailable and HIV-related symptoms exist. It is not
useful in the asymptomatic patient.
•
Thus, in the absence of CD4 cell testing, asymptomatic HIV-infected
patients (WHO Stage I) should not be treated because there is currently no
other reliable marker available in severely resource constrained settings.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 57
Introduction Case 1 Answers
■ A) The statement : ART therapy is not indicated for an
individual with a TLC count > 1200/mm3 is incorrect
■ if CD4 counts are unavailable, it is recommended that
individuals receive ART when TLC is < 1200/mm3 in clinical
stage 2 disease only. If an individual has clinical stage III or
IV disease, therapy is indicated regardless of TLC.
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
57
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 58
Introduction Case 1 Answers
■ D) The statement: WHO stage IV disease is
considered clinical AIDS and is the only indication to
begin ART therapy in resource limited settings is false.
■ Indications for starting ART therapy include:
■ If CD4 testing available:
– Stage IV regardless of CD4 count
– Stage III with consideration of CD4 counts < 350/ mm3
– Stage I or II if CD4 < 200/ mm3
■ If CD4 testing unavailable:
– Stage III or IV disease regardless of TLC
– Stage I or II if TLC < 1200/mm3
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
58
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 59
USA CDC Indications for ART Initiation
Clinical
Category
Symptomatic
(AIDS, severe
symptoms)
Asymptomatic,
AIDS
Asymptomatic
T Cell Count
Plasma
HIV RNA
Recommendation
Any Value
Any Value
Treat
T cells
< 200
Any Value
Treat
T cells
200 – 350
Any Value
Tx generally
offered
T cells
> 350
> 55,000
(bDNA or RT-PCR)
Some experts
rec Tx *
< 55,000
(bDNA or RT-PCR)
Many experts
defer Tx #
•
* Some experts would recommend treatment, recognizing the 3-year risk of
developing AIDS in untreated patients is >30%. Some would defer and monitor
more frequently.
•
# Many experts would defer treatment and observe, recognizing the 3-year risk of
developing AIDS in untreated patients is <15%.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 60
Antiretroviral Therapy
Principals
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 61
What is HAART?
■ HAART = Highly Active Antiretroviral Therapy
■ HAART is not a cure. Cannot not eliminate HIV completely with
HAART
■ A regimen of at least three compatible antiretroviral agents
■ If treatment is stopped, the virus will come back
■ Treatment:
■ Controls HIV
■ Allows the body to rebuild its immune system (its ability to fight infections)
■ Reduces the chance that a mother will pass HIV to her baby during
pregnancy, birth or breastfeeding
Session 2: HIV - Stages of Disease
61
•
In the past, doctors prescribed anti-HIV drugs one at a time (monotherapy). By
mid-1996, it was discovered that these drugs are far more effective when three or
more are taken at the same time.
•
This is because triple combination therapy attacks HIV at two (or three) different
points in its life cycle at the same time, greatly reducing the chance that viruses
with resistance to one drug will be able to carry on copying themselves.
•
This may be a good time to refer to handout 2.1 to identify how long the drugs
have been available.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 62
What Does HAART Require?
■ Recognition and
treatment of comorbidities
■ Proper monitoring of side
effects and disease
progression
■ Always use at least 3
ARVs or more together
■ Avoid use of medications
that could reduce the
level of ART in the blood
■ Use ART in correct
doses and schedules
■ Strict adherence
■ Rational sequencing of
drugs
Session 2: HIV - Stages of Disease
•
62
Rational sequencing of drugs
• First regimen is the best regimen
• Preservation of future treatment options
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 63
What Does HAART
Require? (cont.)
■ The development of resistant strains of HIV can be
avoided by optimal suppression of viral reproduction in
the majority of patients.
■ The main factors determining the effectiveness of
HAART:
■ potency of regimen
■ absence of severe immune suppression
■ adherence to therapy
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
63
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 64
Goals of ART Therapy
■ Improve the length and quality of the patient’s life.
■ Increased Total Lymphocyte Count (TLC) and CD4 cell
count allowing preservation or improvement of immune
function
■ Reduce HIV-related morbidity and mortality
■ HIV RNA < 400 copies/mL or “undetectable” within 4-6
months of ART initiation *
* Ultrasensitive assay goal is < 50 copies/mL
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
64
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 65
Factors to Consider When
Starting Therapy
■ Ethiopia ARV guidelines (August 2004)
■ Potential side effects
■ Concurrent health
conditions
■ Including abnormal
laboratory values
■ Drug interactions
■ Prior antiretroviral use
■ Antiretroviral resistance
■ Future treatment options
■ Conditions for storing
medications
■ Patient ability to follow-up
in clinic and laboratory
monitoring requirements
■ Potential for pregnancy
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
65
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 66
Factors to Consider When
Starting Therapy (cont.)
■ Potential barriers to adherence
■ Recent HIV diagnosis (limited time to process information)
■ Patient life-style and preferences
■ Limited ability to follow-up in clinic
■ They live far away
■ Not affordable (ability to sustain payment)
■ Compromised food access
■ Limited support from family / friends
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
66
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 67
How Long Will Treatment Keep
People Alive?
■ We don’t know
■ ART is still very new in Africa and Asia
■ BUT:
■ Where enough drugs are available to take several
combinations, people are still doing well after 7 – 8 years with
good adherence to treatment
■ We are all working together in a great effort to make the best
of limited resources
■ Everyone has a part to play
Session 2: HIV - Stages of Disease
67
•
Access to ARV drugs will improve survival and quality of life of people living with HIV/AIDS. This
have been shown in developed countries and in very few middle- income countries where these
drugs are available at affordable prices. How long will treatment keep people alive?
•
Many important questions relating to the best use of ART remain unanswered, including, for
example, when is the best time to start therapy, and which are the best drugs to use. Nonetheless,
the prognosis for people with HIV who have access to ART is significantly better than for those who
do not. In Europe and North America, the majority of those who started taking ART in 1996 and who
have taken it ever since are still alive.
•
In the developing world, ART is new. Although early signs are promising, we do not know if the
same level of success is as sustainable as in richer nations. This is because patients in the richer
nations have usually taken several combinations of drugs since starting ART. When one
combination fails, another is available to replace it. This will be less easy in the developing world,
because the cost of ARVs which can be used as `second line` treatment is much higher than the
cost of drugs used as first-line treatment.
•
It is important that where second line drugs are not easily available, people with HIV and the
communities in which they live are prepared for the possibility that treatment may fail. Although
taking medication is the responsibility of the patient, everyone is responsible for helping people with
HIV to take medication successfully. We are all working together to make the best use of limited
resources!
•
It is important that everyone involved in the care and support of people understands that people
with HIV who experience difficulties in taking medication need help and support, not blame and
control.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 68
Conditions for Implementing
HAART Country-wide
■ Easy access to VCT for early diagnosis of HIV.
■ Identification of sufficient resources to pay for HAART
on a long-term basis.
■ Counselling for the patient and environment on HAART,
treatment compliance, timing of drug intake and
possible side effects.
■ Follow-up counselling of the patient and environment to
ensure continued psychosocial support and to enhance
adherence to treatment.
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
68
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 69
Conditions for Implementing
HAART Country-wide (cont.)
■ Capacity to recognise and appropriately manage
common HIV related illnesses, opportunistic infections
and adverse reactions to ARVs.
■ Reliable laboratory monitoring services for the detection
of drug toxicity and response to therapy.
■ Assurance of an adequate supply of quality drugs.
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
69
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 70
Conditions for Implementing
HAART Country-wide (cont.)
■ Availability of trained interdisciplinary health teams,
including doctors, nurses, pharmacists, counsellors,
social workers. These teams should work closely with
support groups of PWHA and their caregivers.
■ Availability of a system for training, continuous
education, monitoring and feedback on management of
HIV disease and HAART.
■ Availability of appropriate care, support services and
referral mechanisms in case of treatment failure.
Session 2: HIV - Stages of Disease
•
70
PWHA = Persons with HIV or AIDS
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 71
The Basics of Anti-HIV Therapy
■ There are three main types of antiretroviral drugs:
■ Nucleoside and nucleotide analogue reverse transcriptase
inhibitors (NRTIs) which target an HIV protein called reverse
transcriptase.
■ Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
which also target reverse transcriptase.
■ Protease inhibitors (PIs) which target an HIV protein called
protease.
Session 2: HIV - Stages of Disease
71
•
Antiretrovirals do not directly kill the virus. Instead, the drugs interfere with the way
the virus reproduces or infects new cells. By controlling the virus, antiretroviral
treatment preserves the immune system from further damage and allows the
immune system to recover its ability to fight infections.
•
The anti-HIV drugs that are predominantly in use fall into three main categories
that each interfere in a different way with a stage of the HIV infection and
reproduction process:
•
Reverse transcriptase inhibitors
•
Non-nucleoside reverse transcriptase inhibitors
•
Protease inhibitors
•
Not all antiretrovirals are available in every country.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 72
Recommended Combinations
■ 1st Line
■ 2 NRTIs + 1 NNRTI
■ 2nd Line
■ 2NRTIs + 1 PI or ‘boosted’ PI
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
72
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 73
First Line Regimen: Ethiopia
First Line Regimens
Cost *
REGIMEN 1
D4T/3TC/NVP
cost - 197.80 birr/mo
OTHER REGIMENS
ZDV/3TC/NVP
cost - 279.00 birr/mo
D4T/3TC/EFV
cost - 482.60 birr/mo
ZDV/3TC/EFZ
cost - 563.80 birr/mo
* All cost information taken from a Hospital in Addis Ababa, 10/04
•
Unless contraindicated, all patients will commence therapy on Regimen 1:
D4T/3TC/NVP (dosing will be discussed later)
•
For patients with contraindications, the provider can make the following
substitutions:
•
•
d4T can be replaced with AZT
•
NVP can be replaced with EFZ
•
If patient develops hepatotoxicity or severe skiing reaction with Regimen 1
Æ Replace NVP by EFV
•
If patient develops severe peripheral neuropathy or pancreatitis with D4T Æ
Replace d4T by AZT
For those who can tolerate NVP-based regimen, the fixed dose combination (FDC)
tablet (d4T + 3TC + NVP) can be started after the 2-week NVP lead-in period.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 74
Algorithm for HAART in adults and adolescents
The first-line regimen for HAART in the public sector is d4T/3TC/NVP
HIV positive diagnosis
History,
Physical Examination and Laboratory testing
(incl. CD4 cell count)
AZT=zidovudine
3TC=lamivudiine
NVP=nevirapine
EFV=efavirenz
d4T=stavudine
Regular follow-up
Frequency depends on
clinical stage and
symptoms
WHO clinical stage IV
or
3
CD4<200 cells/mm
NO
YES
TB patient , or patient
with abnormal ALT
YES
Active TB,
abnormal
ALT
NO
Patient without active
TB, or patient with
normal ALT
EFV*
+
d4T+3TC
NVP
+
d4T+3TC
Refer to enlarged image at end
of handout
Regular counselling and clinical follow-up
Refer to support organizations and services
* Efavirenz (EFV) should not be given to pregnant women or women of
reproductive age unless they are on a reliable contraceptive method.
•
Refer to copy of slide in participant manual.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 75
HIV: Stages of Disease &
Initiation of Treatment
CASE STUDIES
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 76
CASE 2
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
76
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 77
Case 2
■ 37 yo Ethiopian woman presents with 1 yr history of
recurrent and persistent vaginal candidiasis, not
responding to over the counter antifungal. HIV ELISA
test was negative 1 yr ago. Repeat ELISA was positive
and referred to your clinic.
■ PMH: negative per her history.
■ SH: lives alone, earns 500 birr/mo, no ETOH, has no
current sex partner but does not use condom or birth
control, poor literacy.
■ ROS: non-contributory.
Session 2: HIV - Stages of Disease
•
PMH = Past medical history
•
SH = social history
•
ROS = review of systems
Reference Manual for Trainers
77
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 78
Case 2 - Physical Examination
■ Tearful woman
■ Temp 37, Wt 55kg, Ht 5’5”
■ HEENT: no thrush, no OHL, no adenopathy
■ CVS, Lungs, Abdomen: all normal
■ Skin: seborrheic dermatitis of face
■ Pelvic: thick, white discharge, KOH+
Session 2: HIV - Stages of Disease
78
•
HEENT = head, eyes, ears, nose, and throat
•
CVS = cardiovascular system
•
KOH stands for potassium hydroxide. Discharge can be examined diluting one
sample in KOH solution. Yeast of pseudohyphae of candida species are more
easily identified in the KOH specimen, vs bacterial vaginosis which is better
detected in a saline solution.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 79
Case 2 - Questions
■ What is her current WHO stage?
■ Is she a candidate for ART?
■ What are the immediate health care issues to be
addressed at initial visit?
■ What other issues need to be addressed before ART is
considered?
Session 2: HIV - Stages of Disease
79
•
Her current WHO stage is: Stage III
•
1 year history of persistent vaginal candidiasis (Stage III)
•
Seborrheic dermatitis of face (Stage II)
•
Check to determine if there has been any weight loss to assess for wasting
•
By symptoms, she is a Stage III. If CD4 testing is available, a CD4 <350 may be
helpful in determining the immediacy for starting treatment.For example pulmonary
TB may occur at any CD4 level and other conditions may be mimicked by non-HIV
etiologies. (eg. Chronic diarrhea, prolonged fever). If CD4 testing is unavailable, it
is appropriate to begin therapy.
•
Her immediate health concerns include:
•
Treatment of persistent vaginal candidiasis. No response to topical agents.
•
Determine what she has tried already and treat with an alternative topical, if
appropriate or oral treatment (e.g., fluconazole)
•
Re-confirm HIV diagnosis if she does not bring appropriate paperwork.
•
Obtain baseline labs.
•
Assess TLC/CD4. Determine if at risk for other opportunistic infections. Begin
appropriate prophylaxis as needed.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 80
Case 2 – Answers
■ Her current WHO stage is: stage III:
■ 1 year history of persistent vaginal candidiasis (stage III)
■ Seborrheic dermatitis of face (stage II)
■ Check to determine if there has been any weight loss to assess for
wasting
■ By symptoms, she is Stage III. If CD4 testing is available, a
CD4 <350 may be helpful in determining the immediacy for
starting treatment. For example pulmonary TB may occur at
any CD4 level and other conditions may be mimicked by
non-HIV etiologies. (eg. chronic diarrhea, prolonged fever).
If CD4 testing is unavailable, it is appropriate to begin
therapy.
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
80
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 81
Case 2 – Answers (cont.)
■ Her immediate health concerns include:
■ Treatment of persistent vaginal candidiasis. No response to
topical agents. Determine what she has tried already and
treat with an alternative topical if appropriate or oral treatment
(e.g., fluconazole)
■ Re-confirm HIV diagnosis if she does not bring appropriate
paperwork
■ Obtain baseline labs
■ Assess TLC/CD4. Determine if at risk for other opportunistic
infections. Begin appropriate prophylaxis as needed.
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
81
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 82
Case 2 – Answers (cont.)
■ Other Issues that should be addressed
■ Refer her to counselor to discuss HIV prevention efforts
■ Assess potential for pregnancy
■ Perform physical exam
■ Sexual history
■ Social history
Session 2: HIV - Stages of Disease
82
•
Refer her to counselor to discuss HIV prevention efforts, alerting partners about
their potential HIV-positive status.
•
Assess potential for pregnancy. Refer her to counselor to discuss vertical
transmission risk as appropriate.
•
Perform good physical exam, as well as sexual and social history including
finances and determining her support system (refer to support group if available
and needed)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 83
CASE 3
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
83
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 84
Case 3
■ John is a 28 year old man from a rural area who has been HIV+
for 3 or more years. He recently moved into the city and is
establishing care at the local hospital. He is antiretroviral (ARV)
naïve and wishes to consider starting medications as he has
heard about the new HIV medications that are helping people
with HIV live longer and thinks this would be good for him. His
TLC is 1350; he feels fatigued; has lost about 4 kg over the last 3
months and has noticed that his neck feels swollen and tender
on one side; he does not report every having a serious infection
or illness.
■ What stage of disease is he (explain your answer)?
■ Should John consider starting ART? Why or why not?
■ What factors should be considered in deciding whether to start
medications or not for John?
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
84
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 85
Case 3 – Answers
■ He is Stage II
■ TLC is > 1200
■ PGL = Stage I
■ What was his previous weight ? You find it was 73 Kg,
therefore Weight loss (< 10% of body weight) = Stage II
■ Fatigue = Stage II (symptomatic, normal activity)
■ He DOES NOT need to be treated now, but in the
future (all things being equal), suggest the first line
regimen recommended by the Ethiopian Guidelines
■ Stavudine + Lamivudine + Nevirapine
Session 2: HIV - Stages of Disease
•
•
•
85
NO – don’t start therapy, he is in stage – II. You would wait to start therapy until
his immune system is more compromised. Starting therapy early exposes patients
to medication side effects longer, has great expense, and narrows future options if
experience resistance development early on. Current recommendations suggest
waiting until patient’s disease stage progresses (TLC drops below 1200 and in
stage II or III or develops a condition from Stage IV, regardless of TLC).
•
TLC is > 1200
•
PGL = Stage I
•
What was his previous weight ? You find it was 150 lbs, therefore
Weight loss (< 10% of body weight) = Stage II
•
Fatigue = Stage II (symptomatic, normal activity)
He DOES NOT need to be treated now, but in the future (all things being equal),
for initial therapy suggest the first line regimen recommended by the Ethiopian
Guidelines.
•
Stavudine
•
Lamivudine
•
Nevirapine
Rationale is on the next slide.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 86
Case 3 – Answers (cont.)
■ He does not appear to have any contraindications to
D4T, 3TC, NVP.
■ Draw baseline labs and take good history to ensure no
medication would be contraindicated.
■ Cost
■ The regimen is dosed twice daily and generally well
tolerated
■ He has not had ARVs before, resistance shouldn’t exist
■ WHAT OTHER THINGS SHOULD BE CONSIDERED?
Session 2: HIV - Stages of Disease
86
•
He does not appear to have any contraindications to this regimen. Would need to
draw baseline labs and take good history to ensure no medication would be
contraindicated.
•
This regimen is the cheapest.
•
It’s dosed twice daily (better than three times daily for adherence).
•
The regimen is generally well tolerated.
•
He has never had ARVs before so no resistance should exist.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 87
Case 3 – Answers (cont.)
■ What other things should be considered?
■ Income sustainability, etc.
■ Barriers to adherence
■ Understanding of the development of resistance
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
87
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 88
CASE 4
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HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 89
Case Study 4
■ TC is a 43 year old who recently came to Addis Ababa from
Jimma. He presents with a 5 day history of fever and
swollen glands. TC suspects that he has the flu as he feels
achy and hasn't felt like eating for the last several days.
Upon further examination, it is discovered that TC has
secondary syphilis.
■ Suppose TC has a very astute clinician who suspects that
this might be an Acute Retroviral Syndrome. TC reveals
that he has had unsafe sex several times within the last
several months.
■ TC asks whether he will need to take medication if his test
results indicate that he is HIV-infected. How would you
respond to TC?
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89
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 90
Case Study 4 – Response to TC
■ He has a new diagnosis, but he does not need to
start medications now
■ Expensive, side effects, potential for resistance
development and limiting future options when his immune
system is weaker
■ But, knowing the diagnosis now is beneficial so that
he can take precautions to prevent infecting others,
discuss his diagnosis with any previous partners.
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HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 91
Case Study 4 – Response
to TC (cont.)
■ He can also engage in care with an HIV-specializing
physician that can monitor him over time to ensure better
health.
■ He can also focus on taking care of himself by improving his
diet, taking vitamins, limiting excessive alcohol or drug
intake, ensuring proper rest, exercising, etc. as needed.
■ He should be referred to a counselor that can review what it
means to live with HIV, what it means for him over the long
term and encourage him to involve family and friends in his
health care as he will benefit greatly from the social support.
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HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 92
Case Study 4 Questions
■ What factors should be considered in deciding which
medications would be best for an antiretroviral-naïve
individual?
■ If a person was to start on ART, what type of ARTrelated information should the pharmacist counsel them
about?
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HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 93
Case Study 4 –
Answers: Factors
■ Ethiopia ARV guidelines (August 2004)
■ Potential side effects
■ Concurrent health conditions
including abnormal laboratory
values
■ Drug interactions
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
■ Potential for pregnancy
■ Prior antiretroviral use
■ Antiretroviral resistance
■ Future treatment options
■ Conditions for storing
medications
93
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 94
Case Study 4 –
Answers: Factors (cont.)
■ Patient ability to follow-up in
clinic and laboratory
monitoring requirements
■ Potential barriers to
adherence
■ Recent HIV diagnosis (limited
time to process information)
■ Patient life-style and
preferences
■ Limited ability to follow-up in
clinic
■ They live far away
■ Not affordable (ability to sustain
payment)
■ Compromised food access
■ Limited support from family /
friends
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94
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 95
Case Study 4 – Answers:
Pharmacist Counseling
■ Define monitoring parameters
■ Review medication side effects, short and long-term
■ Potential drug-drug or drug-food interactions to watch
out for
■ Which medications should be taken with or without food
■ Medication dosing and how to handle missed doses
■ Importance of regular follow-up
Session 2: HIV - Stages of Disease
•
95
PHARMACIST COUNSELING
• Define HIV, TLC, and CD4 cell count and viral load (if applicable) so that
patient understands these concepts and how they fit into monitoring their
care
• Medication side effects, short and long-term
• Potential drug-drug or drug-food interactions to watch out for
• Encourage them to share their complete medication list with
their provider and pharmacist and make sure to stick to one
pharmacist so drug-interactions can be caught ahead of time
• Which medications should be taken with or without food
• Medication dosing
• How to handle missed doses
• Importance of regular follow-up
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 96
Case Study 4 – Answers:
Pharmacist Counseling (cont.)
■ Importance of adherence (and how that impacts
resistance development)
■ How to reach you if they have a question
■ Provide written drug information if possible
■ Reassure the patient that you will keep any information
related to them and their health care confidential
Session 2: HIV - Stages of Disease
•
96
PHARMACIST COUNSELING (cont.)
• Importance of adherence (and how that impacts resistance development)
• Work with them on ideas to improve their adherence
• How to reach you if they have a question
• Provide written drug information if possible
• Reassure the patient that you will keep any information related to them and
their health care confidential
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 97
CASE 5
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97
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 98
Case 5 - Introduction
■ AG, a 25 year old male, presents to your clinic
following hospitalization 1 week ago for
severe headaches (presumed toxoplasmosis)
where he just learned he is HIV positive. He
brings documentation confirming his HIV
status. Also currently being treated for
pulmonary TB x 4 months, responding well.
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HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 99
Case 5 (cont.)
■ Physical exam
■ Significant for lower leg numbness and weakness.
■ Current weight = 47kg (down from 54kg).
■ PMH
■ Hx of Pulmonary TB 2 years ago (treated x 8 months)
■ Labs
■ TLC – 350
CD4 – 56 (5%)
■ Hgb – 14.1
HCT – 40%
■ AST - 32
ALT - 28
Session 2: HIV - Stages of Disease
•
PMH = Past Medical History
•
Hx = history
•
TLC = total lymphocyte count
•
Hgb = hemoglobin
•
HCT = hematocrit
•
AST and ALT are liver function tests
Reference Manual for Trainers
99
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 100
Case 5 (cont.)
■ Social History
■ Single male with girlfriend (not present).
■ Currently working, earning 800 birr/mo.
■ Moderate alcohol use with sporadic binging.
■ Current Medications
■ Isoniazid and Ethambutol x 4 months
■ Fansidar x 7 days
■ B-Complex daily
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HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 101
Case 5 – Questions
■ Is he a good candidate for ARVs at this time? And
why?
■ What is his WHO HIV disease stage? List all factors
involved in your decision.
■ Will you start ART now?
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101
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 102
Case 5 – Answers
■ YES, he is a candidate
■ He is W.H.O. Stage IV
■ CD4 Count <200
■ TLC <1200
■ Presence of Toxoplasmosis (WHO Stage IV)
■ Weight loss > 10% body weight (WHO Stage III)
■ Pulmonary TB within last year (WHO Stage III)
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HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 103
Case 5 – Answers (cont.)
■ But NO . . . Don’t start medications yet
■ Provider should gather more information today (ART ≠
emergency)
■ Provider should refer him to the pharmacist for more
education about HIV, the medications, and their cost. Nursing
staff can also provide patient with more information
■ He should come back to clinic in 2-4 weeks.
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HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 104
Case 5 – More Questions
■ Would you like to know some additional
information to determine a good regimen for
him?
■ If so, what?
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104
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 105
Case 5 – More Questions (cont.)
■ How much / how often does he consume
alcohol? Does it interfere with daily functioning?
■ His moderate alcohol use is not contraindicated with
HAART. He can continue to drink in moderation. Binge
drinking however can be a problem and he should try to
stop. Becoming drunk can negatively impact adherence
as patients forget to take their doses during those times
■ Is his income consistent?
■ He states that he has a stable job. If he needed to, he
could talk to family as well to gain social support.
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105
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 106
Case 5 – More Questions (cont.)
■ Does he take any other medications?
■ Other than the medications for TB and toxoplasmosis he has
already told us about, the only other thing he takes is a Bcomplex vitamin that they gave him when he started his INH
■ What is in the B-Complex vitamin?
■ It has thiamin, cyanacobalamin, and niacin. It does not
contain Pyridoxine (vitamin B6). You can never make
assumptions about the medications. If possible, have patients
bring their medications in to show you so you can determine
exactly what they are. This is most likely what is causing his
lower leg numbness, which can be resolved by taking vitamin
B6 to replace the B6 being lost by INH
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HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 107
Case 5 – Factors to Consider
when Starting Therapy
■ Ethiopia ARV guidelines (August 2004)
■ Prior antiretroviral use and
antiretroviral resistance
■ Potential side effects
■ Future treatment options
■ Concurrent health conditions,
including abnormal laboratory
values
■ Conditions for storing
medications
■ Drug interactions
■ Potential for pregnancy
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
■ Patient ability to follow-up in
clinic and laboratory
monitoring requirements
107
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 108
Case 5 – Factors (cont.)
■ Potential barriers to adherence
■ Recent HIV diagnosis (limited time to process information)
■ Patient life-style and preferences
■ Limited ability to follow-up in clinic
■ They live far away
■ Not affordable (ability to sustain payment)
■ Compromised food access
■ Limited support from family / friends
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
108
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 109
Key Points
■ HIV infection compromises the immune system and increases
vulnerability to infection
■ ART is an important piece of the clinical care of the HIV patient
but is not the entire care spectrum and is NOT an emergency
■ Initiate ART at appropriate WHO staging and when adherence
can be maximized
■ Numerous factors must be considered before starting ART
■ A multidisciplinary team approach is essential to patient
adherence and favorable patient outcomes
Session 2: HIV - Stages of Disease
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109
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 110
References
■ Behrens, C. MD, Harborview Medical Center, Seattle, WA, USA, 2004.
■ Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
■ Fauci AS, Pantaleo G, Stanley, Weissman D. Immunopathogenic mechanisms
of HIV infection. Ann Intern Med 1996;124:654-63.
■ Frick, P. PharmD, MPH Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
■ Horwitch, C. MD, MPH, Virginia Mason Hospital, Seattle, WA, USA, 2004.
■ Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
■ Levy JA, Infection by human immunodeficiency virus--CD4 is not enough.
N Engl J Med. 1996 Nov 14;335(20):1528-30.
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
110
HIV Care and ART: A Course for Pharmacists
Unit 2: HIV - Stages of Disease & Initiation of Treatment
Slide 111
References (cont.)
■ Marra, S. MD, Divisione di Malattie Infettive, Ospedale “Casa del Sole,” Palermo, Italy
http://members.xoom.it/Aidsimaging
■ Netherda, M. MD Medical Director, County of Sonoma Center for HIVPrevention and
Care, Santa Rosa, California, USA.
■ McGilvray, M, Willis, N. All About Antiretrovirals: A Nurse Training Programme,
Trainer’s Manual, Africaid 2004.
■ Namibia Ministry of Health and Social Services, Training on the Use of the Namibia
Guidelines for Antiretroviral Therapy (ART), 2004.
■ Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999;
Chicago, IL. Abstract 92.
■ Vitiello, MA. MSN, CS, ACRN, Senior Technical Consultant, International Training and
Education Center on HIV (I-TECH), Seattle, WA, USA, 2004.
■ WHO Staging System for HIV Infection and Disease in Adults and Adolescents (in
Guidelines for Use of Antiretroviral Drugs in Ethiopia, Ministry of Health, July 2004).
■ Zewditu Hospital, Cost information, 2003.
Session 2: HIV - Stages of Disease
Reference Manual for Trainers
111
HIV Care and ART: A Course for Pharmacists
Handout 2.1- Antiretroviral FDA Approval Dates
Antiretroviral
zidovudine (AZT)
didanosine (DDI)
zalcitabine (DDC)
stavudine (D4T)
lamivudine (3TC)
saquinavir (SQV-hgc)
indinavir (IDV)
nevirapine (NVP)
nelfinavir (NFV)
delavirdaine (DLV)
combivir (AZT + 3TC) dosed BID
saquinavir (SQV-sgc)
efavirenz (EFV)
abacavir (ABC)
amprenavir (AMP)
ritonavir (RTV)
lopinavir/ritonavir (LPV/r)
didanosine-EC (Videx-EC)
trizivir (AZT + 3TC + ABC) dosed BID
tenofovir (TDF)
stavudine-XR (D4T)
enfuvirtide (T-20)
atazanavir (ATZ)
emtricitabine (FTC)
fos-amprenavir (f-AMP)
truvada (TDF + FTC) dosed QD
epzicom (ABC + 3TC) dosed QD
HIV Care and ART for Pharmacists
Reference Manual for Trainers
FDA Approval Date
3/19/1987
10/9/1991
6/19/1992
6/17/1994
11/17/1995
12/7/1995
3/14/1996
6/24/1996
3/14/1997
4/4/1997
9/27/1997
11/7/1997
9/18/1998
12/17/1998
4/15/1999
6/30/1999
9/15/2000
10/31/2000
11/14/2000
10/26/2001
12/31/2002
3/13/2003
6/20/2003
7/2/2003
10/21/2003
~ 8/1/2004
~ 8/1/2004
WHO Staging and Starting Therapy
Unit 2-7
Handout 2.2 – Algorithm for HAART in Adults & Adolescents
The first-line regimen for HAART in the public sector is d4T/3TC/NVP
Republic of Namibia MoHSS Guidelines for Antiretroviral Therapy, April 2003. Fig.1, pg 5.
HIV positive diagnosis
History,
Physical Examination and Laboratory
testing (incl. CD4 cell count)
Regular follow-up
Frequency depends on
clinical stage and
symptoms
WHO clinical stage IV
or
3
CD4<200 cells/mm
AZT=zidovudine
3TC=lamivudiine
NVP=nevirapine
EFV=efavirenz
d4T=stavudine
NO
YES
TB patient or patient
with abnormal ALT
YES
Active TB,
abnormal
ALT
NO
Patient without active
TB, or patient with
normal ALT
EFV*
+
d4T+3TC
NVP
+
d4T+3TC
Regular counselling and clinical follow-up
Refer to support organizations and services
* Efavirenz (EFV) should not be given to pregnant women or women of
reproductive age unless they are on a reliable contraceptive method.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
WHO Staging and Starting Therapy
Unit 2-8
References
Behrens, C. MD, Harborview Medical Center, Seatle, WA, USA, 2004.
Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS, Harborview
Medical Center, Seattle, WA, USA, 2004.
Fauci AS, Pantaleo G, Stanley, Weissman D. Immunopathogenic
mechanisms of HIV infection. Ann Intern Med 1996;124:654-63.
Frick, P. PharmD, MPH Clinical Pharmacist, HIV/AIDS, Harborview
Medical Center, Seattle, WA, USA, 2004.
Horwitch, C. MD, MPH, Virginia Mason Hospital, Seattle, WA, USA, 2004.
Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
Levy JA, Infection by human immunodeficiency virus--CD4 is not enough.
N Engl J Med. 1996 Nov 14;335(20):1528-30.
Marra, S. MD, Divisione di Malattie Infettive, Ospedale “Casa del Sole,”
Palermo, Italy http://members.xoom.it/Aidsimaging
Netherda, M. MD Medical Director, County of Sonoma Center for HIV
Prevention and Care, Santa Rosa, California, USA.
McGilvray, M, Willis, N. All About Antiretrovirals: A Nurse Training
Programme, Trainer’s Manual, Africaid 2004.
Namibia Ministry of Health and Social Services, Training on the Use of the
Namibia Guidelines for Antiretroviral Therapy (ART), 2004.
Paterson, et al. 6th Conference on Retroviruses and Opportunistic
Infections; 1999; Chicago, IL. Abstract 92.
Vitiello, MA. MSN, CS, ACRN, Senior Technical Consultant, International
Training and Education Center on HIV (I-TECH), Seattle, WA, USA, 2004.
WHO Staging System for HIV Infection and Disease in Adults and
Adolescents (in Guidelines for Use of Antiretroviral Drugs in Ethiopia,
Ministry of Health, July 2004).
Zewditu Hospital, Cost information, 2003.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
WHO Staging and Starting Therapy
Unit 2-9
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
WHO Staging and Starting Therapy
Unit 2-10
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 3
Clinical Pharmacology of
Antiretroviral Therapy
Unit 3: Clinical Pharmacology of Antiretroviral Therapy
Aim: The aim of this unit is to introduce participants to the antiretroviral classes and
common side effects of antiretrovirals.
Learning Objectives: By the end of this unit, participants will be able to:
•
Understand the mechanism of action for the four different antiretroviral
classes
•
List the common ARV doses and reasons for dose modifications
•
List the common side effects of ARVs and identify how to help patients cope
with these side effects
•
Recognize the role of the pharmacist in HIV care
Unit Overview:
5 Hours
Step
Time
Activity/
Method
Resources
Needed
Content
1
10 minutes
Question-Answer
Introductory Case Study and
Question Slides (3.2-3.3)
Overhead or LCD
Projector
2
155 minutes
Lecture
Clinical Pharmacology of
Antiretrovirals (Slides 3.4 - 3.128)
Overhead or LCD
Projector
3
60 minutes
Small Group Exercise
Side Effects (Slide 3.129-3.136)
Worksheet (3.1) in
workbook. Flip chart
paper and markers.
4
65 minutes
Case study Exercise
Case Studies (Slides 3.137-3.176)
Worksheets (3.2, 3.3,
3.4, & 3.5) in
workbook. Three flip
chart stands with
paper and markers.
5
10 minutes
Summary
Presentation of Key Points and
References (Slides 3.177 - 3.181)
Overhead or LCD
Projector
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART Clinical Pharmacology
Unit 3-2
Resources Needed
•
Flip Chart and Paper
•
Markers
•
Overhead or LCD Projector
•
The following materials can be found in the Participant Handbook:
-
•
FDA Approved Antiretrovirals (Handout 3.1)
HIV Life Cycle (enlarged Slide 3.6)
HIV Receptors (enlarged Slide 3.7)
Abacavir Hypersensitivity Signs and Symptoms Reported (n=636) (enlarged Slide
3.29)
Time and Onset of Cases (enlarged Slide 3.30)
Patients on the HAART Laboratory Schedule (enlarged Slides 3.124-125)
Reference Handout 1.4 and Worksheets 3.1, 3.2, 3.3, 3.4, and 3.5, which are
located in the Course Workbook.
Key Points
1. Antiretrovirals cannot kill existing virus; they can only prevent the production
of new virus.
2. The four antiretroviral classes are (1) nucleoside reverse transcriptase
inhibitors, (2) non-nucleoside reverse transcriptase inhibitors, (3) protease
inhibitors, and (4) fusion inhibitors.
3. A combination of at least three drugs is necessary in order to overcome
resistance.
4. Some side effects can have psychosocial implications as well as physical
implications.
5. The side effects of some antiretrovirals can be managed , while others may
require a dose modification or a change in the antiretroviral regimen.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART Clinical Pharmacology
Unit 3-3
Step 1
Step 2
Step 3
Introductory Case Study (10 minutes)
•
Ask a participant to read the case study on Slide 3.2.
•
Ask participants to silently attempt to answer the question on
Slide 3.3.
•
Explain that the question will be answered and the case
discussed more fully as the unit progresses.
Lecture (155 minutes)
•
This unit will introduce participants to the antiretroviral classes
and common side effects of antiretrovirals.
•
Begin by reviewing the learning objectives on Slide 3.4. Ask the
participants if they have any questions about the objectives
before continuing.
•
Present and discuss the antiretroviral classes, the mechanism of
action for each class, common ARV doses, and common side
effects in the PowerPoint presentation, “Clinical Pharmacology
of Antiretrovirals” (Slides 3.5-3.128).
•
Refer participants to “FDA Approved Antiretrovirals” (Handout
3.1) located in the Participant Handbook and “Abbreviations”
(Reference Handout 3.2) located in the Course Workboo, as
necessary as you go through this material.
Small Group Exercise (60 minutes)
• Side Effects of Antiretrovirals Small Group Exercise: If a local
protocol already exists for when patients should be referred for
medical attention, it is important to highlight the contents as part
of this training session.
• Spend up to 10 minutes for an introductory discussion identifying
the main ARVs used in the locality with the whole group (refer to
local protocols if a limited set of combinations will be prescribed).
List on a flipchart.
• Divide participants into groups of four. Provide each group with
flip chart paper and markers and Side Effects of Antiretrovirals
Group Exercise (Worksheet 3.1). Ask the groups to identify a
recorder and presenter, and then spend 30 minutes on small
group discussion.
• Each group should list the main side effects of ARVs used in
Ethiopia, dividing side effects into two groups: (1) serious and
life threatening (2) side effects which can be relieved. They
should then brain storm local remedies that might relieve less
serious side effects
• Ask each group to share their lists with the main group. Maintain
two lists – one of the serious side effects that require medical
attention, the other of local remedies. Establish consensus on
each and highlight any absences or potential issues with drug
interactions where local remedies are used.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART Clinical Pharmacology
Unit 3-4
Step 4
Step 5
Case Study Exercise (65 minutes)
•
Case Study Group Exercise: Divide participants into three to five
work groups, depending on the number of participants. Provide
each work group with one of the three Adult ART Case Studies
in the Workbook (Worksheets 3.2, 3.3, 3.4, 3.5.) Ask the groups
to identify a recorder and a presenter, and then spend twenty
minutes discussing the case study together and answering the
related questions on flip-chart paper.
•
Ask each work group to share their decisions and answers.
Discuss each case thoroughly and use this time to answer
questions and clarify misinformation. Prepare yourself by
reviewing the case studies in the “Clinical Pharmacology of
Antiretroviral Therapy” PowerPoint presentation (3.137-3.176).
Try to spend 15 minutes discussing each case.
•
An alternative way to discuss these case studies when time is
limited is to go through each one with all participants as a large
group. Ask individual participants to read the case studies and
ask for volunteers to answer the questions.
•
Use the answers to each question provided in the PowerPoint
slides to discuss the cases and questions with participants.
Unit Summary (10 minutes)
•
Summarize the lesson by reviewing the Key Points presented in
this Unit (Slide 3.177) and tell participants they can find the
references in their Participant Manuals.
•
Answer final questions from participants.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART Clinical Pharmacology
Unit 3-5
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes
for reference during the planning and implementation of this course. The
facilitation notes and talking points are included in the “notes” section of the
accompanying PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART Clinical Pharmacology
Unit 3-6
Unit 3: Clinical Pharmacology of ART
Slide 1
Clinical Pharmacology of
Antiretroviral Therapy
Unit 3
HIV Care and ART: A Course for Pharmacists
This unit should take approximately 5 hours to complete.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 2
Introductory Case
■ A 40 year old Tigrinian woman presents to the
pharmacy for her 2 week follow-up after starting ART
(efavirenz, lamivudine and stavudine).
■ She appears tired. When you ask her how she is doing
on her medication, she replies that she does not
understand why she is feeling worse after starting these
medications. She has not been able to sleep because
she is awoken in the night with nightmares. She has
trouble falling asleep, which leaves her feeling tired in
the morning.
Unit 3: Clinical Pharmacology of ART
2
•
Ask a participant to read the case.
•
Ask participants if they have any questions about the information presented.
•
Note: Do not give them further information on the case. Just ask them to consider
the information provided to them.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 3
Introductory Case Question
■
Which of the following statements describing the problems
that this patient is experiencing are true?
A. These problems are most likely due to side effects from efavirenz.
Central nervous system (CNS) side effects will not likely go away
and patients must get used to less sleep.
B. The side effects described are most likely due to stavudine and
should go away over time.
C. Trouble sleeping and nightmares are generally protease inhibitor
related side effects.
D. The side effects are most likely due to efavirenz. Over 50% of
patients who take efavirenz may experience CNS side effects.
Unit 3: Clinical Pharmacology of ART
3
•
Ask participants to silently attempt to answer the question.
•
Explain that the answer to the question will be discussed as the unit progresses.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 4
Unit Learning Objectives
■ Understand the mechanism of action for the four
different antiretroviral classes.
■ List the common ARV doses and reasons for dose
modifications.
■ List the common side effects of ARVs and identify how
to help patients cope with these side effects.
■ Recognize the role of the pharmacist in HIV care.
Unit 3: Clinical Pharmacology of ART
4
•
Review these objectives with participants.
•
Ask them to identify other objectives for the session related to pharmacology and
ART.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 5
Antiretroviral Drugs
•
Antiretrovirals that are listed as first or second line agents in the Guidelines for use
of antiretroviral drugs in Ethiopia, Ministry of Health, Aug 2004 are in regular print.
ARVs that are not listed in the guidelines (and may not be readily available) are in
italics. Adjust as needed as additional medications are available in Ethiopia.
•
This is a good time to call attention to FDA Approved Antiretrovirals and
Abbreviations (Handouts 3.1 and 3.2).
•
Here is the format for drug notes:
•
FDA Approval:
•
Nucleoside Analog:
•
Mechanism of Action:
•
Bioavailability (F): %
•
CSF Levels: % of serum levels
•
T1/2: hours
•
Intracellular T1/2: hours
•
Elimination:
•
Pediatric Dose:
•
Pregnancy: (Category )
•
Drug Interaction:
•
Resistance:
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 6
HIV Life Cycle
Fusion-Inhibitors
Unit 3: Clinical Pharmacology of ART
•
6
Refer to copy of slide in the Participant Handbook.
•
Gray = blood
•
Blue circle = CD4 cell
•
Purple circle = CD4 cell nucleus
•
Once HIV has bound to and invaded the host cell, part of the virus, an enzyme
called reverse transcriptase (RT) translates HIV’s genetic material (single stranded
RNA) into a form compatible with human DNA (double stranded DNA, the building
block of all human cells).
•
This viral DNA can then become part of the CD4 cell’s DNA within the nucleus and
transform the cell into a factory for making more HIV (think of the viral DNA
combined with the host cell’s DNA like a complete blueprint for making new virus).
•
The complete DNA (i.e., the blueprint) undergoes translation and creates complex
HIV proteins.
•
These new HIV proteins are not infectious until the protease enzyme cuts each
complex protein chain into smaller functional proteins that can be used to build the
new virus (e.g., the core, the envelope).
•
These smaller functional proteins are then stuck together to form new HIV virus.
•
These complete virus can then leave the CD4 cell and enter the plasma to infect
new host cells.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 7
HIV Receptors
Unit 3: Clinical Pharmacology of ART
Levy JA, NEJM, 335(20); 1528-1530
7
•
HIV normally binds gp120 to the CD4 receptor and co-receptors (CXCR4 or
CCR5) on the CD4 cell. Then gp120 shifts to expose gp41.
•
Once exposed, gp41 pierces the CD4 cell and pulls it in close enough to allow
viral-cell fusion.
•
Fusion inhibitors bind to the HR1 site in the gp41 subunit of the viral envelope
glycoprotein and prevent the conformational change that is needed to allow virus
to enter the cell.
•
This is where the newest class of ARVs work, they prevent entry into the CD4 cell.
This class of drugs is reserved for patients who are highly treatment experience
with few options left for treatment
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 8
Classes of Antiretrovirals
■ Fusion inhibitors
■ Prevents fusion of the virus into a CD4 cell
■ Nucleoside reverse transcriptase inhibitors (NRTIs) or
nukes (zidovudine, lamivudine)
■ Mimic naturally occurring nucleosides
■ Blocks viral DNA construction
Unit 3: Clinical Pharmacology of ART
Refer to enlarged image at end of handout
8
•
HIV normally binds gp120 to the cd4 receptor and co-receptors (CXCR4 or CCR5)
on the CD4 cell. Then gp120 shifts to expose gp41. Once exposed, gp41 pierces
the CD4 cell and pulls it in close enough to allow viral-cell fusion.
• Fusion inhibitors bind to the HR1 site in the gp41 subunit of the viral envelope
glycoprotein and prevent the conformational change that is needed to allow virus
to enter the cell.
• There are two different classes of anti-HIV drug that target reverse transcriptase:
All of the other classes of ARVs stop the HIV virus once it has entered the cell
NRTIs
• This class has been available in the US since 1987. NRTIs are commonly called
nucleoside analogues. (A newer type of drug, nucleotide analogues, inhibits RT in
exactly the same way but has a different chemical structure). Both types of drugs
mimic naturally occurring nucleosides (normal DNA building blocks, like guanine,
thymidine, and cytosine) so that they can deceive reverse transcriptase and defeat
its attempts to construct viral DNA.
• As the DNA is being built, when reverse transcriptase comes across a NRTI, like
ZDV, instead of a naturally occurring nucleoside, the DNA construction stops (i.e.,
the remainder of the viral DNA cannot be completed) so the rest of the HIV
replication cycle cannot continue. Both types of NRTIs, or ‘nukes,’ are often
combined in pairs. The combination of two NRTIs is considered the `backbone` of
antiretroviral therapy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 9
Classes of Antiretrovirals
■ Non- nucleoside reverse transcriptase inhibitors
(NNRTIs) or non-nukes (Nevirapine or Efavirenz)
■ Bind to the reverse transcriptase enzyme
■ Protease Inhibitors (PIs) (Kaletra or Nelfinavir)
■ Prevents cleavage of the protease chain
Unit 3: Clinical Pharmacology of ART
Refer to enlarged image at end of handout
9
NNRTIs
•
The other class of drugs that interferes with reverse transcriptase are nonnucleoside reverse transcriptase inhibitors, which are also known as non-nukes.
Like NRTIs, they also attack reverse transcriptase, but in a very different way.
•
These drugs bind to the enzyme itself so that it cannot move and work. The
NNRTIs currently available do not work against HIV-2 or HIV-1 subtype O because
the shape of the binding site differs for those viruses.
Protease Inhibitors
•
The protease is a different HIV enzyme. Once HIV has taken control of a cell, its
machinery begins to produce chains of viral protein to be packaged into new virus
particles. New HIV particles are not infectious until the protease enzyme cuts each
protein chain into smaller functional proteins. By binding protease, protease
inhibitors prevent an infected cell from producing more infectious virus.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 10
HIV Life Cycle
Fusion-Inhibitors
Unit 3: Clinical Pharmacology of ART
•
•
10
Compare how ARVs work to a copy machine
•
Fusion inhibitors would inhibit you from putting the paper in the machine
•
Nukes would replace the paper with transparency
•
Non nukes would be like pulling the plug on the machine, slowing down production
•
PIs would not release paper from the machine
This CD4 cell will eventually die, however, Virus will not be able to leave this cell to infect many other
CD4 cells.
•
Gray = blood
•
Blue circle = CD4 cell
•
Purple circle = CD4 cell nucleus
•
Once HIV has bound to and invaded the host cell, part of the virus, an enzyme called reverse
transcriptase (RT) translates HIV’s genetic material (single stranded RNA) into a form compatible with
human DNA (double stranded DNA, the building block of all human cells).
•
This viral DNA can then become part of the CD4 cell’s DNA within the nucleus and transform the cell
into a factory for making more HIV (think of the viral DNA combined with the host cell’s DNA like a
complete blueprint for making new virus).
•
The complete DNA (i.e., the blueprint) undergoes translation and creates complex HIV proteins.
•
These new HIV proteins are not infectious until the protease enzyme cuts each complex protein chain
into smaller functional proteins that can be used to build the new virus (e.g., the core, the envelope).
•
These smaller functional proteins are then stuck together to form new HIV virus.
•
These complete virus can then leave the CD4 cell and enter the plasma to infect new host cells.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 11
Antiretroviral Therapy (ART) or
HAART
■ Combination of at least 3 drugs, usually:
■ 2 NRTIs
■+
■ 1 NNRTI or 1-2 PIs
■ Therapy with only one or two agents allows HIV to
overcome therapy through resistance mutations
Unit 3: Clinical Pharmacology of ART
11
•
The key to therapy is to combine agents with different mechanisms of action so
that each drug will support the other drugs and together, they can prevent
replication of new HIV virus.
•
Antiretrovirals cannot kill existing virus, they can only prevent the production of
new virus (i.e., these medications cannot kill all virus, they are not a cure for HIV)
•
In 1987, we used monotherapy (zidovudine alone) to fight HIV and found that the
virus would mutate itself and render the drug inactive. Combining 3 or more
antiretrovirals, however, is strong enough to fight the virus and delays the
development of resistance.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 12
Example Triple Drug Regimens
and Associated Costs
First Line Regimens
Cost *
D4T/3TC/NVP
cost - 197.80 birr/mo
ZDV/3TC/NVP
cost - 279.00 birr/mo
D4T/3TC/EFV
cost - 482.60 birr/mo
ZDV/3TC/EFV
cost - 563.80 birr/mo
* All cost information taken from a hospital in Addis Ababa, 10/04
Unit 3: Clinical Pharmacology of ART
12
•
When considering what therapy is appropriate for a particular patient, cost of the
regimen should be considered. Currently the cheapest regimen in Ethiopia is D4t,
3tc and nvp
•
All of these are examples of triple drug regimens, utilizing 2 classes of drugs (2
NRTIs + 1 NNRTI)
•
We will discuss more about appropriate medication combinations later
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 13
Nucleoside Reverse
Transcriptase Inhibitors
■ Lamivudine (Avolam®)
■ Abacavir (ABC, Ziagen®)
■ Stavudine (Avostan®)
■ Emtricitabine (FTC,
Emtriva®)
■ Zidovudine (ZDV,
Retrovir®)
■ Didanosine (DDI,
Videx®)
Unit 3: Clinical Pharmacology of ART
■ Tenofovir (TDF, Viread®)
■ Zalcitabine (DDC,
Hivid®)
13
•
Also known as NRTIs or nukes
•
The top 5 NRTIs are currently available in Ethiopia- is ZDV available as a single
drug?
•
The remaining NRTIs (in italics) are not yet available, but are approved by US
FDA.
•
Various different combination tablets available in different countries – these 3 are
FDA approved in US
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 14
NRTI Combination Tablets
■ Zidovudine (ZDV) + Lamivudine (3TC)
■ (Combivir ®or Lamuzid ® or Duovir®)
■ Zidovudine + Lamivudine + Abacavir (Trizivir®)
■ Tenofovir + Emtricitabine (Truvada®)
■ Abacavir + Lamivudine (Epzicom®)
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
14
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 15
Zidovudine (ZDV)
■ Dosing: 300mg BID
■ Reduce dose for renal compromise
■ Food Interactions
■ None – with or without food is ok
■ Food decreases ZDV-related nausea
Unit 3: Clinical Pharmacology of ART
15
•
Zidovudine was the first ARV approved in 1987 when monotherapy was the
standard of care. 15 years have passed, and ZDV is still a common component of
ARV regimens. In the 1980s, ZDV was dosed 5 times daily and the toxicities were
much greater. Now, the drug is better tolerated, though it does still have
significant side effects (nausea, anemia), see next slide for more S/E info
•
Zidovudine (non-combination tablet) not available in Ethiopia?
•
FDA Approval: March 1987 (first ARV approved)
•
Nucleoside Analog: Thymidine analogue
•
Mechanism of Action: It is phosphorylated 3 times to the active metabolite,
zidovudine 5’-triphosphate.
•
Bioavailability (F): 60%
•
CSF Levels: 60% of serum levels
•
T1/2: 1 hour
•
Intracellular T1/2 (NRTIs exert their effect intracellulary, duration of action is based
on intracellular half-life): 3 hours
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 16
Zidovudine (cont.)
■ Elimination
■ Pediatric Dose
■ Pregnancy Category
■ Drug interactions
■ Avoid use with D4T
■ Use with caution with ribavirin
■ Other bone marrow suppressing drugs
■ Resistance
Unit 3: Clinical Pharmacology of ART
•
•
•
•
•
•
•
•
16
Elimination: Metabolized by liver to 5’-glucuronylzidovudine which is renally
excreted. Reduce dose with renal compromise: CrCl < 10 ml/min = 100mg Q8H.
Dosing with hepatic failure is 200mg BID.
Pediatric Dose: < 90 days: 2mg/kg Q6H, Pediatric: 160mg/m2 Q8H. Doses of ARV
in pediatric patients are listed in the guidelines Aug 2004
Pregnancy: (Category C). We will talk more about pregnancy categories later in
the section on women and HIV. ZDV is Present in breast milk and crosses
placenta. Advocated for pregnant women beyond the 1st trimester. During
delivery, IV dose is 2mg/kg over 1 hour, then 1 mg/kg/hour until delivery
Drug Interaction: Zidovudine and stavudine compete for activation by thymidine
kinase. The combination of these agents is antagonistic in vitro and in vivo and
they should not be combined.
Ribavirin used for the treatment of Hep C antagonizes the phosphorylation of
zidovudine in vitro. Consequently, the monophosphate form accumulates in cells
which impairs reverse transcriptase activity. Thus compromising zidovudine
activity. Use with caution.
Use with caution with other bone marrow suppressing drugs: TMP-SMX,
ganciclovir, dapsone, pyrimethamine, sulfadiazine, amphotericin B.
Probenecid increases ZDV levels; see high incidence of rash reactions to
probenecid.
Resistance: NAMs are M41L, E44D, D67N, K70R, V118I, L210W, T215Y/F, and
K219Q/E. 3 to 6 mutations result in a 100-fold decrease in sensitivity. If have
M184V induced by lamivudine or abacavir, see increased zidovudine susceptability
for HIV-1 unless have multiple TAMs
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 17
Zidovudine Toxicity
■ Nausea
■ Bone Marrow Suppression
■ Anemia (fatigue)
■ Granulocytopenia
■ Neutropenia
■ Headaches
Unit 3: Clinical Pharmacology of ART
•
•
•
•
•
•
•
•
17
Nausea is most common side effect for ZDV, eating prior to dose helps reduce nausea
Anemia means a shortage of red blood cells. Red blood cells transport oxygen around the body, so anaemia can
cause symptoms of tiredness and breathlessness.
Laboratory monitoring of patients should include haemoglobin counts where possible. Anaemia can be caused
by opportunistic infections, and is common in the population due to poor iron intake in food. It can also be caused
or made worse by ZDV treatment. Anemia may occur within 4 to 6 weeks. More common in advanced disease
(7%), than early disease (1%).
For severe anemia (Hgb < 7-8g/dl), discontinue or reduce ZDV dose {or manage with erythropoietin}. Hgb
typically recovers in 1 to 2 weeks. If anaemia returns when a full dose of ZDV is restored, it is best to switch to
another drug. In severe cases, blood transfusion may be needed.
Macrocytosis is common and not associated with anemia, see increase in MCV of 25-40 units after 6-24 weeks,
serves as crude indicator of adherence.
Neutropenia means a shortage of blood cells called neutrophils. Neutrophils are white blood cells that mainly
attack bacteria and fungi, so people who have neutropenia are at increased risk from these infections. usually
seen after 12 to 24 weeks. More common in advanced disease (37%), than early disease (8%). If ANC <
750mm3 discontinue or reduce ZDV dose {or manage with G-CSF}. Symptoms may include: Fever, aches,
pains, chills and sweating; sores in the mouth or gums; chest infections – cough producing lots of green mucus;
very sore throat and fever; ear ache and fever; discharge from the genitals; sudden swelling around cuts or sores
on the skin; myalgiasThrombocytopenia (low platelet count). Platelets are cells in the blood that help the blood to clot. If you do not
have enough platelets you may bleed more often and it can be difficult to stop the bleeding. If thrombocytopenia
becomes severe, blood loss may become serious, or internal bleeding may occur. This is a rare but serious side
effect of ZDV. A platelet count below 10 million per ml indicates serious thrombocytopenia.
Where it is not possible to carry out a complete blood count that includes a platelet count, signs of developing
thrombocytopenia include: Nose bleeds, frequent bruising, small pinpoint red spots, blood in the stools or urine,
more severe: coughing up blood. Switching treatment from ZDV is recommended if this is the likely cause.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 18
Zidouvidine Toxicity (cont.)
■ Myalgias
■ Insomnia
■ Pigmentation of nail beds
■ Lactic acidosis, fatty Liver
Unit 3: Clinical Pharmacology of ART
•
18
Rare, dose-related effect, usually leg and gluteal pain and/or weakness. Often see
increased CPK. If stop ZDV, see improvement within 2-4 weeks.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 19
ZDV-Related Fingernail
Discoloration
Unit 3: Clinical Pharmacology of ART
•
19
Nail Hyperpigmentation – can be seen on hands and feet after 2-6 weeks, usually
dark bluish-black vertical-line discoloration. More common among African
population.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 20
Lamivudine (3TC, Avolam®)
■ Dosing: 150mg BID or 300mg QD
■ Reduce dose with renal compromise
■ Food Interactions: no food interactions
■ Toxicity
■ Headache
■ Occasional nausea
■ Avolam® (3TC) Cost: 72.70 birr / month
■ Also indicated for Hep B, dose=100-300mg qd
Unit 3: Clinical Pharmacology of ART
20
•
Minimal Side Effects: Best tolerated of all antiretrovirals. 3TC is recommended
to be included in all first line regimens
•
3TC is available in Ethiopia
•
Use for Hep B: 3TC is a potent inhibitor of HBV, good for patients with co-infection.
The dose for HBV only is 100mg QD. For HIV/HBV co-infection, dose is 300mg
QD. HBV develops resistance at a rate of 20%-25% per year. Tenofovir is active
against 3TC-resistant HBV.
•
FDA Approval: November 1995
•
Nucleoside Analog: Cytosine analogue
•
Mechanism of Action: It is phosphorylated 3 times by thymidine kinase to the
active metabolite, 3TC-triphosphate
•
Bioavailability (F): 86%
•
CSF Levels: 13% of serum levels (these levels have been shown to clear HIV RNA
from CSF)
•
T1/2: 3-6 hours
•
Intracellular T1/2: 12 hours
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 21
Lamivudine (cont.)
■ Kinetics
■ Pediatric dose
■ Pregnancy
■ Drug interactions
■ Resistance
Unit 3: Clinical Pharmacology of ART
21
•
Elimination: 71% Renally excreted. Reduce dose with renal compromise: CrCl 1049ml/min = 100-150mg QD, < 10 ml/min = 25-50mg QD. No data for hepatic
failure, use usual dose.
•
Pediatric Dose: 2-4mg/kg BID
•
Pregnancy: (Category C) Crosses placenta. Use in pregnancy is safe and
effective.
•
Drug Interaction: No significant interactions
•
Resistance: High-level resistance to 3TC develops rapidly in-vitro. Presence of
the M184V mutation confers high-grade resistance to 3TC and makes the HIV
virus less-fit than wild-type virus (and also enhances susceptibility to ZDV, d4T,
and tenofovir, but reduces susceptability to ABC when combined with other
NAMs). Q151M complex and the T69 insertion mutation are associated with 3TC
resistance and broad NRTI resistance.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 22
Lamivudine + Zidovudine
■ Dosing: 1 Tablet (150/300mg) BID
■ Combination tablet should not be used in patients with renal
compromise
■ Food Interactions
■ None – with or without food is ok
■ Food decreases ZDV-related nausea
■ Lamuzid® Cost: 184.30 birr / month
Unit 3: Clinical Pharmacology of ART
•
22
Duovir is available in Ethiopia
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 23
Stavudine (d4T, Avostan®)
■ Dosing
■ 40 mg BID for weight > 60 kg
■ 30 mg BID for weight < 60 kg
■ Reduce dose in patients with renal compromise
■ Food Interactions: None
■ Cost: 30.40 birr / month
Unit 3: Clinical Pharmacology of ART
23
•
FDA Approval: June 1994
•
Nucleoside Analog: Thymidine analogue
•
Mechanism of Action: It is phosphorylated 3 times, first by thymidine kinase, 2nd by
thymidylate kinase, and 3rd by pyrimidine diphosphate kinase to the active metabolite,
stavudine triphosphate.
•
Bioavailability (F): 86%
•
CSF Levels: 30% - 40% of serum levels
•
T1/2: 1 hour
•
Intracellular T1/2: 3.5 hours
•
Elimination: 50% renally excreted. Reduce dose with renal compromise: If weight > 60kg:
CrCl 26-50mg/min = 40mg QD, CrCl < 10 ml/min = 20mg QD. If weight < 60kg: CrCl 2650mg/min = 30mg QD, CrCl < 10 ml/min = 15mg QD. No data , use usual dose in hepatic
failure.
•
Pediatric Dose: 1mg/kg BID (children weighing more than 30kg should receive adult dose)
•
Pregnancy: (Category C) Crosses placenta. Safe and effective. Do not use d4T/ddI
combination for pregnant women due to increased risk of lactic acidosis. Only use d4T +
ddI when the “potential benefit clearly outweighs the risk”.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 24
Stavudine (cont.)
■ Toxicity
■ Drug interactions
■ Peripheral Neuropathy (515%, pain, tingling, and
numbness in extremities)
■ Avoid use with ZDV (these
2 drugs are antagonistic)
■ Nausea
■ Use with caution: Other ‘D’
drugs, INH
■ Lactic acidosis, fatty liver
■ Pancreatitis
■ Hepatitis
Unit 3: Clinical Pharmacology of ART
24
•
Stavudine is a “D” drug – side effect profile is similar for all “D” drugs
•
Side effects: Peripheral neuropathy and pancreatitis are dose-related side effects. Use lower dose
to reduce risk of S/E development for patients < 60kg.
•
Peripheral Neuropathy: Onset of peripheral neuropathy is usually after 2-6 months of therapy. If
patient develops peripheral neuropathy discontinue d4T at onset (or reduce dose to 20mg Q12H if
weight > 60kg, or 15mg Q12H if < 60kg). Symptoms will dissipate slowly after stopping d4T or
reducing dose. Following improvement in peripheral neuropathy, can re-introduce agent at reduced
dose if needed. If provider does not discontinue therapy (or reduce dose) at onset, peripheral
neuropathy will become permanent and increasingly painful and debilitating.
•
Pancreatitis: If develops, discontinue therapy. When symptoms resolve, do not re-challenge with
stavudine
•
Liver function: Modest elevations of hepatic trasaminases are common, but significant elevations
and clinical hepatitis are uncommon.
•
Syndrome of ascending extremity weakness (beginning in lower extremities) has been identified,
but rare. Syndrome accompanied by lacticacidosis.
•
Drug Interaction: Zidovudine and stavudine compete for activation by thymidine kinase. The
combination of these agents is antagonistic in vitro and in vivo and they should not be combined.
•
Because of the potential for additive neurotoxocity, most experts advise against the use of
stavudine with zalcitabine. Use with caution with other neurotoxic drugs such as ethambutol,
isoniazid, and phenytoin.
•
Coadministration with ddI is associated with increased risk of lactic acidosis, pancreatitis, and
peripheral neuropathy. Do not use d4T/DDI combination for pregnant women due to increased risk
of lactic acidosis.
•
Resistance: NAMs are M41L, E44D, D67N, K70R, V118I, L210W, T215Y/F, and K219Q/E. If have
M184V induced by lamivudine or abacavir, see increased stavudine susceptability for HIV-1 unless
have multiple NAMs
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 25
Introduction Case – Answers I
■ The statement B): The CNS side effects described
(insomnia and nightmares) are most likely due to
stavudine and should go away over time is false.
■ The most common possible side effects due to
stavudine are peripheral neuropathy and pancreatitis.
CNS side effects are not a side effect that would be
expected to occur due to stavudine.
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
25
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 26
Abacavir (ABC)
■ Dosing: 1 x 300mg tablet BID
■ Food Interactions: no food interactions
■ Toxicity
■ Allergic reaction
■ Occurs within first 6 weeks of therapy
■ Nausea, Diarrhea
■ Headache
■ Lactic acidosis, fatty liver
Unit 3: Clinical Pharmacology of ART
Refer to enlarged image at end of handout
26
•
Abacavir is generally well tolerated. Patients should be counseled about abacavir
hypersensitivity reaction (see next slides).
•
FDA Approval: December 1998
•
Nucleoside Analog: Guanine analogue
•
Mechanism of Action: It is phosphorylated 3 times to the active metabolite.
•
Bioavailability (F): 83%
•
CSF Levels: 27%-33% of serum levels
•
T1/2: 1.5 hours
•
Intracellular T1/2: > 12 hours
•
Elimination: 81% metabolized by alcohol dehydrogenase and glucouronyl transferase with
renal excretion of metabolites; 16% recovered in stool, and 1% unchanged in urine. Dose
does not need to be adjusted for compromised renal function. No data on hepatic failure, use
usual dose.
•
Pediatric Dose: 8mg/kg BID
•
Pregnancy: (Category C) Crosses placenta.
•
Drug Interaction: Alcohol increases ABC levels by 41%. Abacavir does not impact alcohol
levels. Clinically, moderate alcohol use appears to be fine, do not need to adjust dose.
•
Resistance: ABC selects for the following mutations: 65, 74, 115, and 184. The 184 mutation
leads to complete cross-resistance with 3TC, but by itself does not significantly decrease
ABC susceptibility. Mutations at codons 65 and 74 lead to cross-resistance to ddI and ddC.
Significant resistance requires multiple mutations, usually in addition to the 184 mutation. If
have M184V + at least 3 NAMS, expect ABC failure.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 27
Hypersensitivity to Abacavir
■ Observed in
approximately 5% of all
patients receiving
abacavir
■ Multi-organ system
involvement
■ Most common signs and
symptoms:
■ Fever
■ Rash (maculopapular or
urticarial)
■ Fatigue
■ Flu-like symptoms
■ GI (nausea, vomiting,
diarrhea, abdominal pain)
Unit 3: Clinical Pharmacology of ART
27
•
Clinically, when patients experience the hypersensitivity reaction, they note that the
symptoms appear 1-2 weeks after initiation of ABC (up to 6 weeks). They feel the onset of
the symptoms after a dose. In between doses the symptoms begin to improve. Following
the next dose they feel worse than they did after the previous dose. Again they feel
symptoms improve between doses and then worse again after next dose. The symptoms
appear to worsen with each dose.
•
This can be contrasted against other allergic reactions (e.g., nevirapine or TMP/SMX),
where the onset of rash or other symptoms when they do occur are immediate and do not
worsen with each dose.
•
Counsel patients that if they experience any of the hypersensitivity symptoms that they
should return to or call their provider or pharmacist immediately if they note skin rash plus
fever, typical GI symptoms, cough, dyspnea, or other symptoms, especially during the first
month of therapy.
•
Based on the patient’s report of the symptoms, the provider or pharmacist will determine if
they feel that the symptoms are related to abacavir, a different medication, or the onset of
an upper respiratory infection. If the symptoms are felt to be related to abacavir, the
patient should be told that they do in fact have an allergy and they should NEVER be
given abacavir again. If the symptoms are felt to result from another cause or it is unclear,
continue administration of doses under observation to see if symptoms worsen wiith each
dose.
•
Patients should NOT be counseled to stop abacavir if symptoms occur because their
symptoms may not actually be related to abacavir, but if they stop the medication, the real
cause cannot be determined and subsequently must be assumed to be abacavir,
consequently, abacavir can never be used again for this patient (i.e., an NRTI has been
wasted for this patient).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 28
Hypersensitivity to Abacavir (cont.)
■ Other signs and symptoms:
■ Edema
■ Headache
■ Musculoskeletal
■ Respiratory
■ Constitutional symptoms (lethargy, malaise, etc)
Unit 3: Clinical Pharmacology of ART
28
•
Abacavir should be reserved for reliable patients. If the provider does not feel that
the patient could be adherent to their medications during the first 2-4 weeks of
therapy, they should not be given abacavir. Nonadherence during the first 2-4
weeks could prevent accurate diagnosis of potential hypersensitivity reaction and
result in anaphylactic-like reaction.
•
The high level of concern related to development of abacavir hypersensitivity
stems from the 20% risk of anaphylactic-like reaction upon re-challenge.
Symptoms include hypotension, bronchoconstriction, and/or renal failure. Rechallenge among persons with the abacavir hypersensitivity has been associated
with death in at least 3 patients. If anaphylactic reaction develops, treatment is
supportive with IV fluids, dialysis, etc. Steroids and histamines are not usually
effective.
•
Laboratory changes may include: increased CPK, elevated liver function tests, and
reduced lymphocyte count
•
Abacavir treatment should be stopped immediately following provider assessment
and never restarted if the health care provider suspects hypersensitivity. Death
can occur within hours of restarting abacavir therapy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 29
Abacavir Hypersensitivity Signs
and Symptoms Reported (n=636)
100
90
%of Cases
80
70
60
50
40
30
20
10
Symptoms
m
ou ch
th ills
/th
ro
at
ra
sh
na
us
vo ea
m
iti
ng
m
al
ai
se
di
ar
rh
oe
a
pr
ur
itu
he
s
ad
ac
he
fa
tig
ue
m
ya
lg
ia
fe
ve
r
0
Hetherington S et al. In: Abstracts of the 7th Conference of Retroviruses and Opportunistic
Infections. San Francisco, CA. January 30- February 2, 2000, Poster No. 60.
Unit 3: Clinical Pharmacology of ART
•
29
This bar graph depicts the rate of occurrence of each symptom as part of the
hypersensitivity reaction (information taken from a study of 636 patients). Most
common symptoms listed from left to right.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 30
Time to Onset of 636 Cases
60
No. of Cases
50
Median time to onset 11 days
93% of reported cases
occurred within the first 6
weeks of initiating abacavir
40
30
20
10
0
1
15
29
43
57
71
85
99
Days
113 127 141 155 169
One additional ABC HSR Reported at
318 days
*
Hetherington S et al. In: Abstracts of the 7th Conference of Retroviruses and Opportunistic
Infections. San Francisco, CA. January 30- February 2, 2000, Poster No. 60.
Unit 3: Clinical Pharmacology of ART
•
30
Over 93% of hypersensitivity reactions occur within the first 6 weeks of therapy.
Median time of onset is 9 days.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 31
Tenofovir Disoproxil
Fumarate (TDF)
■ Toxicity
■ Actually, a nucleoTIDE
■ Headache
■ Dosing: 1 x 300mg tablet
QD
■ Nausea, Diarrhea
■ Reduce dose with renal
compromise
■ Lactic acidosis
■ Renal insufficiency (rare)
■ Food Interactions: Can
be taken with or without
food
Unit 3: Clinical Pharmacology of ART
31
•
TDF is very well tolerated, side effects are minimal. It is dosed once daily. It also
has activity against Hepatitis B.
•
Monitor for renal impairment monthly: decreasing CrCl; glucose, phosphate, or
protein in urine, low serum phosphate or potassium. Renal compromise is rare,
but TDF should be stopped if patient develops renal compromise
•
FDA Approval: October 2001
•
Nucleotide Analog: TDF is different from nucleosides in that it has already been
phosphorylated once.
•
Mechanism of Action: Tenofovir disoproxil fumarate is a pro-drug of tenofovir. After
oral administration, TDF is rapidly cleaved by nonspecific extracellular
carboxyesterases into tenofovir. Once inside cells tenofovir is metabolized by
adenylate cyclase and nucleoside diphosphate kinase to the active moiety,
tenofovir diphosphate (PMPApp).
•
Bioavailability (F): 25% (fasting) to 40% (with food). Bioavailability improves with
food, especially high-fat meals.
•
CSF Levels: unknown % of serum levels
•
T1/2: 12 to 18hours
•
Intracellular T1/2: 10 to 50 hours
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 32
Tenofovir disoproxil fumarate
(TDF) (cont.)
■ Also has activity against Hepatitis B
■ Dosed 300mg QD
Unit 3: Clinical Pharmacology of ART
32
•
Elimination: Renally eliminated. Reduce dose for renal compromise: CrCl=3050ml/min=300mg every 2 days, CrCl 10-29=300mg every 3-4 dyas,
CrCl<10ml/min=300mg every 7 days. Avoid use during hepatic failure.
•
Pediatric Dose: Safety and efficacy in pediatrics not yet established
•
Pregnancy: (Category B) Crosses placenta.
•
Drug Interaction: Tenofovir increases ddI AUC levels by 40%-60%. May be due to
competition between TDF and DDI at the proximal tubule level (OAT1). When
combining ddI with tenofovir, decrease Videx-EC dose to 250mg QD (wt > 60kg).
The combination can be dosed with or without food.
•
TDF reduces atazanavir levels Æ Combine ATZ with RTV when dosed with TDF:
ATZ 300mg QD + RTV 100mg QD
•
Kaletra increases TDF levels 30%, no dosage adjustment is necessary
•
Resistance: Susceptibility is decreased in patients with 3 or more NAMs (M41L,
E44D, D67N, K70R, V118I, L210W, T215Y/F, and K219Q/E). The 41L and 210W
mutations are most important. Susceptibility is maintained with other NAM patterns
and increased with M184V unless have multiple NAMs. Susceptibility is
substantial lost with K65R and T69 insertion, but it is maintained with Q151M
complex.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 33
Didanosine (ddI)
■ Dosing
■ 1 x 400mg enteric coated capsule QD (if <60kg: 250mg QD)
OR
■ 2 x 100mg buffered tab BID or 4 x 100mg QD (if <60kg: 125
mg BID or 250mg QD)
NOTE: If use buffered tablets, 2 or more tablets must be
used at each dose to provide adequate buffer.
OR
■ 250mg buffered powder* BID (if <60kg: 167mg BID)
Unit 3: Clinical Pharmacology of ART
* Mix with water
33
•
ddI requires a basic environment, so it is either dosed as an enteric coated capsule, a
buffered tablet (each dose must contain 2 or more tablets in order to provide enough buffer to
prevent breakdown of the drug by gastric acid), or a buffered powder for reconstitution (mix
pediatric powder with liquid antacid). Currently in the US, the enteric formulation is used,
unsure of which formulation will eventually available in Ethiopia. ddI also needs to be taken
on an empty stomach, which can be more difficult on patients from an adherence standpoint.
Both the enteric coated formulation and the buffered tablet can be dosed once daily.
•
FDA Approval: October 1991
•
Nucleoside Analog: Inosine analogue
•
Mechanism of Action: It is phosphorylated 3 times to the active metabolite, 2’, 3’dideoxyadenosine 5’-triphosphate (ddATP)
•
Bioavailability (F): 30-40%. Food decreases bioavailability by 55% - doses should be taken on
an empty stomach. ddI is degraded by gastric acid. Consequently it is dosed with buffer
(buffered chewable tablets) or enteric coated for delayed release (Videx-EC®).
•
CSF Levels: 20% of serum levels
•
T1/2: 1.5 hours
•
Intracellular T1/2: 25-40 hours
•
Elimination: 40% renally excreted unchanged in urine. Reduce dose with renal compromise:
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 34
Didanosine (cont.)
■ Food Interactions: take on empty stomach
■ If taken with tenofovir (TDF), can take + or – food
■ The dose must be reduced to 250 mg qd with tenofovir
■ Dose should be reduced for patients with renal
compromise
Unit 3: Clinical Pharmacology of ART
Formulation
Videx-EC
Body Weight
> 60kg
< 60kg
Buffered Tab
> 60kg
< 60kg
Buffered Powder > 60kg
< 60kg
•
•
•
34
CrCl 30-49ml/min
200mg QD
125mg QD
200mg QD or
100mg BID
150mg QD or
75mg BID
100mg BID
100mg BID
10-29ml/min
125mg QD
125mg QD
150mg QD
<10ml/min
125mg QD
Use other formulation
100mg QD
100mg QD
75mg QD
167mg QD
100mg QD
100mg QD
100mg QD
Hepatic Failure: No data, but consider empiric dose reduction.
Pediatric Dose: 120mg/m2 Q12H Pregnancy. Reconstitute pediatric powder with 200ml water and
200ml extra strength antacid liquid. Final concentration should be 10mg/ml.
Pregnancy: (Category B) Crosses placenta. Do not use d4T/ddI combination for pregnant women
due to increased risk of lactic acidosis. Only use d4T + ddI when the “potential benefit clearly
outweighs the risk”.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 35
Didanosine (cont.)
■ Drug interactions
■ Alcohol
■ Other ‘D’ drugs
■ Drugs that require gastric acidity for absorption
■ INH
Unit 3: Clinical Pharmacology of ART
•
•
•
•
•
•
•
•
35
Drug Interaction: Tenofovir increases ddI AUC levels by 40%-60%, when
combining ddI with tenofovir, decrease Videx-EC dose to 250mg QD (wt > 60kg).
The combination can be dosed with or without food.
When combining buffered tablets with drugs that require gastric acidity for
absorption, separate doses by 2 hours. Examples of drugs that require gastric
acidity include: dapsone, indinavir, ritonavir, delavirdine, ketoconazole,
itraconazole, tetracyclines, and fluoroquinolones.
Use with caution along with other drugs that also cause pancreatitis: d4T,
ethambutol, pentamidine, hydroxyurea, allopurinol, and alcohol abuse (moderate
alcohol consumption is not a problem).
Use with caution along with other drugs that also cause peripheral neuropathy:
ethambutol, isoniazid, ddC, d4T.
Allopurinol increases ddI concentrations; avoid co-administration.
Oral ganciclovir increases ddI AUC by 100% if dosed within 2 hours of each other.
Monitor for ddI toxicity and consider dose reduction.
Ribavirin increases ddI levels, avoid coadministration or use cautiously
Resistance: L74V and K65R are the most important resistance mutations. The
K65R mutation causes cross-resistance with abacavir and tenofovir.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 36
Didanosine Toxicity
■ Peripheral Neuropathy
■ Nausea
■ Diarrhea
■ Abdominal pain
■ Pancreatitis
■ Lactic acidosis, fatty liver
Unit 3: Clinical Pharmacology of ART
36
•
ddI is a “D” drug
•
Side Effects: Peripheral neuropathy and pancreatitis are dose-related side effects. Use lower dose
to reduce risk of S/E development for patients < 60kg.
•
Peripheral Neuropathy: Frequency is 5%-12%. Onset of peripheral neuropathy is usually after 2-6
months of therapy. If patient develops peripheral neuropathy discontinue ddI at onset (or reduce
dose to 250mg QD). Symptoms will dissipate slowly after stopping ddI or reducing dose. Following
improvement in peripheral neuropathy, can re-introduce agent at reduced dose if needed. If
provider does not discontinue therapy (or reduce dose) at onset, peripheral neuropathy will become
permanent and increasingly painful and debilitating.
•
Pancreatitis: Reported in 1%-9%, fatal in 6%. Risk factors include: renal failure, alcohol abuse,
morbid obesity, history of pancreatitis, increased triglycerides, gall stones, and concurrent use of
d4T, hydroxyurea, allopurinol, or pentamidine. If develops, discontinue therapy. When symptoms
resolve, do not re-challenge with didanosine.
•
Peripheral neuropathy has been reported in 6-15% of patients taking ddI, but it may be more
common (and severe) in patients taking other neurotoxic drugs such as d4T. Since peripheral
neuropathy is a reversible, dose-related side effect, if patients develop peripheral neuropathy
discontinue offending agent at onset or reduce dose. Symptoms will dissipate within a few weeks of
discontinuation (or reducing dose). Following improvement in peripheral neuropathy, can reintroduce agent at reduced dose if needed. If provider does not discontinue therapy or reduce dose
at onset, peripheral neuropathy will become permanent and increasingly painful and debilitating.
•
Pancreatitis: Inflammation of the pancreas has been reported in about 1-9% of the patients taking
ddI, and it can be fatal. Symptoms include nausea, vomiting and abdominal pain. Blood tests may
find elevated levels of pancreatic enzymes. The incidence is dose related, underscoring the need to
dose ddI properly by body weight, and is increased in patients who have had pancreatis or
gallstones in the past. Other risk factors include alcohol and obesity. ddI or other “d” drugs should
be permanently discontinued if pancreatitis is confirmed.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 37
Emtricitabine (FTC)
■ Dosing: 1 x 200mg capsule QD
■ Dose should be reduced for patients with renal compromise
■ Food Interactions: no food interactions
■ Toxicity
■ Mild abdominal discomfort
■ Occasional nausea
Unit 3: Clinical Pharmacology of ART
37
•
Emtricitabine is the flourinated version of lamivudine. The flourinated version was
designed to reduce toxicity and prolong drug half-life, but clinically there does not
appear to be any difference between the 2 drugs. FTC has demonstrated activity
against Hepatitis B, but it is not FDA approved for this indication.
•
FDA Approval: July 2003
•
Nucleoside Analog: Cytosine analogue
•
Mechanism of Action: It is phosphorylated 3 times to the active metabolite,
emtricitabine 5’-triphosphate
•
Bioavailability (F): Good oral bioavailability.
•
CSF Levels: Estimated to be low (in monkeys, CSF level was 4% of serum levels)
•
T1/2: 8-9 hours
•
Intracellular T1/2: > 20 hours
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 38
Emtricitabine (FTC)
■ Elimination
■ Pediatric dose not established
■ Drug interactions
■ Resistance
Unit 3: Clinical Pharmacology of ART
•
38
Elimination: It is predominantly renally excreted. More than 85% of dose is
excreted in urine as unchanged emtricitabine. Most likely the dose will not need to
be adjusted for hepatic impairment. Dosage should be adjusted for patients with
renal compromise:
•
CrCl 30-49ml/min = 200mgQ48H
•
CrCl 15-29ml/min = 200mgQ72H
•
CrCl < 15ml/min = 200mg Q96H
•
Pediatric Dose: Not established (Research has been done with dose of 6mg/kg
QD, data pending)
•
Pregnancy: Information pending (safe in animals).
•
Drug Interaction: No clinically significant drug interactions.
•
Resistance: Drug resistance to emtricitabine develops rapidly and results from a
single point mutation at 184 (M184V or M184I mutations). This mutation confers
cross resistance to lamivudine and also increased sensitivity to zidovudine,
stavudine, and tenofovir for HIV-1 unless have multiple NAMs.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 39
Zalcitabine (ddC)
■ Dosing: 1 x 0.75mg tablet TID
■ Food Interactions: take on empty stomach, no
antacids (food or antacids ↓ plasma levels 25-39%)
■ Toxicity
■ Nausea, Oral aphthous ulcers
■ Peripheral neuropathy
■ Pancreatitis
■ Rash
■ Lactic acidosis, fatty liver
Unit 3: Clinical Pharmacology of ART
39
•
ddC is a “D” drug
•
Clinically ddC is not used much in the US. It does not offer any advantages over other
NRTIs but has more potential concerns: thrice daily dosing (which can negatively impact
adherence), has to be taken on an empty stomach, and a more significant side effect
profile.
•
Side Effects: Peripheral neuropathy and pancreatitis are dose-related side effects.
•
Peripheral Neuropathy: Frequency is 17%-31% (higher than for ddI and d4T). Onset of
peripheral neuropathy is usually after 10-18 weeks of therapy. If patient develops
peripheral neuropathy discontinue ddc at onset. Symptoms will worsen for 5 weeks after
discontinuation of ddC and then will dissipate slowly. Following improvement in peripheral
neuropathy, can re-introduce agent at ½ dose if needed. If provider does not discontinue
therapy (or reduce dose) at onset, peripheral neuropathy will become permanent and
increasingly painful and debilitating.
•
Pancreatitis: Reported in <1%, fatal in 6%. Risk factors include: renal failure, alcohol
abuse, morbid obesity, history of pancreatitis, increased triglycerides, gall stones, and
concurrent use of d4T, hydroxyurea, allopurinol, or pentamidine. If develops, discontinue
therapy. When symptoms resolve, do not re-challenge with didanosine.
•
Oral aphthous ulcers occur in 2-4% of persons. They most commonly occur on the buccal
mucosa, soft palate, tongue, or pharynx. They are usually self-limited and resolve with
continued therapy.
•
A mild erythematous maculopapular rash was shown to develop in 14 out of 20 patients in
a small study. It commonly develops after 10 to 14 days of therapy and is usually selflimited.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 40
Zalcitabine (ddC)
■ Not used very much in the US
■ Dose adjust for renal insufficiency
■ Drug interactions
Unit 3: Clinical Pharmacology of ART
40
•
ddC has activity against Hepatitis B virus (not FDA approved for this indication)
•
FDA Approval: June 1992
•
Nucleoside Analog: Cytosine analogue
•
Mechanism of Action: It is phosphorylated 3 times to the active metabolite, zalcitabine 5’triphosphate.
•
Bioavailability (F): 70%-88%
•
CSF Levels: 20% of serum levels
•
T1/2: 1.2 hours
•
Intracellular T1/2: 3 hours
•
Elimination: 70% renally excreted. Reduce dose with renal compromise: CrCl 10-50ml/min
= .75mg BID, CrCl < 10 ml/min = .75mg QD. With severe liver disease, use usual dose.
•
Pediatric Dose: 0.01mg/kg Q8H
•
Pregnancy: (Category C) Crosses placenta.
•
Drug Interaction: Use with caution with other drugs that cause peripheral neuropathy: ddI,
d4T, ethambutol, isoniazide, and phenytoin.
•
Resistance: Mutations that confer resistance include: 65R, 69D/N/A, 74V, and 184V. 74
and 184V mutations suppress zidovudine resistance unless also have multiple NAMs.
ddC susceptibility also decreased by NAMs (41L, 44D, 67N, 70R, 118I, 210W, 215Y/F,
and 219Q/E).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 41
NRTI Class Side Effects
■ Nausea
■ Headache
■ Peripheral Neuropathy
(ddC > d4T/ddI)
■ Lipoatrophy
■ Lactic Acidosis, fatty liver
■ ddC/ddI/d4T > 3TC > ZDV
> ABC
■ Tenofovir is lower risk,
but need more info to
rank
■ Pancreatitis (DDI > DDC >
D4T)
Unit 3: Clinical Pharmacology of ART
41
•
As with all antiretrovirals, side effects are the worst during the first 1 to 2 weeks of therapy.
As therapy continues, patients are better able to tolerate the medications. Counsel
patients about the potential for side effects with a regimen so that they know what to
expect and provide them with advice about how to handle side effects (whether they can
manage the side effect at home, should call to touch base, or need to come to clinic to be
seen). Also reassure them that side effects do improve over time, so it’s important not to
give up too quickly on the medications unless having severe side effects.
•
Peripheral neuropathy and pancreatitis are most noted with the “D” drugs – ddC, d4T, ddI.
Rates of occurrence differ by drug (see slide). Note: peripheral neuropathy can develop as
a result of HIV infection alone.
•
Peripheral neuropathy is damage to the peripheral nervous system. Onset usually occurs
after 2-6 months of therapy. The symptoms range from tingling, numbness, aching, or
burning sensations to severe pain usually in the feet, legs and sometime in the arms and
hands. It often begins in the toes and/or fingers bilaterally and evolves on hands in a glove
pattern or on feet in a sock pattern. Numbness and muscle weakness can also occur.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 42
NRTI Mitochondrial Toxicity
■ Inhibition of
mitochondrial DNA
polymerase-γ
■ ↓ oxidative metabolism, ↓
ATP generation
■ Implicated in lactic
acidosis with hepatic
steatosis
■ Other possible
manifestations:
■ Neuropathy (d4T, ddI)
■ Lipoatrophy (d4T)
■ Pancreatitis (ddI)
■ Myopathy (ZDV)
■ Cardiomyopathy (d4T,
ZDV)
Unit 3: Clinical Pharmacology of ART
•
42
In vitro, d4T/ddi/ddc worse than ZDV/3tc/abc
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 43
Facial Lipoatrophy
•
Also known as facial wasting. The look is distinct. It is characterized by thinning in
cheeks. This has become concerning to patients as they fear that the lipoatrophy
will enable other people to recognize that they have HIV.
•
Appears to be most common with long-term stavudine use, but difficult to
determine because combination therapies are typically used.
•
If facial lipoatrophy develops, discontinue the offending agent and use an alternate
medication. Facial wasting is usually not reversible, but by changing medications, it
prevents progression of the side effect.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 44
Hyperlactatemia / Lactic Acidosis
■ Rare but potentially fatal syndrome
■ Linked to prolonged use of NRTIs, especially ddI and
d4T1-4
■ Acute or subacute onset
1. John M et al. AIDS 2001;15:717-23.
2. Gerard Y et al. AIDS 2000;14:2723-2730
3. Boubaker K et al. CID 2001;33:1931-7
Unit 3: Clinical Pharmacology of ART
4. Moyle GJ et al. AIDS 2002;16:1341-9.
5. Schambelan M et al. JAIDS 2002;31:257-75
44
•
Lactic acidosis is a very rare but serious side effect of the nucleoside analogue
class of anti-HIV drugs. Although extremely rare when it does occur there is a high
chance of death even if it is treated immediately. Lactic acidosis may occur in
conjunction with a severely enlarged liver.
•
Lactate or lactic acid is a by-product of sugar (glucose) processing by cells. Little
organs inside each human cell called mitochondria process glucose to provide
energy for the cell. Lactate is a by-product of this process. Lactic acidosis occurs
when there is an over-accumulation of lactate in the body that the liver is unable to
clear.
•
Nucleoside analogues disrupt mitochondria function inside the cell. This could
cause excessive lactate production, which could lead to lactic acidosis is the liver
is not functioning properly.
•
Many of the other side-effects of nucleoside analogues may also be associated
with damage to mitochondria including peripheral neuropathy (numbness or pain in
the feet and hands); bone marrow suppression; pancreatitis (inflammation of the
pancreas); hepatic steatosis (accumulation of fat in the liver); and myopathy
(muscle damage).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 45
Hyperlactatemia /
Lactic Acidosis (cont.)
■ Common symptoms
■ Lethargy, fatigue
■ Weight loss
■ Nausea, abdominal pain
■ Dyspnea
■ Cardiac arrhythmias5
■ Concomitant hepatotoxicity common with
hepatomegaly, hepatic steatosis, and even ascites and
encephalopathy5
5. Schambelan M et al. JAIDS 2002;31:257-75
Unit 3: Clinical Pharmacology of ART
45
•
Between 30-60% of people taking nucleoside analogues have elevated levels of
lactate in their body, but levels are rarely high enough to induce the symptoms of
lactic acidosis. These symptoms include general gastrointestinal symptoms such
as nausea (feeling sick), vomiting, bloating, abdominal pain and lack of appetite,
as well as malaise, and difficulty in breathing. Of course, these symptoms can also
occur for many other reasons.
•
In people who have lactic acidosis, the liver may be swollen and tender
(hepatomegaly), and liver enzymes, which are measured by a liver function test,
may be abnormally high. Serum lactate levels are usually > 5 mmol/L. May also
see elevated CPK.
•
Lactic acidosis may be more common in those who have been taking nucleoside
analogues for an extended period, especially d4T containing regimens. It usually
occurs after 1-20 months of drug exposure.
•
Other risk factors for developing lactic acidosis include pregnancy, obesity and
women may be at greater risk than men. Avoid use of d4T and DDI together in
pregnant women or obese women due to increased risk of lactic acidosis. Only
use d4T + ddI when the “potential benefit clearly outweighs the risk”. There is
some evidence of a link with severe infection and malnutrition.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 46
Lactic Acidosis Suggested Management
■ If lactate level > 10 mmol/L, or > 5 mmol/L and symptomatic
■ d/c antiretrovirals until symptoms resolve and lactate levels
normalize1 (may take months2) & offer supportive care
■ Agents used for treatment of congenital mitochondrial
disorders3 may hasten recovery (thiamine, riboflavin,
coenzyme Q, L-carnitine)
■ Consider NRTI-sparing regimen if resumption of HAART
indicated
■ Re-initiation of therapy using ‘mitochondria-sparing’ NRTIs
(ZDV, 3TC, abacavir) reasonably safe in one small study4
Unit 3: Clinical Pharmacology of ART
1. Schambelan M et al. JAIDS 2002; 31(3):257-75.
2. Carr A et al. AIDS 2000;13:F25-32.
3. Peterson PL. Biochem Biophys Acta 1995;1271:275-80.
4. Lonergan T et al. 42nd ICAAC, San Diego, 2002, Abstract H-1080.
46
•
If there is evidence of lactic acidosis, then treatment with nucleoside analogues
should be stopped immediately until symptoms resolve and lactate levels
normalize.
•
If mild case, change to NRTIs with lower lactic acidosis risk.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 47
NRTI Recap
■ All NRTIs require dose
adjustment for renal
insufficiency except for
ABC
■ Duration of action is
based on intracellular
half life
■ ZDV= 3 h, D4T 3.5 h, 3TC
& ABC= 12 h, TDF 10-50
h, DDI-25-40 h
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
■ Class effects
■ Nausea, headache
■ Lactic acidosis, fatty liver
■ DDC/DDI/D4T > 3TC > ZDV
> ABC (TDF lower risk)
■ Lipoatrophy
■ Mitochondrial toxicity:
D4T/DDI/DDC >
ZDV/3TC/ABC
47
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 48
NRTI Recap (cont.)
■ Side effects (ZDV)- review presentation
■ Nausea, anemia may occur in first 4-6 weeks (dc if Hgb< 7-8),
should reverse in 1-2 weeks, neutropenia (dc if ANC < 750),
thrombocytopenia, GIT symptoms, myopathy
■ Side effects (“D” drugs)
■ Peripheral neuropathy after 2-6 months: DDC > D4T/DDI
■ Pancreatitis: discontinue, do not rechallenge: DDI > DDC > D4T
■ Hypersensitivity to ABC
■ Lamivudine and tenofovir effective against Hep B
Unit 3: Clinical Pharmacology of ART
48
•
Anemia symptoms shortness of breath, fatigue
•
If ANC < 750mm3 discontinue or reduce ZDV dose {or manage with G-CSF}.
Symptoms may include: Fever, aches, pains, chills and sweating; sores in the
mouth or gums; chest infections – cough producing lots of green mucus; very sore
throat and fever; ear ache and fever; discharge from the genitals; sudden swelling
around cuts or sores on the skin; myalgias.
•
Sx thrombocytopenia nose bleed, blood in urine, frequent bruising, small pinpoint
red spots
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 49
NRTI Recap (cont.)
■ Drug interactions
■ D4T + ZDV = contraindicated
■ Tenofovir + DDI (Must reduce DDI to 250 mg qd)
■ Ribavirin +ZDV may compromise ZDV activity
■ ZDV + other bone marrow suppressing drugs: caution
■ Bactrim, dapsone, pyrimethamine, ganciclovir
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
49
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 50
Non-Nucleoside Reverse
Transcriptase Inhibitors
■ NNRTIs
■ Nevirapine (NVP, Nevipan®)
■ Efavirenz (EFV, Stocrin®)
■ Delavirdine (DLV, Rescriptor®)
Unit 3: Clinical Pharmacology of ART
50
•
2 NNRTIs available in Ethiopia.
•
Delavirdine is not available in Ethiopia at this time, nor is it used in the US (it
doesn’t offer any advantage over the other two NRTIs).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 51
Nevirapine (NVP, Nevipan®)
■ Dosing: 200 mg QD x 2 weeks, then 200 mg BID
■ Food Interactions: None
■ Toxicity
■ Hepatitis (8 – 18%)
■ Rash (17%)
■ Nausea
■ Cost: 94.70 birr / month
Unit 3: Clinical Pharmacology of ART
51
•
NVP should not be used for PEP because of risk of hepatotoxicity for health care professional.
•
FDA Approval: June 1996
•
Mechanism of Action: Nevirapine binds to the enzyme reverse transcriptase and causes a
conformational change which makes reverse transcriptase ineffective (can’t form DNA from viral
RNA).
•
Bioavailability (F): 93%
•
CSF Levels: < 45% of peak serum levels
•
T1/2: 25-30 hours. This half-life supports once daily dosing of NVP (e.g., 400mg QD), but the peak
associated with this dose was associated with increased risk of hepatotoxicity and consequently is
not recommended.
•
Hepatotoxicity that occurs in the first 8 weeks appears to be a hypersensitivity reaction and may be
accompanied by drug rash, eosinophilia, and systemic symptoms. Some patients on NVP develop
hepatotoxicity later in the course of treatment. This form of hepatitis is more benign and similar to
hepatitis seen with other anti-HIV drugs.
•
8-18% of persons on NVP could develop hepatitis and some of those cases could be fatal. Some
patients have presented with nonspecific symptoms of hepatitis and progressed to hepatic failure.
The risk of hepatitis is greatest in the first 6 weeks of therapy. 9% of persons on NVP develop
asymptomatic increase in LFTs > 5 times the upper limit of normal (ULN). Symptomatic events are
observed in 4% of persons. Half of these cases were associated with rash.
•
Risk factors for hepatitis: It may be more common in patients with a history of alcohol abuse,
coinfection with hepatitis B or C and in patients who are older or are women. In addition, persons
with higher CD4 cell counts or elevated LFTs at baseline appear to be at higher risk.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 52
Nevirapine (cont.)
■ Monitor for hepatitis, rash
■ Occurs in the first 6 weeks of therapy
■ Up to the first 18 weeks
■ Counsel patients on symptoms of hepatitis
■ More common in women
Unit 3: Clinical Pharmacology of ART
•
•
•
•
•
•
•
•
52
Monitoring for Hepatitis: Check LFTs at baseline, 2 weeks, 4 weeks, 3 months, and every 6 months. Check for
HBV or HCV at baseline.
•
If LFTs > 2 x ULN
•
And have hypersensitivity reaction Æ stop NVP and do not rechallenge
•
No hypersensitivity reaction Æ continue NVP and monitor
•
If LFTs > 5 x ULN
•
And no hypersensitivity reaction Æ stop NVP. Rechallenge when LFTs normal
•
If LFTs are unknown and patient presents with hypersensitivity reaction Æ check LFTs to determine
next step.
Counsel Patients about Hepatitis: If patient develops signs or symptoms of hepatitis (anorexia, malaise,
jaundice, nausea, vomiting, bilirubinemia, hepatomegaly, and hepatic tenderness. Other constitutional
symptoms may include fever, arthralgia, fatigue, and other findings of generalized organ dysfunction), severe
skin reactions or other hypersensitivity signs, then discontinue NVP and seek medical attention immediately.
Nevirapine-induced rash is seen in about 17% of patients. Usually maculopapular and erythematous, with or
without itching. It is usually located on the trunk, extremities, and sometimes face. Nevirapine should be
discontinued if patient develops severe rash or has mucous membrane involvement, or if there are symptoms
consistent with hypersensitivity syndrome. 7% of patients that develop the rash will need to discontinue
nevirapine. Steven’s-Johnson syndrome is a life-threatening hypersensitivity syndrome that has been reported
in about 0.3% of the patients who have taken nevirapine. Symptoms include fever, swelling, pain in the
muscles and joints, and hepatitis all of which occur before the rash, and sometimes without a rash even
developing. Nevirapine treatment should be stopped as such a reaction can prove fatal (3 deaths related to
nevirapine-rash have been reported).
Management of NVP-induced rash:
•
Assess rash and check liver function tests
If the rash is mild or moderate [i.e, itching is tolerable, no constitutional symptoms (fever, blistering, oral
lesions, conjunctivitis, facial edema, and myalgia/arthralgia)] and liver function tests have not increased Æ
continue nevirapine and monitor for worsening of rash or increased liver function tests (check LFTs in 2-weeks
or sooner if symptoms indicate).
Treat symptomatically – can use hydrocortisone cream on skin and use anti-histamines (like
diphenhydramine) for itching.
If rash is severe [i.e., severe itching + constitutional symptoms, or SJS, or TEN] or rash is accompanied with
organ dysfunction or have rash along with increased LFTs Æ discontinue therapy and do not re-challenge.
Women appear to be at greater risk of developing rash than men. Women with CD4 counts >250 are ar
highter risk of develping hepatitis. Women starting NVP have an 11 % risk of developing hepatitis vs 0.9 % of
men
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 53
Nevirapine-Induced Rash
•
Counsel Patients: to call their provider or pharmacist or return to clinic if they develop a
rash or have any blistering in the mouth, and if they develop fever, arthralgias, or
myalgias.
•
RASH: In order to reduce the risk of nevirapine-induced rash, the dose should be
escalated over the first 2 weeks – starting at 200mg QD for 2 weeks and then increasing
to 200mg BID. This dosing makes sense because nevirapine autoinduces hepatic
cytochrome P450 enzymes (CYP3A4), which reduces its own half-life over 2 to 4 weeks
from 45 to 25 hours.
•
The rash most commonly appears on the body and arms, usually within the first month of
therapy, although occasionally it may start a few weeks later. Patients that do experience
a rash during the 2-week lead-in should not increase the dose until the rash has resolved
(mean duration of rash is 14 days). If the patient experiences rash and stops nevirapine
on their own, provider would not reintroduce nevirapine with the dose escalation until the
rash has resolved.
•
Patients that stop their medications for > 7 days should restart their regimen with the dose
escalation: Daily dosing for 2-weeks, then increase to 200mg BID.
•
It is suggested that nevirapine and other medications that often cause rash (e.g., abacavir
and SMX/TMP) should not be started simultaneously so that the offending agent can more
easily be identified if a rash develops. For example, for a new patient arriving in clinic that
meets criteria for ART and PCP prophylaxis, start SMX/TMP at first visit and monitor for
side effects, then start nevirapine at least 1 month later as part of ART regimen.
•
Prednisone and antihistamines are not effective in preventing nevirapine rash. In fact,
prednisone administration during the first 2 weeks of nevirapine therapy appears to
increase the incidence of rash.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 54
Rash Management
Time to Onset of Rash
■ Risk is greatest in the first 6 weeks
Incidence of Rash
■ Frequency is 14.8%
■ Frequency of severe rash is 1.5%
■ Stevens-Johnson syndrome (SJS) 0.3%
■ Women appear to be at higher risk of developing rash than men
Unit 3: Clinical Pharmacology of ART
•
•
•
•
•
Boehringer Ingelheim Pharmaceuticals, Inc.
54
Prednisone and antihistamines are not effective in preventing nevirapine rash. In fact, prednisone
administration during the first 2 weeks of nevirapine therapy appears to increase the incidence of rash.
Nevirapine-induced rash is seen in about 17% of patients. Usually maculopapular and erythematous,
with or without itching. It is usually located on the trunk, extremities, and sometimes face. Nevirapine
should be discontinued if patient develops severe rash or has mucous membrane involvement, or if
there are symptoms consistent with hypersensitivity syndrome. 7% of patients that develop the rash
will need to discontinue nevirapine. Steven’s-Johnson syndrome is a life-threatening hypersensitivity
syndrome that has been reported in about 0.3% of the patients who have taken nevirapine. Symptoms
include fever, swelling, pain in the muscles and joints, and hepatitis all of which occur before the rash,
and sometimes without a rash even developing. Nevirapine treatment should be stopped as such a
reaction can prove fatal (3 deaths related to nevirapine-rash have been reported).
Management of NVP-induced rash: Assess rash and check liver function tests
• If the rash is mild or moderate [i.e, itching is tolerable, no constitutional symptoms (fever,
blistering, oral lesions, conjunctivitis, facial edema, and myalgia/arthralgia)] and liver function
tests have not increased Æ continue nevirapine and monitor for worsening of rash or increased
liver function tests (check LFTs in 2-weeks or sooner if symptoms indicate). Treat
symptomatically – can use hydrocortisone cream on skin and use anti-histamines (like
diphenhydramine) for itching.
• If rash is severe [i.e., severe itching + constitutional symptoms, or SJS, or TEN] or rash is
accompanied with organ dysfunction or have rash along with increased LFTs Æ discontinue
therapy and do not re-challenge.
The following 5 slides are included in your packet as a handout for reference on management of Rash
and hepatotoxicity with Viramune
This section describes time to onset of rash, incidence of rash, risk factors and patient management
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 55
Rash Management (cont.)
Patient Management
■ Dosage is 200-mg once-daily for 14 days, followed by 200 mg
twice daily to reduce rash.
■ Do not increase the dose of VIRAMUNE in the presence of rash
■ If VIRAMUNE is interrupted for >7 days, reintroduce with the 14day, 200-mg once-daily lead-in dose
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
Boehringer Ingelheim Pharmaceuticals, Inc.
55
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 56
Rash Management Algorithm
Assess Rash and Evaluate ALT/AST
Mild or moderate rash with no
constitutional symptoms.
Rash and no increase in ALT or AST
Severe rash or
Rash + constitutional
symptom ± organ
dysfunction or
Rash + increased ALT/ AST
Can continue
Permanently discontinue
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
Boehringer Ingelheim Pharmaceuticals, Inc.
56
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 57
Management of Hepatic Events
Time to Onset of Hepatic
Events
■ Risk is greatest in the first 6 weeks
of therapy. However, monitor
closely for the first 18 weeks of
treatment.
Incidence of Hepatic Events
■ VIRAMUNE is associated with
asymptomatic ALT/AST >5X ULN†
in 8.8% of patients
Symptomatic hepatic events
are observed in 4.0%
■ About half of these cases were
associated with rash
■ Women more likely than men to
experience Symptomatic
hepatic events during the first 6
weeks of therapy
■ Women are at greater risk when
CD4+ cell counts <250
cells/mm3
■ Men are at greater risk when CD4+
cell counts >400 cells/mm3
Unit 3: Clinical Pharmacology of ART
Boehringer Ingelheim Pharmaceuticals, Inc.
57
•This section describes time to onset of hepatic events, incidence of hepatic events,
risk factors and patient management
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 58
Management of
Hepatic Events (cont.)
Risk Factors for Symptomatic Hepatic Events
■ Elevated pretreatment ALT or AST
■ HBV and/or HCV coinfection‡
■ Higher CD4+ cell count at initiation of VIRAMUNE therapy
■ Female gender
■ Women with CD4+ cell counts >250 cells/mm3, including
pregnant women receiving chronic treatment for HIV infection,
are at considerably higher risk of hepatotoxicity, including fatal
events
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
Boehringer Ingelheim Pharmaceuticals, Inc.
58
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 59
Management of Hepatic Events Patient Management
■ Counsel patients that if signs or
symptoms of hepatitis, severe
skin reactions, or
hypersensitivity occur, then
discontinue VIRAMUNE and
seek medical evaluation
immediately
■ If hepatic symptoms occur:
■ Frequent clinical and laboratory
monitoring is essential,
especially during the first 18
weeks of treatment—extra
vigilance is warranted during
the first 6 weeks
■ Evaluate patient for other
causes, including HBV/HCV
coinfection, alcohol use, and
coadministered medications
■ Baseline assessments should
include LFTs and HBV/HCV
status
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
■ Permanently discontinue
VIRAMUNE
■ Consider stopping all potential
hepatotoxins, including
concomitant antiretrovirals
■ Continue to monitor patient until
symptoms resolve
■ In some cases, hepatic injury
has progressed despite
discontinuation of treatment
59
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 60
Management of
Hepatic Events (cont.)
Evaluate patient regularly: clinical, ALT/AST evaluations
If no symptoms
Can continue
Unit 3: Clinical Pharmacology of ART
•
If symptoms
of hepatitis occur
Permanently discontinue
Boehringer Ingelheim Pharmaceuticals, Inc.
60
An algorithm for the management of hepatic events.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 61
Nevirapine (cont.)
■ Pregnancy
■ Prevention of perinatal transmission
■ Drug interactions (induces liver enzymes)
■ NVP reduces AUC for ethinyl estradiol (EE) by ~ 30%. An
alternate or additional form of birth control should be used
■ NVP reduces ketoconazole levels by 63% and NVP levels
increase 15% - 30%. Do not co-administer
■ Rifampin reduces NVP 37%. Do not combine NVP and
Rifampin
Unit 3: Clinical Pharmacology of ART
•
•
•
•
61
Elimination: Metabolized by cytochrome P450 3A4 (CYP3A4) to hydroxylated metabolites,
80% of metabolites are excreted in the urine. Dosage adjustments are not needed for
renal or hepatic impairment.
Pediatric Dose: 120mg/m2 QD x2wks, then 120-200mg/m2 Q12H
Pregnancy: (Category C) Crosses placenta. NVP can be used as an option for prevention
of perinatal tranmission for HIV-infected women who present at term with no prior therapy.
A single oral dose of 200mg is given at the onset of labor, and a single dose (2mg/kg) is
given to the infant at 48-72 hours. The W.H.O. considers Nevirapine to be a preferred
regimen for HIV infected women who are pregnant or for women whom effective
contraception cannot be assured in resource-limited areas.
Drug Interaction (NVP induces CYP3A4), Maximum induction takes 2-4 weeks:
• NVP reduces AUC for ethinyl estradiol (EE) by ~ 30%. An alternate or additional
form of birth control should be used to prevent pregnancy.
• NVP reduces ketoconazole levels by 63% and NVP levels increase 15% - 30%. Do
not co-administer NVP and ketoconazole.
• NVP reduces Rifabutin levels by 16%. Dose change not needed.
• Rifampin reduces NVP 37%. Do not combine NVP and Rifampin (Some resources
say that 300mg BID with normal dose Rifampin could be used together).
• NVP reduces methadone levels by 50%. Could induce opiate withdrawal – may
need to increase methadone dose 15% to 25%
• NVP reduces clarithromcyin AUC by 30% but also increases the active 14-OH
metabolite, so no dosage adjustment is needed.
• Do not combine NVP with St. Johns Wort as levels of NVP are decreased.
• The safety and efficacy of dual NNRTIs has not been established – do not
combine NVP with EFV
• NVP with Protease Inhibitors
• Refer to algorithm in Section 1 of the workbook.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 62
Nevirapine (cont.)
■ NVP drug interactions with PIs
■ May need to increase dose of the PI
■ Kaletra, indinavir
■ Resistance
■ Single point mutation.
■ Missed doses = treatment failure and cross class resistance
Unit 3: Clinical Pharmacology of ART
•
•
62
****If adding NVP to a PI-based regimen where a drug interaction exists, increase the PI
dose to the doses recommended below at the same time you add NVP. If on an adjusted
dose PI along with NVP and then the NVP is stopped, continue the PI at the increased
dose for an additional 2 weeks, then reduce the PI back to it’s normal dose. If switching
from NVP to a PI, use the recommended increased PI dose for the first 2 weeks on the PI,
then drop down to the normal dose. If switching from a PI to NVP, dosage changes are
not needed. These measures reduce the chance of PI resistance development.
• NVP reduces indinavir 28%. Increase IDV to 1,000mg Q8H if not combined with
RTV.
• NVP reduces Lopinaivr/ritonavir 55%. Increase LPV/r to 4 capsules BID.
• NVP reduces RTV 11%, SQV 25%, and increases NFV 10%, but no doses
changes are needed.
Resistance: Accumulation of 2 or more of the following mutations substantially reduces
the clinical utility of all of the currently approved NNRTIs: L100I, V106A, Y181C/I,
G190S/A or M230L. There is cross-resistance within the NNRTI class, usually seen with
K103N or Y188L (only a single mutation is needed to be resistant to all NNRTIs). Counsel
patients about the importance of adherence related to this class of medications.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 63
Efavirenz (EFV, Stocrin®)
■ Dosing: 3 x 200mg capsules QHS
■ Food Interactions
■ Take with low-fat meal
■ High-fat meals increase absorption 50% Æ increases side effects
Unit 3: Clinical Pharmacology of ART
63
•
FDA Approval: September 1998
•
Mechanism of Action: Efavirenz binds to the enzyme reverse transcriptase and causes a
conformational change which makes reverse transcriptase ineffective (can’t form DNA from viral
RNA).
•
Bioavailability (F): 40%-45% with or without food. High-fat meals increase absorption by 50% and
should be avoided.
•
CSF Levels: .25%-1.2% of serum levels (these levels are above the IC95 for wild-type HIV)
•
T1/2: 40-55 hours
•
Elimination: Metabolized by CYP450 3A4. 14% to 34% excreted in urine as glucuronide metabolites
and 16% to 61% in stool. Do not need to adjust dose for renal or hepatic compromise.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 64
Efavirenz (cont.)
■ Toxicity
■ CNS Changes (52%) - Insomnia, nightmares, poor
concentration, mood change, dizziness, dysequilibrium,
depression, psychosis
■ Rash (15-27%)
■ Nausea
■ CONTRAINDICATED DURING PREGNANCY
■ Cost: 379.50 birr / month
Unit 3: Clinical Pharmacology of ART
•
•
•
•
64
Side Effects: CNS changes are very common (noted in 52% of patients), but require
discontinuation in a much smaller percentage (2%-5%). Onset is usually at initiation of
therapy and usually resolve after 2 to 4 weeks. They include: confusion, abnormal
thinking, impaired concentration, abnormal dreams (Very vivid, bizarre dreams, most
concerning if they are nightmares. Some patients enjoy the dreams and are not worried at
all by them.) and dizziness. Other side effects include: drowsiness, insomnia, amnesia,
hallucinations, and euphoria. Counsel patients that these side effects could occur, but that
they usually resolve after 2 to 4 weeks. Avoiding high-fat meals at time of dose
consumption reduces side effect intensity. Also counsel patients to take their dose at
bedtime so that they sleep through the peak of the side effects. If they wake up in the
middle night, they should use caution so they don’t fall. In addition, patients should use
caution if operating a car or other heavy machinery during the day or night if they
experience these symptoms to prevent accidents, especially during the first 2 weeks of
therapy. For patients that experience insomnia (which can be associated with the peak
level), pharmacists can advise them to take their dose 1 to 2 hours prior to going to bed.
In addition, splitting the dose: take 1 capsule in the morning and 2 capsules in the evening
can help improve side effects.
A minority of patients experience severe psychiatric symptoms including delusions, manic
episodes and severe depression. They may even become suicidal and require antipsychotic medication. This is particularly common in people with a history of mental illness
or recreational drug abuse. For patients with a history of psychosis or severe depression,
only use EFV if no other options are available.
Rash occurs in 15%-27% of persons, which is usually morbiliform and does not require
discontinuation of EFV. Symptoms can be treated as needed (e.g., hydrocortisone cream and
antihistamines for itching). If patient develops a more serious rash (blistering of mucous
membranes or skin, seen in about 1%-2% of cases; or SJS) EFV should be discontinued. Median
time of onset of the rash is 11 days and the duration is 14 days.
EFV can cause hepatotoxicity. The rate is less frequent and less severe than seen with NVP. 2%8% of patients can experience an increase in LFTs > 5 ULN. Increase risk of occurrence if coinfected with HCV or also taking other hepatotoxic medications.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 65
Introduction Case – Answers 2
■ The statement A) : Central nervous system (CNS) side
effects from efavirenz will not likely go away and
patients must get used to less sleep is false.
■ The onset of CNS side effects (such as insomnia
and nightmares) is usually at the start of therapy
and usually resolves after 2 to 4 weeks. Rarely,
CNS side effects continue after the first month of
therapy.
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
65
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 66
Introduction Case - Answers
■ The statement D): The CNS side effects described are
most likely due to efavirenz. Over 50% of patients who
take efavirenz may experience CNS side effects is true.
■ CNS changes are very common (noted in 52% of
patients), but require discontinuation in a much
smaller percentage (2%-5%). Patients must be
counseled appropriately to prepare them for
possible CNS side effects from efavirenz.
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
66
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 67
Efavirenz (cont.)
■ Contraindicated in pregnancy!!
■ Known to cause birth defects
■ Drug interactions (Induces liver enzymes)
■ EFV increases levels of ethinyl estradiol by 37% Æ encourage
women to use an alternate contraceptive method Rifampin
decreases EFV levels by 25% Æ increase dose of EFV to
800mg QHS
■ EFV decreases levels of phenytoin, phenobarbital, and
carbamazepine Æ Need to monitor anticonvulsant levels.
■ EFV decreases clarithromycin levels by 39% and rate of rash
increases to 46%Æ do not combine EFV and clarithromycin
Warfarin
Unit 3: Clinical Pharmacology of ART
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Pediatric Dose: 10-<15kg=200mg QHS
15-<20kg=250mg QHS
20-<25kg=300mg QHS
25-<32.5kg=350mg QHS
32.5-<40kg=400mg QHS
> 40kg=600mg QHS
Pregnancy: (Category C) Crosses placenta. CONTRAINDICATED DURING PREGNANCY,
ESPECIALLY 1st TRIMESTER. Known to cause birth defects in monkeys, and a single human case
when EFV was used during conception and early pregnancy. For women of child-bearing age, avoid
EFV if cannot ensure reliable contraceptive protection. Ensure a negative pregnancy test for women of
child-bearing age prior to initiation of EFV.
Drug Interaction: EFV both inhibits and induces the CYP450 3A4 metabolic enzymes. In addition, EFV
inhibits CYP450 2C9 and 2C19.
• The following drugs are contraindicated with EFV: terfenadine, midazolam, triazolam, cisapride,
and ergot alkaloids.
• Rifampin decreases EFV levels by 25% Æ increase dose of EFV to 800mg QHS
• EFV reduces Rifabutin levels by 35% Æ increase rifabutin dose to 450mg QD or 600mg
3x/week
• EFV increases levels of ethinyl estradiol by 37% Æ encourage women to use an alternate
contraceptive method.
• EFV decreases levels of phenytoin, phenobarbital, and carbamazepine Æ Need to monitor
anticonvulsant levels.
• EFV decreases methadone levels by 52% Æ titrate methadone levels up to avoid opiate
withdrawal.
• EFV decreases clarithromycin levels by 39% and rate of rash increases to 46%Æ do not
combine EFV and clarithromycin
• Monitor warfarin therapy carefully if on EFV
• PI interactions with EFV
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 68
Efavirenz Drug Interactions
■ Efavirenz may decrease levels of protease inhibitors
■ Adjust dose accordingly
■ For example EFV + kaletra: must increase kaletra dose to 4 caps bid
■ Reduce the PI dose when discontinuing EFV
■ Changing from a EFV to a PI, may need to increase
dose of PI for first two weeks
■ Resistance
■ Single point mutation
■ Counseling points
Unit 3: Clinical Pharmacology of ART
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****If adding EFV to a PI-based regimen where a drug interaction exists, increase the PI dose to the
doses recommended below at the same time you add EFV. If on an adjusted dose PI along with
EFV and then the EFV is stopped, continue the PI at the increased dose for an additional 2 weeks,
then reduce the PI back to it’s normal dose. If switching from EFV to a PI, use the recommended
increased PI dose for the first 2 weeks on the PI, then drop down to the normal dose. If switching
from a PI to EFV, dosage changes are not needed. These measures reduce the chance of PI
resistance development.
• EFV decreases IDV 31% Æ increase IDV to 1000mg Q8H or combine IDV 800mg BID with
RTV 200mg BID
• EFV increases RTV 18% and RTV increases EFV by 21% Æ If use RTV alone, dose RTV
500-600mg BID
• EFV increases NFV 20% Æ No NFV dosage change
• EFV decreases SQV 62% & SQV decreases EFV 12% Æ Do not use SQV alone with EFV.
Combine SQV 400mg BID with RTV 400mg BID or SQV 1200mg BID + RTV 200mg BID
• EFV decreases APV 36% Æ Increase APV dose to 1200mg TID or add RTV 100mg-200mg
BID to APV 600mg BID
• EFV decreases LPV/r 40% Æ Increase LPV/r dose to 4 capsules (533mg/133mg) BID
• If combine APV, LPV/r, and EFV Æ APV 750mg BID + LPV/r 4 capsules BID + EFV 600mg
QHS
Resistance: Accumulation of 2 or more of the following mutations substantially reduces the clinical
utility of all of the currently approved NNRTIs: L100I, V106A, Y181C/I, G190S/A or M230L. EFV
mutations associated with reduced susceptibility are at codons: 100, 108, 181, 225, 188L. There is
cross-resistance within the NNRTI class, usually seen with K103N or Y188L (only a single mutation
is needed to be resistant to all NNRTIs). Counsel patients about the importance of adherence related
to this class of medications.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 69
Delavirdine (DLV)
■ Dosing: 2 x 200mg TID
■ Food interactions: None
■ Separate from antacids
■ Side Effects
■ Rash (18%)
■ Headache
■ Hepatitis
Unit 3: Clinical Pharmacology of ART
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•
Clinically, delavirdine is rarely used in the US.
•
Side Effects: Rash noted in about 18%; 4% require drug discontinuation. Rash is
diffuse, maculopapular, red, and predominantly on upper body and proximal arms.
Duration of rash averages 2 weeks and usually does not require dose reduction or
discontinuation (after interrupted treatment). Rash accompanied by fever, mucous
membrane involvement, swelling, or arthralgias should prompt discontinuation of
treatment. Erythema multiforme and SJS have been reported with DLV.
•
Hepatotoxicity is less frequent and less severe than with NVP.
•
FDA Approval: April 1997
•
Mechanism of Action: Delavirdine binds to the enzyme reverse transcriptase and
causes a conformational change which makes reverse transcriptase ineffective
(can’t form DNA from viral RNA).
•
Bioavailability (F): 85%. Antacids, buffered ddI, and gastric achlorhydria decrease
absorption. Patients with achlorhydria should take delavirdine with an acidic
beverage such as cranberry or orange juice.
•
CSF Levels: 2% of serum levels
•
T1/2: 5.8 hours
•
Elimination: Primarily metabolized by CYP450 3A4 enzymes. DLV inhibits P450
CYP3A4, inhibiting its own metabolism as well as other PIs. Excretion is in urine
(50%) and stool (44%). The standard dose is recommended in renal failure.
Consider empiric dosage reduction in hepatic failure.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 70
Delavirdine (cont.)
■ Not approved for use in children
■ Drug interactions (Liver enzyme inhibitor)
■ Anticonvulsants (phenobarbital, phenytoin, and
carbamazepine) decrease DLV levels Æ Do not combine
agents
■ DLV decreases Ethinyl estradiol levls 20% Æ Use alternative
or additional method of birth control
■ Rifampin decreases DLV levels 96% Æ Do not combine
Rifampin and DLV
■ Antacid in DDI buffered tablets or powdered suspension
decrease absorption of DLV Æ Separate doses by 2 hours.
Unit 3: Clinical Pharmacology of ART
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Pediatric Dose: Not approved for use in children
Pregnancy: (Category C) Unknown if crosses placenta or into breast milk. Teratogenic in
rodents.
Drug Interaction: Inhibits CYP450 3A4 enzymes. The following drugs should not be
combined with delavirdine: Rifampin, rifabutin, simvastatin, lovastatin, ergot derivatives,
astemizole, cisapride, midazolam, triazolam, simvastatin, lovastatin, ketoconazole, H2
blockers, and proton pump inhibitors.
• Rifampin decreases DLV levels 96% Æ Do not combine Rifampin and DLV
• DLV decreases Ethinyl estradiol levls 20% Æ Use alternative or additional method
of birth control
• Anticonvulsants (phenobarbital, phenytoin, and carbamazepine) decrease DLV
levels Æ Do not combine agents
• Antacid in DDI buffered tablets or powdered suspension decrease absorption of
DLV Æ Separate doses by 2 hours.
• DLV increases ketoconazole levels 50% Æ do not co-administer DLV and
ketoconazole
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 71
Delavirdine (cont.)
■ Drug interactions with PIs
■ Limited data
■ May need to decrease PI dose
■ Cross resistance with other NNRTIs
Unit 3: Clinical Pharmacology of ART
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Protease Inhibitors
• DLV increases IDV > 40% Æ decrease dose of IDV to 600mg Q8H
• DLV increases RTV 70% Æ No data
• DLV increases SQV 5x Æ Decrease SQV to 800mg TID + DLV
600mg BID (limited data for this DLV dose)
• DLV increases APV 125% and APV decreases DLV 60% Æ Not
recommended to combine these agents
• DLV increases LPV 8%-134% Æ Limited data
• DLV increases NFV 2-fold and NFV decreases DLV 50% Æ NFV
1250mg BID + DLV 600mg BID (limited data)
Resistance: Accumulation of 2 or more of the following mutations
substantially reduces the clinical utility of all of the currently approved
NNRTIs: L100I, V106A, Y181C/I, G190S/A or M230L. There is crossresistance within the NNRTI class, usually seen with K103N or Y188L (only
a single mutation is needed to be resistant to all NNRTIs). The major DLV
mutations associated with resistance are at codons 103, 181, and 236,
which also confer cross-resistance to efavirenz and nevirapine. Counsel
patients about the importance of adherence related to this class of
medications.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 72
NNRTI Class Effects
■ Side effects
■ Rash
■ EFV > DLV > NVP
■ Elevated transaminase
■ Across the class
■ Essentially a one shot class of drugs
■ Cross Resistance across entire class
Unit 3: Clinical Pharmacology of ART
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Rash and liver toxicity can occur on either nevirapine or efavirenz. However, these
drugs do not appear to cause rash and hepatitis in the same manner. Patients who
experience rash or liver toxicity on nevirapine can probably be safely switched to
efavirenz (and vice versa), unless the toxicity on nevirapine was very severe. Just
because a patient gets a rash to one medication does not mean they will develop
rash to the other agent.
•
Rate of Rash: EFV (15%-27%) > DLV (18%) > NVP (17%)
•
Rate of rash that requires discontinuation of the offending agent: NVP (7%)
> DLV (4.3%) > EFV (1.7%).
•
Rate of hepatotoxicity: NVP (8-18%; 4% symptomatic and 9%
Asymptomatic with LFTs increase > 5 x ULN ) > EFV (2-8%)
Resistance: A single mutation, the K103N, causes high-level resistance to all 3
drugs in this class: EFV, NVP, and DLV. Counsel patients about the importance of
adherence related to this class of medications, only a single mutation is needed to
make a person resistant to all NNRTIs.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 73
Co-formulated Reverse
Transcriptase Inhibitors
■ ZDV/3TC
(Combivir, Generic Brands:
Duovir, Virocomb, Zidolam )
■ Nevirapine/d4T/3TC
(Generic Brands: Triomune,
Viro LNS, Nevilast)
■ D4T/3TC
(Lamivir-S, Viro LIS,
Lamistar)
■ Nevirapine/ZDV/3TC
(Generic brand: Duovir-N)
■ Abacavir/ZDV/3TC
(Trizivir or Trisivir, Generic
Brands: Virol LZ )
■ Efavirenz/ddI/3TC
(Generic brand: Odivir Kit)
Unit 3: Clinical Pharmacology of ART
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•
Co-formulated Reverse Transcriptase Inhibitors
Slide 13
•
A number of reverse transcriptase inhibitors and NNRTIs have been formulated
into one pill. They are listed below by common names and then brand names or
generic brand names where applicable.
•
ZDV/3TC (Combivir, Generic Brands: Duovir, Virocomb, Zidolam, Lamuzid)
•
D4T/3TC (Lamivir-S, Viro LIS, Lamistar)
•
abacavir/ZDV/3TC (Trizivir or Trisivir, Generic Brands: Virol LZ )
•
Nevirapine/d4T/3TC (Generic Brands: Triomune, Viro LNS, Nevilast)
•
Nevirapine/ZDV/3TC (Generic brand: Duovir-N)
•
Efavirenz/ddI/3TC (Generic brand: Odivir Kit)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 74
Protease Inhibitors
■ Lopinavir + Ritonavir
(Kaletra®)
■ Saquinavir-HGC
(Invirase®)
■ Nelfinavir (Viracept®)
■ Amprenavir
(Agenerase®)
■ Saquinavir-SGC
(Fortovase®)
■ Ritonavir (Norvir®)
■ Atazanavir (Reyataz®)
■ Fosamprenavir (Lexiva®)
■ Indinavir (Crixivan®)
Unit 3: Clinical Pharmacology of ART
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* The protease inhibitors (PIs) on the left are recommended as second line
treatment agents. Saquinavir boosted is recommended as second line
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 75
Ritonavir (RTV)
■ Dosing: 6 x 100mg Q12 hrs
■ Food Interactions: take with food to increase absorption and
tolerability
■ Toxicity
■ Nausea, abdominal discomfort, Diarrhea
■ Tingling around mouth, Bitter taste in mouth
■ Hepatitis, use with caution in hepatic impairment
■ Fat redistribution, Lipid abnormalities
■ Refrigeration recommended, but OK at room temperature for up
to 30 days
Unit 3: Clinical Pharmacology of ART
75
•
Ritonavir’s principal side effects are gastrointestinal (nausea, diarrhea, vomiting,
anorexia, abdominal pain and taste perversion). At full dose, patients can also
experience perioral paresthesias (numbness and tingling around the mouth) about
1 hour after dose consumption – this side effect improves with continued time on
therapy. Ritonavir, compared to other PIs, is more frequently associated with lipid
abnormalities, and hepatotoxicity.
•
Ritonavir is a potent inhibitor of CYP450 3A4. This inhibitory effect is used to
boost the levels of other PIs. RTV is rarely used as a sole PI at this time. Instead
it is combined with other PIs which allows for reduced RTV doses as well as
reduced doses of the other PIs, resulting in better tolerability to both agents.
•
Ritonavir is rarely used as a single PI anymore b/c of it’s side effect profile.
Instead, it is more often combined with other PIs to take advantage of it’s
pharmacokinetic inhibitory properties so that when combined, both PI doses can
be reduced. However, if RTV were to be used alone, follow this dose escalation
schedule: RTV 300mg BID x 4 days, 400mg BID x 4 days, 500mg BID x 4 days,
then to full dose, 600mg BID.
•
Ritonavir needs to be refrigerated to ensure stability, but it can be left at room
temperature for 30 days. Hot temps should be avoided.
•
FDA Approval: June 1999
•
Mechanism of Action: Inhibitor of the protease enzyme
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 76
Ritonavir – Drug Interactions
■ Separate from antacids
■ (including DDI buffered tabs) by 2 hours
■ Metabolized by 3A4 > 2D6
■ Ritonavir potent inhibitor of liver enzymes
■ Contraindications: amiodarone, astemizole, bepridil,
cisapride, encainide, flecainide, lovastatin, midazolam,
ergot alkaloids, pimozide, propafenone, quinidine,
simvastatin, terfenadine, triazolam, and St. John’s wort
Unit 3: Clinical Pharmacology of ART
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Bioavailability (F): 60%-80%. Levels increased 15% when taken with food. Separate
doses from antacids (including ddI buffered tablets or powder) by 2 hours.
CSF Levels: No detectable levels in CSF
T1/2: 3 to 5 hours
Elimination: Metabolized by CYP450 3A4 > 2D6. Use standard doses for renal failure.
Use with caution in patients with hepatic impairment.
Pediatric Dose: 350-400mg/m2 BID
Pregnancy: (Category B) Crosses placenta.
Drug Interaction: Ritonavir is a potent inhibitor of CYP450 3A4 and 2D6 2C9, 2D19, and to
a lesser degree, 2A6, 1A2, and 2E1. Drug levels for other medications metabolized
through these pathways may be increased. Conversely, RTV is metabolized by 3A4 and
2D6, so drugs that induce these enzymes could decrease RTV drug levels. Knowing the
CYP450 pathways that medications are metabolized through allows providers to predict
potential drug interactions and make appropriate dosage adjustments. See below for a
list of some RTV drug interactions. As new information is published, continue to update
the drug interaction list.
RTV is contraindicated with the following agents: amiodarone, astemizole, bepridil,
cisapride, encainide, flecainide, lovastatin, midazolam, ergot alkaloids, pimozide,
propafenone, quinidine, simvastatin, terfenadine, triazolam, and St. John’s Wort.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 77
RItonavir – Drug
Interactions (cont.)
■ Rifampin reduces RTV levels 35% Æ Can NOT use
RTV alone (can use with SQV, dosing 400/400 BID or
1000/100 BID) and Rifampin dose of 600mg QD
■ Decreases EE 40% Æ use alternative method
■ Decreases phenobarbital, phenytoin and
carbamazepine
■ Monitor antiseizure activity
■ Used to boost other PIs to prevent subtherapeutic
levels and development of resistance
Unit 3: Clinical Pharmacology of ART
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RTV increases clarithromycin AUC 77% Æ reduce clarithromycin doses for renal failure.
RTV decreases Methadone levels 36% Æ titrate methadone dose as needed to prevent opioid withdrawal.
The buffered form of ddI and other liquid antacids reduces absorption of RTV Æ Separate doses by at least 2 hours.
Ketoconazole levels are increased 3-fold Æ Do not exceed ketoconazole dose of 200mg/day
Rifampin reduces RTV levels 35% Æ Can NOT use RTV alone (can use with SQV, dosing 400/400 BID or 1000/100 BID)
and Rifampin dose of 600mg QD
RTV reduces Rifabutin levels 4-fold Æ Decrease Rifabutin dose to 150mg QOD or 150mg 2 to 3 days/week
RTV decreases ethinyl estradiol levels 40% Æ Use alternative or additional method of birth control
RTV decreases Theophylline levels 47% Æ Monitor theophylline levels and adjust dose accordingly
RTV decreases Phenobarbital, phenytoin, and carbamazepine levels Æ Monitor antiepileptic drug levels and antisiezure
activity
RTV increases sildenafil AUC 2 to 11-fold Æ Do not use > 25mg of sildenafil every 48 hours
RTV increases the illicit drug MDMA (crystal methamphetamine), potentially fatal reaction has been reported Æ Do not
combine RTV and MDMA if possible. If need to combine, decrease dose of MDMA.
RTV with other antiretrovirals:
•
NVP decreases RTV 11% Æ No dosage adjustment needed
•
DLV increases RTV 70% Æ Do not combine
•
EFV increases RTV 18% and RTV increases EFV 21% Æ Use normal doses of both. If patient does not tolerate
side effects associated with full RTV dose, reduce RTV doses to 500mg BID
•
RTV increases SQV 20 fold Æ Reduce doses of both: SQV 400mg BID + RTV 400mg BID (considered a dual PI
regimen); or SQV 1000mg BID + RTV 100mg BID; or SQV 1600mg + RTV 100mg PO QD
•
RTV increases IDV 2 to 5 fold Æ Reduce doses of both: IDV 800mg + RTV 100-200mg PO BID; or IDV 400mg +
RTV 400mg PO BID
•
RTV increases APV 2.5 fold Æ Reduce doses of both: APV 600mg BID + RTV 100mg BID; or APV 1200mg QD
+ RTV 200mg QD; or APV 600mg PO BID + RTV 100-200mg PO BID + EFV 600mg PO QHS
•
RTV increases NFV 1.5-fold Æ RTV 400mg BID + NFV 500-750mg BID (limited data, clinically this regimen is not
used)
•
When combine atazanavir with Efavirenz or tenofovir add RTV to regimen to boost ATZ levels Æ ATZ 300mg QD
+ RTV 100mg QD (this dosing is commonly used even when EFV or TDF are not part of regimen)
•
Fos-amprenavir can be dosed with RTV to create daily dosing Æ f-AMP 1400mg QD + RTV 200mg QD; or f-AMP
1400mg QD + RTV 300mg QD + EFV 600mg QHS; or for PI experienced persons, must use f-AMP BID dosing +
RTV Æ f-AMP 700mg BID + RTV 100mg BID
Resistance: Resistance correlates with primary mutations on the protease gene at codons 82 and 84. Other common
mutations can occur at codons: 10, 20, 32, 33, 36, 46, 54, 71, 77, 82, 84, and 90.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 78
Lopinavir/ritonavir (LPV/r)
■ Dosing: 3 caps (400 mg lopinavir/100 mg ritonavir) BID
■ Each capsule contains LPV 133mg / RTV 33mg
■ Food Interactions: take with food
■ Toxicity
■ Nausea, Diarrhea
■ Lipid abnormalities
■ Hyperglycemia
■ Refrigeration recommended, but OK at room
temperature for up to 2 months
Unit 3: Clinical Pharmacology of ART
78
•
Lopinavir/r is approximately 10 times more potent than RTV alone against wild-type HIV.
•
Lopinavir/ritonavir is generally well tolerated. LPV/r most commonly causes mild to
moderate diarrhea, weakness, and elevations in cholesterol and triglycerides. Pancreatitis
has been reported in adults, possibly due to high triglyceride levels.
•
This medication needs to be refrigerated to ensure stability, but is stable at room
temperature for 2 months. Hot temps should be avoided.
•
FDA Approval: September 2000
•
Mechanism of Action: Inhibitor of the protease enzyme
•
Bioavailability (F): ~80% with food and 48% on an empty stomach, but by combining LPV
with ritonavir (in the capsule), LPV levels are increased significantly.
•
CSF Levels: unknown %, likely low because LPV is 98-99% protein bound
•
T1/2: 5 to 6 hours (for LPV when combined with RTV)
•
Elimination: Metabolized primarily by CYP450 3A4 enzymes. Less than 3% is excreted
unchanged in urine. Do not need to adjust doses for renal compromise. Use with caution in
patients with hepatic impairment.
•
Pediatric Dose: 230mg/m2 LPV / 57.5mg/m2 RTV BID
•
Pregnancy: (Category C) Crosses placenta.
•
Drug Interaction: The major effect is due to inhibition of CYP3A4. This effect is less than
seen with full doses of RTV.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 79
Lopinavir/ritonavir (cont.)
■ Contraindicated drugs same as ritonavir
■ Rifampin reduces LPV/r by 75%
■ Use 400mg LPV/100mg RTV + 300mg RTV BID and Rifampin
600mg QD.
■ LPV/r decreased ethinyl estradiol AUC 42%
■ Use additional or alternative methods of birth control to
prevent pregnancy
■ Anticonvulsants decrease LPV/r
■ May decrease anticonvulsant levles
Unit 3: Clinical Pharmacology of ART
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Drugs contraindicated with LPV/r include: astemizole, terfenadine, flecainide,
propafenone, simvastatin, lovastatin, midazolam, triazolam, cisapride, pimozide,
ergot derivatives, and St. John’s Wort.
Rifampin reduces LPV/r by 75% Æ use 400mg LPV/100mg RTV + 300mg RTV
BID and Rifampin 600mg QD.
LPV/r increased Rifabutin levels 3-fold Æ reduce Rifabutin dose to 150mg QOD
LPV/r decreased methadone levels 53% Æ titrate methadone dose as needed to
prevent opioid withdrawal.
LPV/r increased atorvastatin AUC by 6x Æ use with caution (starting dose 10mg
QPM) or use alternative, such as pravastatin
LPV/r increased pravastatin levels 33% Æ Do not need to adjust doses
LPV/r increased ketoconazole levels 3-fold Æ Do not exceed ketoconazole
200mg/day
LPV/r decreased ethinyl estradiol AUC 42% Æ use additional or alternative
methods of birth control to prevent pregnancy
LPV/r increased sildenafil levels Æ Do not exceed dose of 25mg sildenafil every
48 hours
Anticonvulsants decrease LPV levels Æ monitor anticonvulsant levels
LPV/r may decrease Atovaquone levels Æ May need to adjust atovaquone dose
upwards.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 80
Lopinavir/ritonavir (cont.)
■ Interactions with other ARVs
■ EFV and NVP decrease LPV/r levels
■ Increase LPV/r to 4 caps bid
■ LPV/r may decrease amprenavir levels
■ Increase amprenavir dose to 750 mg bid + LPV/r to 4 caps BID
■ This regimen consists of 18 pills a day, without the NRTIs
Unit 3: Clinical Pharmacology of ART
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LPV/r with other antiretrovirals:
•
EFV decreases LPV/r levels Æ increase LPV/r dose to 4 caps BID
•
NVP decreases LPV Cmin 55% Æ Increase LPV/r dose to 4 caps BID
•
LPV/r may decrease amprenavir levels Æ increase APV dose to 750mg BID
+ LPV/r 3 or 4 caps BID
•
LPV/r increases IDV Cmin levels 3-fold Æ IDV 600mg BID + LPV/r 3 caps
BID
•
LPV/r increases SQV Cmin 3.6-fold Æ SQV 800mg BID + LPV/r 3 caps BID
•
No data concerning LPV/r combined with NFV
•
Delavirdine increases LPV/r levels 8%-134% Æ limited data, do not
combine
Resistance: Major resistance mutations have not been clearly defined. Resistance
results from multiple PI resistance mutations reflecting prior PI-containing
regimens at codons: 10, 20, 24, 32, 33, 46, 47, 50, 53, 54, 63, 71, 73, 82, 84, and
90. The accumulation of 6 or more (and possibly as few as 4) of these mutations
is associated with a diminished response to LPV/r. Mutation L63P when combined
with multiple other mutations is associated with clinical failure.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 81
Nelfinavir (NFV)
■ Dosing: 5 x 250mg tablets BID
■ Food Interactions: take with meal
■ Toxicity
■ Diarrhea (10%-30%)
■ Nausea
■ Fat redistribution
■ Lipid abnormalities
Unit 3: Clinical Pharmacology of ART
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Nelfinavir: The most common adverse effects on nelfinavir are diarrhea (10%-30%),
abdominal pain, flatulence and rash. Taking the dose after the meal can help reduce
diarrhea symptoms. Patients should be given a prescription for an antidiarrheal at the
time they are prescribed nelfinavir and taught how to mange the diarrhea if it should occur
(e.g., take 1 to 2 doses of loperamide at onset of diarrhea and then take 1 loperamide for
each loose stool after that, up to a maximum of 8 loperamide per day. If patients find that 1
loperamide 3 times daily [or any other regimen] controls their diarrhea, they can follow that
regimen regularly to prevent diarrhea before it occurs). Other options for diarrhea control
include calcium 500mg BID, psyllium 1 tablespoon once or twice daily mixed in water
once or twice daily with ½ the water volume (120ml), oat bran 1500mg BID, or pancreatic
enzymes at 1 to 2 tablets with each meal. If diarrhea cannot be controlled with an
antidiarrheals, patients should consult with their provider or pharmacist, it may be
necessary to change to another PI or NNRTI. If constipation develops from antidiarrheal
use, the patient should reduce their loperamide dose or other agents.
FDA Approval: March 1997
Mechanism of Action: Inhibitor of the protease enzyme
Bioavailability (F): 20% to 80% with meals. Food increases absorption by 2 to 3-fold.
Fatty meals improve absorption further.
CSF Levels: No detectable levels in CSF
T1/2: 3.5 to 5 hours
Elimination: Primarily metabolized by CYP450 3A4. Only 1% to 2% is found in urine. Up
to 90% is found in stool, primarily as a hydroxylated metabolite designated M8, which is
as active as nelfinavir against HIV. No dosage adjustments needed with renal
compromise. Use with caution in patients with hepatic impairment.
Pediatric Dose: 20-45mg/5kg TID
Pregnancy: (Category B) Present in breast milk and minimal concentration crosses
placenta.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 82
Nelfinavir (cont.)
■ Nelfinavir is not as potent as a liver enzyme inhibitor as
ritonavir
■ Use anticonvulsants with caution
■ May decrease ARV level and anticonvulsant
■ EE levels decreased 47%
■ Do not coadminister with rifampin
■ Decreases NFV levels 82%
■ No effect on ketoconazole or clarithromycin
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Drug Interaction: Drug interactions are predominantly mediated through the
CYP450 3A4 pathway.
Drugs that are contraindicated with NFV: simvastatin, lovastatin, rifampin,
astemizole, terfenadine, cisapride, misazolam, triazolam, ergot derivatives, and St.
John’s Wort.
Rifampin decreases NFV levels 82% Æ Do not combine these agents
NFV increases Rifautin levels 2-fold and NFV levels are decreased 32% Æ
increase NFV to 1000mg TID and decrease rifabutin to 150mg QD or 300mg 2 to 3
times per week
NFV decreases levels of ethinyl estradiol 47% Æ Use alternate or additional form
of birth control to prevent pregnancy
Phenobarbital, phenytoin, and carbamazepine may decrease NFV levels
substantially Æ monitor anticonvulsant levels (??? Increase NFV dose to 1gm TID)
NFV reduces methadone levels 30% to 50% Æ Monitor for opioid withdrawal
symptoms, but in most cases no dose change is required
NFV increases atorvastatin levels 74% Æ Use with caution. Start atorvastatin at
low dose (10mg QPM)
NFV has no effect on ketoconazole Æ No dosage adjustment needed
NFV has no effect on clarithromycin Æ No dosage adjustment needed
NFV increases sildenafil AUC 2 to 11-fold Æ sildenafil dose should not exceed
25mg every 48 hours
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 83
Nelfinavir (cont.)
■ NFV interactions with other ARVs
■ Limited data on combinations
■ Clinically NFV not used often in combination with other PIs
■ Class resistance is a possibility
■ Some believe that this is less problematic with NFV
Unit 3: Clinical Pharmacology of ART
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NFV interactions with other antiretrovirals:
• NVP increases NFV levels 10% Æ No dosage adjustment needed
• EFV increases NFV levels 20% Æ No dosage adjustment needed
• DLV increases NFV 2-fold and NFV decreases DLV 50% Æ NFV 1250mg
BID + DLV 600mg BID (limited data)
• IDV increases NFV 80% and NFV increases IDV 50% Æ IDV 1200mg BID
+ NFV 1250mg BID (limited data)
• RTV increases NFV 1.5-fold Æ RTV 400mg BID + NFV 500-750mg BID
(limited data, clinically this regimen is not used)
• SQV increases NFV 20% and NFV increases SQV 3 to 5-fold Æ NFV
1250mg + SQV 1200mg PO BID
• NFV increases APV 1.5-fold and APV increases NFV 15% Æ NFV 750mg
TID + APV 800mg TID; or NFV 1250mg BID + APV 1200mg BID (limited
data for TID and BID dosing schedules)
• No data concerning interactions between NFV and LPV/r
Resistance: The primary mutation conferring NFV resistance is the D30N
mutation, which is associated with phenotypic resistance to NFV but not to other
PIs. The L90M mutation can also occur, however, and unlike D30N, it confers
cross-resistance to other PIs. Other secondary mutations are those at codons 10,
36, 46, 71, 77, 82, 84, and 88. Some authorities believe cross-resistance is less
problematic with NFV, thus making rescue treatment with other PIs more likely to
succeed.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 84
Saquinavir – Soft Gel
Capsules (SQV)
■ Dosing: 6 x 200mg capsules TID OR 8 x 200mg BID
■ Food Interactions: take with large meal
■ Poor bioavailability (food increases “F” 3-fold)
■ Toxicity
■ Nausea, Diarrhea
■ Fat redistribution
■ Lipid abnormalities
■ Refrigeration recommended, but OK at room
temperature for up to 3 months
Unit 3: Clinical Pharmacology of ART
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Saquinavir: The primary toxicities are mild gastrointestinal disturbances, such as
nausea, diarrhea and abdominal pain (5% to 15% for hard-gel cap formulation,
20% to 30% for soft-gel cap formulatioin); headache; and reversible elevations in
liver enzymes. Nausea and diarrhea are more common with the soft-gel
formulation than with the hard-gel formulation as a result of better bioavailability
(i.e., more drug is absorbed so potential for more side effects), as well as a
component of the soft-gel capsules, which causes diarrhea.
•
In the US, currently the soft-gel capsule (Fortovase) formulation is predominantly
used. The hard-gel capsule (Invirase) is not used regularly, but may be reemerging because of better GI tolerabiltiy. SQV is rarely used alone, it is
commonly combined with RTV.
•
Standard dose for soft-gel capsule with RTV: SQV 400mg BID + RTV 400mg BID;
or 1000mg SQV BID + 100mg RTV BID; or SQV 1600mg QD + RTV 100mg QD
•
The hard-gel capsule should ALWAYS be dosed with RTV, dosing same as for
soft-gel capsules.
•
The hard-gel capsules can be stored at room temperature
•
Saquinavir soft-gel caps should be stored in the refrigerator, but can be left at
room temperature for up to 90 days. Hot temps should be avoided.
•
FDA Approval: Hard-Gel Capsules were approved in December 1995, and the
soft-gel capsules were approved in November 1997.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 85
Saquinavir – Soft Gel
Capsules (cont.)
■ Food increases SQV 6 fold
■ Take with a large meal if not taken with ritonavir
■ If coadministered with ritonavir, absorption is not influenced by
food
■ Drug interactions
■ Do not use saquinavir with rifampin alone (SQV levels
decreased 84%)
■ Adjust dose to SQV 400 mg bid + ritonavir 400 mg bid
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Mechanism of Action: Inhibitor of the protease enzyme
Bioavailability (F): Percent absorption is not established for the soft-gel capsules, but it is
known to be better than for the hard-gel capsules (4% for hard-gel capsules with high-fat
meal). Food increases SQV-soft gel caps 6-fold, so if taken without RTV, SQV should be
taken following within 2 hours of a large meal. When SQV is taken with RTV, absorption
is not influenced by food, whether it’s the soft or hard-gel caps.
CSF Levels: Negligible CSF penetration
T1/2: 1 to 2 hours
Elimination: Hepatic metabolism by CYP450 3A4; 96% biliary excretion, 15 urinary
excretion. Use standard dose for renal failure. Use with caution in patients with hepatic
impairment.
Pediatric Dose: 50mg/kg Q8H
Pregnancy: (Category B) Crosses placenta.
Drug Interaction: Mediated through CYP450 3A4. All doses recommended below are for
the soft-gel capsules (if SQV is combined with RTV, the dose would be the same for hardgel caps as well)
Drugs that are contraindicated with SQV: terfenadine, astemizole, cisapride, triazolam,
midazolam, ergot alkaloids, simvastatin, lovastatin, and St. John’s Wort.
Rifampin decreases SQV levels 84% Æ Do not use SQV alone, can combine with RTV:
RTV 400mg BID + SQV 400mg BID + Rifampin 600mg QD or Rifampin 600mg 2 to 3
times/week
Rifabutin decreases SQV levels 40% Æ Do not use SQV alone, can combine with RTV:
RTV 400mg BID + SQV 400mg BID + Rifabutin 150mg QOD or 3 times per week.
Unknown effect of SQV alone on ethinyl estradiol. If combine SQV with RTV Æ Use
alternate or additional method of birth control to prevent pregnancy
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 86
Saquinavir – Soft Gel
Capsules (cont.)
■ Anticonvulsants may decrease SQV levels substantially
■ Garlic supplements decrease SQV levels by 50%
■ May only use SQV with NNRTI if ritonavir boosted
■ NVP decreases SQV by 25%
■ EFV decreases SQV by 62%
■ PI Cross resistance
Unit 3: Clinical Pharmacology of ART
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Ketaconazole increases SQV levels 3-fold Æ Do not need to adjust doses
Clarithromycin increases SQV levels 177% and SQV increases clarithromycin levels 45% Æ Do not need to
adjust doses
Phenobarbital, phenytoin, and carbamazepine may decrease SQV levels substantially Æ Avoid combination if
possible, monitor anticonvulsant levels
Dexamethasone decreases SQV levels Æ Avoid combination if possible
SQV decreases Methadone levels 8%-10% Æ Do not need to adjust doses unless combine SQV with RTV,
then titrate methadone dose to prevent opioid withdrawal.
Garlic supplements decrease SQV levels 50% Æ Do not consume large amounts of garlic if on SQV only
Grapefruit juice increases SQV levels Æ Do not need to adjust dose
SQV interactions with antiretrovirals:
• NVP decreases SQV 25% Æ Combine SQV with RTV: RTV 400mg BID + SQV 400mg BID + NVP at
normal dose
• EFV decreases SQV 62% and SQV decreases EFV 12% Æ Do not combine EFV and SQV unless add
RTV to regimen: SQV 400mg BID + RTV 400mg BID + EFV 600mg QHS
• DLV increases SQV 5-fold Æ SQV 800mg TID + DLV 600mg TID; monitor liver function tests
• RTV increases SQV 20-fold Æ SQV 400mg BID + RTV 400mg PO BID (considered a dual PI regimen);
or SQV 1000mg BID + RTV 100mg PO BID; or SQV 1600mg BID + RTV 100mg PO QD
• NFV increases SQV 3 to 5-fold and SQV increases NFV 20% Æ SQV 1200mg + NFV 1250mg PO BID
• IDV increases SQV 4 to 7-fold Æ Insufficient data to provide recommendation
• APV decreases SQV 19% and SQV decreases APV 32% Æ SQV 800mg TID + APV 800mg TID
(limited data)
• LPV/r increases SQV 3 to 5-fold Æ SQV 1000mg BID + LPV/r 3 capsules BID
Resistance: Major resistance mutations are L90M (most common, results in a 3-fold decrease in sensitivity) and G48V (less
common and 30-fold decrease in sensitivity). Minor mutations conferring resistance are at codons 10, 54, 71, 73, 77, 82,
and 84. Patients with clinical resistance to SQV frequently have mutations associated with resistance to RTV, and clinical
resistance to NFV has been demonstrated following SQV failure, despite the lack of the characteristic NFV resistance
mutation at D30N.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 87
Indinavir (IDV)
■ Dosing: 2 x 400mg q 8
hours
■ Food Interactions: take
on empty stomach, or
with low fat snack (e.g.
non-fat milk)
■ Capsules are sensitive to
moisture
Unit 3: Clinical Pharmacology of ART
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■ Toxicity
■ Nausea, Diarrhea
■ Nephrolithiasis (flank pain,
↑ SrCr, hematuria, pyuria)
■ Dry lips, dry skin
■ Hyperbilirubinemia
■ Fat redistribution, Lipid
abnormalities
87
If indinavir is taken with a low fat snack, such as dry toast with jelly, juice, coffee (with
skim milk), or cereal with skim milk (as opposed to an empty stomach, defined as 1 hour
before or 2 hours after a meal), patients are more able to tolerate the gastrointestinal side
effects. Coordinating 3 doses every 8 hours on an empty stomach can be very difficult for
most patients. If this dosing is chosen, patients should be counseled about adherence.
The most serious side effect of indinavir in adults and children is the formation of kidney
stones, seen in about 10%-28% of patients (depending on duration of treatment, age, and
fluid prophylaxis); it may be more frequent in hot climates. Temporary abnormal kidney
function, including acute kidney failure, and inflammation have been observed in some
patients with nephrolithiasis. The condition may be signalled by severe pain beneath the
ribs with or without blood in the urine. Indinavir may need to be interrupted for a few days.
The condition may recur in half of the patients if indinavir is restarted. Patients taking
indinavir must drink plenty of fluids to prevent the development of kidney stones — at least
1.5 liters of water daily and more in hot weather. (Cafienated or alcholic bevarages do not
promote hydration and should not be counted in the 1.5 liter daily fluid requirement).
Interstitial nephritis with pyuria and renal insufficiency is reported in about 2% of IDV
recipients.
Elevated bilirubin (> 2.5mg/dl) has been seen in about 10% - 15% of patients receiving
indinavir; in most cases the maximum bilirubin elevation was observed after one or more
weeks of treatment; jaundice (yellowing of the skin) and elevations in liver enzymes have
been reported only rarely. In most cases patients with elevated bilirubin are
asymptomatic.
Indinavir may also cause dry skin, bald patches in the hair, dry lips and ingrown toe or
finger nails. About three percent of patients develop acid reflux.
Currently indinavir is commonly combined with RTV in order to improve dosing schedule
(can change to BID dosing) and food requirements as well as reduce gastrointestinal and
lipid abnormalities. 1.5 liters of water are still required to prevent kidney stones even
when combined with RTV.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 88
Indinavir (cont.)
■ A full meal decreases IDV levels by 77%
■ Take 1 hr before or 2 hrs after a meal
■ If combined with ritonavir
■ Take with food, twice daily
■ Do not use near term in pregnancy
■ Concern is elevated indirect bilirubin and nephrolithiasis which
may occur in the fetus
Unit 3: Clinical Pharmacology of ART
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FDA Approval: March 1996
•
Mechanism of Action: Inhibitor of the protease enzyme
•
Bioavailability (F): 65% in fasting state or with a low-fat snack. A full meal
decreases IDV levels 77% (make sure to dose 1 hour before or 2 hours
after a meal to meet empty stomach requirements). If IDV is combined with
RTV, food has minimal effect on IDV levels – it is recommended to take the
dose with food.
•
CSF Levels: 6%-16% of serum levels. This is superior to that of other PIs
and is adequate to inhibit IDV-sensitive strains. CSF trough levels of IDV
increase > 5-fold when combined with RTV.
•
T1/2: 1.5 to 2 hours
•
Elimination: Metabolized by hepatic glucoronidation and CYP450 3A4
enzymes. Urine shows 5% to 12% unchanged drug and glucuronide and
oxidative metabolites. Dosage does not need to be adjusted for renal
compromise. Reduce dose to 600mg Q8H for patients with hepatic failure.
•
Pediatric Dose: 500mg/m2 Q8H
•
Pregnancy: (Category C) Crosses placenta. Some authorities are
concerned about the elevated indirect bilirubin and nephrolithiasis in the
event that these complications may occur in the fetus.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 89
Indinavir (cont.)
■ Drug interactions
■ As with other PIs, Contraindicated with: rifampin, ergot
derivatives, lovastatin, simvastatin
■ Separate from buffered DDI by at least 2 hrs
■ IDV needs an acidic env for absorption
■ EFV decreases IDV levels 31%
■ Increase IDV to 1000 mg q8h or
■ Use ritonavir 200 mg bid with IDV 800 mg bid
Unit 3: Clinical Pharmacology of ART
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Drug Interaction: Most drug interactions occur through the CYP450 3A4 pathway.
The following agents are contrindicated with IDV: Rifampin, astemizole, terfenadine, cisapride, midazolam,
triazolam, ergot derivatives, simvastatin, lovastatin, and St. John’s wort.
Rifampin reduces IDV levels 89% Æ Do not combine Rifampin with IDV
Rifabutin decreases IDV levels 32% and rifabutin levels are increased 2-fold Æ reduce rifabutin dose to 150mg/day
or 300mg 2 to 3 times/week and increase IDV dose to 1000mg q8H
Ketoconazole and itraconazole increases IDV levels 70% Æ decrease IDV dose to 600mg Q8H
IDV increases Clarithromycin levels 53% Æ No dose change
Grapefruit juice reduces IDV levels 26% Æ Do not consume grapefruit juice if taking IDV
IDV increases norethindrone levels 26% and inicreases ethinyl estradiol levels 24% Æ Use alternate or additional
form of birth control to prevent pregnancy
Carbamazepine decreases IDV levels Æ Consider an alternate anti-epileptic
IDV increases sildenafil 340% Æ Maximum recommended dose of sildenafil is 25mg every 48 hours
St. John’s wort decreases IDV levels by 57% Æ Do not combine St. John’s wort with IDV
Interactions with other antiretrovirals:
•
IDV needs acid to be absorbed Æ separate IDV doses by at least 2 hours from buffered ddI or liquid
antacids
•
NVP decreases IDV levels 28% Æ increase IDV dose to 1000mg Q8H
•
EFV decreases IDV levels 31% Æ increase IDV to 1000mg Q8H; or add 200mg RTV BID to IDV 800mg
BID + EFV 600mg QHS
•
DLV increases IDV levels 40% Æ IDV 600mg Q8H + DLV 400mg TID
•
RTV increases IDV levels 2 to 5-fold Æ IDV 800mg + RTV 100-200mg PO BID (associated with more
nephrotoxicity); or IDV 400mg + RTV 400mg PO BID (associated sith more GI intolerance)
•
SQV increases IDV levels 4 to 7-fold Æ Insufficient data to provide recommendation (possible in vitro
antagonism)
•
IDV increases NFV 80% and NFV increases IDV 50% Æ IDV 1200mg BID + NFV 1250mg BID (limited
data)
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IDV increases APV 33% and APV decreases IDV 38% Æ APV 800mg TID + IDV 800mg TID
•
LPV/r increases IDV 3-fold Æ IDV 600 or 666mg BID + LPV/r 3 caps BID
Resistance: Mutations at codons 10, 20, 24, 32, 36, 46, 54, 71, 73, 77, 82, 84, and 90 correlate with reduced in vitro activity.
Mutations at codons 46, 82, and 84 are major mutations that predict resistance but are not necessarily the first mutations. In
general, at least 3 mutations are necessary to produce phenotypic resistance. IDVs resistance pattern overlaps with RTV,
consequently, if persons is resistant to one, they are usually resistant to both. The IDV resistance profile does not overlap with
other PIs very extensively, but multiple mutations generally imply class resistance.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 90
Amprenavir (APV)
■ Dosing: 8 x150 mg
capsules BID or 1400mg
BID for oral solution
■ Food Interactions: +
food, avoid taking with
high fat meal b/c
decreases absorption
■ Toxicity
■ Nausea
■ Diarrhea
■ Rash (sulfa allergy)
■ Fat redistribution
■ Lipid abnormalities
■ Avoid in pregnancy
Unit 3: Clinical Pharmacology of ART
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Amprenavir alone has a high pill burdern (16 large gel-capsules per day),
consequently, clinically providers usually combine amprenavir with ritonavir to
reduce pill burden and side effects. Standard doses are: APV 600mg BID + RTV
100mg BID; or APV 1200mg QD + RTV 200mg QD
The most common side effects associated with amprenavir are headache (6%),
nausea (5%), rash (11%), diarrhea (14%), vomiting (5%) and tingling around the
mouth (28%). The incidence of nausea and vomiting may be significantly
increased when amprenavir is used together with zidovudine (ZDV).
Amprenavir is a sulfonamide. Use caution in persons with mild sulfa allergy – have
them take first dose in clinic and monitor for difficulty breathing for 2 hours. If dose
is tolerated, patient can continue on therapy. For persons with serious sulfa
allergy (e.g., anaphylaxis or SJS, etc.) do not use amprenavir.
The oral solution of APV contains 55% propylene glycol, compared with 5% for the
capsules. The oral solution is contraindicated in patients with renal failure, heptaic
failure, in prenant women, or in patients receiving disulfiram or metronidazole.
Patients treated with the oral solution should be monitored for adverse effects of
propylene glycol (seizures, stupor, tachycardia, hyperosmolarity, lactic acidosis,
renal failure, and hemolysis). Patients taking the oral solution should change to
the capsule from when able to do so, and they should avoid alcoholic beverages
when taking the oral solution.
FDA Approval: April 1999
Mechanism of Action: Inhibitor of the protease enzyme
Bioavailability (F): 89%. High-fat meals decrease AUC 21%. APV can be taken
with or without meals, but avoid a high-fat meal
CSF Levels: Unknown
T1/2: 7 to 10.6 hours
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 91
Amprenavir (cont.)
■ Pregnancy
■ Avoid use because of high Vitamin E content
■ APV 2400mg/day = 1,744 units/day
■ High poplylene glycol
■ Metabolism through liver
■ Drug interactions
■ Do not use with rifampin
Unit 3: Clinical Pharmacology of ART
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Elimination: Hepatic metabolism predominantly through CYP450 3A4 pathway. Most is found
in stool; 14% in urine. Do not need to adjust dose for renal compromise. In Hepatic disease
APV’s AUC increases 2.5-fold Æ decrease doses to 450mg BID with moderate hepatic
impairment. APV AUC increases 4.5-fold with severe cirrhosis Æ decrease dose to 300mg
BID.
Pediatric Dose: <50kg=20mg/kg BID (max=2400mg/day for caps & for oral sol
max=2800mg/day)
Pregnancy: (Category C) Crosses placenta. Avoid APV use in pregnancy because of high
Vitamin E content and propylene glycol.
Drug Interaction: Predominantly mediated through CYP450 3A4
The following drugs are contraindicated for concurrent use with APV: astemizole, bepridil,
cisapride, ergot derivatives, midazolam, terfenadine, triazolam, rifampin, simvastatin,
lovastatin, and St. John’s wort.
Rifampin decreases APV levels 82% Æ Do not combine rifampin with APV
Rifabutin decreases APV levels 15% and APV increases rifabutin levels 193% Æ decrease
rifabutin dose to 150mg QD or 300mg 2 to 3 times per week.
Ethinyl estradiol and norethrindrone decrease APV levels Æ Use alternate form of birth
control
Clarithromycin increases APV 18% Æ Do not need to adjust doses
Ketoconazole increases APV 32% and APV increases ketoconazole 44% Æ
recommendations for concurrent use are not available.
APV increases sildenafil 2 to 11-fold Æ sildenafil dose should not exceed 25mg per 48 hour
APV contains a large amount of vitamin E (APV 2400mg/day = 1,744 Vit E units/day).
Patients taking vitamin E supplements could develop bleeding problems. Patients should not
take extra vitamin E supplements.
APV decreases methadone levels 35% and methadone also decreases APV levels Æ
Consider alternative antiretroviral agent. If used together, monitor for methadone withdrawal.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 92
Amprenavir (cont.)
■ Phenobarbital, phenytoin, carbamazepine may
decrease APV levels
■ Use alternate anticonvulsant (sodium valproate) if possible or
monitor anticonvulsant levels.
■ APV with other antirtrovirals:
■ EFV decreases APV levels 24% and APV increases EFV
levels 15%
■ APV 1200mg PO TID + EFV 600mg PO QHS; or APV 600mg PO BID
+ RTV 100-200mg PO BID + EFV 600mg PO QHS
■ NVP interaction, no data available
Unit 3: Clinical Pharmacology of ART
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Phenobarbital, phenytoin, carbamazepine may decrease APV levels Æ Use alternate
anticonvulsant if possible or monitor anticonvulsant levels.
APV with other antiretrovirals:
• EFV decreases APV levels 24% and APV increases EFV levels 15% Æ APV
1200mg PO TID + EFV 600mg PO QHS; or APV 600mg PO BID + RTV 100200mg PO BID + EFV 600mg PO QHS
• NVP interaction, no data available
• DLV increases APV levels 25% and APV decreases DLV levels 60% Æ Not
recommended to combine these agents
• APV decreases IDV levels 38% and IDV increases APV levels 33% Æ IDV 800mg
TID + APV 800mg TID
• NFV increases APV levels 1.5-fold and APV increases NFV levels 15% Æ NFV
750mg TID + APV 800mg TID
• SQV decreases APV levels 32% and APV decreases SQV levels 19% Æ SQV
800mg TID + APV 800mg TID (limited data)
• RTV increases APV levels 2.5-fold Æ APV 600mg BID + RTV 100mg BID; or APV
1200mg QD + RTV 200mg QD
• LPV/r can increase or decrease APV and APV can decrease LPV/r or no change
Æ APV 750mg BID + LPV/r 3 or 4 caps BID
Resistance: I50V and I84V are major mutations for APV. At least two mutations, at
codons 46, 47, and/or 50, are required to increase phenotypic resistance 10-fold. The
I50V mutation was originally thought to cause no cross-resistance with other PIs, but it
now appears to causes reduced susceptibility to LPV/r. Mutations at codons 10, 54, 84,
and 90 foster cross-resistance to other PIs. Low trough levels of APV are associated with
the I54L/M mutation, and the I50V mutation is associated with the highest levels of APV
resistance.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 93
Atazanavir (ATZ)
■ Dosing: 2 x 200mg capsules QD
■ Dosed with ritonavir 100mg QD, Atazanavir dose = 2 x 150mg
QD (for PI experienced patients)
■ Food Instructions: take with food
■ Toxicity:
■ Nausea
■ Diarrhea
■ Elevated bilirubin
Unit 3: Clinical Pharmacology of ART
93
•
ATZ is the first once daily dosed PI and is well tolerated. Preliminary research shows that
ATZ has minimal effect on lipid profile
•
Atazanavir competitively inhibits the uridine diphosphate-glucuronosyl transferase (UDPGT) 1A1 enzyme; this enzyme catalyzes conjugation of bilirubin. Persons that are UGT
deficient may be at higher risk of developing hyperbilirubinemia. If patient develops
jaundice (including yellow eyes), stop ATZ and change to an alternate regimen.
Hyperbilirubinemia will resolve following discontinuation.
•
Asymptomatic hyperbilirubinemia (60%)
•
Grade 3 to 4 bilirubin elevation (40%)
•
Jaundice (typically occurs with a BiliT= 2 to 4 (6%)
•
FDA Approval: June 2003
•
Mechanism of Action: Inhibitor of the protease enzyme
•
Bioavailability (F): Taking the dose with a light meal increases plasma AUC by 70%,
taking it with high fat meal increases plasma AUC by 35%. Doses should be taken with a
light or fatty meal
•
CSF Levels: Unknown, 86% plasma protein bound
•
T1/2: 6.5 – 8.5 hours
•
Elimination: Hepatically metabolized by CYP450 3A4. For patients with moderate hepatic
impairment, use a dose of 300mg QD. For patients with severe hepatic compromise, ATZ
is not recommended. For 75% excreted in urine unchanged. Insufficient pharmacokinetic
data for patients with reduced renal function to recommend a reduced dosage with renal
compromise.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 94
Atazanavir (cont.)
■ Pregnancy
■ Potential for ATZ to cause hyperbilirubinemia in neonates
■ Drug interactions
■ Inhibits liver enzymes
■ If used with RTV, decrease dose to 300 mg qd + RTV 100 mg
qd
■ The nucleoside analog TDF decreases ATZ levels
■ Use boosted ATZ with TDF
■ Use boosted ATZ with any NNRTI
Unit 3: Clinical Pharmacology of ART
94
•
Pediatric Dose: Do not use in child < 3 mo (hyperbilirubinemia), dose for children
under investigation
•
Pregnancy: (Category B) It is not known whether ATZ is present in breast milk or
crosses placenta. The potential for ATZ to cause hyperbilirubinemia in neonates
or young infants.
•
Drug Interaction: ATZ inhibits 3A4, 1A2, 2C9, and UGT
•
RTV increases ATZ levels Æ Reduce ATZ dose to 300mg QD + RTV 100mg QD
•
TDF decreases ATZ levels Æ Combine ATZ with RTV when dosed with TDF: ATZ
300mg QD + RTV 100mg QD
•
EFV and NVP decrease ATZ levels Æ Combine ATZ with RTV when dosed with
NNRTIs: ATZ 300mg QD + RTV 100mg QD
•
Resistance: Major ATZ mutation is I50L. When administered to patients as the
initial PI, ATZ selects for the mutations I50L and A71V. When used as a
subsequent PI in combination with SQV, ATZ selects I54L, I84V. In vitro, ATZ
selects for V32I, M46I, I84V, and N88S. Although other mutations, such as V82A
and L90M, have not been selected for by atazanavir either in vitro or in vivo, these
mutations have been shown to confer cross-resistance to ATZ, particularly when
present in combination with each other or with other known PI resistance
mutations.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 95
Fos-amprenavir (f-APV)
■ Dosing: 2 x 700mg BID
■ 2 x 700mg QD + RTV 200mg QD
■ 1 x 700mg BID + RTV 100mg BID*
■ Food Instructions: take with or without food
■ Toxicity:
*Dosing for PI
experienced
■ Nausea, Diarrhea
■ Rash (8% - fos-amprenavir is a sulfa)
■ Lipid abnormalities
Unit 3: Clinical Pharmacology of ART
95
•
Fos-amprenavir is an amprenavir prodrug that is well tolerated. 700mg of fos-amprenavir
calcium is equivalent to 600mg of amprenavir. Following absorption, fos-amprenavir
undergoes nearly complete metabolism by enzymes in the gut to amprenavir. Fosamprenavir has a lower Cmax (lower peak avoids side effects) and an equal or higher
Cmin (trough is same) than amprenavir. f-APV does appear to be better tolerated than
APV.
•
Like amprenavir, f-APV is a sulfonamide. Use caution in persons with mild sulfa allergy –
have them take first dose in clinic and monitor for difficulty breathing for 2 hours. If dose is
tolerated, patient can continue on therapy. For persons with serious sulfa allergy (e.g.,
anaphylaxis or SJS, etc.) do not use fos-amprenavir.
•
FDA Approval: October 2003
•
Mechanism of Action: Inhibitor of the protease enzyme
•
Bioavailability (F): Not yet established. Taking doses with or without food does not
change drug absorption.
•
CSF Levels: CSF levels unknown, but 90% of drug is plasma protein bound.
•
T1/2: Unknown
•
Elimination: Hepatically metabolized. 14%-75% of APV metabolites are eliminated in
urine and feces, respectively. Only 1% of parent drug is eliminated in urine unchanged. If
have mild to moderate hepatic failure, adjust dose down to 700mg BID. Not recommended
with severe liver failure. Renal impairment is not anticipated to impact dosing.
•
Pediatric Dose: dose currently under investigation
•
Pregnancy: (Category C) Unknown if crosses placenta
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 96
Fos-amprenavir (cont.)
■ Contraindicated
medication
■ lovastatin, simvastatin,
midazolam, ergot
derivatives
■ Ethinyl estradiol and
norethrindrone decrease
APV levels.
■ Must use another form of
OC
■ Rifampin decreases APV
levels by 82%
■ Do not combine
■ Anticonvulsant may
decrease APV levels
■ Monitor for antiseizure
activity or use alternative if
possible
Unit 3: Clinical Pharmacology of ART
96
•
Drug Interaction: Predominantly mediated through CYP450 3A4
•
The following drugs are contraindicated for concurrent use with APV: astemizole, bepridil,
cisapride, ergot derivatives, midazolam, terfenadine, triazolam, rifampin, simvastatin,
lovastatin, and St. John’s wort.
•
Rifampin decreases APV levels 82% Æ Do not combine rifampin with APV
•
Rifabutin decreases APV levels 15% and APV increases rifabutin levels 193% Æ
decrease rifabutin dose to 150mg QD or 300mg 2 to 3 times per week.
•
Ethinyl estradiol and norethrindrone decrease APV levels Æ Use alternate form of birth
control
•
Clarithromycin increases APV 18% Æ Do not need to adjust doses
•
Ketoconazole increases APV 32% and APV increases ketoconazole 44% Æ
recommendations for concurrent use are not available.
•
APV increases sildenafil 2 to 11-fold Æ sildenafil dose should not exceed 25mg per 48
hour
•
APV contains a large amount of vitamin E (APV 2400mg/day = 1,744 Vit E units/day).
Patients taking vitamin E supplements could develop bleeding problems. Patients should
not take extra vitamin E supplements.
•
APV decreases methadone levels 35% and methadone also decreases APV levels Æ
Consider alternative antiretroviral agent. If used together, monitor for methadone
withdrawal.
•
Phenobarbital, phenytoin, carbamazepine may decrease APV levels Æ Use alternate
anticonvulsant if possible or monitor anticonvulsant levels.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 97
Fos-amprenavir (cont.)
■ F-APV with other antirtrovirals:
■ EFV decreases APV levels 24% and f-APV increases EFV
levels 15%
■ F-APV 1200mg PO TID + EFV 600mg PO QHS; or f-APV 600mg PO
BID + RTV 100-200mg PO BID + EFV 600mg PO QHS
■ NVP interaction, no data available
Unit 3: Clinical Pharmacology of ART
•
•
97
APV with other antiretrovirals:
• EFV decreases f-APV levels 24% and f-APV increases EFV levels 15% Æ f-APV
1200mg PO TID + EFV 600mg PO QHS; or f-APV 600mg PO BID + RTV 100200mg PO BID + EFV 600mg PO QHS
• NVP interaction, no data available
• DLV increases APV levels 25% and APV decreases DLV levels 60% Æ Not
recommended to combine these agents
• APV decreases IDV levels 38% and IDV increases APV levels 33% Æ IDV 800mg
TID + APV 800mg TID
• NFV increases APV levels 1.5-fold and APV increases NFV levels 15% Æ NFV
750mg TID + APV 800mg TID
• SQV decreases APV levels 32% and APV decreases SQV levels 19% Æ SQV
800mg TID + APV 800mg TID (limited data)
• RTV increases APV levels 2.5-fold Æ APV 600mg BID + RTV 100mg BID; or APV
1200mg QD + RTV 200mg QD
• LPV/r can increase or decrease APV and APV can decrease LPV/r or no change
Æ APV 750mg BID + LPV/r 3 or 4 caps BID
Resistance: I50V and I84V are major mutations for APV. At least two mutations, at
codons 46, 47, and/or 50, are required to increase phenotypic resistance 10-fold. The
I50V mutation was originally thought to cause no cross-resistance with other PIs, but it
now appears to causes reduced susceptibility to LPV/r. Mutations at codons 10, 54, 84,
and 90 foster cross-resistance to other PIs. Low trough levels of APV are associated with
the I54L/M mutation, and the I50V mutation is associated with the highest levels of APV
resistance.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 98
PI Class Side Effects
■ Metabolic Disorders
■ GI Intolerance
■ Hepatotoxicities
■ Drug Interactions
■ Hyperglycemia, insulin
resistance
■ CYP450 3A4 Inhibition
■ Lipid abnormalities
■ RTV > IDV = NFV = APV
>SQV
■ Fat redistribution
■ Bone Disorders
Unit 3: Clinical Pharmacology of ART
98
•
Whilst many side effects develop in the first few weeks on new medication, some do not
emerge until the medication has been used over the longer term.
•
As more information becomes available about the mechanisms that cause long-term side
effects, it will be more possible to develop effective interventions to prevent and treat
these side effects. Of the side effects to emerge over the past few years, ART-associated
metabolic disturbances have caused the greatest concern in developed countries.. The
metabolic changes may be responsible for serious side effects such as lactic acidosis,
diabetes, the body fat changes known as lipodystrophy, and potentially heart disease.
•
Metabolism disorders— the basics: Antiretroviral treatment seems to have complex
effects upon metabolism in people with HIV. Metabolism is a general term for the
breakdown of food and production of energy within the body. Sugar and fat are sources of
energy. Abnormalities in sugar and fat levels or abnormalities in the processing of fats and
sugars may indicate metabolic disorders and cause physical symptoms.
•
A number of metabolic disorders have been reported among people taking anti-HIV
therapy. These include hyperlipidemia (high levels of fat in the blood); diabetes, high
blood sugar (hyperglycemia), and insulin resistance; and high levels of lactate (a byproduct of sugar metabolism in the body); elevated ALT (a liver enzyme); and
lipodystrophy (fat redistribution).
•
Drug interactions: In addition, PIs are known to interact with multiple other medications.
The role of the pharmacist is critical for recognizing and identifying and preventing
potential drug interactions through dosage adjustment or preventing co-administration of
contraindicated medications.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 99
Introduction Case – Answers III
■ The statement C): Trouble sleeping and nightmares are generally
protease inhibitor related side effects is false.
■ In general, protease inhibitors are not known to cause CNS side
effects.
■ Efavirenz can cause drowsiness or insomnia, abnormal dreams
(Very vivid, bizarre dreams, most concerning if they are
nightmares. Some patients enjoy the dreams and are not
worried at all by them), confusion, abnormal thinking,
impaired concentration, and dizziness.
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
99
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 100
Hepatotoxicity
■ RTV use linked to increased risk of severe
hepatotoxicity (Sulkowski, JAMA 2000; 283:74).
■ Increased LFT’s observed with all PI’s.
■ More common in pts with chronic viral hepatitis (HBV,
HCV).
■ Data do not support withholding PI’s from pts coinfected with HBV or HCV.
Unit 3: Clinical Pharmacology of ART
100
•
Hepatitis: All PIs can cause liver inflammation, though ritonavir has been more
frequently associated with severe liver toxicity.
•
Elevated liver enzymes in the blood can occur at any time during PI treatment.
•
Symptoms of liver toxicity include: weight loss, loss of appetite, nausea and
vomiting, fever, abdominal pain, itchy skin, an enlarged or tender liver, and
jaundice.
•
Liver toxicity is more common in patients who: drink too much alcohol; had high
liver enzymes on blood tests when treatment started; use other medication that
can cause toxicity to the liver such as d4T; or are coinfected with hepatitis B or C.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 101
HIV/HAART Toxicities Insulin Resistance
■ Progression to frank diabetes mellitus possible
■ Monitor with fasting glucose values
■ Improvement often seen with switching out of PI-based
regimens
■ Some success with metformin
■ Caution - metformin also causes lactic acidosis
Unit 3: Clinical Pharmacology of ART
101
•
Diabetes, hyperglycemia and insulin resistance: Diabetes mellitus is a condition
caused by the inability to use sugar in the blood properly. Low levels of insulin, a
hormone used to regulate sugar in the blood, and insulin resistance are often
causes of diabetes.
•
Insulin resistance means the body is not able to use insulin properly to process
blood sugar and can lead to high levels of sugar in the blood. A high level of blood
sugar (hyperglycemia) is thus a sign of diabetes. Diabetes due to protease
inhibitors seems to be a relatively rare metabolic side effect. A family history of
diabetes may increase a person’s risk of developing diabetes on ART.
•
Insulin resistance occurs in up to 40% of patients treated with PIs, and
hyperglycaemia (high blood sugar), new cases of diabetes mellitus and worsening
of pre-existing diabetes mellitus have also been reported. High blood sugar has
been reported in 3-17% of patients receiving PIs; about 1% of these patients
develop clinical evidence of diabetes.
•
Patients receiving PIs should be advised about the warning signs of
hyperglycaemia, such as excessive thirst, excessive urination, and excessive
appetite. Hyperglycaemia resolves in some but not all patients after the
discontinuation of therapy. Most experts, however, would continue ART with
supportive therapy (oral hypoglycaemic drugs or insulin) in the absence of severe
diabetes.
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HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 102
HIV/HAART Toxicities Lipid Abnormalities
■ Hypertriglyceridemia; risk of pancreatitis
■ Low HDL, high LDL
■ Increased deaths from coronary artery disease noted
among persons on HAART
■ Generally treated w/ fibrates and/or statins
■ Inconsistent results from switch studies
■ Beware of drug interactions between ART, statins, and
fibrates Æ risk of myositis
Unit 3: Clinical Pharmacology of ART
102
•
Hyperlipidaemia: Lipid abnormalities include: Elevated LDL cholesterol and triglycerides,
lowered HDL cholesterol. Hyperlipidaemia has been linked to treatment with all the PIs,
although the increases tend to be higher in patients receiving ritonavir. Whether this will lead to
a higher rate of cardiovascular disease or pancreatitis, is unclear.
•
Cholesterol and triglycerides: The general term for body fats is lipids. There are two main types
of lipids: cholesterol and triglycerides. Cholesterol is made in the liver from saturated fats in
food and is essential for the production of the sex hormones, as well as the repair of cell
membranes. To move around the body, cholesterol joins up with special proteins to form
‘lipoproteins' which are carried in the blood. There are two kinds of lipoproteins; low-density
lipoproteins (LDL), which carry cholesterol from the liver to the cells and high-density
lipoproteins (HDL), which return excess cholesterol to the liver. One may often hear cholesterol
described as ‘good' and ‘bad'. HDL, or ‘good' cholesterol clears cholesterol from the arteries to
the liver, where it is removed from the body. LDL or ‘bad' cholesterol is associated with
hardening of the arteries (atherosclerosis). This can lead to angina, heart attack and stroke.
•
Fatty substances in the blood like LDL and HDL cholesterol are often grouped together with
triglycerides and called blood lipids. Triglycerides are one of the basic building blocks from
which fats are formed.
•
People with AIDS often had raised LDL cholesterol and declining HDL cholesterol. People on
protease inhibitor therapy have been shown to have higher levels of lipids compared to people
not on protease inhibitors. Rises in cholesterol and triglycerides may put someone at increased
risk of heart disease particularly if they smoke, are overweight or have high blood pressure. If
tryglyceride levels are extremely high, there is a risk of acute necrotising pancreatitis, a
potentially fatal but very rare condition.
Reference Manual for Trainers
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Unit 3: Clinical Pharmacology of ART
Slide 103
HAART and the Heart
■ Some HIV drugs, especially PIs, can increase fats and sugar
levels which may increase heart disease risk.
■ Several large studies have found no relationship between
increased fats and sugars and heart disease risk.
■ The DAD study found the longer you are on HAART, the higher
the risk of heart disease.
■ Still fairly low risk, and benefits of HAART outweigh risks, in short
term.
■ Stop smoking, eat healthily, and exercise more.
Unit 3: Clinical Pharmacology of ART
103
•
Heart disease: ART-related changes in the body's metabolism, such as high HDL
cholesterol levels, could increase the risk of heart disease. Some studies have
shown thickening of and damage to the arteries among people taking protease
inhibitors. Other risk facts such as smoking, high blood pressure or diabetes, preexisting heart conditions, and age also play roles in the development of heart
disease. Male sex may also play a role: the risk of coronary heart disease in men
occurs ten years earlier than in women. As medical developments improve the
prognosis for people with HIV, general health conditions such as heart disease,
which more commonly affects middle aged or older people, are likely to grow in
importance for people with HIV.
•
Some HIV drugs, especially PIs, can increase fats and sugar levels which may
increase heart disease risk.
•
Several large studies have found no relationship between increased fats and
sugars and heart disease risk.
•
The DAD study found the longer you are on HAART, the higher the risk of heart
disease.
•
Still fairly low risk, and benefits of HAART outweigh risks, in short term.
•
Stop smoking, eat healthily, and exercise more.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 104
Lipodystrophy
■ After 3-4 years of combination therapy 30-40% of people will
devleop body fat changes
■ People who are overweight
■ More likely to complain of increase in central fat
■ The most likely conditions for developing lipodystrophy are when:
■ Taking nukes and PIs together
■ Cause of body fat changes still unknown
■ No studies conducted to date have been carefully designed to show whether
one drug or another is more closely linked to body fat changes
■ Body fat changes may have a serious effect on a patient’s quality of life
Unit 3: Clinical Pharmacology of ART
•
104
There is some evidence to suggest that the following might increase the risk further if in those taking
combination therapy:
•
Research shows that the longer a person takes combination therapy, the more likely he or she is to have
changes in body fat. Studies in well-resourced countries have shown that after three years on a combination
of nucleoside analogues and a protease inhibitor, 30 to 40% of people will develop body fat changes. It is not
yet clear whether the risk carries on growing after this point, or whether most people who will eventually get
lipodystrophy can expect to do so within three years of starting treatment with a protease inhibitor and NRTIs.
•
People who are overweight are more likely to complain of an increase in central fat.
•
Fat loss is more commonly reported in men than women, although women with average or low body weight
are more likely to observe loss of fat than women who are overweight.
•
Older people are more likely to report both central fat gain and fat loss from the arms, legs, and face. Some of
these changes could be being confused with the usual body fat changes that occur with ageing; because the
syndrome is new, it will take time to be sure.
•
The extent of immune system damage before starting, and the recovery after, treatment also seems to
influence the risk of body fat changes. A large CD4 cell rise and a past CD4 cell count below 200 have been
associated with more severe fat redistribution (but this may be an indication of very successful treatment or
the length of time a person has been on treatment, both of which have been suggested as causes of the body
fat changes).
•
Body fat changes have been less common in children, but tend to become more noticeable in teenagers.
•
The causes of body fat changes in people with HIV are still unknown. This makes it very difficult to give clear
advice about how to avoid lipodystrophy and how to treat the problem. At first, people with HIV and doctors
thought protease inhibitors caused body fat changes. In fact, the changes have also been seen in people who
have never taken protease inhibitors, but not as often.
•
It is hard to tell whether particular drugs are more likely to cause fat wasting, or fat gain. This is because none
of the studies conducted so far has been large enough or carefully enough designed to show whether one
drug or another is more closely linked to body fat changes.
•
Until studies can be designed and carried out which address all these problems, it will not be possible to say
for sure whether any specific drugs are more likely to cause body fat changes than others.
•
Nevertheless, we do know that some protease inhibitors cause changes in the body’s handling of fats and
sugar when they are given to people without HIV. This shows that in HIV-positive people, it is the drugs
themselves, and not just the disease or the effects of the drugs on the immune system, which are contributing
to the problem.
•
It is not clear how nucleoside analogues (NRTIs), such as ZDV, d4T, 3TC, abacavir and ddI contribute to the
problem. However, fat loss has been seen at a lower rate in people who just took two nucleoside analogues
with no protease inhibitor, in people who took a protease inhibitor and a non-nucleoside reverse transcriptase
inhibitor with no NRTIs, and in people who took protease inhibitors with no other drugs.
•
In other words, the most likely conditions for getting lipodystrophy seem to be when taking nucleosides and
protease inhibitors together.
•
Are body fat changes dangerous or harmful?
•
Body fat changes alone do not appear to substantially contribute to poor future health. However, they
may be stigmatising, uncomfortable, or embarrassing and so worry many people when they occur.
Reference Manual
for Trainers
HIV Care
and
for Pharmacists
Persistent
changes in fat and sugar metabolism,
together
withART:
central A
fatCourse
increases however,
could
increase the risk of heart disease if a someone also has other risk factors for heart disease (such as
smoking or a family history)
Unit 3: Clinical Pharmacology of ART
Slide 105
What Causes Lipodystrophy?
A number of factors have
been associated with body fat
changes
Type and duration of anti-HIV
therapy
Not just caused by protease
inhibitors
Duration of HIV infection or
low CD4 count
Fat accumulation and fat loss
may have separate causes
Gender
Treatment with protease
inhibitors and nucleoside
analogues together
Age
Specific drugs
Higher body mass and fat
prior to treatment
Unit 3: Clinical Pharmacology of ART
•
•
•
•
•
•
•
Race
105
Lipodystrophy (changes in body fat distribution) have been reported in as many as 80% of patients
receiving PIs. In addition, they have also been described in connection with nucleoside analogue
therapy (particularly d4Tcontaining regimens). These changes are gradual and generally not
apparent until months after the initiation of therapy.
Lipodystrophy is the medical name used to describe body fat changes. Three patterns of body fat
changes are being seen in people with HIV who are taking HAART. These are:
• Gaining fat on the abdomen/ belly (central fat), or between the shoulder blades, or around
the neck, or in the breasts (mostly in women)
• Losing fat from under the skin, which becomes most obvious in the arms, legs, buttocks
and face; this can result in facial wasting, shrunken buttocks and prominent veins on the
arms and legs
• A mixture of both fat gain and fat loss
The fat gain is not sub-cutaneous fat (the soft fat directly under the skin). Central fat gain is within
the abdomen. This makes the belly feel harder. Some people have described it as feeling taut, like
a football or like pregnancy. This fat accumulation may also interfere with food intake.
The majority of people who develop these changes experience a mixture of both types of body fat
change. These fat changes are often referred to as “fat redistribution”.
The body fat changes can be accompanied by metabolic changes (rises in levels of fats and sugar
in the blood).
A few people will also develop small, unusual fat deposits on other parts of the body. These are
called lipomas.
Who will develop body fat changes?
• People taking protease inhibitors and nucleoside analogues (NRTIs) together seem more
likely to develop some or all of these changes than people taking these agents alone.
Reference Manual for Trainers
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Unit 3: Clinical Pharmacology of ART
Slide 106
Lipodystrophy –
Morphologic Changes
■ Fat Accumulation (lipohypertrophy)
■ Dorsocervical fat
■ Visceral adiposity
■ Breast enlargement
■ Fat Loss (lipoatrophy)
■ Facial fat loss
■ Subcutaneous fat loss of extremities
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
106
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 107
Symptoms of Lipodystrophy
Fat Gain
(lipohypertrophy)
- Increased waist size
Fat Loss
(lipoatrophy)
Metabolic
Disorders
- Increased breast size
- Facial wasting, especially
of the cheeks
- Changes in blood fat
(lipid) levels
- ‘Buffalo hump’ (fat
accumulation around the
neck and upper back)
- Loss of subcutaneous fat
in all parts of the body,
most visibly in the limbs
- Blood sugar increases
- Fat accumulation around
the neck and jaw
(‘moon face’)
- Wasting of the buttocks
- Insulin resistance
- Prominent leg veins
- Fat deposits in other
locations
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
107
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 108
Fat Redistribution Syndromes
•
Note weight loss in buttocks and extremities and central obesity
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Unit 3: Clinical Pharmacology of ART
Slide 109
Dorsocervical Fat Pad
“Buffalo hump” in HAART-treated patient
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Unit 3: Clinical Pharmacology of ART
Slide 110
Buffalo Hump – Side View
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Unit 3: Clinical Pharmacology of ART
Slide 111
Central Fat Accumulation
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Unit 3: Clinical Pharmacology of ART
Slide 112
Lipoatrophy
•
Notice the thinning of the face through the cheek area
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Unit 3: Clinical Pharmacology of ART
Slide 113
Lipodystrophy – Implications
Psychosocial
Clinical
■ Self-esteem
■ Neck pain
■ Stigmatization
■ Respiratory difficulty
■ Antiretroviral
adherence
■ Umbilical hernia
■ Pain associated with
breast enlargement
■ Gastroesophageal reflux
Unit 3: Clinical Pharmacology of ART
113
•
Lipodystrophy can be very distressing for patients. They can feel as though
people on the street will now be able to recognize that they are HIV-positive.
•
It is important to explain the risk of lipodystrophy to patients and to also convey
that the benefits of therapy outweigh the risks. Counsel patients about how
lipodystrophy will present so that they can recognize it and bring it to the attention
of their provider or pharmacist as soon as possible.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 114
Lipodystrophy Management Approaches
■ Many approaches tried but outcomes minimal or
unsatisfactory
■ For lipoatrophy on d4T, changing to either abacavir or
tenofovir (if available) may prevent progression
■ Weight-bearing exercise to maintain muscle mass and
diet can be beneficial to prevent the development of
and treat lipodystrophy
■ Plastic surgery has provided temporary cosmetic
improvement when available
Unit 3: Clinical Pharmacology of ART
114
•
All of these have been tried with variable effects.
•
Nothing has resulted in reversal of the condition although some patients report
improvements. Fat loss appears to be permanent.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 115
CT Scans of the Abdomen of a Patient with
Lipodystrophy: At Baseline (left) and After 4
Months of Controlled Diet and Exercise (right)
Roubenoff R et al. Clin Infect Dis 2002 Feb 1;34(3):390-3
•
The exercise prescription consisted of 4 months of progressive cardiovascular and
resistance training at a local fitness center. Exercise was done 3 times each week
on nonconsecutive days. Each session included a general warm-up, 20 min of
cardiovascular exercise, 10 min of stretching and core exercises for the low back
and abdominal muscles, 40 min of strength training, and 5 min of general cooldown.
•
Cardiovascular exercise was performed on an elliptical training machine at an
intensity of 80%85% of the maximum heart rate, as determined by aerobic
capacity testing. A heart rate monitor was worn during all sessions to ensure that
proper training intensity was maintained. Three sets of 8 repetitions were
performed for all core and strength training exercises. Five resistance training
exercises targeting the large muscle groups of the body (leg press, chest press,
leg extension, seated row, and knee flexion) were performed on weight-stack
machines that were "selectorized" (i.e., the weight could be selected using a lever
system). Approximately one-third of the exercise sessions were supervised by a
trainer; the remaining exercise sessions were performed without supervision.
•
The dietary goals established for the study were as follows: energy intake, 1.3
times the resting energy expenditure, as measured by indirect calorimetry; protein
intake, 15% of total calorie intake or 1.31.5 g/kg; total fat intake, 30% of total
calories; saturated fat intake, 10% of total calories; fiber intake, 25 g per day; and
simple sugars, 10% of total calories. Carbohydrates were from foods with a low
glycemic index. The patient was seen weekly for nutrition counseling sessions
during the 16-week study period.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 116
Bone Disorders
■ Osteopenia, osteoporosis, and avascular necrosis are
being reported in patients with HIV infection.
■ Associated with PI-containing HAART regimens.
■ Various risk factors may contribute to their
development.
■ Be aware of this potential complication and treat early.
■ Further study is needed on:
■ Etiology of loss of bone mineral density
■ Identification of risk factors & appropriate prevention
strategies
Unit 3: Clinical Pharmacology of ART
•
116
Bone disorders (weakening and destruction of bone and cartilage): have been
reported in adults and children on ART. The risk appears higher in patients
receiving PIs than in those on regimens that do not contain PIs.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 117
Avascular Necrosis of the
Humeral Head
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 118
Enfuvirtide (T-20)
■ First fusion inhibitor
■ Binds to gp41 and prevents HIV entry into host cell
■ Used as part of salvage regimen for ART experienced patients
■ Dosing: 90 mg BID by subcutaneous injection
■ Injection sites: Abdomen, upper thighs, back of upper arms
■ Food interaction: None
■ Toxicity
■ Injection site reactions (98%)
■ Nausea, diarrhea, fatigue, hypersensitivity (< 1%)
Unit 3: Clinical Pharmacology of ART
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•
•
•
•
•
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118
Fusion inhibitors are the newest class of medications to fight HIV. The T-20 molecule is very large. T-20 is available as a kit
containing 60 doses w/ syringes, diluent & alcohol pads. The medication needs to be reconstituted at time of or within 24
hours of dose administration (108mg vial diluted with 1.1 mL sterile water for injection giving a volume of 1.2ml). Once
reconstituted, the vial must be used or placed in the refrigerator within 30 minutes. SQ injections can be given in the upper
arm, anterior thigh, or abdomen. Each injection should be given at a site different from the preceding injection site.
Injection site reactions are very common (98%), but only require discontinuation of therapy for 3%. Typical symptoms include:
pain and discomfort, swelling, itching, redness, nodules or cysts at site, and bruising. Providers can instruct patient that they
can decrease pain associated with injection site reaction by placing the needle bevel side down or by pushing the dose in
slowly over 10 seconds (not a fast bolus).
•
Reaction can be small Æ will resolve in 1-2 weeks
•
More severe = nodule Æ Can take a long time, even years to resolve
Hypersensitivity reaction can occur, and may reoccur on rechallenge. Hypersensitivity reactions have included individually and
in combination: rash, fever, nausea and vomiting, chills, rigors, hypotension, and increased liver function tests. If patient
experiences a hypersensitivity reaction, discontinue T-20 and have patient seek medical attention. Do not rechallenge.
T-20 (Fuzeon) is very expensive. It costs approximately 20,000 USD per year
FDA Approval: March 2003
Mechanism of Action: HIV normally binds to gp120 on CD4 receptor as well as another co-receptor (CXCR4 or CCR5). Then
gp120 shifts to expose gp41. Once exposed, gp41 pierces the CD4 cell and pulls it in close enough to allow viral-cell fusion.
Fusion inhibitors bind to the HR1 site in the gp41 subunit of the viral envelope glycoprotein and prevent the conformational
change that is needed to allow virus to enter the cell.
Absorption: Well absorbed from subcutaneous site with an absolute bioavailability of 84.3% (+/- 15.5%)
CSF Levels: unknown, but likely to be low b/c of large molecule size and 92% protein binding.
T1/2: 3.8 hours
Intracellular T1/2: hours
Elimination: The exact pathway of T-20 metabolism is unknown. In vitro, T-20 undergoes a non-NADPH dependent hydrolysis.
For CrCl > 35 ml/min, dose = 90mg SC Q12H; for CrCl < 35 ml/min, dose is unknown, but usual dose is likely. For hepatic
insufficiency, do data available.
Pediatric Dose: < 6 years of age: no data to establish dose 6 to 16 years of age: 2mg/kg BID up to a max of 90mg BID SQ.
Pregnancy: (Category B) Animal studies revealed no evidence of harm to fetus from T-20. There are no adequate and wellcontrolled studies in pregnant women. Only use if risks outweigh benefits
Drug Interaction: None
Resistance: No cross-resistance with other existing antiretrovirals. Mutations can occur around the binding area. A 21-fold
(range: <1 to 422-fold) decrease in susceptibility to T-20 has been correlated with genotypic changes in gp41 amino acids 36,
38, 40, 42, 43, and 45. In vitro, clinical isolates resistant to NRTIs, NNRTIs, or PIs, retained susceptibility to T-20
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 119
Contraception and ART
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 120
Contraception and ART
■ Efavirenz is contraindicated in pregnancy.
■ NNRTIs and PIs interfere with blood levels of
combination oral contraceptives.
■ Additional barrier methods are recommended to
prevent pregnancy and transmission of HIV and STIs.
■ Dual methods of contraception highly recommended for
sexually active EFV users: barriers plus
■ Progestins (Depo-Provera)
■ IUCD
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
120
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 121
Laboratory Monitoring
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 122
Regimen
ART
Lab Test
1
D4T/3TC/NVP
ALT
TLC or CD4
Baseline, 2, 4, & 8 wks, & q6 mos
Baseline & q6 months
Other
D4T/3TC/EFV*
ALT
TLC or CD4
Baseline & Symptom directed
Baseline & q6 months
ZDV/3TC/EFV*
ALT
TLC or CD4
Hgb
Baseline & Symptom directed
Baseline & q6 months
Baseline, 4, and 12 weeks, thereafter
symptom directed
ZDV/3TC/NVP
ALT
TLC or CD4
Hgb
Baseline, 2, 4, & 8 wks, & q6mos
Baseline & q6 months
Baseline, 4, and 12 weeks, thereafter
symptom directed
Unit 3: Clinical
Frequency
* Pregnancy
Test at Baseline when of EFV
Pharmacology of ART
•
122
These are the laboratory guidelines from the “Guidelines for use of antiretroviral
drugs in Ethiopia, July, 2004”
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 123
HAART: Baseline Labs
■ HIV antibody test
■ Urine dipstick
■ Full blood count and
differential
■ Hep B surface antigen
■ AST or ALT
■ Serum amylase (for
patients on d4T or ddI)
■ Serum creatinine or blood
urea nitrogen
■ Serum glucose
■ Pregnancy tests for
women
Unit 3: Clinical Pharmacology of ART
•
■ Serum RPR
■ Serum lipids (for pts. with
other cardiac risk factors
or to receive PIs or EFV)
■ CD4 lymphocyte count
123
If you were able to order all needed labs, this list provides a thorough baseline
assessment which can help you to decide which medications the patient can use.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 124
Patients on HAART: Laboratory Schedule
Class/Agent Adverse Event
Baseline, 4-6wks, q 3-6mo
Baseline, q 12 months
Cytopenia
Hepatotoxicity
Serum
amylase/ lipase
CBC/diff
LFTs
Baseline and symptoms of
abdominal pain
Baseline, q 12 months
Baseline, q 12 months
Cytopenia
Hepatotoxicity
CBC/diff
LFTs
Baseline, q 12 months
Baseline, q 12 months
Hepatic steatosis/
Lactic acidosis
ZDV
Cytopenia
Hepatotoxicity
DDI
Pancreatitis
DDC
D4T
3TC
ABC
•
Laboratory
Serum
electrolytes;
lactate, if
symptoms
CBC/diff
LFTs
NRTIs
Indication/Screening
Fatigue, muscle aches, Gi
symptoms, dyspnea
(continued)
Reference for Madison Clinic HIV treatment Guidelines, Harborview Medical
Center, University of Washington, Seattle, WA (prepared by Pamela Frick,
PharmD, MPH and Trudy Jones, ARNP).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 125
Class/Agent
Adverse Event
Laboratory
Indication/Screening
Nevirapine
Hepatotoxicity
LFTs
Baseline, 2 & 4wks, 3 months, then q
6mo.
Sustiva
Hyperlipidemia/Lipodystr
ophy
Fasting Lipid
Profile
Baseline, 3mo, 6mo.,then q 12mo, if
stable
PIs
Indinavir
Saquinavir
Ritonavir
Nelfinavir
Amprenavir
Kaleetra
Hyperlipidemia/Lipodystr
ophy
Fasting Lipid
Profile
Baseline, 3mo, 6mo.,then q 12mo, if
stable
Hepatitis/Hepatotoxicity
LFTs
Baseline, 3mo, then q 6 mo.
Cytopenias
CBC/diff
Baseline, 4-6wks, then q 12mo.
Diabetes Mellitus
Fasting glucose
Baseline,, then q 12mo
Nephrolithiasis
Urinalysis/creatini
ne
Baseline, q 6mo. or if hematuria/flank
pain
Indinavir
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 126
HAART: Recommended
Baseline Labs
Recommendation
Basic
Baseline Laboratory Tests
CBC with differential
LFTs
SrCr and/or BUN
*Women, pregnancy test
Serum Glucose
CD4 count or TLC
Desirable
Bilirubin & serum lipids, (amylase)
Optional
Viral Load
Unit 3: Clinical Pharmacology of ART
Reference Manual for Trainers
† Confirm HIV Diagnosis
126
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 127
ART Dosing Adjustments for Renal Compromise
Med
Normal Dose
CrCl 10-50mL/min
CrCl <10mL/min
ddI
200mg tabs bid
400mg qd (EC)
200mg qd
125-200mg qd
100mg q24-48h
125mg qd
3TC
150mg bid
100-150mg qd
50mg qd
d4T
30-40mg bid
50% q12-24h
> 60kg: 20mg qd
< 60kg: 15mg qd
TDF
300mg* qd
CrCl=30-50, * q 2 days
Cr Cl=10-29, * q 3-4 days
300mg q 7 days
ddC
0.75mg q8h
0.75mg bid
0.75mg qd
ZDV
300mg bid
300mg bid
100mg q8h
200mg# qd
#
FTC
CrCl=30-49, q 2 days
CrCl=15-29, # q 3 days
CrCl<15= #q 4 days
•
CrCl=(140-age)(IBW{kg}) ÷ (72)(SrCr{mg/dL}) (x 0.85 for women)
•
TDF dosing is:
•
•
Normal Dose = 300mg QD
•
CrCl 30-50ml/min = 300mg q 2 days
•
CrCl 10-29ml/min = 300mg q 3-4 days
•
CrCl < 10 ml/min = 300mg q 7 days
FTC dosing is:
•
Normal Dose = 200mg QD
•
CrCl 30-49 ml/min = 200mg Q 2 days
•
CrCl 15-29 ml/min = 200mg Q 3 days
•
CrCl < 15 ml/min = 200mg Q 4 days
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 128
ART Dosing Adjustments for
Hepatic Failure
Medication
Dose for hepatic failure
3TC, d4T, ABC
No data, usual dose
TDF
Avoid
ddC
Usual dose
ZDV
200mg BID
IDV
600mg Q8H
APV (moderate)
450mg BID
(severe impairment)
300mg BID
ATZ (moderate)
300mg QD, Don’t use for severe
f-APV (moderate)
700mg BID, Don’t use for severe
LPV/r, NFV, RTV, SQV
No dose change, use with caution
ddI, NVP, EFV, DLV
Consider empiric dose reduction
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 129
Clinical Pharmacology of
Antiretroviral Therapy
Cases and Exercises
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 130
Group Exercise: Side Effects
1. Divide into groups of four
2. List the main side effects of ARVs used in the locality
3. Divide side effects into two groups
a. Serious and life threatening
b. Side effects which can be relieved
4. Brain storm local remedies that might relieve less serious side
effects
5. Feed back to the main group
Unit 3: Clinical Pharmacology of ART
130
•
Group exercise: How can we relieve side effects, and when should patients seek medical attention?
Refer participants to Worksheet 3.1 in their Course Workbooks.
•
Note: if a local protocol already exists for when patients should be referred for medical attention, it is
important to highlight the contents as part of this training session
•
Exercise objectives
•
To help participants review the information on drug side effects
•
To help participants identify local resources that may assist in the management of side effects
•
Equipment: Flip chart and markers for each group
•
Time: Up to 10 minutes for introductory discussion, 30 minutes for small group discussion and 20
minutes feedback to main group (dependent on overall size of the group)
•
Instructions:
•
Identify the main ARVs used in the locality with the whole group (refer to local protocols if a
limited set of combinations will be prescribed). List on a flipchart.
•
Divide into groups of four
•
List the main side effects of ARVs used in Ethiopia
•
Divide side effects into two groups
•
•
•
Serious and life threatening
•
Side effects which can be relieved
Brain storm local remedies that might relieve less serious side effects
Feed back to the main group – maintain two lists – one of the serious side effects that require medical
attention, the other of local remedies. Establish consensus on each and highlight any absences or
potential issues with drug interactions where local remedies are used.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 131
Key Side Effects by
Drug or Drug Class
See ART Table
Unit 3: Clinical Pharmacology of ART
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131
Refer Participnats to Handout 3.1 in their Participant’s Handbook.
The more common side effects of ART are described below by drug or drug class. It should be
noted that the incidence of the following side effects have been determined largely by studies
conducted in the US and Europe. Side effects may be more or less common among
populations living in resource-limited settings.
Nucleoside analogue reverse transcriptase inhibitors:
Class-specific: lactic acidosis
Lactic acidosis, is the accumulation of dangerously high levels of lactic acid in the blood
stream. It is a very rare syndrome, but if it goes unrecognised, mortality can be high. Patients
experiencing it may complain of weakness, abdominal pain, nausea and vomiting, shortness
of breath, fatigue and hypotension. It is more common in women, those with high body mass,
prolonged NRTI use (in particular d4T), and, possibly, pregnancy. The initial symptoms are
variable; an early clinical syndrome may include generalized fatigue and weakness. These
may observed as soon as one month or as late as 20 months after starting therapy. All drugs
should be stopped at once because the longer a patient is on therapy the more symptoms
worsen.
Abacavir is well tolerated by most patients. However, in developed countries, approximately 35% of adults and children who have taken abacavir develop a potentially fatal hypersensitivity
syndrome.
Abacavir Hypersensitivity syndrome: The reaction appears to produce a wide variety of
symptoms that appear suddenly and grow worse with each dose of abacavir. These include
fever, nausea, vomiting, diarrhoea, abdominal pain, malaise, fatigue, sore throat, cough and
shortness of breath. There is often no rash to speak of. Although these symptoms can be
present with a lot of other illnesses, the sudden onset of booth respiratory and gastrointestinal
symptoms after starting abacavir is suggestive of a hypersensitivity reaction. Patients who
have recently started abacavir who experience these symptoms should seek medical care as
soon as possible. Abacavir treatment should be stopped immediately and never restarted if
the health care provider suspects hypersensitivity. Death can occur within hours of restarting
abacavir therapy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 132
Key Side Effects by
Drug or Drug Class
See ART Table
Unit 3: Clinical Pharmacology of ART
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132
Didanosine. The most common symptoms associated with ddI are diarrhoea, nausea,
vomiting and/or abdominal pain, with an incidence of 5-18%. Two of the more serious side
effects are peripheral neuropathy and pancreatitis.
• Peripheral neuropathy is damage to the peripheral nervous system. The symptoms
range from tingling, or burning sensations to severe pain usually in the feet, legs
and sometime in the arms and hands. Numbness and muscle weakness can also
occur. Peripheral neuropathy has been reported in 6-15% of patients taking ddI,
but it may be more common (and severe) in patients taking other neurotoxic drugs
such as d4T. Symptoms usually resolve within a few weeks of stopping drug.
• Pancreatitis. Inflammation of the pancreas has been reported in about 1-7% of the
patients taking ddI, and it can be fatal. Symptoms include nausea, vomiting and
abdominal pain. Blood tests may find elevated levels of pancreatic enzymes. The
incidence is dose related,, underscoring the need to dose ddI properly by body
weight, and is increased in patients who have had pancreatis or gallstones in the
past. Other risk factors include alcohol and obesity. ddI should be permenantly
discontinued if pancreatitis is confirmed.
Lamivudine is fairly well tolerated. Patients may experience transient headache, fatigue
and gastrointestinal upset. The major serious reported toxicities are pancreatitis, primarily
in children with advanced disease who are receiving treatment, and peripheral
neuropathy. On rare occasions, the drug may cause toxicity to the liver and neutropenia (a
drop in the levels of a type of blood cell that fights bacterial infections).
Stavudine’s most significant toxicity is peripheral neuropathy. As with ddI, this condition is
dependent upon dose, duration of therapy and the use of other neurotoxic drugs such as
ddI. Symptoms usually resolve within 2-3 weeks after the discontinuation of d4T. d4T may
also be more frequently associated with lactic acidosis and liver toxicities.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 133
Key Side Effects by
Drug or Drug Class
See ART Table
Unit 3: Clinical Pharmacology of ART
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133
Zidovudine’s most common side effects are blood related: severe anaemia and/or low
white blood cell counts occur in over 5-10% of patients. These side effects are doserelated and more common in patients with advanced HIV disease. Medications such as
ganciclovir and hydroxyurea may aggravate the condition. Fatigue, headache and nausea
occur in 5-10% of zidovudine-treated patients but are usually temporary, going away after
a few weeks on continued therapy. Zidovudine can also cause reversible muscle pain,
weakness and wasting in about 17% of patients.
Non-nucleoside reverse transcriptase inhibitors
Class-specific: rash and hepatitis
Rash and liver toxicity can occur on either nevirapine or efavirenz. However, these drugs
do not appear to cause rash and hepatitis in the same manner. Patients who experience
rash or liver toxicity on nevirapine can probably be safely switched to efavirenz, unless the
toxicity on nevirapine was very severe.
Efavirenz’s most serious adverse effects are to the central nervous system and to the
fetus when taken by pregnant women.
• Efavirenz CNS effects: Possibly half of patients on efavirenz experience some
neuroligical side effects ranging from altered senses, dizziness, headache,
insomnia, depression, impaired concentration, agitation, nightmares, and
drowsiness. Some of these symptoms may be manageable by taking the drug
before bedtime. A minority of patients experience severe psychiatric symptoms
including delusions, manic episodes and severe depression. They may even
become suicidal and require anti-psychotic medication. This is particularly common
in people with a history of mental illness or recreational drug abuse.
• Efavirenz-associated birth defects: Efavirenz caused significant birth defects in
primates exposed to it in utero. Efavirenz is particularly dangerous during the first
trimester, so pregnancy should be avoided by women taking the drug. Women who
may become pregnant while on ART should be advised to use a different drug, if
possilbe.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 134
Key Side Effects by
Drug or Drug Class
See ART Table
Unit 3: Clinical Pharmacology of ART
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134
Nevirapine most commonly causes a skin rash, though in some patients it can cause
hepatitis and a life-threatening hypersensitivity reaction (see below). In developed
countries, about 17% of the patients appear to develop a rash on nevirapine, the rash can
be severe leading about 6-8% of patients to quit treatment. It may occur more often in
women and in persons of Asian descent. The rash most commonly appears on the body
and arms, usually within the first month of therapy, although occasionally it may start a few
weeks later. Nevirapine should be stopped if the rash is severe or effects the mucosa, or if
there are symptoms consistent with hypersensitivity syndrome.
• Steven’s-Johnson syndrome is a life-threatening hypersensitivity syndrome that
has been reported in about 0.3% of the patients who have taken nevirapine.
Symptoms include fever, swelling, pain in the muscles and joints, and hepatitis all
of which occur before the rash, and sometimes without a rash even developing.
Nevirapine treatment should be stopped as such as reaction can prove fatal.
• Nevirapine-associated hepatitis can occur in about 13-17% of patients, severe
hepatitis may occur in 1-9%. It may be more common in patients with a history of
alcohol abuse, coinfection with hepatitis B or C and in patients who are older or are
women.
Protease inhibitors
Class-specific: insulin resistance/diabetes.
Insulin resistance occurs in up to 40% of patients treated with PIs, and hyperglycaemia
(high blood sugar), new cases of diabetes mellitus and worsening of pre-existing diabetes
mellitus have also been reported. High blood sugar has been reported in 3-17% of
patients receiving PIs; about 1% of these patients develop clinical evidence of diabetes.
Patients receiving PIs should be advised about the warning signs of hyperglycaemia, such
as excessive thirst, excessive urination, and excessive appetite. Hyperglycaemia resolves
in some but not all patients after the discontinuation of therapy. Most experts, however,
would continue ART with supportive therapy (oral hypoglycaemic drugs or insulin) in the
absence of severe diabetes.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 135
Key Side Effects by
Drug or Drug Class
See ART Table
Unit 3: Clinical Pharmacology of ART
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•
•
•
135
Class-specific: hyperlipidaemia (elevated triglycerides and/or cholesterol) have been
linked to treatment with all the PIs, although the increases tend to be higher in patients
receiving ritonavir. Whether this will lead to a higher rate of cardiovascular disease or
pancreatitis, is unclear.
Class-specific: lipodystrophy (changes in body fat distribution) have been reported in as
many as 80% of patients receiving PIs. They have also been described in connection with
nucleoside analogue therapy (particularly d4Tcontaining regimens). These changes are
gradual and generally not apparent until months after the initiation of therapy.
Class-specific: increased bleeding episodes in haemophiliacs have been reported in
patients with haemophilia A or B who are receiving PIs. They may develop skin
hematomas (a swelling of clotted blood caused by a broken blood vessel). Serious
bleeding in the gastrointestinal tract or within the skull has been reported rarely. Bleeding
episodes usually begin to occur about three weeks after the initiation of PI therapy.
Class-specific: hepatitis: All PIs can cause liver inflammation, though ritonavir has been
more frequently associated with severe liver toxicity. Elevated liver enzymes in the blood
can occur at any time during PI treatment. Liver toxicity is more common in patients who:
drink too much alcohol; had high liver enzymes on blood tests when treatment started; use
other medication that can cause toxicity to the liver such as d4T; or are coinfected with
hepatitis B or C.
Class-specific: bone disorders (weakening and destruction of bone and cartilage) have
been reported in adults and children on ART. The risk appears higher in patients receiving
PIs than in those on regimens that do not contain PIs.
Amprenavir: The most common side effects associated with amprenavir are headache,
nausea, rash, diarrhoea, vomiting and tingling around the mouth. The incidence of nausea
and vomiting may be significantly increased when amprenavir is used together with
zidovudine (ZDV).
Indinavir: kidney stones/and elevated bilirubin
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 136
Key Side Effects by
Drug or Drug Class
See ART Table
Unit 3: Clinical Pharmacology of ART
•
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•
•
136
The most serious side effect of indinavir in adults and children is the formation of
kidney stones, seen in about 9% of patients; it may be more frequent in hot
climates. Temporary abnormal kidney function, including acute kidney failure, and
inflammation have been observed in some patients with nephrolithiasis. The
condition may be signalled by severe pain beneath the ribs with or without blood in
the urine. Indinavir may need to be interrupted for a few days. The condition may
recur in have of the patients if indinavir is restarted. Patients taking indinavir must
drink plenty of fluids — at least 1.5 litres of water daily and more in hot weather.
Elevated bilirubin has been seen in about 10% of patients receiving indinavir; in
most cases the maximum bilirubin elevation was observed after one or more
weeks of treatment; jaundice (yellowing of the skin) and elevations in liver
enzymes have been reported only rarely.
Indinavir may also cause dry skin, bald patches in the hair, dry lips and ingrown
toe or finger nails. About three percent of patients develop acid reflux.
Lopinavir/ritonavir (Kaletra) most commonly causes diarrhoea, weakness, and
elevations in cholesterol and triglycerides. Pancreatitis has been reported in adults,
possibly due to high triglyceride levels.
Nelfinavir: The most common adverse effects on nelfinavir are diarrhoea,
abdominal pain, flatulence and rash.
Saquinavir: The primary toxicities are mild gastrointestinal disturbances, such as
nausea, diarrhoea and abdominal pain; headache; and reversible elevations in
liver enzymes. Nausea and diarrhoea are more common with the soft-gel
formulation than with the hard-gel formulation.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 137
Adult ARV Therapy
Case Studies
•
Refer participants to Worksheets 3.2 to 3.5 in their Course Workbooks.
•
These case studies may be done in small groups and findings reported back to the
larger group or they may be discussed as a large group when time is limited.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 3: Clinical Pharmacology of ART
Slide 138
Case 1
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
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Adult ARV Case Studies
Case 1
A 25 year old man was tested for HIV
because his wife tested positive in a prenatal
clinic. He has seborrheic dermatitis and
enlarged bilateral posterior cervical lymph
nodes. He weighs 72 kg. Otherwise, he has
felt well, and his physical exam is otherwise
normal. His HIV antibody test was positive,
and his CD4+ lymphocyte count was 140
cells/mm3. His other baseline laboratory tests
were normal, and he fulfilled the CD4 criteria
to start antiretroviral therapy.
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Adult ARV Case Studies
Case 1 (cont.)
He started cotrimoxazole prophylaxis 6 weeks
ago. He began treatment with stavudine,
lamivudine and nevirapine 2 weeks ago. At his
first follow-up visit he reported perfect adherence
and some itching of his skin. On his exam, he
had mild diffuse erythematous macules on his
torso, arms and legs.
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Adult ARV Case Studies
Case 1 Questions 1 - 2
1. What is your diagnosis?
2. How do you treat him?
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Case 1 – Adult ARV
Answer 1
1. He has a rash probably due to nevirapine. It is less
likely that the rash is due to allergy to cotrimoxazole,
since he has been using the cotrimoxazole without
problems for more than one month.
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Slide 143
Moderate Rash
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Case 1 – Adult ARV
Answer 2
2. The rash is mild, and 90% of the time a mild
rash caused by nevirapine will be self-limited.
There is a risk of progression to serious
complications. He needs to check his ALT as
usual, and should return in one week or sooner
if he gets worse. He can be provided with oral
antihistamines if the itching is very
uncomfortable.
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Case 1 – Adult ARV
Answer 2 (cont.)
■ Nevirapine rash can be part of a dangerous
hypersensitivity syndrome including hepatitis as
well as skin reactions. An ALT must be checked
at this time.
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Adult ARV Case Studies
Case 1 (cont.)
■ He returns one week later. The rash has
spread onto his palms and soles. He now
has fever, conjunctivitis, and oral ulcers.
■ The ALT is normal.
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Adult ARV Case Studies
Case 1 Questions 3 - 4
3. What is your diagnosis?
4. How do you alter his current therapy?
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Case 1 – Adult ARV
Answer 3
3. Now he has Stevens-Johnson syndrome (SJS), or
severe erythema multiforme.
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Slide 149
Severe Rash
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Case 1 – Adult ARV
Answer 4
4. The nevirapine must be stopped immediately. The
stavudine and lamivudine must also be stopped
because otherwise the 2-drug antiretroviral regimen
may select for drug-resistant HIV. Many clinicians
would also stop the cotrimoxazole now, because even
though the reaction is probably caused by nevirapine,
it is possible that it is caused by cotrimoxazole and it
may be safest to treat that possibility also. The use of
steroids in Stevens-Johnson syndrome is
controversial.
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Slide 151
Adult ARV Case Studies
Case 1 (cont.)
Three weeks later the fever, rash and
mucous membrane disease has healed.
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Slide 152
Adult ARV Case Studies
Case 1 Question 5
5. How do you treat him now?
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Case 1 – Adult ARV Answer 5
5. He has recovered from the SJS. He should resume
opportunistic infection prophylaxis. Some clinicians would
prescribe dapsone 100 mg/day. Others would resume
cotrimoxazole, perhaps with desensitization.
He can resume antiretroviral therapy. For patients who
discontinued NVP because of a moderate rash, efavirenz may
be substituted. For those who had a life-threatening rash, it is
safer to avoid NNRTIs. He had SJS, therefore it may be safest
to switch substitute a ‘boosted’ PI, such as lopinavir/ritonavir
(Kaletra) for the nevirapine, continuing the d4t and 3TC.
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Slide 154
Case 2
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Adult ARV Case Studies
Case Study 2
Four months ago TD was started on HAART for the
first time because her T-cells had dropped from
400 to 160. Today she comes to the pharmacy to
refill only her SMX/TMP. When you ask her if she
needs to pick up her antiretrovirals, she replies,
“No, I’m going to stop taking those when I run out
because I’m having so many side effects. I’m
having diarrhea about 8-10 times a day and I can’t
feel my feet sometimes in the morning”.
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Case Study 2 (cont.)
■ Current medications include:
■ Trimethoprim/sulfa DS QD
■ Nelfinavir (Viracept®) 5 x 250mg tabs BID
■ Lamivudine (Avolam®) 150mg BID
■ Stavudine (Avostan®) 1 x 40mg BID
■ Which drugs would most likely cause diarrhea and what
can you recommend to help control the diarrhea?
■ What is the likely culprit for the numbness TD is
experiencing in her feet and what can be done to
alleviate the neuropathy?
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Case Study 2 – Answers
■ Most likely cause of diarrhea is nelfinavir. To control it she
could try any of the following:
■ Loperamide 2mg – take 1 or 2 tablets after first loose stool, then 1
tablet after each subsequent loose stool, not to exceed 8 tablets
per day. She can adjust the dose as needed to control her
diarrhea (e.g., take 2 in the morning, 1 at midday and 1 at
bedtime). She can follow a regimen that works for her.
■ Calcium 500mg BID
■ Psyllium 1 tablespoon mixed in water once or twice daily with ½
the water volume (120ml)
■ Oat bran 1500mg BID
■ Pancreatic enzymes at 1 to 2 tablets with each meal.
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Slide 158
Case Study 2 Answer (cont.)
■ If diarrhea cannot be controlled with an antidiarrheals,
patients should consult with their provider or
pharmacist, it may be necessary to change to another
PI or NNRTI.
■ If constipation develops from antidiarrheal use, the
patient should reduce their loperamide dose or other
agents.
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Slide 159
Case Study 2 Answer (cont.)
■ The most likely cause of her numbness in her feet is the
stavudine (peripheral neuropathy)
■ Timing is correct, she has been on meds for 4 months
(usual onset is after 2-6 months of therapy)
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Slide 160
Case Study 2 Answer (cont.)
■ To alleviate the pain the following options can be tried:
■ Peripheral neuropathy is a reversible, dose-related side effect
■ Discontinue offending agent at onset
■ Reduce dose (to 20mg Q12H if weight > 60kg, or 15mg Q12H if < 60kg).
Symptoms will dissipate within a few weeks of discontinuation (or reducing
dose).
■ Following improvement in peripheral neuropathy, can re-introduce agent at
reduced dose if needed.
■ If provider does not discontinue therapy or reduce dose at onset,
peripheral neuropathy will become permanent and increasingly painful and
debilitating.
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Other options:
•
Amitryptiline (start at 25mg, increase dose as tolerated)
•
Gabapentin (start at 300mg TID and add 300mg every week to a
maximum of 1200mg TID, e.g., 300mg TID x 1 week, then 600mg
QAM, 300mg Q midday, and 300mg QPM x 1 week, then 600mg
QAM and Qmidday and 300mg QPM, etc.)
•
Capsaisin cream
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Unit 3: Clinical Pharmacology of ART
Slide 161
Case 3
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Unit 3: Clinical Pharmacology of ART
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Case Study 3
■ LP is a 38 year old male who has been on nevirapine
and a ZDV + 3TC combination tablet for 5 months.
■ Over the last 2 weeks, he reports that he has become
very tired. In fact, he has missed 4 days of work in the
past 2 weeks because he just couldn’t get out of bed.
He also has felt nauseated on and off over since he
started the medications.
■ He believes these changes are a result of his
antiretroviral medications. Consequently, he started
missing doses frequently.
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Slide 163
Case Study 3 Questions
■ What do you think is going on with LP?
■ What drug(s) might be responsible for his fatigue?
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Slide 164
Case Study 3 – Answers
■ His severe fatigue may be a sign of drug-induced
anemia
■ The drug most likely to cause anemia is ZDV
■ We should check his blood work (Hgb and Hct)
■ The nausea he is experiencing may also be related to
ZDV
■ The drug most likely causing nausea for him is ZDV
■ We should ask him if he eats a meal before every dose?
What type of food does he eat before his doses? Has he
been able to control the nausea at all?
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•
•
•
164
What do you think is going on with TJ?
What drug(s) might be responsible for his fatigue?
What other information would you like to know?
What management strategy would you suggest?
MORAL OF THE STORY – YOU NEED TO USE YOUR PROFESSIONAL KNOWLEDGE
AND ASK THE PATIENT MORE QUESTIONS TO DETERMINE WHERE THE SIDE
EFFECTS ARE COMINIG FROM
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Unit 3: Clinical Pharmacology of ART
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Case Study 3
Case and Question (cont.)
■ His Hgb = 7.2 and his Hct = 20%
He says that he eats food before some of his doses, but
not all of the time. Usually he takes the dose with a
piece of Njera. He hasn’t tried anything else to control
the nausea.
■ What management strategy would you suggest? How
would you counsel the patient?
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Slide 166
Case Study 3 Answers (cont.)
■ He is having severe zidovudine-induced anemia (Hgb and
Hct are both low and clinically he is very fatigued which is
making him unable to work)
■ Call the patient’s provider and recommend that he stop ZDV and
change to another agent. Check to see if D4T is appropriate (no
peripheral neuropathy). You should counsel the patient about the
dosing and potential side effects of D4T.
■ He does not eat before all of his doses which could be
contributing to his nausea
■ His nausea should improve by stopping the ZDV, but counsel him to
eat a full meal before every dose. If the nausea does not improve, he
should come back to see you.
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Slide 167
Case 4
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Slide 168
Case Study 4
TJ is a 32 year old male who has been on nelfinavir and an AZT +
3TC combination tablet since 2001 through the black market. Six
months ago he became distressed by the body shape changes he
is noticing because he’s afraid he may lose his job if his boss finds
out he is HIV positive. He believes these changes are a result of
his antiretroviral medications. Consequently, he started missing
doses frequently. His provider switched his PI to saquinavir 400mg
BID + ritonavir 400mg BID. He also had trouble successfully taking
this regimen and finally quit taking all HAART medications 2 months
ago when his CD4 cell count started dropping and his viral load
went from undetectable to 45,000. Two weeks ago, he and his
provider decided to restart antiretroviral therapy.
Unit 3: Clinical Pharmacology of ART
•
168
This is a lipodystrophy case. If you don’t want to focus on that long-term side
effect, skip this case.
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Unit 3: Clinical Pharmacology of ART
Slide 169
Case Study 4 (cont.)
■ He received the following medications:
■ Lopinavir/ritonavir 4 capsules BID
■ Efavirenz (Sustiva®) 3 x 200mg caps QHS
■ Abacavir (Ziagen®) 300mg BID
■ Didanosine (Videx®) 400 mg qd
■ SMX/TMP QD
■ Today he comes to the pharmacy with a rash on his
extremities, back and trunk that started 3 days ago.
Unit 3: Clinical Pharmacology of ART
•
169
Do you notice any drug interactions in his new regimen? If so , what is the nature
of the drug interaction?
•
YES, between lopinavir/ritonavir and efavirenz. Efavirenz reduces levels of
Lopinavir/ritonavir by 40%
•
Were the doses adjusted appropriately?
•
YES, Kaletra dose was increased from 3 capsules BID to 4 capsules BID
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Unit 3: Clinical Pharmacology of ART
Slide 170
Case Study 4 – Questions
■ What drugs would most likely the cause
lipodystrophy?
■ What drugs might be responsible for the rash?
■ What management strategy would you suggest for
the rash?
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Slide 171
Case Study 4 – Answers
LIPODYSTROPHY
■ Find out more - what type of body changes he is
having?
■ When you ask him he says: his belly has gotten bigger, his
arms and legs are skinnier and this area on his upper back is
starting to poke up.
■ His whole ART regimen can, with the greatest contribution
coming from his protease inhibitors: nelfinavir (he’s been on
that for 2 ½ years) and ritonavir/saquinavir (on for 4 months),
and then his NRTIs
Unit 3: Clinical Pharmacology of ART
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•
171
Research shows that the longer a person takes combination therapy, the
more likely he or she is to have changes in body fat. Studies in wellresourced countries have shown that after three years on a combination of
nucleoside analogues and a protease inhibitor, 30 to 40% of people will
develop body fat changes. It is not yet clear whether the risk carries on
growing after this point, or whether most people who will eventually get
lipodystrophy can expect to do so within three years of starting treatment
with a protease inhibitor and NRTIs.
MORAL OF THE STORY – YOU NEED TO USE YOUR
PROFESSIONAL KNOWLEDGE AND ASK THE PATIENT MORE QUESTIONS
TO DETERMINE WHERE THE SIDE EFFECTS ARE COMINIG FROM
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Unit 3: Clinical Pharmacology of ART
Slide 172
Case Study 4 – Answers (cont.)
■ How can the lipodystrophy be treated?
■ Currently, we do not know how to reverse the lipodystrophy.
■ Weight-bearing exercises and a healthier diet can help
maintain muscle mass and prevent further progression of the
body fat changes. Tell him to return to clinic if he notices
worsening in his body change symptoms
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Slide 173
Case Study 4 – Answers (cont.)
■ Three possible causes of ■ Management strategies
you could suggest:
rash:
■ Efavirenz
■ Abacavir
■ SMX/TMP
■ Ask if he has ever had
SMX/TMP before? Did it
ever give him a rash? He
could have had a rash to
SMX/TMP previously that
was overlooked.
■ He has had SMX/TMP
before for a urinary tract
infection without problem.
■ Determine the rash severity
– mild or severe
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Slide 174
Case Study 4 – Answers (cont.)
■ Is he presenting with any other hypersensitivity symptoms?
Does he have any blistering or mucous membrane
involvement? Why is this important?
■ He says the only thing he has noticed is that the little red
bumps cover his chest, arms, legs, and back. They are itchy,
but he can tolerate it. He does not have any blistering?
■ Have his symptoms worsened with each dose? Does he
have any relief between doses?
■ No, once the rash started it hasn’t worsened or improved.
■ What do his answers lead you to believe is the culprit?
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Slide 175
Case Study 4 – Answers (cont.)
■ The most likely culprit is Efavirenz
■ How can it be treated?
■ Treat him symptomatically
■ Antihistamines
■ Hydrocortisone cream for itching.
■ Counsel him that if his rash worsens, he needs to come back to the
clinic.
■ The rash should gradually improve over the next week
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Slide 176
Case Study 4 – Answers (cont.)
■ It’s difficult to determine his exact resistance profile, but he has
not had an NNRTI in the past so we would expect him to have
good response to it alone with 2 NRTIs.
■ We could stop the lopinavir/ritonavir to give the patient a PI
sparing regimen. Patients have reported improvements with
these measures.
■ He is likely to have resistance to AZT and 3TC, so switching to
DDI + ABC gives the patient a new 3-drug regimen.
■ Make sure that he is >60 kg for appropriate dosing of DDI. We
would like to avoid using D4T as this has been implicated in
the development of lipodystrophy.
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Unit 3: Clinical Pharmacology of ART
Slide 177
Key Points
■ Antiretrovirals cannot kill existing virus; they can only prevent the
production of new virus.
■ The four antiretroviral classes are (1) nucleoside reverse
transcriptase inhibitors, (2) non-nucleoside reverse transcriptase
inhibitors, (3) protease inhibitors, and (4) fusion inhibitors.
■ A combination of at least three drugs is necessary in order to
overcome resistance.
■ Some side effects can have psychosocial implications as well as
physical implications.
■ The side effects of some antiretrovirals can be managed , while
others may require a dose modification or a change in the
antiretroviral regimen.
Unit 3: Clinical Pharmacology of ART
177
•
Summarize these key points.
•
Ask for further questions about content in Unit 3.
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Unit 3: Clinical Pharmacology of ART
Slide 178
References
■ AIDS Therapy, 2nd Edition, (2003). Raphael Dolin, MD, Henry Masur, MD, and
Michael Saag, MD (Eds). Churchill Winston, Philadelphia.
■ Bartlett, John G and Gallant, Joel E. (2003). Medical Management of HIV
Infection, Johns Hopkins University, Baltimore, Maryland.
■ Briggs GG,Freeman RK, Yaffe SJ, Drugs in Pregnancy and Lactation 6th
edition,Baltimore, MD: Williams & Wilkins, 2002.
■ Boubaker K et al. Hyperlactatemia and antiretroviral therapy: the Swiss HIV
Cohort Study. Clin Infect Dis. 2001 Dec 1;33(11):1931-7.
■ Schambelan M et al. JAIDS 2002;31:257-75.
■ Carr A et al. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction
associated with HIV nucleoside analogue therapy: contribution to protease
inhibitor-related lipodystrophy syndrome. AIDS. 2000 Feb 18;14(3):F25-32.
■ Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
■ FDA Consumer Magazine, V. 35(3), May-June, 2001.
Unit 3: Clinical Pharmacology of ART
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Slide 179
References (cont.)
■ Frenkel, L. M.D. Children’s Hospital and Regional Medical Center, Seattle,
WA, USA, September, 2004.
■ Frick, P. PharmD, MPH, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
■ Gerard Y et al. Symptomatic hyperlactataemia: an emerging complication of
antiretroviral therapy. AIDS. 2000 Dec 1;14(17):2723-30.
■ Guidelines for use of antiretroviral drugs in Ethiopia, July 2004.
■ Hetherington S et al. Abstracts of the 7th Conference of Retroviruses and
Opportunistic Infections. San Francisco, CA. January 30- February 2, 2000,
Poster No. 60.
■ Hykes,B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
■ John M et al. Chronic hyperlactatemia in HIV-infected patients taking
antiretroviral therapy. AIDS. 2001 Apr 13;15(6):717-23.
Unit 3: Clinical Pharmacology of ART
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Unit 3: Clinical Pharmacology of ART
Slide 180
References (cont.)
■ Kosel, B. PharmD, Clinical Pharmacist, HIV/AIDS Harborview Medical Center,
Seattle, WA, USA, 2004.
■ Lonergan T et al. 42nd ICAAC, San Diego, 2002, Abstract H-1080.
■ Madison Clinic HIV Treatment Guidelines, Harborview Medical Center,
University of Washington, Seattle, WA (prepared by Pamela Frick, PharmD,
MPH and Trudy Jones, ARNP).
■ McGilvray, M, Willis, N. “Module 6: ARVs in Children” All About Antiretrovirals:
A Nurse Training Programme, Trainer’s Manual, Africaid 2004.
■ Ministry of Health, Guidelines for Use of Antiretroviral Drugs in Ethiopia,
August 2004.
■ Moyle GJ et al. Hyperlactataemia and lactic acidosis during antiretroviral
therapy: relevance, reproducibility and possible risk factors.
AIDS. 2002 Jul 5;16(10):1341-9.
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Slide 181
References (cont.)
■ Namibia Ministry of Health and Social Services, Training on the Use of the
Namibia Guidelines for Antiretroviral Therapy (ART), 2004.
■ Peterson PL. The treatment of mitochondrial myopathies and
encephalomyopathies. Biochim Biophys Acta. 1995 May 24;1271(1):275-80.
■ Physician’s Desk Reference, 57th ed. Montvale, NJ: Thomson PDR; 2004:
3539.
■ Roubenoff R et al. Reduction of abdominal obesity in lipodystrophy associated
with human immunodeficiency virus infection by means of diet and exercise:
case report and proof of principle. Clin Infect Dis. 2002 Feb 1;34(3):390-3.
■ Sulkowski, Hepatotoxicity associated with antiretroviral therapy in adults
infected with human immunodeficiency virus and the role of hepatitis C or B
virus infection. JAMA. 2000 Jan 5;283(1):74-80.
■ Zewditu Hosp, Cost information, 2003
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HIV Care and ART: A Course for Pharmacists
Handout 3.1 FDA Approved Antiretrovirals
JULY 2004
Nucleoside Reverse Transcriptase Inhibitors
Drug
Common
Dose Regimen
Abacavir
®
300mg PO BID
AZT
300mg PO BID
Ziagen
Zidovudine
®
Retrovir
- or -
200mg PO TID
< 60kg 250mg PO QD
- or –
125-200mg QD for renal
compromise
- or –
250mg QD for
peripheral neuropathy
ddC
Zalcitabine
Hivid®
d4T
Stavudine
®
Zerit
3TC
Lamivudine
®
Epivir
FTC
emtricitibine
Emtriva®
AZT/3TC
®
Combivir
AZT/3TC/
Abacavir
®
Diet
Pediatric: 8mg/kg BID
With or without food
< 90 days: 2mg/kg Q6H
2
Pediatric: 160mg/m Q8H
With or without food
Special Considerations
y 100mg capsule
y 300mg tablet
y 10mg/mL solution
Hypersensitivity reaction – DO
NOT RECHALLENGE
No Renal Dosing Adjustments
y Decrease dose if CrCl <
50mL/min (100 mg PO TID)
Adverse Effects
Hypersensitivity rxn:
(fever,N/V,rash, malaise,
congestion); Diarrhea,Insomnia
Anemia, Neutropenia,
Headaches, Nausea, Body
aches, Insomnia
400mg PO QD
- or -
Didanosine
®
Videx-EC
y 300mg tablet
y 20mg/mL oral
Adjusted Dose In
Combo / Pediatric Dose
suspension
> 60kg
ddI
Available
Dosage Forms
0.75mg PO TID
y 400, 250, 200, 125mg
EC capsules
y 25,50,100,150mg
chewable tabs
y 167mg, 250mg oral
powder packet
y Oral suspension
y 0.375mg, 0.75mg
tablet
> 60 kg 40mg PO BID
- or < 60 kg 30mg PO BID
- OR > 60 kg 100mg-XR PO QD
- or < 60 kg 75mg-XR PO QD
150mg PO BID
-or300mg PO QD
200mg QD
1 tablet PO BID
1 tablet PO BID
ddI EC 250mg +TDF 300mg
QD (Taken together with food)
Pediatric: 120mg/m2 Q12H
y
y
Empty stomach
Empty stomach
y 150mg, 300mg tablet
y 10mg/mL oral solution
y 200mg capsule
Peripheral neuropathy,
Pancreatitis, Nausea, Diarrhea
y Extend dosing interval if CrCl <
80mL/min (0.75mg Q12-24H)
Peripheral neuropathy, Mouth
sores
Pediatric: 0.01mg/kg Q8H
(Do not take with
antacids)
Pediatric: 1mg/kg BID
With or without food
y Decrease dose if CrCl <50mL/min
(20mg Q12-24H)
Peripheral neuropathy, Altered
liver function
Pediatric: 2-4mg/kg BID
With or without food
y Decrease dose if CrCl <50mL/min
(50-150mg Q24H)
Headaches, Nausea
Not Established
With or without food
y Decrease if CrCL < 50mL/min
(Q48-Q96h dosing)
Headaches, Nausea
With or without food
y DO NOT use if CrCl < 50mL/min
With or without food
y DO NOT use if CrCl < 50mL/min
y Hypersensitivity reaction – DO
y 15mg, 20mg, 30mg,
40mg capsule, 75mgXR, 100mg-XR
For chew tabs, dose must have
at least 2 tabs to provide
adequate buffer capacity
y Suspension must be refrigerated
& expires 30 days after prepared
y 250mg powder packet = 200mg
chewable tablets
y 300mg AZT/150mg
3TC
y 300mg AZT/150mg
3TC/ 300mg abacavir
NOT RECHALLENGE
Trizivir
Anemia, Neutropenia,
Headaches, Nausea, Insomnia
Hypersensitivity rxn:
(fever,N/V,rash, malaise,
congestion); Anemia,
Neutropenia, Headaches,
Nausea, Diarrhea,Insomnia
Nucleotide Reverse Transciptase Inhibitors
Tenofovir
®
Viread
(TDF)
300mg PO QD
• 300mg tablet
• TDF 300mg QD + ddI EC 250mg QD
(Taken together with or without sfood)
- Safety and efficacy in peds not yet
established
With food
y Decrease dose if CrCl <50mL/min
Headaches, nausea
Handout 3.1 FDA Approved Antiretrovirals
(cont.)
JULY 2004
Non-Nucleoside Reverse Transcriptase Inhibitors
Drug
Common
Dose Regimen
Nevirapin
e
®
400mg QD (investigational)
Delavirdin
e
®
600mg BID (investigational)
Viramune
(NVP)
Rescriptor
(DLV)
Efavirenz
®
Sustiva
(EFV)
200mg QD x 2 wks,
then 200mg PO BID
400mg PO TID
600mg PO QHS
Available
Dosage Forms
Adjusted Dose
In Combination
Diet
Adverse Effects
Special Considerations
y 200mg tablet
y NVP 200mg BID + IDV 1gm Q8H
y NVP 200mg BID + Kaletra 4 BID
y Pediatric: 120mg/m2 QD x2wks, then
120-200mg/m2 Q12H
With or without food
y Dose escalate to avoid rash: 200
mg/day for first 14 days
Rash, Headache, Altered liver
function
y 200mg tablet
y 100mg tablet
y DLV 400 TID + IDV 600 Q8H
y Pediatric: Unknown
With or without food
y Do not take with antacids or ddI
Rash, Headache, Altered liver
function
y EFV 600mg QHS+IDV 1gm Q8H
y EFV 600mg QHS + RTV 200-400mg
BID + SQV 400-1200mg BID
y EFV 600mg QHS+APV 1200mg TID
y EFV 600mg QHS + Lopinavir/r 4 BID
y EFV 600mg QHS+RTV 100-200mg
BID + APV 600mg BID
y Pediatric: 10-<15kg=200mg QHS
15-<20kg=250mg QHS
20-<25kg=300mg QHS
25-<32.5kg=350mg QHS
32.5-<40kg=400mg QHS
> 40kg=600mg QHS
With or without food
y Minimize alcohol intake
y May split dose to manage SE
(200 mg AM; 400mg PM)
Rash, Headache, Diarrhea,
Dizziness, Nausea or Vomiting
- 6-16 y/o: 2mg/kg SQ BID
With or without food
y Rotate injection sites
y 600mg tablet
y 50mg, 100mg, 200mg
capsule
Fusion Inhibitors
Enfuvirtid
e
®
Fuzeon
(ENF or T-20)
Administered dose:
90mg/mL SQ BID
(108mg vial diluted with 1.1
mL SWI)
y Available as kit
containing 60 doses
w/ syringes, diluent &
alcohol pads
Prepared by Kara Lee Yukumoto, Pharm.D. Candidate/Revised, Pamela Frick, PharmD, MPH,
Injection site reaction: pain/discomfort,
induration, erythema, nodule
Other: Diarrhea, N/V, fatigue, insomnia
MAP/JAF/BWK 7/04
Madison Clinic Pharmacy, Harborview Medical Center, University of Washington, Seattle, Washington.
Handout 3.1 FDA Approved Antiretrovirals
(cont.)
JULY 2004
Protease Inhibitors
Drug
Ritonavir
®
Common
Dose Regimen
600mg PO BID
Norvir
(RTV)
(6 x 100mg capsule/dose)
Saquinavir
®
(8 x 200mg capsule/dose)
Fortovase
(SQV)
Indinavir
®
Crixivan
(IDV)
Nelfinavir
®
Viracept
(NFV)
- or 1200mg PO TID
800mg PO Q8H
(2 x 400mg capsule/dose)
- or 750mg PO TID
y 200mg, 333mg, 400
mg capsule
y 250 mg tablet
y Pediatric powder
available 50mg/scoop
1200mg PO BID
(3 x 133/33mg
capsule/dose)
400mg QD
(2 x 200mg capsules/dose)
y 50mg, 150mg capsule
y 15mg/ml oral solution
y 133mg lopinavir +
33mg ritonavir
y 100mg, 150mg, 200mg
capsule
(ATV)
(f-AMP)
Food enhances
absorption
(Do not take with
antacids)
y
y
y
y
y
SQV 1000mg + RTV 100mg PO BID
SQV 1600mg + RTV 100mg PO QD
SQV 400mg + RTV 400mg PO BID
SQV 1200mg + NFV 1250mg PO BID
Pediatric: 50mg/kg Q8H
MAY TAKE WITH FOOD
y IDV 800mg + RTV 100-200mg PO BID
y IDV 400mg + RTV 400mg PO BID
y IDV 1000mg PO Q8H + EFV 600mg
PO QHS
y IDV 1000mg PO Q8H + NVP 200mg PO
BID
y Pediatric: 500mg/m2 Q8H
Food enhances
absorption (large
meal)
(Do not take with
antacids)
Empty stomach
(Do not take with
antacids)
Special Considerations
Adverse Effects
y Refrigerate capsules
y May store at room temperature
up to 30 days
y DO NOT refrigerate oral solution
(may crystallize)
y Dose escalate to full dose for
improvement in GI intolerance
Nausea, Vomiting, Numbness around
the mouth, Altered taste
y Refrigerate capsules
y May store at room temperature
up to 90 days
Diarrhea, Nausea, Headache, Altered
liver function
y If intolerable, take with light,
non-fat snack
y At least 1.5 liters of fluids (water,
fruit juice, non-caffeinated)
y No grapefruit juice (decr IDV
level)
Nausea, Vomiting, Kidney stone
formation, Heartburn, Increased
bilirubin
y NFV 1250mg + SQV 1200mg PO BID
y Pediatric: 20-45mg/5kg TID
Food enhances
absorption
(fatty meal)
y Important to send patient home
with anti-diarrheal agent
Diarrhea, Nausea, Vomiting,
Abdominal pain
(3 x 250mg tablet/dose)
400mg lopinavir +
100mg ritonavir BID
Fosampre
navir
Lexiva®
y multiple; see concurrent PI for dosing
y Pediatric: 350-400mg/m2 BID
Diet
1250mg PO BID
(5 x 250mg tablet/dose)
Lopinavir/
ritonavir
®
Atazanavir
Reyataz®
y 200mg capsule
Adjusted Dose
In Combination
(6 x 200mg capsule/dose)
(8 x 150mg capsule/dose)
Kaletra
(LPV/r)
y 100mg capsule
y 80mg/mL oral solution
1600mg PO BID
Amprenav
ir
®
Agenerase
(APV)
Available
Dosage Forms
1400mg PO BID
y 700mg tablet
y APV 600mg BID + RTV 100mg BID
y APV 1200mg QD + RTV 200mg QD
y APV 1200mg PO TID + EFV 600mg PO
QHS
y APV 600mg PO BID + RTV 100-200mg
PO BID + EFV 600mg PO QHS
y Pediatric: <50kg=20mg/kg BID
(max=2400mg/day for caps & for oral
sol max=2800mg/day)
y lopinavir/r 3-4 caps BID + APV 750mg
BID
y lopinavir/r 4 caps BID + EFV 600mg
QHS
y lopinavir/r 4 caps BID + NVP 200mg
BID
y Pediatric: 230mg/m2 LPV / 57.5mg/m2
RTV BID
y With Efavirenz or tenofovir: ATV
300mg QD + RTV 100mg QD
y Many other drug interactions – refer to
package insert
y Do not use in child < 3 mo (hyper
bilirubinemia), dose for children under
investigation
y fAMP 1400mg QD + RTV 200mg QD
y fAMP 1400mg QD + RTV 300mg QD +
EFV 600mg QHS
y fAMP 700mg BID + RTV 100mg BID
(use BID + RTV dosing for PI experienced)
y Pediatric: dose currently under
investigation
With or without food
(Do not take with
antacids)
y Vitamin E 109IU in each capsule
y DO NOT use additional Vitamin
E as supplement
y Daily multivitamin is okay
y Sulfonamide drug (use with
caution if documented sulfa
allergy)
Diarrhea, Nausea, Headache, Altered
liver function
With or without food
(Do not take with
antacids)
Food enhances
absorption
(Do not take with
Proton Pump
Inhbitors/antacids)
With or without food
y Refrigerate capsules
y May store at room temperature
up to 60 days
Consider dose adjustment in
patient with mild to moderate
hepatic insufficiency
- Sulfonamide drug (use with
caution if documented sulfa
allergy).
- For mild to moderate hepatic
insufficiency, use 700mg fAMP
BID. Do not use with severe
hepatic insufficiency
Diarrhea, Nausea, Headache,
Abnormal stools
Diarrhea, Nausea, Headache, Fatigue,
Increased indirect bilirubin, Jaundice
Rash, Diarrhea, Nausea, Headache,
Perioral parethesias
Slide 3.6 HIV Life Cycle
Fusion-Inhibitors
Slide 3.7 HIV Receptors
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART Clinical Pharmacology
Unit 3-10
Slide 3.29 Abacavir Hypersensitivity Signs and Symptoms
100
90
80
% of Cases
70
60
50
40
30
20
10
Sym ptom s
ch
th ills
/th
ro
at
m
ou
ra
s
na h
us
vo ea
m
iti
ng
m
al
ai
se
di
ar
rh
oe
a
pr
ur
itu
he
ad s
ac
he
fa
tig
ue
m
ya
lg
ia
fe
ve
r
0
Slide 3.30 Time to Onset of 636 Cases
Time to Onset of 636 Cases
60
No. of Cases
50
Median time to onset 11 days
93% of reported cases
occurred within the first 6
weeks of initiating abacavir
40
30
20
10
0
1
15
29
43
57
71
85
99
Days
113 127 141 155 169
One additional ABC HSR Reported at
318 days
*
Hetherington S et al. In: Abstracts of the 7th Conference of Retroviruses and Opportunistic
Infections. San Francisco, CA. January 30- February 2, 2000, Poster No. 60.
Clinical Pharmacology of ART
HIV Care and ART for Pharmacists
Reference Manual for Trainers
31
ART Clinical Pharmacology
Unit 3-11
Slides 3.124-125
Patients on HAART: Laboratory Schedule
Class/Agent
NRTIs
Adverse Event
Hepatic steatosis/
Lactic acidosis
ZDV
Cytopenia
Hepatotoxicity
DDI
Pancreatitis
DDC
D4T
3TC
ABC
Laboratory
Serum
electrolytes;
lactate, if
symptoms
CBC/diff
LFTs
Indication/Screening
Fatigue, muscle aches, Gi
symptoms, dyspnea
Baseline, 4-6wks, q 3-6mo
Baseline, q 12 months
Cytopenia
Hepatotoxicity
Serum
amylase/ lipase
CBC/diff
LFTs
Baseline and symptoms of
abdominal pain
Baseline, q 12 months
Baseline, q 12 months
Cytopenia
Hepatotoxicity
CBC/diff
LFTs
Baseline, q 12 months
Baseline, q 12 months
(continued)
Class/Agent
Adverse Event
Laboratory
Indication/Screening
Nevirapine
Hepatotoxicity
LFTs
Baseline, 2 & 4wks, 3 months, then q
6mo.
Sustiva
Hyperlipidemia/Lipodystr
ophy
Fasting Lipid
Profile
Baseline, 3mo, 6mo.,then q 12mo, if
stable
PIs
Indinavir
Saquinavir
Ritonavir
Nelfinavir
Amprenavir
Kaleetra
Hyperlipidemia/Lipodystr
ophy
Fasting Lipid
Profile
Baseline, 3mo, 6mo.,then q 12mo, if
stable
Hepatitis/Hepatotoxicity
LFTs
Baseline, 3mo, then q 6 mo.
Cytopenias
CBC/diff
Baseline, 4-6wks, then q 12mo.
Diabetes Mellitus
Fasting glucose
Baseline,, then q 12mo
Nephrolithiasis
Urinalysis/creatini
ne
Baseline, q 6mo. or if hematuria/flank
pain
Indinavir
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART Clinical Pharmacology
Unit 3-12
References
AIDS Therapy, 2nd Edition, (2003). Raphael Dolin, MD, Henry Masur, MD, and
Michael Saag, MD (Eds). Churchill Winston, Philadelphia.
Bartlett, John G and Gallant, Joel E. (2003). Medical Management of HIV Infection,
Johns Hopkins University, Baltimore, Maryland.
Briggs GG,Freeman RK, Yaffe SJ, Drugs in Pregnancy and Lactation 6th
edition,Baltimore, MD: Williams & Wilkins, 2002.
Boubaker K et al. Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort
Study. Clin Infect Dis. 2001 Dec 1;33(11):1931-7.
Schambelan M et al. JAIDS 2002;31:257-75.
Carr A et al. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction
associated with HIV nucleoside analogue therapy: contribution to protease inhibitorrelated lipodystrophy syndrome. AIDS. 2000 Feb 18;14(3):F25-32.
Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
FDA Consumer magazine Volume 35, Number 3 May-June 2001.
Frenkel, L. M.D. Children’s Hospital and Regional Medical Center, Seattle, WA,
USA, September, 2004.
Frick, P. PharmD, MPH, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
Gerard Y et al. Symptomatic hyperlactataemia: an emerging complication of
antiretroviral therapy. AIDS. 2000 Dec 1;14(17):2723-30.
Guidelines for use of antiretroviral drugs in Ethiopia, July 2004.
Hetherington S et al. Abstracts of the 7th Conference of Retroviruses and
Opportunistic Infections. San Francisco, CA. January 30- February 2, 2000, Poster
No. 60.
Hykes,B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical Center,
Seattle, WA, USA, 2004.
John M et al. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral
therapy. AIDS. 2001 Apr 13;15(6):717-23.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART Clinical Pharmacology
Unit 3-13
References (cont.)
Kosel, B. PharmD, Clinical Pharmacist, HIV/AIDS Harborview Medical Center,
Seattle, WA, USA, 2004.
Lonergan T et al. 42nd ICAAC, San Diego, 2002, Abstract H-1080.
Madison Clinic HIV Treatment Guidelines, Harborview Medical Center, University of
Washington, Seattle, WA (prepared by Pamela Frick, PharmD, MPH and Trudy
Jones, ARNP).
McGilvray, M, Willis, N. “Module 6: ARVs in Children” All About Antiretrovirals: A
Nurse Training Programme, Trainer’s Manual, Africaid 2004.
Ministry of Health, Guidelines for Use of Antiretroviral Drugs in Ethiopia, August
2004.
Moyle GJ et al. Hyperlactataemia and lactic acidosis during antiretroviral therapy:
relevance, reproducibility and possible risk factors.
AIDS. 2002 Jul 5;16(10):1341-9.
Namibia Ministry of Health and Social Services, Training on the Use of the Namibia
Guidelines for Antiretroviral Therapy (ART), 2004.
Peterson PL. The treatment of mitochondrial myopathies and
encephalomyopathies. Biochim Biophys Acta. 1995 May 24;1271(1):275-80.
Physicians Desk Reference 57th ed. Montvale, NJ: Thomson PDR; 2004: 3539.
Roubenoff R et al. Reduction of abdominal obesity in lipodystrophy associated with
human immunodeficiency virus infection by means of diet and exercise: case report
and proof of principle. Clin Infect Dis. 2002 Feb 1;34(3):390-3.
Sulkowski, Hepatotoxicity associated with antiretroviral therapy in adults infected
with human immunodeficiency virus and the role of hepatitis C or B virus infection.
JAMA. 2000 Jan 5;283(1):74-80.
Zewditu Hosp, Cost information, 2003
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART Clinical Pharmacology
Unit 3-14
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART Clinical Pharmacology
Unit 3-15
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 4
Changing Therapy
Unit 4: Changing Therapy
Aim: The aim of this unit is to introduce participants to the reasons for ART failure
and identify when an ART regimen should be changed.
Learning Objectives: By the end of this unit, participants will be able to:
•
Identify reasons for ART failure
•
Determine how to change ART due to toxicity, failure or concomitant disease
•
Describe factors to consider when changing ART
•
Describe appropriate laboratory monitoring procedures for ART over time
Unit Overview:
2 Hours 10 minutes
Step
Activity/
Method
Time
1
10 minutes
2
60 minutes
Question-Answer
Content
Resources
Needed
Introductory Case Study and
Question Slides (4.2-4.3)
Overhead or LCD
Projector
Changing Therapy (Slides 4.4 - 4.36)
Overhead or LCD
Projector
Lecture
Small Group Exercise
Paper and pens
3
50 minutes
Case Study Group
Exercise
Case Studies (Slides 4.37 - 4.53)
Worksheets (4.1, 4.2)
in the Wiorkbook.
Two flip chart stands
with paper and
markers.
4
10 minutes
Summary
Presentation of Key Points (Slide
4.54)
Overhead or LCD
Projector
Resources Needed
•
•
•
•
•
Flip Chart and Paper
Markers
Overhead or LCD Projector
Paper
Pens
•
The following materials can be found in the Participant Handbook:
- Antiretroviral Therapy: Failure to Suppress (enlarged Slide 4.25)
- Antiretroviral Therapy: Viral Therapy (enlarged Slide 4.26)
- Routinely Recommended Laboratory Monitoring Parameters (enlarged Slide
4.34)
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Changing Therapy
Unit 4-3
Key Points
1. Treatment failure occurs because of preexisting resistance, limited regimen
potency, imperfect adherence, poor absorption, rapid elimination, or drug-drug
interactions.
2. Therapy should not be changed unless absolutely necessary.
3. The main reasons for changing ART are treatment failure and drug toxicity.
4. Other reasons for changing ART include problems with adherence or other
medical conditions or illnesses that may impact choice of therapy.
5. Ongoing laboratory monitoring is necessary to detect all side effects and to
monitor success or failure of therapy.
Step 1
Step 2
Introductory Case Study (10 minutes)
•
Ask a participant to read the case study on Slide 4.2.
•
Ask participants to silently attempt to answer the question on
Slide 4.3.
•
Explain that the question will be answered and the case
discussed more fully as the unit progresses.
Lecture (60 minutes)
•
This unit will introduce participants to the reasons for ART failure
and for changing therapy.
•
Begin by reviewing slide 4.4 of the PowerPoint presentation,
“Changing Therapy.” Ask the participants if they have any
questions about the objectives before continuing.
•
Present and discuss the PowerPoint presentation, “Changing
Therapy” (Slides 4.5-4.36).
•
Small Group Exercise (Slide 4.15: What are the Key Reasons for
Treatment Failure):
•
Divide class into groups of four.
•
Pass out paper and pen to each group.
•
Give groups ten minutes to summarise the key reasons
why treatment succeeds or fails.
•
Spend fifteen minutes for feedback to the group to review
the key learning points.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Changing Therapy
Unit 4-4
Step 3
Step 4
Case Study Group Exercise (50 minutes)
•
Case Study Group Exercise: Divide participants into two work
groups. Provide each work group with one of the two Adult ART
Case Studies (Worksheets 4.1, 4.2. in the workbook.) Ask the
groups to identify a recorder and a presenter, and then spend
thirty minutes discussing the case study together and answering
the related questions on flip-chart paper.
•
Ask each work group to share their decisions and answers.
Discuss each case thoroughly and use this time to answer
questions and clarify misinformation. Review the case studies in
the “Changing Therapy” PowerPoint presentation (4.37 – 4.53).
Spend 15 minutes discussing each case.
Summary (10 minutes)
•
Summarize the presentation, review the Key Points presented in
this Unit (Slides 4.54), and answer final questions.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Changing Therapy
Unit 4-5
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes
for reference during the planning and implementation of this course. The
facilitation notes and talking points are included in the “notes” section of the
accompanying PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Changing Therapy
Unit 4-6
Unit 4: Changing Therapy
Slide 1
Changing Therapy
Unit 4
HIV Care and ART: A Course for Pharmacists
•
This unit should take approximately 2 hours, 10 minutes to complete.
•
For abbreviations, students should refer to Reference Handout 1.4
•
ART= antiretroviral therapy
•
ARV= antiretroviral
•
OH= orthostatic hypotension
•
IV= intravenous
•
ULN= upper limit of normal
•
SCr= serum creatinine
•
ANC= absolute neutrophil count
•
AST= aspartate amino transferase
•
ALT= amino alanine transferase
•
Pltc= platelets
•
TG= triglycerides
•
Chol= cholesterol
•
Hgb= hemoglobin
•
WBC= white blood cells
•
H/H= hemoglobin and hematocrit
•
CBC= complete blodod count
•
DDI = didanosine
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 2
Introductory Case
■ BG is a 28 year old male diagnosed with AIDS who has been
taking his triple drug ART regularly for the past 6 months without
difficulties. He has a history of PCP pneumonia and oral thrush 1
year ago at which time he began therapy.
■ CD4/TLC and or VL monitoring is not available in his region.
■ Today is diagnosed with toxoplasmosis and is hospitalized for
treatment with Fansidar.
■ Which of the following statements about the need to change
therapy are true?
Unit 4: Changing Therapy
Reference Manual for Trainers
2
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 3
Introductory Case Questions
A. A change in ART therapy should only done when a
patient experiences virologic failure.
B. A change in therapy should not be done because this
patient is not experiencing side effects from this
regimen.
C. A change in therapy should be done for a patient who
experiences a new opportunistic infection on ART.
D. A change in therapy should be made as soon as a
patient starts to miss doses to avoid treatment failure.
Unit 4: Changing Therapy
Reference Manual for Trainers
3
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 4
Unit Learning Objectives
■ Identify reasons for ART failure
■ Determine how to change ART due to toxicity, failure or
concomitant disease
■ Describe factors to consider when changing ART
■ Describe appropriate laboratory monitoring procedures
for ART over time
Unit 4: Changing Therapy
4
•
More abbreviations:
• D4T= stavudine
• ABC= abacavir
• 3TC= lamivudine
• ZDV= zidovudine
• TDF= tenofovir
• LPV/r= lopinavir/ritonavir boost
• IDV/r= indinavir/ritonavir boost
• NFV=nelfinavir/ritonavir
• SQV/RTV= saquinavir/ritonavir
• NNRTI = nonnucleoside reverse transcriptase inhibitor
• NRTI= nucleoside reverse transcriptase inhibitor
• PI= protease inhibitor
•
At some point, the first-line ART regimen may need to be changed. Reasons for
changing ART include treatment failure, drug toxicity, problems with adherence or
other medical conditions or illnesses that may impact choice of therapy (ie.
pregnancy or tuberculosis).
When changing ART, many factors must be considered in order to choose a
regimen that the patient can be successful with for the long term. The new ART
regimen may necessitate monitoring that is different from the first-line regimen.
•
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 5
Reasons Treatment May Fail
Treatment fails if:
■ The drugs are not strong enough to control the virus (most
likely in very sick patients) or the patient has many other
infections
■ The drugs are not taken every day as prescribed (poor
adherence)
■ The patient cannot tolerate ART due to side effects
■ Other medicines stop ART from working
Unit 4: Changing Therapy
5
•
Many patients will achieve viral suppression, immune restoration and develop an improvement in their
overall well-being, however, these drugs are not a cure.
•
In some patients treatment may start too late. This may be because they have very high levels of HIV in
their blood, and the drugs are not strong enough to control HIV. Or it may be because they have several
serious infections which cannot be treated successfully. Although ART helps the immune system
recover, it may be too late to stop some infections or conditions such as cancers.
•
If a person stops taking the drugs, HIV levels will rise again. ART controls HIV by stopping the virus from
making new copies of itself. ART cannot kill the virus when it is `hiding` in cells. If treatment is stopped,
these `hidden` viruses will form the new `seed corn` that quickly restores high levels of the virus
throughout the body.
•
HIV can also become resistant to the drugs that then stop working, particularly, if doses are missed or if
the medications are not taken properly. Everyone has a role to play in making sure that patients are able
to take their medication the right way – doctors, pharmacists, nurses, other community health care
workers, family and friends.
•
Resistance not only reduces the benefits of the current combination — it may limit any future treatment
options. Furthermore, resistant virus can be transmitted to uninfected people, limiting the effectiveness of
available treatments for others and for the prevention of mother-to-child transmission.
•
Oftentimes, side effects of ART limit a patient’s ability to take the medication properly. This may lead to
the development of resistance as the levels of the drug in the body are not consistent. This give the virus
a chance to make new copies of itself.
•
Even when a patient takes his or her medication properly every day, they are at risk for treatment failure
due to drug-drug interactions. Drug-drug interactions will be discussed in more detail later.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 6
Reasons Treatment May
Fail (cont.)
■ Too sick (clinical failure)
■ The patient may have several serious infections which are not
treatable
■ Must differentiate from Immune Reconstitution
■ Clinical manifestation of a sub-clinical infection already
present at baseline brought on by ART- induced reconstitution
of the immune system
■ Typically seen with the first several weeks after initiating ART
Unit 4: Changing Therapy
6
•
In some very sick patients, their disease progresses despite taking ART. This may
be because they have very high levels of HIV in their blood, and the drugs are not
strong enough to control HIV.
•
This may also happen because there was not enough time to help the immune
system recover. They may experience clinical failure, which may be seen in the
development of a new opportunistic infection, or by the failure of existing illness to
improve. It may be too late to stop some infections or conditions such as cancers.
•
However, illness which occurs soon after starting a new regimen might indicate
immune reconstitution syndrome.
•
Immune reconstitution syndrome can be seen within the first several weeks after
the initiation of therapy if a sub-clinical infection is present at baseline. This is a
sign that the immune system is functioning more effectively as a result of ART.
•
Immune reconstitution syndrome may also result in an atypical presentation of
some opportunistic infections. Although management of immune reconstitution
syndrome is challenging, switching the antiretroviral regimen in this circumstance
is not indicated.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 7
Reasons Treatment May
Fail (cont.)
Poor adherence
■ If the drugs are not taken every day, drug levels fall and HIV
becomes resistant
■ Missing more than three doses a month increases the risk that
treatment will fail
■ Encouraging good adherence is vital
■ Everyone has a part to play in good adherence, not just the
patient – doctor, nurse, other clinic staff, pharmacists,
community health workers, family, friends
Unit 4: Changing Therapy
7
•
We refer to adherence as a term that implies that the patient is an “active”
participant in their care.
•
In order for ART to work properly against the virus, it must be taken as prescribed.
•
Patients need to be aware what poor adherence means (i.e. missing doses,
taking partial doses, taking the medication incorrectly: for example, taking a drug
that is supposed to be taken with food on an empty stomach, which will impair
absorption of the drug and ultimately lead to failure of the regimen.)
•
Emphasize that ‘near perfect adherence’ (>95%) is required for successful
treatment. Missing more than three doses a month increases the risk that
treatment will fail.
•
Pharmacists can play a crucial role in assisting patients with adherence to their
regimens. It can be helpful to ask patients if they have a family member or friend
that can help remind them to take their doses.
•
It is important to talk with patients before they start medication so that they
understand that poor adherence can lead to treatment failure. We will talk more
about adherence in a separate lecture.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 8
Introductory Case Answers
■ The statement D): A change in therapy should be
made as soon as a patient starts to miss doses to avoid
treatment failure is false. If it is determined that a
patient is missing doses, it is best to try to determine
the cause and to identify a solution to assist the patient
with adherence
■ Changing therapy should only be done when absolutely
necessary.
Unit 4: Changing Therapy
Reference Manual for Trainers
8
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 9
Reasons Treatment May
Fail (cont.)
■ Other medicines may stop ART from working
■ By reducing levels of ART in the blood
■ e.g. TB drug rifampicin
■ Important:
■ patients must be told that herbal medicines could reduce ART drug
levels
■ traditional healers must be told that their medicines could reduce ART
drug levels
Unit 4: Changing Therapy
9
•
Interactions with other drugs can also reduce the effects of ART, by reducing drug
levels. Other drugs may stop the antiretrovirals from being processed properly in
the body. One example is the TB medication rifampicin, which can reduce the
levels of some ARVs.
•
Other drugs may affect the absorption of ART (eg. Antacids and DDI)
•
This problem concerns not only the medicines prescribed by doctors, but any
traditional herbal remedies too. The effects of many of the herbal medicines used
by traditional healers on levels of antiretrovirals is still unknown, and it is possible
that some could either reduce ARV levels or raise ARV levels in such a way that
the patient suffers dangerous side effects.
•
It is important that any efforts to provide ART in a community, to involve traditional
healers, who need to know about the possible risks of prescribing traditional herbal
medicines to people taking ARVs.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 10
Reasons Treatment May
Fail (cont.)
■ The patient cannot tolerate the available drugs
■ Liver damage, nerve damage and anaemia are possible
serious side effects
■ Diarrhoea, nausea and vomiting caused by the drugs may
sometimes be too much to bear
■ Treatment may have to be stopped if these side effects
become serious and replacement drugs are not available
Unit 4: Changing Therapy
10
•
Side effects of antiretrovirals may necessitate a change in regimen, even if a patient is
otherwise responding to treatment.
•
Side effects can vary in frequency and morbidity. Some are potentially fatal (eg. lactic
acidosis, pancreatitis) whereas hyperlipidemia may cause a substantial long-term risk of
cardiovascular disease, and some drugs cause almost predictable gastrointestinal
intolerance.
•
There are some side effects which occur early on and others that can occur later. (Eg. The
risk of hepatitis (which appears to be a hypersensitivity reaction) with nevirapine is
greatest within the first 6 weeks of therapy whereas stavudine induced peripheral
neuropathy is unlikely to occur until after 2-6 months)
•
It is best to educate patients about the potential side effects of an ART regimen BEFORE
they start the medication. They should be aware of the side effects that may begin early
on or which may occur later. If the side effect should occur, they should know if they
should expect it to resolve on its own, or if they need to seek medical attention.
•
If the side effects can be pinned to one drug in the regimen, it may be possible to switch
just that offending drug.
•
In situations where the toxicity cannot be pinned to one single drug, it may be necessary
to switch the entire regimen.
•
In some patients, antiretroviral drugs can have toxic side effects that can be life
threatening. For example, liver damage and nerve damage can be so serious that a
patient must stop ART. If suitable replacement ARVs are not available, the patient may no
longer benefit from ART.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 11
Clinical Indications to Change
ART Due to Toxicity
Symptom
Nausea
Severe discomfort or minimal intake for > 3 days
Vomiting
Severe vomiting of all foods/fluids in 24 hrs, orthostatic
hypotension or need of IV fluids
Diarrhea
Bloody diarrhea, orthostatic hypotension or need of IV
fluids
Fever
Unexplained fever of > 39.6 C
Headache
Severe or requires narcotics
Allergic Reaction
Generalized urticaria, angioedema or anaphylaxis
Peripheral Neuropathy
Severe discomfort, objective weakness, loss of 2-3
previously present reflexes or sensory dermatomes
Fatigue
Normal activity reduced > 50%
•
At what point is is necessary to change ART due to toxicity? There are
certain clinical indications to guide you in this decision making process. If a
patient experiences side effects from the ART, they must utilize their doctor,
pharmacist or nurse to determine how to best handle the particular side
effect.
•
Patients must be counseled on the potential side effects of the ART regimen so
that they know the difference between side effects are that are considered more
severe and need urgent medical attention versus those that are less threatening.
•
Pharmacists have the opportunity to ask the patient questions about the side
effects they are experiencing to determine if the patient should come in to the
hospital to be evaluated or if they should continue taking their ART. (Eg. If a
patient is experiencing mild diarrhea from their ART, they may be able to change
their diet to include more foods that are more constipating or they may be able to
take another medicine to control the diarrhea).
•
However, if the patient is having bloody diarrhea or if they are becoming severely
dehydrated from the diarrhea, it will be necessary to change therapy. The
pharmacist must be able to relay the information that they have extracted from the
patient to the doctor so that the appropriate measures are taken to resolve the
side effect, which may include a change in the ART regimen.
•
It is important to tell the patient that if they stop taking their medication, that they
should stop taking ALL OF their ART to avoid the development of resistance.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 12
LAB Indications to Change ART Due to Toxicity
Parameter
Hematology
Chemistries
Pancreatic Enzymes
< 7.0 g/dL
ANC
< 750/mm3
M: 13.8 – 17.2 g/dL
F: 12 – 15.6 g/dL
1500 to 7000/mm3
Pltc
< 49,000/mm3
130-400/mm3
> 3-7.5 x ULN*= 3.99.75mg/dL
≤ 1.3 mg/dL
> 1.7-2.0 (adult)
≤ 1.2 mg/dL
5-10 x ULN* = 210420 U/L, 240-480
U/L
≤ 42 U/L , ≤ 48U/L
> 2-3 x ULN*
23-85 U/L, 0-160 U/L
8.49- 13.56 mmol/L
< 200 mg/dL
1.6-2.0 X ULN
< 200 mg/dL
Bilirubin
AST / ALT
Amylase, Lipase
Lipids
Normal Reference Values
Hgb
SCr
LFTs
Grade 3 Toxicity
TG
Chol
* ULN = Upper Limit of Normal
•
Certain laboratory abnormalities signal the need for a change in ART regimen.
•
One should consider changing ART in Grade 3 reactions and treatment should be
stopped if there is a Grade 4 adverse event.
•
Grade 4 Toxicity: Hgb < 6.5 g/dL, ANC < 500 mm3, TG 13.56 mmol/L, Chol 2.0 X
ULN
•
Therefore, it is crucial that patients get their scheduled follow-up laboratory
monitoring tests (blood tests) to
•
make sure that the ART is not causing any harm to organs (eg. Liver, kidneys,
pancreas) or the blood.
•
This is important because many times, patients may not have symptoms although
the ART is causing damage.
•
For example: a patient may not “feel the side effect” from a medication that may
cause an increase in the serum creatinine, indicating kidney toxicity
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 13
Changing Therapy Due to Toxicity
■ ~ 50 percent of patients treated for three years with
good viral suppression will require a change in therapy
due to an adverse reaction
Unit 4: Changing Therapy
Reference Manual for Trainers
13
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 14
Causes of ART Failure:
Summary
Preexisting Resistance
Limited Potency of Regimen
Imperfect Adherence
Poor Absorption
Rapid Elimination
Drug-Drug Interactions
Persistent Viral Replication
Drug Failure
Unit 4: Changing Therapy
14
•
There are many potential causes of ART failure. In order for the patient to be
successful with their ART, all variables must be addressed.
•
Some of the causes can be addressed eg. Be aware of potential drug-drug
interactions and avoid the offending drugs.
•
Other causes may not be able to be identified upfront, eg. Preexisting resistance
(if you do not have the ability to get a genotype)
•
Each visit is an opportunity to identify any NEW variables that may cause therapy
to fail. When patients come in for follow-up appointments for blood work or a visit
with their doctor, or to pick up refills of their medication, the pharmacist is able to
ask the patient how they are taking their medication, eg. are they taking their
medication with food if that is required for adequate absorption?
•
Routine laboratory monitoring is important to detect both toxicity and virologic
success/failure.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 15
What are the Key Reasons
for the Success or Failure
of ARV Treatment?
Small Group Exercise
•
Objectives
•
To help participants review reasons for potential treatment failure, and key
information needed to prevent treatment failure
•
To prepare participants for the probability that a proportion of very sick
patients will experience failure of antiretroviral therapy, and that this should
not be seen as a sign that ART is ineffective for all.
•
Equipment: Paper and pen
•
Time: 10 mins for small groups, 15 mins for review
•
Instructions:
•
Divide into small groups
•
Ask the groups to summarise the key reasons why treatment succeeds or
fails.
•
Feedback to the group to review the key learning points.
•
Ask that each participant in the group provide at least one reason to
encourage participation in the group.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 16
Changing Therapy
■ Not done unless absolutely necessary!
■ Two Main Reasons to Change
■ Intolerable toxicities or side effects
■ Treatment Failure
■ Clinical failure
■ Immunologic failure
■ Virologic failure
Unit 4: Changing Therapy
16
•
Therapy must be changed only when absolutely necessary to avoid loss of
effective ART for future regimens.
•
There are two main reasons to change therapy:
•
Side effects or toxicities
•
Treatment failure: this may be picked up by CD4 count decline or failure to rise, or
by loss of virologic control. It can also be detected clinically during physical exam;
the development of new OIs, or progression of disease
•
Note:Therapeutic failure is most commonly associated with non-adherence. It is
critical to evaluate adherence to ART prior to changing therapy for presumed
therapeutic failure and to try an make an intervention to improve adherence. If the
patient cannot adhere to their regimen, if possible, you may need to try to change
to an easier regimen.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 17
Introductory Case Answers (cont.)
■ The statement A): A change in ART therapy should
only done when a patient experiences virologic failure is
false.
■ Virologic failure is only one possible reason that a
change in therapy may be necessary. Other reasons to
change therapy include:
■ Intolerable toxicities or side effects
■ Treatment Failure
■ Clinical failure or Immunologic failure
Unit 4: Changing Therapy
Reference Manual for Trainers
17
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 18
Factors to Consider When
Changing Regimen
■ Ethiopia ARV guidelines
■ Side effects
■ Changing to 3 new ARVs
when possible when
changing due to failure
■ Barriers to adherence
■ Prior antiretroviral history
■ Ability to follow-up in clinic
■ Antiretroviral resistance
■ Drug interactions
■ Patient life-style and
preferences
■ Cost and sustainability
Unit 4: Changing Therapy
18
•
Always refer to the guidelines when making a change in regimen. Before starting
second line therapy, try to determine why first line therapy failed.
•
There are many factors that can have a dramatic impact on the success or failure
of therapy.
•
The following must be considered when changing regimens:
•
If the regimen has failed, changing to 3 new ARVs when possible to increase
potency of the regimen, if changing regimens due to toxicity and the offending drug
cannot be determined, you may need to change all 3 ARVs. Obtain prior
antiretroviral history to determine previous toxicities and/or response to therapy,
determine antiretroviral resistance, be aware of previous side effects and of the
side effect profile of the suggested new regimen, identify barriers to adherence
and help the patient to resolve adherence issues, identify patient life-style and
preferences, ascertain their ability to follow-up in clinic for lab monitoring, identify
and avoid potential drug interactions, identify other disease states which may
impact success with therapy, cost and sustainability.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 19
Changing Therapy Due to
Toxicity
■ Intolerable side effects
■ Patient reported
■ Physical examination finding
■ Organ Dysfunction
■ Significant lab abnormalities
■ If the offending drug can be identified, may replace just
that drug
■ If the offending drug cannot be identified, must replace
entire regimen
Unit 4: Changing Therapy
19
•
Toxicity or side effects may be identified either by physical exam or by patient
report.
•
Organ dysfunction can be identified by significant lab abnormalities
•
If the offending drug can be identified, may replace just that drug
•
If the offending drug cannot be identified, must replace entire regimen
Important Note to the Facilitator:
•
Due to the long half-lives of the NNRTIS (nevirapine and efavirenz) and their
relatively low levels of resistance (ie. Single mutational changes leading to classwide resistance), some experts prefer to stop these agents 5 –7 days before
discontinuing the other agents in a regimen when possible. It is not yet common
practice in the US to continue the nucleoside backbone for several days after
discontinuing a NVP or EFV based regimen, to minimize risk of NVP/EFV
resistance based on their longer half lives. However, in the absence of published
data or formal recommendations, trainers should mention this as an approach
under discussion.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 20
Changing One Drug Due
to Toxicity
■ Example: moderate-severe peripheral neuropathy due
to D4T develops on D4T/3TC/nevirapine:
■ Change to ZDV/3TC/nevirapine
■ Example: rash develops on D4T/3TC/nevirapine:
■ Change to D4T/3TC/efavirenz in non-pregnant patient
■ Change to D4T/3TC/PI-Rtv for life threatening rash or during
pregnancy
■ Example: Hgb < 7 g/dL develops
onZDV/3TC/nevirapine
■ Change to D4T/3TC/nevirapine
Unit 4: Changing Therapy
•
•
•
•
20
Here are a few examples of when a change in one drug is appropriate.
We know that peripheral neuropathy is most likely caused by the “d” drugs including
stavudine and therefore, if the neuropathy is moderate to severe, it would be appropriate to
change to zidovudine. If the neuropathy is mild, you may consider lowering the dose at the
onset of the neuropathy to 20 mg Q12H if weight >60 kg, or 15 mg Q12H if<60 kg.
• If the provider does not discontinue therapy (or reduce the dose) at the onset,
peripheral neuropathy will become permanent and increasingly painful and
debilitating.
The second example is when Efavirenz is contraindicated in pregnancy.
• A rash in a patient on nevirapine with mucosal involvement or associated with
fever/systemic symptoms/derangement in liver functions should be treated as
Grade4 toxicity. ALL antiretroviral drugs should be stopped immediately. Patients at
primary care should be referred to a specialist for advice regarding restarting
antiretrovial treatment.
• The patient should never be re-challenged with nevirapine or swapped with efavirenz
if Grade 4 or Steven Johnson syndrome occurs. If the reaction is non life threatening
or Grade 4, efavirenz can be substituted with close monitoring. In the guidelines, a
grade 4 toxicity pertaining to rash would involve: exfoliative dermatitis or mucous
membrane involvement or erythema multiforme or suspected Stevens-Johnson
syndrome or necrosis requiring surgery.
The third example is one of laboratory toxicity. A hemoglobin of less than 7 g/dL is a severe
laboratory abnormality, indicating severe anemia, which would require a change in therapy.
Most likely the patient would be experiencing symptoms of anemia (eg. fatigue, weakness
or breathlessness) as well.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 21
Changing Therapy Due
to Failure
■ Failure defined by
■ Clinical criteria of disease progression
■ New or recurrent OI
■ Do not confuse with immune reconstitution syndrome
■ Onset or recurrent WHO Stage III condition
■ Falling CD4 Count
■ Fall of >50% from the peak
■ Return to baseline or below
Unit 4: Changing Therapy
21
•
Failure may be detected by disease progression or by immunologic parameters
(declining CD4 or TLC count)
•
Clinical disease progression should be differentiated from the immune
reconstitution syndrome as discussed earlier.
•
Clinical Signs of treatment failure include new or recurrent OI or the onset or
recurrence of WHO Stage III conditions including, but not restricted to: HIV
wasting, chronic diarrhea of unknown etiology, prolonged fever of unknown
etiology, recurrent bacterial infections, recurrent/ persistent mucosal candidiasis
•
Treatment failure is also defined immunologic parameters:
•
•
Falling CD4 Count
•
Fall of >50% from the peak
•
Return to baseline or below
Where CD4 counts and viral load tests are unavailable, the WHO recommends
using clinical evaluation and, where possible, CD4 count alone to define treatment
failure.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 22
Introductory Case Answers (cont.)
■ The statement B): A change in therapy should not be
done because this patient is not experiencing side
effects from this regimen is false. Where CD4 counts
and viral load tests are unavailable, the WHO
recommends using clinical evaluation to define
treatment failure.
■ This patient is experiencing clinical failure defined as
the development of a new opportunistic infection (in this
case toxoplasmosis) while on ART.
Unit 4: Changing Therapy
Reference Manual for Trainers
22
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 23
Introductory Case Answers (cont.)
■ The statement C): A change in therapy should be done
for a patient who experiences a new opportunistic
infection on ART is true. Where CD4 counts and viral
load tests are unavailable, the WHO recommends using
clinical evaluation to define treatment failure.
Unit 4: Changing Therapy
Reference Manual for Trainers
23
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 24
Changing Therapy Due
to Failure (cont.)
■ Virologic failure:
■ Failure of viral load to become undetectable (failure to
suppress)
■ Reappearance of detectable virus after a period of
undetectability (loss of virologic control)
■ Less than one log (10-fold) decrease in viral load from
baseline after 8-12 weeks of ART
Unit 4: Changing Therapy
24
•
Failure may be detected by disease progression also by measurement of virologic
parameters (increasing viral load). Measuring viral load is not currently an
affordable option in most resource-limited settings and, thus, is not recommended
for the routine monitoring of antiretroviral therapies.
•
Although most centers do not have the ability to monitor viral loads, virologic
failure will be discussed for future reference.
•
Virologic failure is defined as:
•
Failure of viral load to become undetectable ( this is termed failure to
suppress)
•
Reappearance of detectable virus after a period of undetectability (less than
50 copies/mL (loss of virologic control)
•
Less than one log (10-fold) decrease in viral load from baseline after 8-12
weeks of ART
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 25
Antiretroviral Therapy:
Failure to Suppress
100000
Medications Started
HIV RNA
10000
1000
100
50
50
10
TIME
Unit 4: Changing Therapy
DHS/ARV Rx/PP
25
•
Refer Participants to the enlarged copy of this slide in their Participant Handbooks.
•
This slide depicts an ART regimen that failed to achieve viral suppression.On the
vertical axis, you see the viral load, the horizontal access represents time. The red
box indicates the lowest level of detection or undetectable with the current assay
(50 copies).The patient's viral load never became undetectable.This is termed
failure to suppress.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 26
Antiretroviral Therapy:
Viral Failure
100000
Medications
Started
HIV RNA
10000
1000
100
50
10
Unit 4: Changing Therapy
TIME
50
DHS/ARV Rx/PP
26
•
Refer Participants to the enlarged copy of this slide in their Participant Handbooks.
•
On the other hand, this graph depicts a regimen that was initially successful
(became undetectable, less than 50 copies/mL) and then over time, the viral load
rebounded leading to treatment failure or viral failure.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 27
Second Line Regimens
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 28
Alternative Regimens
First Line Regimen
2nd Line Regimen for Tx Failure
D4T or ZDV
+
3TC
+
NVP/EFV
ABC or TDF or ZDV (if not taken)
+
DDI
+
LPV/r or SQV/RTV OR NFV or IDV/r
Unit 4: Changing Therapy
28
•
The table above shows the second-line regimens for adults and adolescents. When (d4T or ZDV)
+ 3TC are used as part of the first-line regimen, nucleoside cross-resistance may compromise the
potency of the nucleosides in the 2nd regimen (ie, the first regimen is always the best regimen and
efforts should be made to ensure good adherence to that 1st regimen so that it will last as long as
possible). In this situation it is necessary to make empirical alternative choices with a goal of
providing as much antiviral activity as possible. However, from an availability and cost point of view
and high genetic barrier to emergence of resistance in the NRTI category one can still use ZDV, if
not used in the first regimen as a NRTI backbone in the second line regimen.
•
Because of the diminished potency of almost any second-line nucleoside component, a ritonavirenhanced (PI/r) PI component (e.g., lopinavir/r, saquinavir/ritonavir, or indinavir/r is preferable to
nelfinavir given their potency).
•
For patients without access to a secure cold chain for storing their ritonavir or saquinavir, nelfinavir
can be used as an alternative.
•
Indinavir can cause kidney stones if patients are not well hydrated and should be considered an
alternative to the other PI-enhanced regimens. When indinavir is taken with ritonavir, both should
be taken together with food.
•
The cost and hypersensitivity with ABC is an issue of concern. Furthermore, high level ZDV/3TC
core-resistance confers diminished susceptibility to ABC.
•
TDF can be compromised by multiple nucleoside mutations (NAMs) but often retains activity
against nucleoside-resistant viral strains. It is attractive in that, like DDI, it is given once daily. If
TDF is taken with DDI, both can be taken with or without food once daily. If TDF is given with DDI,
the dose of DDI must be reduced from 400 mg to 250 mg qd in order to reduce the chance of DDIassociated toxicity (eg. Neuropathy and pancreatitis). Note that normally, DDI must be taken alone,
on an empty stomach, at least 1 hour before (or at least 2 hours after) a meal. When using the
buffered tablets, each dose must contain 2 or more tablets in order to provide enough buffer to
prevent breakdown of the drug by gastric acid. The buffered tablets should be chewed or dissolved
in at least 30 ml of water. The enteric coated tablet does not need to be dissolved.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 29
Second-Line Therapy in
the Public Sector
■ Selection based on:
■ WHO recommendations for entirely new regimen with one
drug from a new class
■ Change to NRTIs not previously used
■ Change to a potent drug from a new class
■ Anticipate some cross-resistance may be present (ie.,
ZDV and d4T)
■ Try to determine and correct reasons for first-line failure
(ie., adherence issues)
Unit 4: Changing Therapy
29
•
The WHO recommends that if a switch in antiretroviral regimen is needed because
of treatment failure, an entirely new regimen will need to be used.
•
It is important to distinguish between the need to change therapy due to drug
failure versus drug toxicity. In the latter case, it is appropriate to substitute one or
more alternative drugs of the same potency and from the same class of agents as
the agent suspected to be causing the toxicity.
•
As with the initiation of ARV, the decision to change regimens should be
approached with careful consideration of several complex factors. Failure of a
regimen may occur for many reasons, including viral resistance to one or more
agents, altered absorption or metabolism of the drug, multi-drug pharmacokinetics
that adversely affects drug levels, and poor patient adherence to a regimen. It is
important to carefully assess patient adherence prior to any ARV change. WHO
recommends that patients failing treatment should switch from a first-line regimen
to a completely different second-line combination regimen.
•
Potential cross resistance among nucleoside analogues may compromise the
overall potency or the second-line regimen, even when the dual nucleoside is
changed. WHO recommends using tenofovir in this setting, if available.
•
Note: tenofovir should not be combined with abacavir until there is further
information about the effectiveness of this combination.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 30
Second-Line Therapy in the
Public Sector: Examples
■ The second-line therapy for patients with drug failure on
d4T/3TC/nevirapine or efavirenz:
■ ZDV + DDI + IDV/r or
■ TDF +DDI + LPV/r
■ The second-line therapy for patients with drug failure on
ZDV/3TC/nevirapine or efavirenz:
■ TDF + DDI + IDV/r or
■ TDF +DDI + LPV/r
Unit 4: Changing Therapy
•
30
Possible choices for second line nucleoside analogues are:
•
D4T/3TC- change to ABC/DDI, AZT/DDI or TDF/DDI (some cross
resistance between D4T and ZDV is likely)
•
ZDV/3TC- change to ABC/DDI, TDF/DDI
•
If a PI or NNRTI has been used for first-line therapy, there should be a switch of
drug class from one to the other
•
For second-line therapy. There is almost complete cross-resistance between EFV
and NVP so a switch between these two is not advisable when there has been
treatment failure.
•
If the original first line regimen contains an NNRTI (EFV or NVP), ritonavir-boosted
PIs are preferred for NFV alone, because of their higher potency. Small doses of
ritonavir result in large increases in blood levels of protease inhibitors when dosed
together.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 31
Second-Line Therapy in the
Public Sector: Boosted PIs
■ Adult dose LPV/r
■ Each capsule = 133 mg lopinavir and 33 mg ritonavir
■ 3 capsules twice daily provides 400 mg lpv/100 mg rtv bid
■ Adult dose IDV/r
■ Indinavir 400 mg caps 2 bid WITH
■ Ritonavir 100 mg caps 1 bid
Unit 4: Changing Therapy
31
•
Note: lopinavir/ritonavir (LPV/r) cannot be kept out a secure cold chain for more
than 60 days. It should not be used with rifampicin. If there are no other options, a
dose adjustment is required and will be discussed later.
•
Indinavir/ritonavir cannot be used with rifampicin. This combination requires a high
fluid intake (1.5 liters per day) due to the potential for indinavir crystals to
accumulate in the kidneys. This can result in nephrolithiasis which is an extremely
painful condition that causes internal bleeding in the kidneys. Patients may require
hospitalization if they develop this condition.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 32
Second-Line Therapy in the
Public Sector: Boosted PIs (cont.)
■ Adult dose SQV/RTV
■ Saquinavir 200 mg caps- 2 (400 mg) bid WITH
■ Ritonavir 100 mg caps - 4(400 mg) bid
OR
■ Saquinavir 200 mg caps- 5 (1000 mg) bid WITH
■ Ritonavir 100 mg cap -1 bid
■ Adult dose NFV
■ Nelfinavir 250 mg tab 5 bid
Unit 4: Changing Therapy
32
•
Saquinavir/ritonavir can be used with rifampicin
•
WHO also recommends an alternate dosing regimen with saquinavir/ritonavir:
1600 mg of saquinavir (8 200 mg soft gel caps) with 200 mg ritonavir (2-100 mg
caps ) once daily. If using with rifampicin, it would be preferable to use the regimen
of saquinavir 400 mg with ritonavir 400 mg bid.
•
Nelfinavir does not require storage in cold chain, therefore it is an option in
resources that do not have access to cold chain.
•
However, it is less potent than the ritonavir boosted regimens.
•
All ritonavir boosted regimens must be taken with food to ensure adequate
absorption
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 33
Monitoring Therapy
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 34
Regimen
ART
Lab Test
1
D4T/3TC/NVP
ALT
Frequency
Baseline, 2, 4, 6 8, 12 wks, q 6 months
& symptom directed for toxicity
TLC or CD4
Other
D4T/3TC/EFV
Baseline, 1 month & q 3-6 months
ALT
Baseline & Symptom directed
TLC or CD4
ZDV/3TC/EFV
Baseline, 1 month & q 3-6 months
ALT
Baseline & symptom directed
CBC/diff
Baseline & q 3-6 months
Baseline, 2, 4, 8 and 12 wks, & q 3-6 months and symptom
directed
SCr
Baseline, 1 month & q 3- 6 months
ALT
Baseline, 2, 4 ,6 8, 12 wks, & q 6 months & symptom
directed
TLC or CD4
CBC/ diff
Refer to slide at end of handbook.
Baseline & q 3-6 months
SCr
TLC or CD4
ZDV/3TC/NVP
Baseline & q 3-6 months
SCr
SCr
Baseline & q 3-6 months
Baseline, 2, 4, 8 and 12 wks, & q 3-6 months and symptom
directed
Baseline, 1 month and q 3- 6 months
•
Refer to the enlarged copy of this slide in the Participant Handbook.
•
The green highlighted items in the tablet are recommendations for Laboratory
monitoring of ARVs that can be found in the “Guidelines for use of Antiretroviral
Drugs in Ethiopia, August 2004”. Also included in this table (in white) are the
routinely recommended laboratory monitoring parameters utilized in the United
States for all first line regimens. These recommendations are provided for future
reference despite the limited availability of certain laboratory tests in Ethiopia.
Certain hospitals may not have the ability to obtain laboratories above or be able
to obtain labs as frequently as recommended.
•
Pregnancy Test at Baseline when considering EFV
•
Ongoing monitoring is critical in to assess clinical efficacy and to detect drug
related toxicity. For the first line regimens: ZDV requires periodic blood counts for
Hgb evaluation at 2, 4, 8 and 12 weeks, then every 3-6 months and symptom
directed. Therefore, if a patient feels fatigued, or has orthostatic hypotension, they
should be evaluated for possible anemia
•
PIs and NNRTIs: ALT/AST requires ongoing monitoring. Nevirapine requires more
stringent monitoring due to the potential for the hypersensitivity reaction that may
occur in the first 6 weeks.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 35
First-Line ART:
Laboratory Monitoring
■ Baseline: ALT, SCr and CD4 or TLC
■ Additional lab monitoring varies with regimen
■ NVP: ALT/AST at 2, 4, 6, 8 weeks, 3 months, then q 6 months
and symptom directed
■ EFV: symptom directed thereafter for ALT, pregnancy test at
baseline for women of childbearing age
■ ZDV: CBC/diff at baseline, 2, 4, 8 and 12 wks, then q 3-6
months and symptom directed
Unit 4: Changing Therapy
35
•
There are laboratory parameters that should be monitored on an on-going basis to
detect drug toxicity.
•
More frequent monitoring may be needed for a particular regimen.
•
It is important to remember to remind patients that although they may be tolerating
a medication,they may still experience side effects from them that they may not
“feel”This is one reason that ongoing laboratory monitoring is necessary. Ongoing
monitoring is also needed to monitor success/failure of therapy.
•
First line Laboratory monitoring:
•
Baseline: ALT, SCr and CD4 or TLC
•
Additional lab monitoring varies with regimen
•
NVP: ALT at 2, 4, 6, 8 weeks, 3 months then q 6 months and
symptom directed
•
EFV: symptom directed thereafter for ALT, pregnancy test at
baseline for women of childbearing age
•
ZDV: CBC/diff at baseline, 2, 4, 8 and 12 wks, then q 3-6 months
and symptom directed
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 36
Second-Line ART:
Laboratory Monitoring
■ Baseline: CBC/diff, ALT, SCr and CD4 or TLC
■ Other lab monitoring varies with regimen
■ ZDV:CBC/diff at baseline, 2, 4, 8, 12 wks, then q 3-6 months and symptom
directed
■ DDI: amylase at baseline and symptoms of abdominal pain, CBC with diff
and LFTs q 12 months
■ TDF: urine protein dipstick and SCr at baseline, 3 months and q 6 months,
CBC/diff and AST/ALT q 12 months
■ PIs: lipids at baseline and q 12 months, AST/ALT at baseline, 3 months
then q 6 months, fasting glucose at baseline, then q 12 months
■ Indinavir: urine dipstick for RBCs with symptoms of flank pain, SCr at
baseline then q 6 months
Unit 4: Changing Therapy
36
•
Note that with the PIs, baseline and ongoing lipid monitoring is essential to detect
abnormalities that may be caused by ARVs.
•
Some patients may require lipid lowering agents to control lipids if they are at high
risk of developing heart disease or if there levels are dangerously high. (eg.
Triglyceride levels that are >500 can put them at risk for pancreatitis)
•
Baseline: CBC/diff, ALT/AST, SCr and CD4
•
Other lab monitoring varies with regimen
•
ZDV:CBC/diff at baseline, 2, 4, 8 and 12 wks, then q 3-6 months and
symptom directed
•
DDI: amylase at baseline and symptoms of abdominal pain, CBC with diff
and LFTs q 12 months
•
TDF: urine protein dipstick and SCr at baseline, 3 months and q 6 months,
CBC/diff and AST/ALT q 12 months
•
PIs: lipids at baseline and q 12 months, AST/ALT at baseline, 3 months
then q 6 months, fasting glucose at baseline, then q 12 months
•
Indinavir: urine dipstick for RBCs with symptoms of flank pain, SCr at
baseline then q 6 months
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 37
Case Studies
•
Case Study Group Exercise:
•
Divide participants into two work groups.
•
Provide each work group with one of the two Adult ART Case Studies
(Worksheets 4.1, 4.2. in the workbook.)
•
Ask the groups to identify a recorder and a presenter, and then spend thirty
minutes discussing the case study together and answering the related
questions on flip-chart paper.
•
Ask each work group to share their decisions and answers. Discuss each case
thoroughly and use this time to answer questions and clarify misinformation.
•
Review the case studies in the “Changing Therapy” PowerPoint presentation (4.37
– 4.53). Spend 15 minutes discussing each case.
•
If time is limited, discuss each case study and answers as a large group instead of
separating participants into smaller groups.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 38
Case 1
■ AG is a 25 year old male (CD4 count 56) who presents to clinic
for F/U 3 weeks after starting ZDV, 3TC and NVP. Two months
ago, he had just learned of his HIV diagnosis due to a recent
hospitalization with CNS toxoplasmosis. He is currently receiving
treatment for toxoplasmosis and has tolerated his medication for
the past two months.
■ At the time of his diagnosis, he had significant lower leg
numbness and weakness due to INH therapy for TB
■ Pyridoxine 40 mg was started to replace his B-complex vitamin (why
would this be necessary?)
Unit 4: Changing Therapy
38
•
Facilitator could ask: was this appropriate to start AG on treatment? Yes, he has
Clinical Stage IV Disease because he has toxoplasmosis infection of the brain. He
can take the Fixed Dose combination of ZDV and 3TC (Lamuzid)
•
Pyridoxine 40 mg (vitamin B6) was started to replace his B-complex vitamin (why
would this be necessary?)
•
Answer: The patient’s peripheral neuropathy was thought to be due to INH which
he is receiving for pulmonary TB. He had been taking a Vitamin B-complex
vitamin which did not have enough pyridoxine to prevent INH induced neuropathy.
INH depletes B6 and requires that it be administered with 25-50 mg of pyridoxine
daily to prevent B-6 deficiency and the development of neuropathy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 39
Case 1 (cont.)
■ He had some nausea the first week on meds, which
has resolved by eating small meals before doses. He
claims to take his medications every day as directed.
He has lost weight and is now 51 kg.
■ Today he presents complaining of an erythematous,
mildly pruritic rash over his trunk and arms which began
2 days ago. He say that he feels tired all day.
Unit 4: Changing Therapy
39
•
He had some nausea the first week on meds, which has resolved by eating small
meals before doses. He claims to take his medications every day as directed. He
has lost weight and is now 51 kg.
•
This slide points out the need to monitor weight as it may necessitate a reduction
in dose to prevent toxicities.
•
He is taking zidovudine, lamivudine and nevirapine, none of which require dose
adjustment for weight.
•
If he had been taking stavudine 40 mg bid and his weight was now < 60 kg, his
dose should be reduced to 30 mg bid if possible.
•
He has been on therapy for 3 weeks and now presents with a rash that is
erythematous and mildly pruritic, over his trunk and arms which began 2 days ago.
He also complains of fatigue.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 40
Case 1 – Gathering Information
■ What do you think is occurring with AG?
■ Should his ART regimen be changed?
■ What additional information would you like to know?
■ What are the laboratory tests that should be done at
today’s visit to monitor AG’s therapy?
Unit 4: Changing Therapy
40
1) What do you think is occurring with AG?
• Nevirapine-related rash. It is common for NVP rash to present on the upper body and arms.
The time course is what we would expect, within the first month.
• He has possible anemia from AZT.
2) Should his ARV regimen be changed?
• AG’s options are d/c NVP or treat nevirapine rash symptomatically with diphenhydramine
and hydrocortisone cream.
• He may be experiencing anemia due to ZDV and you will need to see his lab work to
determine if this warrants a change. If his lab work does not necessitate a change in
therapy, you will need to determine how severe his fatigue is and see if it is affecting his
daily life.
3) What additional information would you like to know?
• Laboratory values. You want to know this to determine if he has any signs of hepatitis from
NVP. Remember that NVP can cause a hypersensitivity reaction during the first 8 weeks of
therapy. The reaction may be accompanied by a drug rash, eosinophilia and systemic
symptoms. The risk of hepatotoxicity is greatest in the first 6 weeks.
• Other medication: you would want to know if he has started taking any other medication
• You should try to find out if the rash is severe:
• Does he have any other areas of the rash, eg. oral blisters, myalgias or fever?
• Has he experienced any severe headaches over the past 3 weeks? You are interested in
knowing if his signs/symptoms of toxoplasmosis have resolved.
• Did he take NVP QD x 2 weeks, then increase to BID? In order to reduce the risk of
nevirapine –induced rash, the dose should be escalated over the first two weeks
• Has he been taking any other medication that may cause a similar drug rash?
• Is he having any trouble remembering doses? Every visit with a patient is an opportunity to
identify any barriers to adherence and to take action to address them.
• Has his peripheral neuropathy resolved or improved after starting pyridoxine?
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 41
Case 1 – Chronic Laboratory Monitoring
Frequency
Laboratory Test
Baseline
ALT, TLC or CD4, SCr, CBC/diff
At 2 and 4 weeks
CBC/diff , SCr (4 weeks)
ALT
At 2 and 3 Months
CBC/diff, ALT
CD4 Count, SCr (3 months)
Every 3- 6 Months
CBC/diff and symptom directed
ALT and symptom directed
CD4 or TLC, SCr
Every 12 Months
Serum triglycerides/ cholesterol
Serum glucose
•
What are the laboratory tests that should be done at today’s visit to monitor AG’s
therapy?
•
CBC, H/H to determine if he has anemia
•
LFTs to determine if he has drug induced hepatitis
•
Viral load testing is recommended where available every 3-6 months along with
the CD4 cell count
•
LFT Baseline, 2, 4,6 weeks and at 2 and 3 months (for nevirapine) & symptom
directed for toxicity
•
CD4: Baseline & q6 months
•
Hgb: Baseline, 2,4 weeks and at 2 and 3 months, thereafter symptom directed
(with WBC)
•
All of the nucleoside analogues must be dose adjusted for renal toxicity, except
for ABC, although not outlined in the guidelines, SCr should be monitored ongoing
and the doses should be adjusted accordingly to avoid drug toxicity.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 42
Case 1 – Results
■ Laboratory Values
■ - WBC: 5.6
- H/H: 6.9 / 27
- LFTs: 31 / 26
■ SCr 0.9 mg/dL
■ How would you interpret these lab results?
■ He has had only minor headaches over the past 3 weeks-what
does this tell us?
■ He does not have any other areas of the rash, oral blisters,
myalgias or fever. What should you do?
■ Did he take NVP QD x 2 weeks, then increase to BID?
■ No, he didn’t, he was confused and took NVP BID
Unit 4: Changing Therapy
42
•
You have asked the patient your follow-up questions and now, look at his lab
values. His H/H are low. Hemoglobin range 13.0-18.0, Hematocrit range 38-50.
You notice that his Hgb is 6.9. This level indicates a Grade 3 toxicity. This is most
likely related to AZT and would necessitate a change in therapy. You remember
that the patient indicated that he has been very tired which you would expect as
physical symptoms in a patient with anemia.
•
His LFTs and SCr are normal.
•
Has he had only minor headaches over the past 3 weeks-this tells us that
•
He has not had a recurrence of his signs and symptoms of toxoplasmosis.
•
He does not have any other areas of the rash, oral blisters, myalgias or fever
•
Clinically, his rash would be graded as a Grade 1 toxicity, therefore you would
recommend that he continue to take NVP and you could recommend that he use
hydrocortisone 1% cream or diphenhydramine to treat through the rash. The
patient should be counseled that if the rash were to progress, if he developed any
oral blisters, vesiculation or ulcers or any new symptoms eg. arthralgias or fever,
that he would need to be seen immediately for further evaluation.He has not
experienced an elevation in his LFTs, therefore another indication to safely
continue therapy.
•
He was confused and took his nevirapine bid from the start which put him at
greater risk of developing a rash. At this point, as long as his rash is not severe, he
should continue to take his nevirapine bid.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 43
Case 1 – Results
■ He has not been having trouble remembering doses
■ He has been taking doses with meals (breakfast and dinner).
■ Peripheral neuropathy symptoms have improved
■ However, he has been missing work due to fatigue
■ How would you interpret this?
Unit 4: Changing Therapy
43
•
Answers to your other questions are as follows: He has been adherent to his
medication, you should acknowledge that he is doing a good job at taking his
medication and that he needs to continue to take them. He will need to have on
going monitoring until he is stable on his medication.
•
Note that his peripheral neuropathy has improved with the addition of pyridoxine
50 mg qd.
•
We know that he has experienced a grade 3 toxicity. Note that he is experiencing
physical symptoms of his anemia, and this is affecting his ability to work.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 44
Case 1 - Would You
Change His ART?
■ Yes, change therapy to:
■ Stavudine (Avostan®) 30mg BID
■ Lamivudine (Avolam®) 150mg BID
■ Nevirapine (Nevipan®) 200mg BID
■ Consider Fixed Dose Combination
Unit 4: Changing Therapy
44
•
You do not need to change the entire regimen because he is not failing, only
experiencing a side effect from one of his medications, zidovudine. An appropriate
switch for zidovudine would be stavudine.
•
Note the dose of stavudine, why is his dose 30 mg bid?
•
Remember his weight is < 60 kg; therefore he should receive the lower dose to avoid
the risk of developing dose-related side effects of pancreatitis and peripheral
neuropathy.
•
You may recall that he had been experiencing peripheral neuropathy from his TB
therapy.
•
•
However, he has been started on B6 (pyridoxine 50 mg) which is the dose used
to prevent peripheral neuropathy. His symptoms have improved.Therefore you
can recommend that he change to stavudine and monitor him for any signs of
neuropathy. At the first sign of neuropathy, he will need to be evaluated to avoid
the development of long term nerve damage from stavudine.
Once stable on the regimen, could use the fixed dose combination of D4T, 3TC and
NVP
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 45
Case 1 Questions- How Would
You Counsel the Patient?
■ Food requirements: None
■ Limit alcohol intake:
■ Stavudine can cause pancreatitis
■ Side effects and how to cope
■ Peripheral Neuropathy
■ ADHERENCE
■ Return to clinic for F/U in 1 month
■ Sooner if rash or PN worsen or other side effects
Unit 4: Changing Therapy
45
•
He can take the regimen with or without meals. The key here is to space out the
doses every 12 hours for best absorption.
•
Side effects:
•
•
The onset of peripheral neuropathy is usually after 2-6 months of therapy. If
he were to develop peripheral neuropathy in the future, you would need to
decrease his dose to 15 mg q12h if his weight remains < 60 kg.
•
If pancreatitis develops, you must discontinue therapy with stavudine. When
symptoms resolve, you cannot re-challenge with stavudine.
•
He should be aware that stavudine has been associated with lipodystrophy.
These changes in body fat distribution are general and generally not
apparent until months after the initiation of therapy.
Adherence:
•
•
This is an opportunity to talk with the patient about the ongoing importance
of adherence.
Follow-up:
•
He needs to follow-up in clinic in 1 month for further evaluation of his rash
and to determine if he is tolerating the new regimen. You want to ensure
that the new regimen does not aggravate his neuropathy. You will need to
monitor his weight, if he gains weight you may need to increase his dose.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 46
Case 1 – Patient Outcomes
at 3 Month F/U Appointment
■ Labs at 3 months
■ CD4 count = 110 (10%) cell/mm3
■ H/H = 13 / 38%
■ WBC = 5.8
■ 55 kg
■ He is tolerating medications except for occasional
numbness in lower extremities. His symptoms have
somewhat improved over last 3 months. Occasional
nausea after taking meds.
■ Claims he is taking all his medications. He takes his
morning dose to work during his break and takes his
Unit
4: Changing Therapy
evening
dose with dinner.
46
•
You notice that his CD4 count has improved while on ART.
•
His H/H has improved. He is able to go back to work and is remembering to take
his doses. He has a plan for adherence.
•
He has occasional nausea after taking meds. This could become a problem as he
may not continue to take his medication if he feels nauseous. He is gaining
weight, which is good. It seems as though his nausea is not limiting him from
getting adequate nutrition. You should clarify and see if this is the case.
•
He has been experiencing some peripheral neuropathy, which is intermittent. This
should be monitored to ensure that it does not increase in frequency or get to the
point that it never goes away.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 47
Case 1 - Are Therapeutic Goals
Being Met?
■ Yes, therapeutic goals are being met
■ Patient energy increased and he’s feeling better
■ Appetite is good and he has gained 4 Kg
■ CD4 increasing ( was 56/5% 2 months ago)
■ H/H normalized
■ But having some side effects:
■ If possible, decrease dose of stavudine to 30mg BID for
neuropathy
■ Encourage food before doses
Unit 4: Changing Therapy
47
•
The therapeutic goals are being met. His anemia has resolved. His quality of life is
better, his immunologic status is improved. He is gaining weight.
•
If his peripheral neuropathy continues, may need to lower the dose, or discontinue
to avoid long term nerve damage that will be irreversible.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 48
Case 2
■ BH is a 30-year-old man who has been stable on
stavudine, lamivudine and nevirapine for the past four
years.
■ History: PCP pneumonia 4 years ago
■ Today his CD4 is 140, his previous CD4 count was
300 and his viral load had risen from undetectable
levels to 50,000 copies/ml.
■ He feels well and has no complaints today
Unit 4: Changing Therapy
48
•
A 30-year-old man has been stable on stavudine, lamivudine and nevirapine for
the past four years.
•
History: PCP pneumonia 4 years ago
•
Today his CD4 is 140, his previous CD4 count was 300 and his viral load had risen
from undetectable levels to 50,000 copies/ml.
•
He feels well and has no complaints today
•
Note: Where CD4 counts and viral load tests are unavailable, the WHO
recommends using clinical evaluation and, where possible, CD4 count criteria to
define treatment failure. There is no accepted definition of immunologic failure that
can be used if CD4 counts are unavailable. Eg. A drop in the TLC cannot be used
to determine failure
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 49
Case 2 Questions
■ What do you think is happening to the patient?
■ What would you want to know?
Unit 4: Changing Therapy
•
•
•
•
•
•
•
49
The patient had achieved virologic success, and his viral load was
undetectable until this visit. Now it seems as though he is experiencing
virologic failure.
If he were asymptomatic and failure was being defined by CD4 count alone,
consideration should be given to performing a confirmatory CD4 cell count,
if resources permit. Since he has also experienced a rise in viral load, this
would be considered treatment failure.
He has experienced a reappearance of detectable virus after a period of
undetectability (loss of virologic control).
He has had a >50% fall from therapy CD4 peak level without other
concomitant infection to explain the transient cell decrease.
You would want to know if he has been adherent to his regimen. You would
want to know if he is still taking his medication. If he has gone off of his
medication on his own, you may be able to help to resolve the issue and get
him restarted on meds.
The new second line regimen should involve drugs that retain activity
against the patient’s virus strain and should preferably include, at least
three, new drugs, one of more of them from a new class, in order to
increase the likelihood of treatment success and minimize the risk of crossresistance.
Before changing to second line regimen, the patient should undergo a
thorough assessment, including identification of possible reasons for failure,
and then undergo treatment readiness and education process again
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 50
Case 2 (cont.)
■ He had been taking his medication as prescribed and
has missed doses recently while he was visiting his
brother in Jimma.
■ Does he require a change in his regimen?
■ What possible regimen can you give to the patient,
based on your local situation?
Unit 4: Changing Therapy
50
•
Many times, patients become nonadherent when they are out of their normal
routine, eg. when they are away from home. Pharmacists can help patients to
come up with a plan for continued adherence even when away from home.
•
Since this is treatment failure, it is recommended that he change the entire
regimen from first line regimen to second line regimen.
•
You could recommend a second line regimen. Some possible regimens: DDI +
TDF + LPV/r, AZT + DDI + IDV/r or AZT +DDI + LPV/r
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 51
Case 2 (cont.)
■ Some possible regimens:
TDF+ DDI + LPV/r
OR
ABC +DDI + LPV/r
■ What are the factors to consider before starting a new
regimen?
■ Identify the reasons for failure
■ Review all factors that must be considered before changing
the regimen
Unit 4: Changing Therapy
51
•
Since the possibility of cross resistance between D4T and ZDV is high, you would
want to use TDF in the next regimen.
•
The second nucleoside analogue could be either ABC or DDI
•
The second regimen should contain a drug from a new class (eg. Protease
inhibitor, preferably a ritonavir boosted regimen.
•
Factors to consider before starting a new regimen:
•
Ethiopia ARV guidelines
•
Changing to 3 new ARVs when possible
•
Prior antiretroviral history
•
Antiretroviral resistance
•
Side effects (DDI may cause pancreatitis or peripheral neuropathy, but ABC
has the potential hypersensitivity reaction which can be life-threatening. All
nucleosides can cause rare lactic acidosis.)
•
Barriers to adherence:come up with a plan for him when he visits his brother
or when he is away from home, so that he can be adherent to his second
regimen.
•
Patient life-style and preferences
•
Ability to follow-up in clinic
•
Drug interactions
•
Cost and sustainability
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 52
Case 2 - Gathering More
Information
■ Side effects
■ Educate BH on the potential side effects of each potential regimen
■ Patient preference
■ BH is very fearful of the ABC hypersensitivity syndrome and would prefer
to avoid ABC in his next regimen
■ Review Drug-drug interactions
■ Cost and sustainability
■ Barriers to adherence
■ Plan ahead for changes in schedule, vacations, etc.
Unit 4: Changing Therapy
52
•
Considering the factors that may affect success to a particular regimen for this
patient in particular:
•
Ethiopia ARV guidelines to determine 2nd line regimens
•
Changing to 3 new ARVs when possible when due to failure as is the case for this
patient
•
Prior antiretroviral history
•
Antiretroviral resistance
•
Side effects (DDI may cause pancreatitis or peripheral neuropathy, but ABC has
the potential hypersensitivity reaction which can be life-threatening. All nucleosides
can cause rare lactic acidosis.)
•
Drug-drug interactions: if BH drinks alcohol while on a DDI containing regimen, he
may be at increased risk of pancreatitis.
•
Barriers to adherence: come up with a plan for him when he visits his brother or
when he is away from home, so that he can be adherent to his second regimen.
Anticipate other potential barriers to adherence.
•
Patient life-style and preferences
•
Ability to follow-up in clinic
•
Drug interactions
•
Cost and sustainability
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 53
Case 2 (cont.)
■ He will begin TDF 300 mg qd +DDI 250 mg qd +LPV/r 3
caps bid
■ How will you monitor his therapy?
■ Clinically
■ Laboratory
■ Does he have to take his DDI apart from LPV/r?
Unit 4: Changing Therapy
53
•
He should follow-up in 1 month to determine that he has been successful with his
new regimen.
•
Monitor for GI distress, diarrhea or nausea with LPV/r, DDI may cause pancreatitis
or peripheral neuropathy,
•
Tenofovir is generally well tolerated, may cause slight headache or nausea.
•
Monitor CD4 (or TLC) every 6 moths with viral load, if able
•
ALT q 6 month to monitor the protease inhibitor (every 3 months if possible)
•
Periodic SCr, if possible to monitor the need for dose adjustment of DDI or TDF.
•
Monitor him for Clinical or disease progression
•
New or recurrent OI
•
Do not confuse with immune reconstitution syndrome
•
•
•
•
Onset or recurrent WHO Stage III condition
Falling CD4 Count
•
Fall of >50% from the peak
•
Return to baseline or below
Rising viral load
Note that since he is taking tenofovir with didanosine, didanosine (DDI) can be
taken together with tenofovir and lopinavir/r and food
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 54
Key Points
■ Treatment failure occurs because of preexisting resistance, limited
regimen potency, imperfect adherence, poor absorption, rapid
elimination, or drug-drug interactions.
■ Therapy should not be changed unless absolutely necessary.
■ The main reasons for changing ART are treatment failure and drug
toxicity.
■ Other reasons for changing therapy include problems with
adherence or other medical conditions or illnesses that may impact
choice of therapy.
■ Ongoing laboratory monitoring is necessary to detect all side effects
and to monitor success/failure of therapy.
Unit 4: Changing Therapy
Reference Manual for Trainers
54
HIV Care and ART: A Course for Pharmacists
Unit 4: Changing Therapy
Slide 55
References
■ Behrens, C. MD , I-TECH Physician Curriculum, May 2003.
■ Frick, P. PharmD, MPH Clinical Pharmacist, HIV/AIDS,
Harborview Medical Center, Seattle, WA, USA, 2004.
■ Hykes, B. Pharm.D. Clinical Pharmacist, HIV/AIDS, Harborview
Medical Center, Seattle, WA, USA, 2004.
■ McGilvray, M, Willis, N. All About Antiretrovirals: A Nurse
Training Programme, Trainer’s Manual, Africaid 2004.
■ Namibia Ministry of Health and Social Services, Training on the
Use of the Namibia Guidelines for Antiretroviral Therapy (ART),
2004.
■ WHO Treatment Guidelines, 2003.
Unit 4: Changing Therapy
Reference Manual for Trainers
55
HIV Care and ART: A Course for Pharmacists
Slide 4.25 Antiretroviral Therapy: Failure to Suppress
Antiretroviral Therapy:
Failure to Suppress
100000
Medications Started
HIV RNA
10000
1000
100
50
50
10
TIME
Refer to slide at end of handbook.
Changing ART Therapy
DHS/ARV Rx/PP
26
Slide 4.26 Antiretroviral Therapy: Viral Failure
Antiretroviral Therapy:
Viral Failure
100000
Medications
Started
HIV RNA
10000
1000
100
50
10
TIME
50
Refer to slide at end of handbook.
Changing ART Therapy
HIV Care and ART for Pharmacists
Reference Manual for Trainers
DHS/ARV Rx/PP
27
Changing Therapy
Unit 4-7
Slide 4.34 Routinely Recommended Laboratory Monitoring
Parameters Utilized in the United States for All First Line Regimens
Regimen
ART
Lab Test
1
D4T/3TC/NVP
ALT
Frequency
Baseline, 2, 4, 6 8, 12 wks, q 6 months
& symptom directed for toxicity
TLC or CD4
Other
D4T/3TC/EFV
Baseline, 1 month & q 3-6 months
ALT
Baseline & Symptom directed
TLC or CD4
ZDV/3TC/EFV
Baseline, 1 month & q 3-6 months
ALT
Baseline & symptom directed
CBC/diff
Baseline & q 3-6 months
Baseline, 2, 4, 8 and 12 wks, & q 3-6 months and symptom
directed
SCr
Baseline, 1 month & q 3- 6 months
ALT
Baseline, 2, 4 ,6 8, 12 wks, & q 6 months & symptom
directed
TLC or CD4
CBC/ diff
Refer to slide at end of handbook.
Baseline & q 3-6 months
SCr
TLC or CD4
ZDV/3TC/NVP
Baseline & q 3-6 months
SCr
SCr
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Baseline & q 3-6 months
Baseline, 2, 4, 8 and 12 wks, & q 3-6 months and symptom
directed
Baseline, 1 month and q 3- 6 months
Changing Therapy
Unit 4-8
References
Behrens, C. MD , I-TECH Physician Curriculum, May 2003.
Frick, P. PharmD, MPH Clinical Pharmacist, HIV/AIDS, Harborview
Medical Center, Seattle, WA, USA, 2004.
Hykes, B. Pharm.D. Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
McGilvray, M, Willis, N. All About Antiretrovirals: A Nurse Training
Programme, Trainer’s Manual, Africaid 2004.
Namibia Ministry of Health and Social Services, Training on the Use of the
Namibia Guidelines for Antiretroviral Therapy (ART), 2004.
WHO Treatment Guidelines, 2003.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Changing Therapy
Unit 4-9
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Changing Therapy
Unit 4-10
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 5
Significant Drug Interactions with
Antiretroviral Therapy
Unit 5: Significant Drug Interactions with ART
Aim: The aim of this unit is to introduce participants to common ART drugs
interactions and the management of drug interactions.
Learning Objectives: By the end of this unit, participants will be able to:
•
Identify primary drug interaction concepts
•
Describe types of interactions and mechanisms
•
Identify drug interactions commonly encountered with antiretroviral (ARV)
medications
•
Describe how to manage known interactions
•
Discuss pharmacokinetic enhancement and protease Inhibitor combinations
Unit Overview:
2 Hours 25 minutes
Step
Time
Activity/
Method
Content
Resources
Needed
1
10 minutes
Question-Answer
Introductory Case Study and
Question Slides (5.2-5.3)
Overhead or LCD
Projector
2
30 minutes
Lecture
Significant Drug Interactions with
Antiretroviral Therapy (Slides 5.4 5.42)
Overhead or LCD
Projector
3
85 minutes
Group Exercise
Case Studies (Slide 5.43-5.65)
Worksheets (5.1, 5.2,
5.3, 5.4 in the
workbook). Five flip
chart stands with
paper and markers.
4
10 minutes
Lecture
Significant Drug Interactions with
Antiretroviral Therapy (Slides 5.66 5.73)
Overhead or LCD
Projector
5
10 minutes
Summary
Review of Key Points (Slides 5.74 5.75)
Overhead or LCD
Projector
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Significant Drug Interactions with ART
Unit 5-3
Resources Needed
•
•
•
Flip Chart and Paper
Markers
Overhead or LCD Projector
•
The following enlarged slides can be found in the Participant Handbook:
- First Pass Effect (Slide 5.5)
- Steady-State IDV Plasma Profile After IDV + RTV 400 mgQ12H with
Food (Slide 5.72)
- Drug Metabolism/Elimination (Slide 5.6)
- CYP P450 Drug-Drug Interactions (Slide 5.13)
- PI/ NNRTI/ Antidepressant Drug Interactions (Slide 5.27)
- Pharmacokinetics Principles (Slide 5.68-69)
- Pharmacokinetic Rationale for Dual Protease Inhibitor Therapy (Slide 5.70)
- An Example of Ritonavir Boosting: Indinavir/Ritonavir BID PK Study (Slide
5.71)
- Steady-State IDV Plasma Profile After IDV + RTV 400 mgQ12H with Food
(Slide 5.72)
•
The following materials can be found in the Course Workbook:
- Handout 5.1: Clinically Significant Drug Interactions
- Worksheets 5.1, 5.2, 5.3 and 5.4
Key Points
1. Pharmacokinetic interactions refer to what the body does to the drug.
2. Pharmacodynamic interactions refer to what the drug does to body.
3. A drug interaction can occur whenever a medication is started or discontinued
or whenever a dose is changed.
4. Pharmacists play a critical role in detecting drug interactions before they
happen.
5. Pharmacists must be knowledgeable about potential drug-drug and drug-food
interactions.
6. Pharmacists should question a patient about their current medications
whenever filling a prescription that is new for them, when a dose is changing,
or when a medication is being discontinued.
7. Patients should be educated that drug interactions can also occur if they stop
or receive a change in dose of their medications.
8. Pharmacists should ask patients about their use of herbal preparations as
they can interact with ARV therapy.
9. Pharmacokinetic enhancement is the concept of combining agents from
different classes, or various agents from similar classes, to improve ARV
pharmacokinetics, improve adherence, minimize side effects, or enhance
antiviral activity.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Significant Drug Interactions with ART
Unit 5-4
Step 1
Step 2
Step 3
Step 4
Introductory Case Study (10 minutes)
•
Ask a participant to read the case study on Slide 5.2.
•
Ask participants to silently attempt to answer the question on
Slide 5.3.
•
Explain that the question will be answered and the case
discussed more fully as the unit progresses.
Lecture (30 minutes)
•
This unit will introduce participants to drug interaction concepts
and the management of interactions.
•
Begin by reviewing slides 5.1-5.2 of the PowerPoint
presentation, “Significant Drug Interactions with Antiretroviral
Therapy.” Ask the participants if they have any questions about
the objectives before continuing.
•
Present and discuss the PowerPoint presentation, “Significant
Drug Interactions with Antiretroviral Therapy” (Slides 5.1 - 5.42).
•
Slide 8-Refer to “Antiretroviral Effect on CYP450” in the
reference section of the Course Workbook as necessary.
Group Exercise (85 minutes)
•
Case Study Group Exercise: Divide participants into five work
groups. Provide each work group with one of the four Adult ART
Case Studies (Worksheets 5.1, 5.2, 5.3, 5.4 in the Course
Workbook) Ask the groups to identify a recorder and a
presenter, and then spend twenty minutes discussing the case
study together and answering the related questions on flip-chart
paper.
•
Ask each work group to share their decisions and answers.
Discuss each case thoroughly and use this time to answer
questions and clarify misinformation. Review the case studies in
the “Significant Drug Interactions with Antiretroviral Therapy”
PowerPoint presentation (5.43 – 5.65). Spend 15 minutes
discussing each case.
Lecture (10 minutes)
•
Step 5
Present and discuss the PowerPoint presentation,
“Pharmokinetic Enhancement” (Slides 5.66-5.73).
Summary (10 minutes)
•
Summarize the presentation, review the Key Points presented in
this Unit (Slides 5.74 - 5.75), and answer final questions.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Significant Drug Interactions with ART
Unit 5-5
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes
for reference during the planning and implementation of this course. The
facilitation notes and talking points are included in the “notes” section of the
accompanying PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Significant Drug Interactions with ART
Unit 5-6
Unit 5: Significant Drug Interactions with ARVs
Slide 1
Significant Drug Interactions with
Antiretroviral Therapy
Unit 5
HIV Care and ART: A Course for Pharmacists
This unit should take approximately 2 hours, 25 minutes to complete.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 2
Introductory Case
■ A 25 year old HIV + woman comes to your pharmacy
with prescriptions for her routine therapy of phenytoin
and bactrim.
■ Her recent labs indicate that her repeat TLC is 1000
and she is going to begin treatment with ART.
■ Today she is given prescriptions for the first line
regimen in Ethiopia: nevirapine, lamivudine and
stavudine.
■ Which of the following statements is true about an
interaction between these medications?
Unit 5: Significant Drug Interactions with ART
•
•
•
2
Ask a participant to read the case.
Ask participants if they have any questions about the information presented.
Note: Do not give them further information on the case. Just ask them to
consider the information provided to them.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 3
Introductory Case (cont.)
A. There is no interaction between ART and phenytoin.
They can safely be administered together.
B. An interaction exists between phenytoin and
nevirapine. The dose of nevirapine must be increased
to account for increased metabolism due to phenytoin.
C. Nevirapine may decrease phenytoin levels and
therefore the dose of phenytoin may need to be
increased to avoid loss of seizure control.
D. An interaction exists between phenytoin and bactrim.
They should not be administered together.
Unit 5: Significant Drug Interactions with ART
3
•
Ask participants to silently attempt to answer the question.
•
Explain that the answer to the question will be discussed as the unit progresses.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 4
Unit Learning Objectives
■ Identify primary drug interaction concepts
■ Describe types of interactions and mechanisms
■ Identify drug interactions commonly encountered with
antiretroviral (ARV) medications
■ Describe how to manage known interactions
■ Discuss pharmacokinetic enhancement and protease
Inhibitor combinations
Unit 5: Significant Drug Interactions with ART
•
Review drug interaction concepts
•
•
Describe types of interactions and mechanisms
Review drug interactions commonly encountered with antiretroviral medications
•
•
4
Describe how to manage known interactions
Discuss pharmacokinetic enhancement: Ritonavir Boosted Protease Inhibitor
combinations
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 5
Basic Definitions
Pharmacokinetic
Pharmacodynamic
■ Refers to what the body
■ Refers to what the drug does to the body
does to the drug
■ “LADME” principle
■ Liberation
■ Absorption
■ Distribution
■ Metabolism
■ Examples
■ Bone marrow toxicity caused by
ganciclovir or AZT
■ Peripheral neuropathy – DDI, D4T,
DDC
■ Pancreatitis – DDI, pentamidine,
alcohol
■ Elimination
Unit 5: Significant Drug Interactions with ART
5
•
A drug interactions occurs when the pharmacologic action of one drug is altered by the
co-administration of another. The mechanism of the interaction may be
pharmacodymanic or pharmacokinetic in nature.
•
Pharmacokinetic interactions refer to what the body does to the drug, impacts time drug
stays in body and distribution patterns
•
PK principles include:
•
Liberation: the release of a drug from it’s dosage form
•
Drugs must be in solution for absorption
•
Absorption: movement of a drug from site of admin to blood circulation: this
occurs mainly in the small intestines because of it’s large surface area (nonionized=lipid soluble favors absorption)
•
Distribution. Drug diffusion or transferred from intravascular space to extra
vascular space(tissue)
•
Metabolism: chemical conversion of drugs into compounds which are easier to
eliminate (water soluble)
•
Elimination: elimination of unchanged drug or metabolite via renal, biliary or
pulmonary processes
•
Pharmacodynamic refers to what drug does to body, these reactions alter the impact of
drug at target site.
•
Less frequent use of “D” drugs together due to increased risk pancreatitis and
neuropathy. Alcohol can cause pancreatitis and the risk is increased in an individual that
takes a “d” drug and drinks heavily.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 6
Mechanisms for Drug
Interactions
■ Pharmacokinetic Interactions
■ Altered intracellular activation
■ Impairment of phosphorylation (D4T, ZDV)
■ Altered drug absorption and tissue distribution
■ Chelation, pH, P-gp
■ Altered drug metabolism
■ Induction/inhibition, GT,P-gp
■ Reduced renal excretion (P-gp)
Unit 5: Significant Drug Interactions with ART
6
•
Pharmacokinetic drug interactions may involve:
•
Fluctuation in intracellular drug concentrations of active drug (D4T, DV) due to impairment
of phosphorylation. Phosphorylation is needed to change the drug to its active state. D4T
and ZDV should NEVER be used together. They are antagonistic.
•
Changes in gastric pH and drug absorption: absorption is sometime dependent upon
acidity of the gut – eg. ketoconazole requires an acid pH for adequate absorption (drugs
and food may change the acidity of the gut and decrease absorption)
•
Other examples of changes in GI absorption: chelation (fluoroquinolones and antacids)
fluroquinolones must be taken at least 2 hours prior to antacids or 6 hours after antacids to
avoid formation of insoluble complex. Binding interactions – divalent or trivalent cations
such as aluminum, magnesium or calcium bind to quinolones and inhibit absorption.
•
Protein binding displacement – temporary increase in free drug – also results in greater
clearance
•
Protein binding displacement interactions give false readings for plasma concentrations –
phenytoin displaced by aspirin – need to measure free phenytoin levels to get accurate
picture of active drug
•
Altered drug metabolism medicated by induction or inhibition of CYP450, glycoronyl
transferase (GT) or mod of P glycoprotein (an efflux protein)
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 7
Mechanisms for Drug
Interactions (cont.)
■ Pharmacodynamic interactions
■ Additive or synergistic interactions
■ Antagonistic or opposing interactions
■ Piscitelli NEJM 2001
Unit 5: Significant Drug Interactions with ART
7
•
Much recent attention has focused on the role of drug transporters such as Pglycoprotein (P-gp) on the disposition of antiretroviral drugs. P-gp transports
substances from cells to intestinal lumen, urine or bile for destruction. P-gp is
expressed in intestinal epithelial cells, in liver and kidney, and at various bloodtissue barriers, (normal P-gp activity may be desirable, it protects the brain from
excessive accumulation of toxic drugs and metabolites) (e.g. selective reduction
of CNS adverse effects) or undesirable (e.g. decreasing the activity of
antiretrovirals within the brain).
•
Some drugs may inhibit P-gp resulting in decreased elimination.
•
Some may induce P-gp (St. John’s Wort) resulting in increased elimination
•
PIs ritonavir, nelfinavir, and amprenavir may strongly induce P-gp expression.
•
Recent work suggests that ritonavir inhibits p-glycotprotein mediated transport in
renal proximal tubules.
•
Changes in renal elimination which may result in increased drug concentrations
in the blood
•
Pharmacodynamic interactions: result in additive effects or synergistic
interactions
•
An example of additive effects: bone marrow toxicity caused by ganciclovir and
AZT
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 8
First Pass Effect
Unit 5: Significant Drug Interactions with ART
Refer to enlarged image at end of handout
8
•
This is a diagram to help visualize where various drug interactions occur
•
Orally administered drugs are absorbed in the gastrointestinal tract then pass
through the portal venous system to the liver where they are subject to first pass
effect which may limit systemic circulation. Once in the systemic circulation,
drugs interact with receptors in target tissues.
•
Drugs that are extensively metabolized result in minimal delivery to systemic
circulation.
•
Absorption of drugs from the GI tract depends on the drug's ability to pass across
intestinal cell membranes, withstand the highly acidic environment of the
stomach, and resist destruction in the liver (first-pass effect).
•
In most cases drugs pass through cell membranes of intestines by simple
diffusion, from an area of high concentration (inside the lumen of the intestines)
to an area of lower concentration (bloodstream).
•
Active transport across the GI mucosa, very much like a shuttle system, is
another way some substances are absorbed
•
(i.e. Vitamin B12). Other factors that may affect absorption of drugs include food
and other medications that may inactivate the drug
•
Metabolism can occur in the intestine, blood or liver. Extensive first pass
metabolism of PIs thru gut wall and liver may account for poor and variable
bioavailability of this class.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 9
Drug Metabolism/Elimination
Unit 5: Significant Drug Interactions with ART
•
•
•
•
•
Refer to enlarged image at end of handout
9
The goal of metabolism is to change the active part of med, making them more
water-soluble and more readily excreted by the kidney.
Metabolism occurs via two types of reactions: phase I and phase II.
• Phase I reactions involve oxidation, hydrolysis, and reduction, take place
primarily in the liver CYP450 (the left side of the diagram)
• Phase II reactions involve conj (adding another compound) to form
glucuronides (the right side of the diagram)
Fecal excretion is seen with drugs that are not absorbed from the intestines or
have been secreted in the bile
Changing the molecular structure of drugs increases water solubility and
decreases their fat solubility, which speeds up the excretion of the drug in the
urine. Oxidative and reduction processes make a molecule's charge more
positive or negative than the original drug. Regardless of the positivity or
negativity, a charged molecule is dissolvable in water. (blood serum is primarily
water) These reactions take place primarily in the liver CYP450. Oxidative
metabolism may result in formation of an active metabolite or inactive
compound., acetates, or sulfates. These reactions make it more prone to
elimination by the kidney.
Excretion through the urine, through the lungs, in the perspiration, or in breast
milk. Three processes by which drugs are eliminated through the urine: by
pressure filtration through active tubular secretion or passive diffusion
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 10
Cytochrome (CYP450)
■ >30 isoenzymes identified in
humans
■ Present in liver, small
intestines, lungs, and brain
■ Isoenzymes:1A2, 2C9/19,
2D6, 3A4 are primarily
responsible for drug
metabolism
■ Primary function is to alter
toxins (drugs) to speed
excretion
■ Also metabolize steroid
hormones, vitamins, toxins,
prostaglandins, fatty acids
■ Nomenclature:
Family<subfamily<individual
gene (called isoenzyme)
■ Knowledge of substrates,
inhibitors and inducers helps
predict drug interactions
■ Enzyme 3A4 (3 =family, A=
subfamily, 4= isoenzyme)
Unit 5: Significant Drug Interactions with ART
•
•
•
•
•
•
•
•
•
10
Cytochrome P450 or CYP450 is a family of enzymes that accounts for the majority of
oxidative metabolism conversion of endogenous substance and drugs.
In humans, cytochrome enzymes are found in many tissues
• CYP1A1 Lung
• CYP1A2 Liver
• CYP2C9 Liver
• CYP2C19 Liver
• CYP2D6 Liver and Brain
• CYP3A4 Liver and Small Intestine
• CYP3A5 Liver, Kidney, and Leukocytes
The primary function of the cytochrome P450 system is to alter toxins (drugs) to speed
excretion
Enzymes are categorized into families (by a number ), which are further subdivided into
subfamilies denoted by a capital letter. Individual proteins within a subfamily called
isoenzymes are identified again by a number
For example: 3A4 (3 =family, A= subfamily, 4= Individual protein called isoenzyme)
Isoenzymes:1A2, 2C9/19, 2D6, 3A4 are primarily responsible for drug metabolism
They also metabolize steroid hormones, vitamins, toxins, prostaglandins and fatty acids
Knowledge of substrates, inhibitors and inducers helps predict drug interactions
This is important as PIs are metabolized 80-95% by the CYP450 isoenzymes in liver and
small intestine
Example: The 20 fold increase in plasma concentration of saquinavir caused by ritonavir is
probably produced by inhibition of CYP3A4 at both sites.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 11
Cytochrome P450 Enzymes
Patient Factors
•Genetics
Outcome of
Drug
Interaction
Drug Factors
•Dose
•Diseases
•Duration
•Diet/Nutrition
•Dosing Times
•Environment
•Sequence
•Smoking
•Route
•Alcohol
Variability
•Dosage Form
Adapted from Philip D. Hansten, Science & Medicine 1998
There is variability in the outcomes of drug interactions involving CYP450.
Outcomes are affected by patient factors as well as drug factors.
Patient Factors:
•
Genetic polymorphisms are associated with certain ethnic groups.
•
5-10% Caucasians are poor metabolizers of 2D6 substrates.
•
Whereas 1-2% of the Asian population are poor metabolizers.
•
Diseases: Liver disease (decreased enzyme activity, may affect 1st pass effect=
increased bioavailability),
•
cardiac failure results in decreased blood flow to the liver
•
Diet/nutrition: grapefruit juice inhibits isoenzyme 3A4 in the intestinal wall
•
Foods: charbroiled meats (due to hydrocarbons) and brussel sprouts can induce 1A2
isoenzyme
•
Smoking: induces CYP 1A1, 1A2, 2E1
•
Alcohol: chronic drinking induces 2E1
Drug Factors:
•
Dose: Fluconazole at doses over 200-400 mg daily, it becomes a potent inhibitor of
3A4.
•
Duration: inhibition of CYP450 has a quick onset and a quick offset, whereas
induction effects have a long onset and offset
•
Route: the intravenous or intramuscular routes bypass the oral 1st pass effect
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 12
P450 Drug Interactions
■ Substrate
■ Medication depends on enzymatic pathway(s) for metabolism
■ Object drug which is affected by inducer or inhibitor
■ Inducer
■ Speeds up metabolism
■ Decreases substrate level (lack of efficacy is concern)
■ Onset/offset is gradual
■ Inhibitor
■ Slows metabolism
■ Increases substrate level (toxicity is concern)
■ Quick onset
Unit 5: Significant Drug Interactions with ART
12
What is the difference between a substrate, and inducer and an inhibitor?
Substrate:
•
Any drug that is metabolized by one or more of the P450 enzymes is said to be a
substrate of that enzyme,
•
It is the object drug which is affected by inducer or inhibitor.
Inducer:
•
Increases the amount of P450 enzyme by binding directly to promoter elements
in the DNA region that regulates expression of the gene. Induction persists for
several days, even after the inducing drug is gone
•
(It takes time to take effect and time to resolve)
Inhibitor:
•
This process is almost always competitive and reversible
•
Inhibition of enzymes slows the metabolism of the substrate drug, increasing the
level of the drug in the blood. This may result in increased risk of toxicity. The
onset of these interactions are quick.
•
Some P450 inhibitors are strong inhibitors, and others are poor
•
Protease Inhibitors: RTV >>IND>NFV>APV> SQV
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 13
CYP P450 Drug-Drug Interactions
■ Pharmacologic action of drug is altered by
coadministration of second drug
■ Co-administration may:
↑effect (eg ritonavir + saquinavir;
↑ ritonavir + simvastatin)
Drug B
New effect (eg, ritonavir + amitriptyline)
Drug A
↓ effect (eg,rifampin + protease
inhibitors, indinavir + coumadin)
No Consequences
Unit 5: Significant Drug Interactions with ART
•
Refer to enlarged image at end of handout
13
Drug-drug interactions can result in a therapeutically desired effect, a negative drug-interaction, a new
side effect of a drug, or there may be no consequence at all.
•
The pharmacologic action of one drug is altered by co-administration of second drug
Drug-Drug Interactions
•
Coadministration of the interacting drug may increase the known effect, resulting in increased
therapeutic effect or increased toxicity. An example, lovastatin and simvastatin undergo extensive firstpass metabolism by CYP3A4, inhibitors of 3A4 (ritonavir) increase the risk of myopathy, in some cases
leading to rhabdomyolysis and acute renal failure. The patient should be alert for evidence of myopathy
(muscle pain or weakness) and dark urine. Ritonavir has been reported to induce 3A4 with chronic
administration. Whereas co-administration of ritonavir and saquinavir results in a significant increase in
saquinavir levels, providing a beneficial interaction and a desired therapeutic effect.
•
Coadministration of the interacting drug also may result in a new effect not previously observed with
either drug alone. An example: ritonavir is an inhibitor of CYP2D6 and 3A4 and the antidepressant
amitriptyline is a substrate of both enzymes. Ritonavir can increase the levels of amitriptyline resulting
in elevated concentrations (resulting in dry mouth, urinary retention, blurred vision, constipation,
tacchycardia and postural hypotension) and possibly a new side effect: cardiac arrhythmia (due to
prolonged QT interval). If used together, amitriptyline should be started at the lowest possible dose
and closely monitored. Another example: cisapride, a gastric motility agent, is proarrhythmic when
serum concentrations increase as a result of decreased metabolism by inhibitor drugs such as
nefazodone.
•
Coadministration of the interacting drug may decrease the known effect, resulting in a decreased
therapeutic effect of the target drug. For example, rifampin induces the metabolism of protease
inhibitors, thereby reducing their concentrations and the antiretroviral effect of these drugs. St. John’s
Wort ( an alternative medicine used by patients for depression) rifampin can substantially reduce
indinavir serum concentrations
•
Rifampin gradually reduces the response to oral anticoagulants, the effect may occur as early as a few
days to a week with rifampicin and the offset usually takes 2-3 weeks. Consider the increased risk of
impaired anticoagulant control and the increased need for monitoring and counseling for signs or
symptoms of lack of anticoagulation control
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 14
Cytochrome P450 Caveats
■ A potent enzyme inhibitor is
likely to inhibit the
metabolism of ANY drug
that is metabolized by that
enzyme
■ Some substrates for a
particular enzyme are also
inhibitors or inducers of that
same enzyme
■ Some inhibitors affect more
than one enzyme
■ Magnitude of inhibition may
depend upon the dose
■ An inhibitor may produce
inhibition of an isozyme at one
dose, but require a larger
dose to inhibit another
isozyme
■ Most CYP450 inhibitors are
eliminated by the liver, but
some are not
■ Enantiomers may be
metabolized by different
enzymes
■ Some ARVs have mixed
effect: EFV, Lop/r, RTV
Unit 5: Significant Drug Interactions with ART
14
A few points to consider when thinking about CYP450 interactions:
• A potent enzyme inhibitor is likely to inhibit the metabolism of ANY drug that is metabolized
by that enzyme.
• Some substrates for a particular enzyme are also inhibitors or inducers of that same
enzyme due to competitive inhibition of enzyme activity (ie. Ritonavir is a substrate and
inhibitor of 3A4)
• Some inhibitors affect more than one enzyme (for example EFV inhibits 2C9, 2C19,
induces 3A4, and is a substrate for 2D6 and 3A4)
• Magnitude of inhibition may depend upon the dose (ie cimetidine 1200 mg/day is a more
potent inhibitor of drug metabolism than 400 mg/day.
• An inhibitor may produce inhibition of an isozyme at one dose, but require a larger dose to
inhibit another isozyme (fluconazole inhibits 2C9 at low doses such as 100 mg daily, but at
large doses 200-400 mg daily, it inhibits 3A4)
• Most CYP450 inhibitors are eliminated by the liver, but some are not (for example,
fluconazole is eliminated renally)
• Enantiomers may be metabolized by different enzymes (For example, the relatively weak
anticoagulant R-warfarin is metabolized primarily by CYP1A2, while the more potent Swarfarin is metabolized by CYP2C9. Thus inhibitors of CYP1A2 tend to produce only small
increases in the hypoprothrombinemic response to warfarin, while CYP2C9 inhibitors (EFV,
metronidazole can sometimes produce large increases in warfarin response.
• Some ARVs have mixed effect: EFV,Lop/r,RTV.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 15
Pharmacist Beware
■ A drug interaction can occur
■ Whenever a new medication is started
■ Whenever a medication is discontinued
■ Whenever a dose is changed
■ Remember:
■ Inducing interactions
■ Gradual onset/offset
■ Inhibiting interactions
■ Quick onset/offset
Unit 5: Significant Drug Interactions with ART
15
When thinking about drug interactions, always keep in mind:
•
That drug interactions can occur in other instances that when a new drug is
begun:
•
Remember that a drug interaction can occur:
•
Whenever a new medication is started
•
Whenever a medication is discontinued
•
Whenever a dose is changed
•
For example: let’s say that a patient is on a drug that is a substrate for an
enzyme and also on a medication that induces that enzyme. If the
inducing drug is discontinued, the level of the substrate drug may now be
increased and could lead to toxicity.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 16
Red Flags for Potential Interactions Pharmacist Beware
■ PIs or NNRTIs +
■ Statins
■ Benzodiazepines
■ Azole antifungals
■ Methadone
■ Antihistamines
■ Alternative medicine
■ Ergot alkaloids
■ Cardiac medicine
■ Anticonvulsants
■ Macrolide antibiotics
■ Anti-tuberculars
(rifamycins)
■ Oral contraceptives
■ Warfarin
Unit 5: Significant Drug Interactions with ART
•
•
•
•
•
•
16
Pharmacists play a critical role in detecting drug interactions, before they happen.
Pharmacists need to ask patients what other medications they are currently taking whenever
dispensing a new medication to avoid potential interactions. Also, be aware that when a
medication dose is changed or discontinued, that can have an effect on any other drug that
it interacts with.
The facilitator can ask the audience if anyone knows what red flags for potential interactions
means clinically.
Answer: Drugs or drug classes that are Red Flags for drug interactions are those that are
known to cause significant interactions with PIs and NNRTIs and should always be
approached with caution, or in some cases avoided completely with ARV medications.
Some of the drugs or drug classes that should be thought of as red flags for drug
interactions include:
PIs or NNRTIs +
• Statins
• Azole antifungals
• Antihistamines
• Warfarin
• Ergot alkaloids
• Anticonvulsants
• Oral contraceptives containing estradiol
• Anti-tuberculars
• Methadone
• Alternative medicine
• Cardiac medicine (amiodarone, quinidine)
• Benzodiazepines
• Macrolide antibiotics
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 17
CYP 3A4 - Substrates
■ alpra-, tria-, mida- zolam
■ calcium channel blockers
■ carbamazepine
■ corticosteroids
■ cyclosporine
■ digoxin
■ methadone
Unit 5: Significant Drug Interactions with ART
17
•
The isoenzyme 3A4 is responsible for the metabolism of the PI and NNRTI class
of ARVs. It is the isoenzyme that is responsible for the majority of drug
interactions that are encountered by a patient on potent ARVs, (which include
either a PI or NNRTI)
•
This is a list of the common substrates, inhibitors and inducers of CYP 3A4.
•
Potent inhibitors that should be red flags for potential drug interactions: macrolide
antibiotics including erythromycin, clarithromycin, antidepressants including
fluoxetine and fluvoxamine, azole antifungals such as ketoconazole and
itraconazole, fluconazole at higher doses > 200 mg/day. (nefazodone, not
available in Ethiopia)
•
Of the protease inhibitors, ritonavir has the greatest inhibitory effect on 3A4,
followed by amprenavir, atazanavir, indinaivr, nelfinavir and saquinavir. Potent
inducers of 3A4 that should be red flags for potential drug interactions include
anticonvulsants, rifamycin antibiotics, and the NNRTIs NVP and EFV (nelfinavir
has been reported to decrease serum concentrations of methadone and ethinyl
estradiol, suggesting that it might be an inducer of 3A4 in some situations. In
general, it is not viewed as an inducer
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 18
CYP 3A4 – Substrates (cont.)
■ pimozide
■ protease inhibitors
■ quinidine
■ terfenadine
■ amitriptyline
■ statins
■ many, many more
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
18
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 19
CYP 3A4 – Inhibitors
erythro-, > clarithromycin
delavirdine
efavirenz
fluoxetine
fluvoxamine
grapefruit juice
keto- , itra- > fluconazole
PIs: ritonavir >>> amprenavir, atazanavir, indinavir, nelfinavir >
saquinavir
Unit 5: Significant Drug Interactions with ART
19
•
(Inducers are listed on the following slide)
•
Substrates of 3A4 may be affected by either inhibition by PIs (which may result in
toxic levels) or by induction from NNRTIs, which may result in loss of therapeutic
efficacy.
•
Other common substrates of 3A4 include: (nefazodone, astemizole, cisapride,
sildenafil, not available in Ethiopia)
•
Some interactions are known and predictable, whereas others are based on
theoretical considerations due to the known metabolism of the drugs.
•
This list may be used later as a reference for the cases we will review.
•
Of note: Grapefruit juice: mainly 3A4 inhibition, some 1A2 and 2D6
•
It takes 2 or 3 8 oz glasses of grapefruit juice per day to cause inhibition
•
This is due to bioflavinoids-naringin (which gives grapefruit its bitter flavor)
not present in other citrus fruits
•
It is metabolized to naringenin which is a potent CYP3A4 inhibitor.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 20
Inducers
■ Inducers
■ carbamazepine, phenytoin, phenobarbital
■ rifampin, rifabutin, St. John’s wort, garlic
■ efavirenz, nevirapine, nelfinavir
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
20
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 21
Introductory Case - Answers
■ The statement A): There is no interaction between ART
and phenytoin, they can safely be administered
together, is false.
■ The interaction between phenytoin and nevirapine is
unknown. Both drugs are cytochrome P450 3A4
inducers and therefore an interaction can be
anticipated.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
21
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 22
Introductory Case –
Answers (cont.)
■ The statement B): The dose of nevirapine must be
increased to account for increased metabolism due to
phenytoin, is false.
■ Phenytoin may decrease the levels of nevirapine,
however, the interaction is unknown. Levels of
nevirapine should not be increased empirically. If there
are no other options for anti-seizure medications for this
patient, and this combination must be used, the patient
should be monitored for loss of virologic control.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
22
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 23
CYP 2C9/19
■ Substrates
■ Inhibitors
■ Inducers
diazepam
cimetidine
carbamazepine
NSAIDs
delavirdine
phenobarbital
phenobarbital
efavirenz
rifampin
phenytoin
fluoxetine
tolbutamide
fluvoxamine
S-warfarin
omeprazole
sertaline
ritonavir
Unit 5: Significant Drug Interactions with ART
Refer to enlarged image at end of handout
23
•
EFV and Ritonavir are inhibitors of 2C9 which may increase the level of certain
substrates, for example: phenytoin. It is not easy to predict the outcome of the
interaction between anticonvulsants and NNRTIs as the effect can be mixed.
•
Anticonvulsants are also inducers of CYP2C9 and 2C19.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 24
Introductory Case –
Answers (cont.)
■ The statement D): An interaction exists between
phenytoin and bactrim is true. The statement, they
should not be administered together, is false.
■ Bactrim is an inhibitor of CYP 2C9 and phenytoin is a
substrate of the same enzyme. The levels of phenytoin
may be increased when bactrim is started (after a few
weeks), however, this patient has been taking both
medications together and is stable on therapy.
■ She can continue to receive these medications
together.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
24
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 25
CYP 2D6 - Substrates
■ amphetamines
■ metoprolol, propranolol
■ codeine-to-morphine
■ phenothiazines
■ encainide, flecainide
■ risperidone
■ haloperidol
■ SSRIs
■ hydrocodone-to-morphine
■ TCAs (amitriptyline)
Unit 5: Significant Drug Interactions with ART
Refer to enlarged image at end of handout
25
•
Substrates of 2D6 may be affected by CYP2D6 inhibitors including ritonavir.
Many antidepressants are metabolized by CYP2D6 and may be affected by PIs.
Amitriptyline is a substrate for 2D6. It is the primary path by which it is
metabolized.
•
What is the best way to manage the known drug interactions between
antidepressants and ARVs? See next slide.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 26
CYP 2D6 - Inhibitors
cimetidine
fluoxetine
haloperidol
methadone
paroxetine
quinidine
ritonavir
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
26
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 27
PI/ NNRTI/ Antidepressant Drug Interactions
Antidepressant
Amitriptyline
Potential for
Interaction
ritonavir,
lopinavir/r,
amprenavir,
Fluoxetine
Sertraline
Effects
Management
Start with lower dose
Levels of
amitriptyline may be (50%) of amitriptyline,
adjust dose when adding
increased
ritonavir. Monitor for side
effects
ritonavir,
lopinavir/r, all
other PIs,
efavirenz
Levels of both
fluoxetine and
ritonavir,
lopinavir/r, all
other Pis,
efavirenz
Levels of sertraline
may be increased.
ARV levels
As above
ARVs may be
increased
As above
not likely to change.
Refer to enlarged image at end of handout
•
•
•
•
•
•
•
•
•
Refer to copy of slide in the participant handout.
Potential interaction with all protease inhibitors or non-nucleoside reverse transcriptase inhibitors is possible with any
antidepressant:
When using antidepressants with ARVs, the message is to start low and go slow.
Example: Co-administered ritonavir (2D6 inhibitor) may increase serum concentrations of amitriptyline, resulting in
amitriptyline toxicity. Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with ritonavir.
Adverse Effect: increased amitriptyline serum concentrations and potential toxicity (anticholinergic effects,like dry mouth,
urinary retention, blurred vision, other effects include: sedation, confusion, cardiac arrhythmias)
Clinical Management: Monitor patients for signs and symptoms of tricyclic antidepressant toxicity (anticholinergic effects,
sedation, confusion, cardiac arrhythmias). Reduce doses of amitriptyline as required. Start with 50% of the normal starting
dose (use 25 mg qhs rather than 50 mg.Maximum 75 mg/day) Severity: moderate Onset: delayed Documentation: fair
Probable Mechanism: decreased amitriptyline metabolism
On the other hand, 3A4 inducers like nevirapine may decrease amitriptyline levels. There is probably not a significant
interaction between amitriptyline and NNRTIs
Other symptoms of anticholinergic toxicity: dry mouth, and rarely, associated sublingual adenitis or gingivitis;blurred vision;
disturbance of accommodation; increased intraocular pressure; mydriasis; constipation; paralytic ileus; urinary retention;
delayed micturition; urinary tract dilation; hyperpyrexia.
Amitriptyline is metabolized by 3A4 and 2D6. 2D6 inhibitors and to a lesser extent 3A4 inhibitors can increase amitriptyline
levels. However, any inhibitor or substrate could potentially increase amitriptyline levels. High levels of amitriptyline can
prolong the QTC interval, which may cause arrhythmias.
•
Fluoxetine + ritonavir:
•
Ritonavir doesn’t need to be adjusted.
•
Ritonavir has documented increases in levels. Monitor for side effects
•
Ritonavir, lopinaivr/ritonavir and efavirenz have documented interactions (i.e case reports or formal studies) and/or have the
most potential for interaction because they use similar pathways of metabolism in the liver. Fluoxetine’s major metabolite
(norfluoxetine) has a very long half life and is also a potent inhibitor of 2D6, thus 2D6 inhibition may persist for several
weeks after stopping fluoxetine.
•
Increased levels of certain antidepressants can cause “serotonin syndrome” which can present as: mental status changes,
agitation, tremor, shivering, sweating, fever, muscle spasm, hypertension seizures.
•
Five cases of serotonin syndrome were reported in HIV-infected patients taking fluoxetine with antiretroviral therapy. In
particular, the use or addition of ritonavir—a potent CYP 2D6 inhibitor—was implicated, though saquinavir, efavirenz, or
grapefruit juice (all primarily CYP 3A4 inhibitors) were also used, suggesting that pharmacokinetic interactions increased
serotonergic stimulation. All five patients were taking multiple additional medications and had complex medical and/or
psychiatric histories. Reducing SSRI dosages by one-half when used with ritonavir has been recommended to minimize
adverse effects from a pharmacokinetic interaction.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 28
ARV Interactions with Pain Medication:
Methadone Interactions
■ Primarily metabolized by 3A4
■ Likelihood for interactions with PIs/NNRTIs is high
■ Numerous studies/case reports
■ Difficult to determine effect due to long half-life of methadone
and differential effects on inactive S(+) enantiomer versus
active R(-) enantiomer
■ Watch for signs of opiate withdrawl
■ Methadone may increase zidovudine levels – watch for
increased nausea/vomiting
Unit 5: Significant Drug Interactions with ART
28
•
Note: if methadone is used for pain, this may result in significant interactions with
PIs or NNRTIs because it is primarily metabolized by 3A4.
•
There are numerous studies/case reports. It is difficult to determine effect due to
long half-life of methadone and differential effects on inactive S(+) enantiomer
versus active R(-) enantiomer Watch for signs of opiate withdrawl.
•
The magnitude of the dose increase if needed may not always parallel the
reduction is total methadone exposure, For example, data reported by Clarke
et.al suggest that despite a decrease of >50% in methadone AUC seen with the
addition of efavirenz, a mean increase in methadone dose of only 22% (in 10 mg
increments) was required to counteract symptoms consistent with opiate
withdrawl.
•
Methadone inhibits glucuronidation of zidovudine and to a lesser extent renal
clearance of zidovudine. Monitor for zidovudine related toxicities, ie, nausea,
vomiting, headaches and myelosuppression (affect all cell lines in the bone
marrow)
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 29
Metabolic Characteristics of ARVs
Source:Antoniu, Tseng Annals of Pharmacotherapy 2002:36:1598-61
•
This is a summary slide of the effects of ARVs on CYP450 for reference.
•
Remember that in general, the NNRTIs are inducers of 3A4 (except for
delavirdine which is no longer used regularly) and the Protease inhibitors are
inhibitors of 3A4, to varying degrees. However, that some ARV have mixed
effects on different enzymes which may make it difficult to predict drug
interactions, and may require close clinical monitoring.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 30
PI – Safer Choices
■ Anxiety/insomnia
■ Use Temazepam or Oxazepam
■ MAI prophylaxis/ treatment
■ Use Azithromycin
■ Antidepressants
■ Start low and go slow!
■ Amitriptyline: 2D6 and 32A4 substrate
■ Fluoxetine and Fluvoxamine: broad CYP450 inhibition (serotonin
syndrome)
■ Sertraline: minimal 3A4 inhibition, may be sig.>150 mg/day
Unit 5: Significant Drug Interactions with ART
•
30
There are safer choices for certain classes of medications where known potential interactions exist
when co-administered with PIs.
•
For the benzodiazepine class, use oxazepam or temazepam, or lorazepam, if available.
•
When given orally, alprazaolam, midazolam and triazolam undergo extensive first pass metabolism by
CYP3A4 in the gut wall and liver. These benzodiazepines are contraindicated with all PIs. The primary
risk of these interactions is impairment of motor skills that could result in falls or motor vehicle
accidents. Alternatively, temazepam, oxazepam or lorazepam are largely glucuronidated and are
unlikely to be affected by CYP3A4 inhibitors.
•
Other benzodiazepines such as diazepam or clonazepam are also at least partially metabolized by
CYP3A4 and may also interact with CYP3A4 inhibitors.
•
When using macrolide antibiotics for MAI prophylaxis, unlike clarithromycin and erythromycin,
azithromycin does not appear to inhibit 3A4.
•
For example: When using clarithromycin with efavirenz, the levels of clarithromycin are decreased by
39%, efficacy of the antibiotic must be monitored. When using clarithromycin with nevirapine, the NVP
levels are increased by 26% and clarithromycin levels are decreased by 30%. When using
clarithromyicn with ritonavir, clarithromycin levels are increase by 77%. No dose adjustment is
recommended unless patients have renal impairment. Clarithromycin can prolong the QT interval at
high doses. Therefore, this combination is avoided, if possible if azithromycin is available.
•
When starting an antidepressant in a patient on a ritonavir containing regimen, the lowest possible dose
should be used and the patient should be monitored for the development of toxicity (dry mouth,
constipation, blurred vision, tachycardia, constipation and postural hypotension).
•
Antidepressants, start with lower dose (50%).
•
Unavailable in Ethiopia: Citalopram, escitalopram, mirtazapine, venlafaxine, use if available.
Paroxetine: potent 2D6 inhibition, Wellbutrin: inhibits 2D6.
•
Both fluoxetine and fluvoxamine have broad CYP450 inhibition (fluoxetine inhibits 2C19, 2D6, and
3A4), fluvoxamine inhibits 1A2, 2C9, 2C19 and 3A4) both are substrates of 3A4. Start at low doses and
slowly increased to effect. If the levels of these drugs are increased, they may result in toxicity.
Sertraline is metabolized primarily by 2C19.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 31
PI – Safer Choices
■ Rifabutin, if possible
■ Requires dose reduction with all PIs and dose increase with efavirenz
■ Rifampin (only use with adjusted doses of EFZ, LPV/r or RIT/SAQ)
■ Anticonvulsants
■ Use sodium valproate, gabapentin or lamotrigene, if possible
■ Migraine therapy
■ Use sumatriptan
■ Antihistamines
■ Use loratadine or cetirizine
Unit 5: Significant Drug Interactions with ART
31
•
Rifabutin is the rifamycin antibiotic of choice for the treatment of TB, if available.
It is a less potent inducer of 3A4 than rifampin.
•
If rifampin is used, careful consideration must be made to the choice of ARV
therapy which will be discussed in detail in the TB portion of the curriculum.
•
When using anticonvulsants with ARV therapy, recognize that sodium valproate
is a better choice as well as gabapentin or lamotrigene if available.
•
Carbamazepine levels are increased when coadministered with ritonavir. Use
with caution and monitor caramazepine levels, if possible.
•
Carbamazepine markedly decreases IDV and SQV and would presumably have
the same effect on all other PIs.
•
Phenytoin decreases the levels of LPV and RTV and the levels of phenytoin are
decreased as well. It is recommended that these drugs should not be
coadministered, if other anticonvulsant possibilities exist. Otherwise the patient
must be monitored for virologic failure or anticonvulsant failure. Monitoring
anticonvulsant levels is suggested if co-administered.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 32
Introductory Case
Answers (cont.)
■ The statement C): Nevirapine may decrease phenytoin
levels and therefore the dose of phenytoin may need to
be increased to avoid loss of seizure control is true.
■ The patient would need to be monitored closely for loss
of seizure control and then the dose would need to be
adjusted accordingly by the physician.
■ The best option would be to gradually switch the patient
from phenytoin to another drug for seizure control, one
that does not interact with ART. Options may include
sodium valproate or gabapentin.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
32
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 33
Ritonavir - Do NOT Co-administer
■ Antiarrhythmics
■ Amiodarone, quinidine
■ Antihistamines – terfenadine*
■ Ergot derivatives* (ergotamine)
■ Herbal Preparations
■ HMC-CoA Reductase Inhibitors – lovastatin*,
simvastatin*
■ Neuroleptic – Pimozide* (Orap)
■ Benzodiazepines – midazolam*
*all PIs
Unit 5: Significant Drug Interactions with ART
33
There are certain drugs that should not be co-administered with all PIs and
certain drugs that cannot be administered with ritonavir
Antiarrhythmics: Amiodarone, quinidine
•
(Others to avoid (not available in Ethiopia bepridil, flecanaid, propafenone)
•
Although data are limited, any CYP3A4 inhibitor could increase the plasma concentrations of amiodarone or quinidine. Toxicity including
cardiac arrythmia could result. Assume that all CYP3A4 inhibitors interact until proven otherwise. Monitor for altered antiarrythmic
response if the CYP3A4 inhibitor is initiated, discontinued or changed in dosage. Monitor for ECG changes indicating antiarrhythmic
toxicity. Monitoring of the antiarrhythmic plasma concentration is warranted.
Antihistamines – terfenadine* and astemizole (not available in US or Ethiopia)
•
Coadministered ritonavir may increase serum concentrations of terfenadine, causing a potential risk of arrhythmias or other serious
adverse effects (Prod Info Invirase(R), 2003; Prod Info Norvir(R), 2000). Ritonavir may be expected to significantly slow terfenadine
metabolism, thereby producing increased serum levels of this agent.
•
Adverse Effect: cardiotoxicity (QT interval prolongation, torsades de pointes, cardiac arrest)
•
Clinical Management: Concurrent use of terfenadine and ritonavir is contraindicated due to potential for serious and/or life-threatening
cardiac arrhythmias.
•
Summary: Coadministered ritonavir may decrease serum concentrations of phenytoin due to effects associated with the cytochrome
P450 system. The clinical significance of this potential interaction is currently undetermined.
•
•
Clinical Management: It may be necessary to monitor phenytoin serum concentrations. Also, observe patients for signs of
decreased phenytoin efficacy, including seizure activity.
•
Severity: moderate Onset: delayed Probable Mechanism: induction of phenytoin metabolism
The effects of anticonvulsants phenytoin, carbamazepine and phenobarbital are unknown. The recommendation is that anticonvulsant
levels should be monitored, and to use with extreme caution.
•
When treating migraines, a safer choice of medication to use with PIs is sumatriptan. It is metabolized hepatically, not by CYP450.
•
Use loratadine or cetriazine for antihistamine therapy. They are safer options that other antihistamines, which may cause cardiac
arrythmias at high doses.
Ergot derivatives* (ergotamine)
•
Summary: The concomitant administration of ritonavir and ergot derivatives is contraindicated due to the potential for serious and/or lifethreatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other
tissues Adverse Effect: an increased risk of ergotism (nausea, vomiting, vasospastic ischemia)
•
Clinical Management: The concurrent use of ergot derivatives and ritonavir is contraindicated.
•
Severity: major Onset: rapid
•
Probable Mechanism: inhibition of cytochrome P450-mediated ergotamine metabolism by ritonavir
•
Herbal preparations can have a negative impact on ART levels, until more is known about ART used in Ethiopia, the
recommendation would be to avoid use.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 34
NNRTIs - Do NOT Co-administer
■ Ergot derivatives (ergotamine)
■ Benzodiazepine: midazolam
■ Rifampin (Nevirapine)
■ Terfenadine (Efavirenz)
■ Herbal – St. Johns wort
Unit 5: Significant Drug Interactions with ART
34
•
Ergot derivatives (ergotamine)
•
Benzodiazepine: midazolam
•
Rifampin (Nevirapine), as stated in the TB curriculum, NVP is only to be used
with rifampin if there are no other choices available
•
Terfenadine (Efavirenz)
•
Herbal – St. Johns Wort
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 35
PI and NNRTI Drug Interactions
Nevirapine (NVP)
■ NVP (standard dose) +
■ Indinavir (increase IDV to 1000 mg q8h or consider IDV/RTV)
■ Ritonavir (dose RTV standard)
■ Saquinavir (use with RTV)
■ Nelfinavir (NFV dose standard)
■ Amprenavir, fos-Amprenavir (no data)
■ Lopinavir/r (use 4 caps bid)
■ Atazanavir ( no data, most clinicians would use with ritonavir)
Unit 5: Significant Drug Interactions with ART
35
•
When using PIs with NNRTIs, it may be necessary to adjust the PI dose to
account for the drug interaction
•
NVP (standard dose) +
•
Indinavir (increase IDV to 1000 mg q8h or consider IDV/RTV)
•
Ritonavir (dose RTV standard)
•
Saquinavir (use with RTV)
•
Nelfinavir (NFV dose standard)
•
Amprenavir, fos-Amprenavir (no data)
•
Lopinavir/r (use 4 caps bid)
•
Atazanavir ( no data, most clinicians would use with ritonavir)
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 36
PI and NNRTI Drug Interactions
Efavirenz (EFV)
■ EFV (standard dose) +
■ Indinavir (increase IDV to 1000 mg q8 or consider IDV/RTV)
■ Ritonavir (dose standard)
■ Saquinavir (SQV nt recommended as sole PI when used with EFV- use
with RTV)
■ Nelfinavir (dose standard)
■ Amprenavir (add RTV 200 mg to standard APV of consider using
APV/RTV 450/200 mg
■ Fos-Amprenavir (use 1400 mg APV with 300 mg RTV once daily or 700
mg APV with 100 mg RTV bid
■ Atazanavir (use ATV 300 mg with RTV 100 mg qd
■ Lopinavir/r (use 4 caps of LPV/r bid)
Unit 5: Significant Drug Interactions with ART
36
•
When using PIs with NNRTIs, it may be necessary to adjust the PI dose to
account for the drug interaction
•
EFV (standard dose) +
•
Ininavir (increase IDV to 1000 mg q8 or consider IDV/RTV)
•
Ritonavir (dose standard)
•
Saquinavir (SQV nt recommended as sole PI when used with EFV- use
with RTV)
•
Nelfinavir (dose standard)
•
Amprenavir (add RTV 200 mg to standard APV of consider using
APV/RTV 450/200 mg
•
Fos-Amprenavir (use 1400 mg APV with 300 mg RTV once daily or 700
mg APV with 100 mg RTV bid
•
Atazanavir (use ATV 300 mg with RTV 100 mg qd
•
Lopinavir/r (use 4 caps of LPV/r bid)
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 37
Nucleoside Interaction
Didanosine and Tenofovir
DDI alone must be taken on an empty stomach
TDF can be taken without regard to meals
The Cmax and AUC of didanosine (buffered formulation or
enteric coated) increased when given with tenofovir.
Increases in didanosine concentrations could increase risk
of adverse events, including pancreatitis and peripheral
neuropathy.
Administration of DDI EC 250mg with TDF staggered or
simultaneously with or without a meal results in similar drug
exposures to DDI EC 400mg alone
Unit 5: Significant Drug Interactions with ART
•
37
We have talked about significant interactions with protease inhibitors and other
medications. Of note, a newly discovered interaction exists between two
nucleoside analogues: DDI and tenofovir
•
Background: DDI alone taken on an empty stomach
•
TDF can be taken without regard to meals
•
The Cmax (highest level of the drug in the blood) and AUC (total amount
of drug in blood) of didanosine (buffered formulation or enteric coated)
increased when given with tenofovir. Increases in didanosine
concentrations could potentiate adverse events, including pancreatitis and
peripheral neuropathy.
•
Administration of DDI EC 250mg with TDF staggered or simultaneously
with or without a meal results in similar drug exposures to DDI EC 400mg
alone
•
Simultaneous administration of ddI EC 250 mg with TDF in the fasted and fed
states resulted in a 14% increase and 11% decrease, respectively, in the DDI
AUC. No significant difference between the two states (fasted or fed)
•
Clinical adverse events did not differ significantly when drugs given alone vs
together
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 38
Dosing Options for Tenofovir (TNF)
and Didanosine (DDI ) Buffered or EC
> 60 kg
< 60 kg
FASTED
(given together) or
STAGGERED DDI
EC given 2 hours
before
FED
(given
simultaneously with
a light meal= 373
kcal,20%fat)
DDI 250 mg
DDI 250 mg
TDF 300 mg
TDF 300 mg
DDI 200-250 mg
DDI 200-250 mg
TDF 300mg
TDF 300mg
Unit 5: Significant Drug Interactions with ART
38
•
IN order to prevent DDI related side effects, the dose must be reduced to 250 mg
for patients weighing > 60 kg
•
And use DDI 200-250 mg in patients who weigh < 60 kg
•
DDI buffered, dispersible comes in 25, 50 and 100 mg ?
•
DDI EC comes as 125mg, 200mg, 250mg and 400mg capsules
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 39
Antiretroviral-Food Interactions
Avoid food:
Take with food:
■ Lopinavir: ↑ 50-130%
■ Saquinavir: 7 fold ↑ (fatty
meal)
■ Nelfinavir: 2-3 fold ↑
■ Ritonavir: 15% ↑
■ Amprenavir: ↓ 23% with high
fat meal (regular food OK)
■ Indinavir: 77% ↓ (fatty meal;
light snack OK)
■ DDI: 47% ↓ with meal
■ Itraconazole caps
■ Efavirenz: ↑ 79% high fat meal
inc. toxicity
■ Atazanavir 70 % ↑
■ Rifampin (food may↑ levels)
■ Ganciclovir ↑ up to 5%
■ Itraconazole liquid
■ atovaquone 24% ↑
■ Isoniazid
Unit 5: Significant Drug Interactions with ART
39
Medications are often recommended to be taken with food for one of two
reasons:
a) To ensure optimal absorption.
•
e.g., Nelfinavir is best absorbed if it is taken with a meal or snack.
•
In some instances, fat content of a meal may be an important factor affecting drug bioavailability. With lipid-soluble agents,
ingestion of dietary fat results in formation of an oil or emulsion phase, with subsequent improvement in solubility. Ingesting
a fatty meal also promotes secretion of gastric fluids, which in turn may lower gastric pH, delay stomach emptying, and
decrease gastrointestinal transit rates. The absorption of saquinavir is significantly increased when taken within 2 hours of
a high-fat meal.
•
Itraconazole caps can be taken with food or cola to increase absorption
•
Administration of a single 400 mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70%
increase in AUC
•
Ganciclovir is poorly absorbed and taking the dose with food increases drug levels at best by 5%
•
Atovaquone must be taken with a fatty meal to ensure absorption(23 g fat: 610 kcal
b) To reduce side effects involving the stomach.
•
Some agents, such as zidovudine do not necessarily need to be taken with food for adequate absorption. However, the
presence of food may often prevent or minimize the risk of stomach upset or nausea. This, in turn, may reduce the chance
of non-adherence due to drug side effects.
•
Amprenavir can be taken with or without meals, avoid a high fat meal which may decrease levels. The relative
bioavailability of amprenavir capsules was assessed in the fasting and fed states in healthy volunteers (standardized highfat meal: 967 kcal, 67 g fat, 33 g protein, 58 g carbohydrate). Those who ate the high fat meal had lower drug levels than
those who were fasting
•
Certain medications may be sensitive to the conditions in the stomach. They need to be taken on an empty stomach, at
least 1 hour prior or 2 hours after a meal.
•
For example, indinavir is better absorbed on an empty stomach. High protein and fat-containing foods can significantly
lower the amount of indinavir that gets into the body. Therefore indinavir should always be taken on an empty stomach or
with a light, low-fat snack such as cereal with skim milk, toast and jam, fresh fruit, yogurt, low-fat pretzels, air-popped
popcorn.
•
Didanosine (ddI) is another drug that needs special conditions in the stomach to be absorbed properly. It is destroyed by
stomach acid, and therefore the didanosine tablets contain an antacid buffer. Didanosine should always be taken on an
empty stomach, since the presence of food might interfere with the action of the buffers. Videx EC should also be taken on
an empty stomach
•
INH should be taken on an empty stomach (peak concentrations and total dose absorbed were reduced when taken with
food), however, it can be taken with food to decrease GI upset
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 40
Avoid Antacids
■ PIs
■ indinavir
■ (fos)amprenavir
■ fluoroquinolones
■ isoniazid
■ amprenavir
■ dapsone
■ atazanavir
■ zalcitabine
■ ketoconazole
■ delavirdine
Unit 5: Significant Drug Interactions with ART
•
40
It is essential to avoid co-administration of antacids with the following medications to ensure
absorption.
Protease inhibitors:
•
Amprenavir and antacid administration have not been specifically studied. However, based on data
available between antacids and other protease inhibitors, it is recommended that the administration
of amprenavir and antacids be separated by at least one hour (Prod Info Agenerase(R), 2000).
•
Omeprazole is contraindicated with atazanavir, only ranitidine given as 300 mg 12 hours apart from
atazanavir can be used as an acid suppressing drug.
•
Fluoroquinolones: Concurrent administration of ciprofloxacin with magnesium/aluminum antacids
should be avoided. Ciprofloxacin may be taken two hours before or six hours after taking an antacid.
An H2 blocker such as ranitidine may be an alternative to antacids in some clinical situations.
•
Severity: moderate
•
Ketoconazole requires an acid pH for adequate absorption (drugs and food may change the acidity
of the gut and decrease absorption)
•
IHN: Aluminum antacids decrease the absorption of isoniazid (Hurwitz & Schlozman, 1974).
•
Adverse Effect: decreased isoniazid effectiveness
•
Clinical Management: Do not administer antacids concurrently with isoniazid. Recommend taking
antacids at least two hours after taking isoniazid.
•
Absorption of dapsone is dependent upon an acidic pH and may be diminished with other drugs,
such as Videx, containing buffers
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 41
Alternative Medicine
■ Some alternative medicine or herbal therapies have
been shown to interact with ART
■ Pharmacists and providers must be aware of the
potential interaction should their patient wish to take
alternative medicine
■ The interactions may increase or decrease ART levels
leading to either an increase in toxicity or loss of
efficacy
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
41
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 42
The Role of a Pharmacist in
Drug Interactions
■ Pharmacists must be knowledgeable about potential
drug-drug, drug-food interactions
■ Pharmacists should question a patient about their
current medications whenever filling a prescription that
is new for them
■ Patients should be educated that drug interactions can
also occur if they stop or receive a change in dose of
their medications
■ Pharmacists should ask patients about their use of
herbal preparations as they can interact with ARV
therapy
Unit 5: Significant Drug Interactions with ART
•
42
Pharmacist Intervention in Drug Interactions
•
Pharmacists must be knowledgeable about potential drug-drug, drug-food
interactions
•
Pharmacists should question a patient about their current medications
whenever filling a prescription that is new for them, when a dose is
changing or when a medication is being discontinued
•
Patients should be educated that drug interactions can also occur if they
stop or receive a change in dose of their medications
•
Pharmacists should ask patients about their use of herbal preparations as
they can interact with ARV therapy
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 43
Drug Interactions
Case Studies
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 44
Case 1
■ DH is 45 year old HIV+ male presenting for routine follow-up. On HAART
two years.
■ CD4 count: 480 cells/mm3
HIV RNA < 50 copies/mL.
■ He comes into your pharmacy after having seen a physician for his
migraines. He is glad to try a new medication as his headaches have been a
problem for him for years. He is so distraught about them, he has begun
taking an herbal product to help with his mood.
■ You ask him his current medication regimen, which is:
■ Nevirapine 200 mg bid
■ Lamivudine 150mg tab bid
■ Zidovudine 300 mg bid
■ An herbal medicine when he feels “down”
■ New medications prescribed today: Ergotamine + caffeine
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
44
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 45
Case 1 Question
■
Which of the following combinations represents a
potential drug-drug interaction?
A. Nevirapine and herbal medicine
B. Zidovudine and ergotamine
C. Ergotamine and nevirapine
D. Caffeine and zidovudine
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
45
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 46
Case 1 Answer
■ C is the correct answer
■ However, you should inquire as to which herbal
medicine he takes as many herbal medicines can
interact with ARVs
Unit 5: Significant Drug Interactions with ART
46
For example, St. John’s Wort is a 3A4 inducer. It is not widely available in Ethiopia,
however, if a patient indicates they take herbal medicine with ARVs, they should be
closely monitored for virologic failure or toxicity. It is difficult to predict drug
interactions between ARVs and herbal medicines.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 47
Case 1 Explanation
■ A: Concomitant use can decrease serum levels of
NNRTIs. St. John's Wort can increase the oral
clearance of nevirapine (Viramune) by 35%.
Subtherapeutic concentrations are associated with
therapeutic failure, development of viral resistance, and
development of drug class resistance. St. John's Wort
induces intestinal and hepatic cytochrome P450 3A4
(CYP3A4) and intestinal P-glycoprotein/MDR-1, a drug
transporter
■ Avoid use with any NNRTI or PI
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
47
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 48
Case 1 Explanation (cont.)
■ Nevirapine is metabolized by CYP3A4. Competition for
this pathway could result in inhibition of ergot
metabolism, creating the potential for ergotism (nausea,
vomiting, vasospastic ischemia).
Unit 5: Significant Drug Interactions with ART
48
•
This is true for EFV as well:
•
Efavirenz and ergot derivatives are both metabolized by the cytochrome P450
3A4 enzyme system. Competition for this pathway could result in inhibition of
ergot metabolism, creating the potential for ergotism (nausea, vomiting,
vasospastic ischemia).
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 49
Case 1 Questions (cont.)
■ What would you recommend to DH for his depression?
■ What would you recommend to him for his migraines?
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
49
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 50
Case 1 Answers (cont.)
■ Answer #1
■ You should refer him to see his provider about his depression.
Untreated depression may lead to non-adherence and
treatment failure as well as poor quality of life. Amitriptyline is
used commonly in Ethiopia. If used with nevirapine, levels
may be decreased
■ Answer #2
■ A better choice for the treatment of migraines in patients on
either a PI or NNRTI is sumatriptan
Unit 5: Significant Drug Interactions with ART
50
•
You should refer him to see his provider about his depression. Untreated
depression may lead to non-adherence and treatment failure as well as poor
quality of life. Amitriptyline is used commonly in Ethiopia. Nevirapine may
gradually reduce the serum levels and effect of amitriptyline. The results of this
interaction may be variable. He should be monitored for altered tricyclic
antidepressant effect. This is unlike the interaction with Pis which could increase
amitriptyline levels.
•
A better choice for the treatment of migraines in patients on either a PI or NNRTI
is sumatriptan
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 51
Case 2
■ A 41 year old female with esophageal candida has just
completed a 10 day course of fluconazole. She has lost
weight because symptoms of thrush made it difficult to
swallow. She weighs 62 kg. She is to begin ARV therapy
today. She comes to your pharmacy to fill her prescriptions.
■ She presents you with the following:
■ Zidovudine 300 mg bid
■ Stavudine 40 mg bid
■ Nevirapine 200 mg once daily for the first 2 weeks, then increase to
200 mg bid
■ Bactrim DS 1 tablet daily
Unit 5: Significant Drug Interactions with ART
51
She qualifies for treatment because she has Grade IV disease in the WHO staging
system.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 52
Case 2 Questions
■ Is this an appropriate regimen for her?
■ Can you identify any possible drug interactions?
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
52
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 53
Case 2 Answers
■ No, this regimen is not appropriate for her. ZDV should
never be used with D4T as they compete for
intracellular phosphorylation.
■ The first line choice of nucleoside therapy should be ZDV +
3TC or D4T + 3TC in combination with nevirapine.
Unit 5: Significant Drug Interactions with ART
•
53
No, this regimen is not appropriate for her. ZDV should never be used with D4T
as they compete intracellulary for phosphorylation
•
The first line choice of nucleoside therapy should be ZDV + 3TC or D4T +
3TC in combination with nevirapine.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 54
Case 2 Questions (cont.)
■ How would you communicate the change that you
recommended to the physician who wrote the
prescription?
■ What would you say to the physician?
Unit 5: Significant Drug Interactions with ART
54
•
The pharmacist must form a relationship with the providers who write
prescriptions for ART. Communication may be made by phone, in person or
through the patient. Whichever way is most efficient and effective for making the
change is acceptable.
•
Always be professional when communicating with the physician. Remember that
you are sharing information with another health care provider.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 55
Case 3
■ A 50 year old male HIV + for 5 years, stable on therapy
presenting to the clinic to get more medication to treat
his thrush.
■ He has been taking his brother’s medication which
seemed to help at first and then stopped working. He
would like to get some more to clear the white plaques
on his tongue.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
55
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 56
Oral Thrush
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
56
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 57
Case 3 (cont.)
■ His current ARV regimen is:
■ Nevirapine 200 mg bid
■ Stavudine 40 mg bid
■ Lamivudine 150 mg bid
■ He has one pill of the medication left from his brother
and the physician brings it to your pharmacy to
determine what medication this is.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
57
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 58
Case 3 Questions
■ You identify the tablet as ketoconazole 200 mg.
■ Is this an appropriate medication to use with his current
ARV regimen?
■ What are some counseling points for this patient?
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
58
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 59
Case 3 Answer
■ Answer #1
■ No, this is not an appropriate therapy for his thrush.
■ Ketoconazole interacts with nevirapine
– Ketoconazole levels are decreased by 63%
– Nevirapine levels are increased by 15-30%
– They should not be co-administered
■ There are better alternatives to treat his thrush
– a better option would be a topical antifungal such as nystatin
suspension
Unit 5: Significant Drug Interactions with ART
59
Answer #1: No, this is not an appropriate therapy for his thrush.
•
Ketoconazole interacts with nevirapine
•
Ketoconazole levels are decreased by 63% and this is most likely the reason that his thrush
was not responding to the medication.
•
Nevirapine levels are increased by 15-30%
•
The bottom line is that they should not be coadministered
•
Ketoconazole and nevirapine should not be given concurrently due to the decrease in
ketoconazole concentrations. Coadministration of nevirapine (200 mg twice daily) with
ketoconazole (400 mg once daily) to 22 HIV+ individuals resulted in a 63% reduction in
ketoconazole AUC and a 40% reduction in Cmax. There was a 15–28% increase in plasma
concentration of nevirapine. Although interaction studies have not been performed, antifungal
medicinal products which are eliminated renally (e.g. fluconazole) may be substituted for
ketoconazole. Studies using human liver microsomes indicated that ketoconazole significantly
inhibited the formation of nevirapine hydroxylated metabolites.
•
•
Lamson M, Robinson P, Lamson M et al. The pharmacokinetic interactions of
nevirapine and ketoconazole. 12th World AIDS Conference, 1998, abstract 12218.
•
Viramune Summary of Product Characteristics, 2001, Boehringer Ingelheim
International.
•
Viramune Product Information, 2000, Roxane Laboratories Inc.
There are better alternatives to treat his thrush, including topical antifungals like nystatin or
fluconazole tablets.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 60
Case 3 (cont.)
■ Counseling points
■ Never share medication with others
■ Always check with your physician or pharmacist BEFORE
starting any medications on your own.
■ Prescription
■ OTC
■ Herbal
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
60
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 61
Case 4
■ A 50 year old male patient who has just completed 9
months of TB therapy (with rifampicin and isoniazid
along with pyridoxine) 3 weeks ago continues on ARVs
(EFV 800 mg qhs, 3TC 150 mg bid and ZDV 300 mg
bid) therapy. He presents to the ER with a bloody nose
and bruises on his arm.
■ Other current medications include
■ coumadin for atrial fibrillation
■ atenolol for blood pressure
■ What do you suspect has happened?
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
61
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 62
Case 4 Question
■ Enzyme inducers such as rifampicin gradually reduce
the response to oral anticoagulants, usually over 1-2
weeks (maybe sooner with rifampicin). The offset of the
effect usually takes place gradually over 2-3 weeks.
Since the patient has just discontinued taking
rifampicin, the response to his coumadin will
presumably increase, leading to supra-therapeutic
levels
■ How should this patient have been counseled before
the TB medication was discontinued?
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
62
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 63
Case 4 Answers
■ The patient should have been counseled that he should
be aware of the result of the discontinuation of his TB
meds and the effect that it could have on his warfarin.
■ leading to supratherapeutic response to warfarin
■ Increased risk of bleeding and bruising
■ He should have had his INR measured to monitor his
anticoagulation
■ His dose of warfarin will need to be adjusted to achieve the
desired therapeutic range
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
63
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 64
Case 4 Answers
■ Take home message
■ If it is necessary to use enzyme inducers and drugs that
are substrates of those enzymes, monitor for altered
response if the inducer is initiated, discontinued or
changed in dosage
■ What other drug interactions should be addressed
today?
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
64
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 65
Case 4 Answers
■ Now that the patient is no longer taking rifampicin,
the dose of his efavirenz should be reduced to
600 mg qhs.
■ This could be done now as he has been off
rifampicin for 3 weeks, the time that it takes for
this effect to offset.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
65
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 66
Pharmacokinetic
Enhancement
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 67
Pharmacokinetic Enhancement
■ Ritonavir used to “boost”
Cmin and increase t½ of
other protease inhibitors
■ Allows for extended
dosing intervals
■ Decreases pill burden
■ Reduces adverse effects
■ May allow salvage in
patients with resistance
and reduced susceptibility
Unit 5: Significant Drug Interactions with ART
■ Ritonavir (cont.)
■ Overcomes enzyme
induction caused by other
drugs
■ Increase drug exposure
■ Remove meal
requirements
■ Activity primarily via
inhibition of CYP450 3A4
■ May also inhibit MDR-PGP
efflux pumps
67
•
We have talked about potential drug-drug interactions that lead to toxic effects of ARVs,
let’s review how ARVs are used in a favorable way to enhance therapy.
•
Pharmacokinetic enhancement is the concept of combining agents from different
classes, or even using various agents from similar classes may be desirable, for a
number of different reasons:
•
To improve antiretroviral pharmacokinetics. Often, the efficacy of an antiretroviral is
limited or affected by its disposition in humans. One may sometimes take advantage of
enzyme inhibiting properties in order to improve the bioavailability and/or
pharmacokinetic profile of one or more drugs.
•
To improve adherence. When certain drugs are combined, dosing regimens may be
simplified, and often pill burden and/or food restrictions may be minimized. For
instance, when indinavir and ritonavir are combined, the dosage of indinavir may be
reduced to 400 mg twice daily. In addition, in the presence of ritonavir, indinavir
absorption is no longer significantly affected by the presence of food.
•
To minimize side effects. The standard dosage of ritonavir is 600 mg twice daily. At this
dosage, many patients may experience significant toxicity. When ritonavir is combined
with saquinavir, a lower dosage may be used, with better tolerance. Another example
may be seen when indinavir is co-administered with ritonavir: indinavir peak levels are
lower, which may potentially be associated with a reduced risk of nephrolithiasis.
•
To enhance antiviral activity. Additive or synergistic antiviral effects may be observed
when various antiretrovirals are administered together.
•
PK enhancement is primarily a result of inhibition of CYP450 3A4. It may also inhibit
MDR-PGP efflux pumps
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 68
Pharmacokinetics Principles
Concentration (ug/mL)
10
Cmax
maximum concentration
correlates with some short-term
side effects, e.g. nausea
8
6
AUC
area under the curve
overall drug exposure
4
2
0
2
4
6
8
10
12
Refer to enlarged image at end of handout
•
Refer to copies of slides 68-72 in the Participant Handbook.
•
Let’s review Pharmacokinetics Principles to better understand Pharmacokinetic
enhancement with ritonavir
•
The horizontal axis represents time and the vertical axis represents drug
concentration
•
Cmax is the maximum concentration of a drug. It correlates with some short-term
side effects, e.g. nausea
•
AUC is the area under the curve which represents overall drug exposure
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 69
Pharmacokinetics Principles
Concentration (ug/mL)
10
Cmin
minimum, or trough concentration
occurs at the end of the dosing interval
correlates with anti-HIV effect for all PIs
8
6
4
2
0
2
4
6
8
10
12
Refer to enlarged image at end of handout
•
The Cmin is the minimum, or trough concentration.
•
It occurs at the end of the dosing interval and correlates with anti-HIV effect for
all PIs
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 70
Unit 5: Significant Drug Interactions with ART
Refer to enlarged image at end of handout
70
•
When a single PI is used, as seen in the left example, it’s peaks may reach well
above the desired concentration for effectiveness and this may lead to drug
toxicity. Also, the levels of the drug may become too low, permitting viral
replication.
•
When PIs are used together as seen in the right example,
•
You are able to achieve lower peak levels which reduces the chance of side
effects and also, achieve higher trough levels which increases potency and
reduces the chance of viral replication.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 71
An Example of Ritonavir Boosting:
Indinavir/Ritonavir BID PK Study
10,000
IDV/RTV q12h:
800/200 High-fat Meal
Indinavir
Plasma
Concentration
(nM)
800/100 High-fat Meal
1,000
400/400 High-fat Meal
IDV q8h:
800 mg Fasted
100
0
2
4
6
8
Time Postdose (hours)
10
12
6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.
Refer to enlarged image
at end of handout
•
This graph depicts the drug levels achieved with a protease inhibitor alone
versus a ritonavir boosted PI.
•
The black line represents the levels for the PI Indinavir when given alone. The
red, blue and gray curves depict the level of indinavir when given with differing
doses of ritonavir and food. Note that when indinavir is given with ritonavir, it is
able to be given with food.
•
The peak levels are a slightly higher with the boosted regimen at first, and the
trough levels remain above the threshold to suppress the HIV virus.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 72
Indinavir Concentration (µg/mL)
Steady-State IDV Plasma Profile After
IDV + RTV 400 mg Q12H With Food
IC90
IDV + RTV 400/400 mg q12h (regular 35%-fat meal)
IDV 800 mg q8h (Fasting)
100
10
1
0.1
0.01
0
4
8
12
Time (h)
E981561A
12
16
20
24
[Hsu et al. AAC 98;42:2784-91]
Refer to enlarged image at end of handout
Over time, you can visualize how the levels of indinavir remain more constant when
dosed with ritonavir. Overall, the peaks are lower and the troughs are higher than
when indinavir is given alone.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 73
Dual Protease Inhibitors
■ Saquinavir + ritonavir
■ SQV 400mg/RTV 400mg BID
■ SQV 1000mg/RTV 100mg BID
■ SQV 1600mg/RTV 100mg QD
■ Indinavir + ritonavir
■ IDV 400mg/RTV 400mg BID
■ IDV 800mg/RTV 100-200mg
BID
■ Amprenavir + ritonavir
■ Lopinavir + ritonavir (Kaletra)
■ 3 Co-formulated capsules BID
■ Atazanavir + ritonavir
■ ATV 300mg/RTV 100mg QD
■ Fosamprenavir + ritonavir
■ F-APV 700mg/RTV 100mg BID
■ F-APV 1400mg/RTV 200mg
QD (FDA approved)
■ APV 600mg/RTV 100mg BID
■ APV 1200mg/RTV 200mg QD
(FDA approved)
Unit 5: Significant Drug Interactions with ART
73
•
Started using PIs in 1996 Rit/Saq increases cmax, cmin, UC (Rit dose does not have
large impact)
•
Mostly affects absorption
•
First comp trial for boosted reg showed that 1000/100 vs 800/100..sig more pts in saq
arm had VL < 400 and they also had lower TG, TC and LDL
•
Rit/Ind increases cmin and AUC, no real effect on cmax (increase dose, increase
effects on all parameters
•
Mostly affects elimination, Metabolism bo CYP3A4 or by p-glycoprotein
•
Rit/Amprenavir increases cmin and AUC, further increases in Rit dose does little to
increase overall drug exposure
•
Rit/Nelfinavir shows no change because is Nel mostly metabolized thru 2C19 and 2D6
•
Metabolite is increased but clinical signals are not known
•
Kaletra 4 caps bid with NFV of EFZ
•
Amprenavir with Kaletra
•
Virus from PI exp pts often retains a degree of phenotypic suscs. to both AMP and
LOP/RIT
•
Trough lop red by 44% with AMP, although remained 45-fold above the mean IC50 for
wild type isolates. Amprenavir levels increased 5 fold with lop/rit
•
Add RIT 200 mg bid , no diff in tolerability or AE, and virologically the is a sig diff, but
no info on the new trough levels
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 74
Key Points
■ Pharmacokinetic interactions refer to what the body does to the
drug.
■ Pharmacodynamic interactions refer to what the drug does to
body.
■ A drug interaction can occur whenever a medication is started or
discontinued or whenever a dose is changed.
■ Pharmacists play a critical role in detecting drug interactions
before they happen.
■ Pharmacists must be knowledgeable about potential drug-drug
and drug-food interactions.
Unit 5: Significant Drug Interactions with ART
74
•
Review these key points with participants
•
Ask for questions about this unit.
Reference Manual for Trainers
Pharmacists
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 75
Key Points (cont.)
■ Pharmacists should question a patient about their current
medications whenever filling a prescription that is new for them,
when a dose is changing or when a medication is being
discontinued.
■ Patients should be educated that drug interactions can also
occur if they stop or receive a change in dose of their
medications.
■ Pharmacists should ask patients about their use of herbal
preparations as they can interact with ARV therapy.
■ Pharmacokinetic enhancement is the concept of combining
agents from different classes, or various agents from similar
classes, to improve ARV pharmacokinetics, improve adherence,
minimize side effects, or enhance antiviral activity.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
75
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 76
References
■ Antoniu, Tseng Annals of Pharmacotherapy 2002:36:1598-613.
■ Bartlet J. MD, Gallant J. MD, MPH. Medical Management of HIV
Infection, 2003.
■ Centers for Disease Control
www.cdc.gov
■ Choudri et al. ICAAC 2000, #1637.
■ An Example of Ritonavir Boosting: Indinavir/Ritonavir BID PK
Study, 6th Conference on Retroviruses and Opportunistic
Infections; 1999. Abstract 362.
■ Facts and Comparisons, 2004.
■ Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS,
Harborview Medical Center, Seattle, WA, USA, 2004.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
76
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 77
References (cont.)
■ Frick, P. PharmD, MPH, Clinical Pharmacist, HIV/AIDS. Harborview Medical
Center, Seattle, WA. USA. 2004.
■ Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and
Adolescents, March 2004.
■ Hansten, P. PharmD Horn, J. PharmD: A Guide to Patient Management, the
Top 100 Drug Interactions, 2002.
■ Henderson L, Yue QY, Bergquist C, et al. St. John’s wort (Hypericum
perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol
2002; 54: 349-356, Piscitelli et al. Lancet 2000.
■ Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
■ HIV/AIDS Treatment Information Service
ww.hivatis.org
■ HIVInsite (UCSF) hivinsite.ucsf.edu
■ Hsu et al. AAC 98;42:2784-91.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
77
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 78
References (cont.)
■ JAMA HIV Page www.ama-assn.org/special/hiv
■ Johns Hopkins AIDS Service www.hopkins_aids.edu
■ Kosel, B. PharmD. Madison Clinic Pharmacy Harborview Mecical
Center Drug Interaction Table B, 2004.
■ Lamson M, Robinson P, Lamson M et al. The pharmacokinetic
interactions of nevirapine and ketoconazole. 12th World AIDS
Conference, 1998, Abstract 12218.
■ Laroche et al. CAHR 1998, #471
■ Medscape – HIV/AIDS www.medscape.com
■ Micromedex 2004
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
78
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 79
References (cont.)
■ National AIDS Treatment Advocacy Project
www.natap.org
■ Natural Medicine Comprehensive Database
www.naturaldatabase.com
■ NW AIDS Education Training Center
www.northwestaetc.org
■ Philip D. Hansten, Science & Medicine 1998.
■ Piscatelli, S. NEJM, Vol. 34, No.13. March 29, 2001.
■ Piscitelli SC, Burstein AH, Welden N, et al. The effect of garlic
supplements on the pharmacokinetics of saquinavir. Clin Infect
Dis 2002; 34(2):234-8.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
79
HIV Care and ART: A Course for
Unit 5: Significant Drug Interactions with ARVs
Slide 80
References (cont.)
■ Product Information Agenerase(R), 2001.
■ Product Information Depakene(R), 1999.
■ Product Information Depakote(R) ER, 2000, Depakote(R) Tablets, 1999.
■ Product Information Invirase(R), 2003.
■ Product Information Kaletra(TM), 2000.
■ Product Information Norvir(R), 2000.
■ Product Information Orap(R), 1999.
■ Product Information Reyataz(TM), 2003.
■ Viramune Summary of Product Characteristics, 2001, Boehringer Ingelheim
International. Viramune Product Information, 2000, Roxane Laboratories Inc.
Unit 5: Significant Drug Interactions with ART
Reference Manual for Trainers
Pharmacists
80
HIV Care and ART: A Course for
Slide 5.5 – First Pass Effect
First Pass Effect
Significant Drug Interaction with ART
9
Refer to enlarged image at end of handout
Slide 5.6 – Drug Metabolism/Elimination
Drug Metabolism/Elimination
Significant Drug Interaction with ART
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Refer to enlarged image at end of handout
10
Significant Drug Interactions with ART
Unit 5-7
Slide 5.13 – CYP P450 Drug-Drug Interactions
CYP P450 Drug-Drug Interactions
■ Pharmacologic action of drug is altered by
coadministration of second drug
■ Co-administration may:
↑effect (eg ritonavir + saquinavir;
↑ ritonavir + simvastatin)
Drug B
New effect (eg, ritonavir + amitriptyline)
Drug A
↓ effect (eg,rifampin + protease
inhibitors, indinavir + coumadin)
No Consequences
Significant Drug Interaction with ART
14
Refer to enlarged image at end of handout
Slide 5.27 – PI/ NNRTI/ Antidepressant Drug Interactions
PI/ NNRTI/ Antidepressant Drug Interactions
Antidepressant
Amitriptyline
Potential for
Interaction
ritonavir,
lopinavir/r,
amprenavir,
Fluoxetine
Sertraline
Effects
Management
Start with lower dose
Levels of
amitriptyline may be (50%) of amitriptyline,
adjust dose when adding
increased
ritonavir. Monitor for side
effects
ritonavir,
lopinavir/r, all
other PIs,
efavirenz
Levels of both
fluoxetine and
ritonavir,
lopinavir/r, all
other Pis,
efavirenz
Levels of sertraline
may be increased.
ARV levels
As above
ARVs may be
increased
As above
not likely to change.
Refer to enlarged image at end of handout
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Significant Drug Interactions with ART
Unit 5-8
Slide 5.68 Pharmacokinetics Principles
Pharmacokinetics Principles
Concentration (ug/mL)
10
Cmax
maximum concentration
correlates with some short-term
side effects, e.g. nausea
8
6
4
AUC
area under the curve
overall drug exposure
2
0
2
4
6
8
10
12
Refer to enlarged image at end of handout
Slide 5.69 Pharmacokinetics Principles
Pharmacokinetics Principles
Concentration (ug/mL)
10
Cmin
minimum, or trough concentration
occurs at the end of the dosing interval
correlates with anti-HIV effect for all PIs
8
6
4
2
0
2
4
6
8
10
12
Refer to enlarged image at end of handout
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Significant Drug Interactions with ART
Unit 5-9
Slide 5.70 Pharmacokinetic Rationale for Dual Protease Inhibitor
Therapy
Significant Drug Interaction with ART
71
Refer to enlarged image at end of handout
Slide 5.71 An Example of Ritonavir Boosting: Indinavir/Ritonavir BID
PK Study
An Example of Ritonavir Boosting:
Indinavir/Ritonavir BID PK Study
10,000
IDV/RTV q12h:
800/200 High-fat Meal
Indinavir
Plasma
Concentration
(nM)
800/100 High-fat Meal
1,000
400/400 High-fat Meal
IDV q8h:
800 mg Fasted
100
0
2
4
6
8
Time Postdose (hours)
10
12
6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Refer to enlarged image
at end of handout
Significant Drug Interactions with ART
Unit 5-10
Slide 5.72 Steady-State IDV Plasma Profile After IDV + RTV 400
mgQ12H with Food
Indinavir Concentration (µg/mL)
Steady-State IDV Plasma Profile After
IDV + RTV 400 mg Q12H With Food
IC90
IDV + RTV 400/400 mg q12h (regular 35%-fat meal)
IDV 800 mg q8h (Fasting)
100
10
1
0.1
0.01
0
4
8
12
Time (h)
E981561A
12
HIV Care and ART for Pharmacists
Reference Manual for Trainers
16
20
24
[Hsu et al. AAC 98;42:2784-91]
Refer to enlarged image at end of handout
Significant Drug Interactions with ART
Unit 5-11
References
Antoniu, Tseng Annals of Pharmacotherapy 2002:36:1598-613.
Bartlet J. MD, Gallant J. MD, MPH. Medical Management of HIV Infection,
2003.
Centers for Disease Control
www.cdc.gov
Choudri et al. ICAAC 2000, #1637.
An Example of Ritonavir Boosting: Indinavir/Ritonavir BID PK Study, 6th
Conference on Retroviruses and Opportunistic Infections; 1999. Abstract
362.
Facts and Comparisons, 2004.
Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS, Harborview
Medical Center, Seattle, WA, USA, 2004.
Frick, P. PharmD, MPH, Clinical Pharmacist, HIV/AIDS. Harborview
Medical Center, Seattle, WA. USA. 2004.
Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and
Adolescents, March 2004.
Hansten, P. PharmD Horn, J. PharmD: A Guide to Patient Management,
the Top 100 Drug Interactions, 2002.
Henderson L, Yue QY, Bergquist C, et al. St. John’s wort (Hypericum
perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol
2002; 54: 349-356, Piscitelli et al. Lancet 2000.
Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
HIV/AIDS Treatment Information Service
ww.hivatis.org
HIVInsite (UCSF) hivinsite.ucsf.edu
Hsu et al. AAC 98;42:2784-91.
JAMA HIV Page www.ama-assn.org/special/hiv
Johns Hopkins AIDS Service www.hopkins_aids.edu
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Significant Drug Interactions with ART
Unit 5-12
References (cont.)
Kosel, B. PharmD. Madison Clinic Pharmacy Harborview Mecical Center
Drug Interaction Table B, 2004.
Lamson M, Robinson P, Lamson M et al. The pharmacokinetic interactions
of nevirapine and ketoconazole. 12th World AIDS Conference, 1998,
Abstract 12218.
Laroche et al. CAHR 1998, #471
Medscape – HIV/AIDS www.medscape.com
Micromedex 2004
National AIDS Treatment Advocacy Project
www.natap.org
Natural Medicine Comprehensive Database www.naturaldatabase.com
NW AIDS Education Training Center
www.northwestaetc.org
Philip D. Hansten, Science & Medicine 1998.
Piscatelli, S. NEJM, Vol. 34, No.13. March 29, 2001.
Piscitelli SC, Burstein AH, Welden N, et al. The effect of garlic
supplements on the pharmacokinetics of saquinavir. Clin Infect Dis 2002;
34(2):234-8.
Product Information Agenerase(R), 2001.
Product Information Depakene(R), 1999.
Product Information Depakote(R) ER, 2000, Depakote(R) Tablets, 1999.
Product Information Invirase(R), 2003.
Product Information Kaletra(TM), 2000.
Product Information Norvir(R), 2000.
Product Information Orap(R), 1999.
Product Information Reyataz(TM), 2003.
Viramune Summary of Product Characteristics, 2001, Boehringer
Ingelheim International. Viramune Product Information, 2000, Roxane
Laboratories Inc.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Significant Drug Interactions with ART
Unit 5-13
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Significant Drug Interactions with ART
Unit 5-14
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 6
Women, HIV & ART in Pregnancy
Unit 6: Women, HIV & ART in Pregnancy
Aim: The aim of this unit is to introduce participants to considerations when caring
for HIV positive women and treating pregnant HIV positive women.
Learning Objectives: By the end of this unit, participants will be able to:
•
Explain the epidemiology of HIV disease in women
•
Describe the natural history of HIV infection in women
•
Recognize the gender differences in ARVs between men and women
•
Identify significant toxicities of antiretroviral therapy that affect women
•
Identify ART that can be used in pregnancy to prevent PMTCT
Unit Overview:
3 Hours
Step
Time
Activity/
Method
Content
Resources
Needed
1
10 minutes
Question-Answer
Introductory Case Study and
Question Slides (6.2-6.3)
Overhead or LCD
Projector
2
90 minutes
Lecture
Women and HIV & ART in Pregnancy
(Slides 6.4 -6.76)
Overhead or LCD
Projector
3
70 minutes
Group Exercise
Case Studies (Slide 6.77-6.93)
Worksheets 6.1, 6.2,
6.3, and 6.4 in the
workbook. Four flip
chart stands with
paper and markers.
4
10 minutes
Summary
Presentation of Key Points (Slides
6.94-6.96)
Overhead or LCD
Projector
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-3
Resources Needed
•
Flip Chart and Paper
•
Markers
•
Overhead or LCD Projector
•
The following materials can be found in the Participant Handbook:
- Management of Rash and Hepatotoxicity with Viramune (Handout 6.1)
- Guidelines for the Use of Antiretrovirals in HIV-1 Infected Adults and
Adolescents: FDA Pregnancy Categories-March 2004 (Handout 6.2)
•
The following materials can be found in the Course Workbook:
-Case Study Worksheets 6.1, 6.2, 6.3 & 6.4
Key Points
1. Women are more susceptible than men to contracting HIV through
heterosexual intercourse.
2. HIV infected women require special care.
3. Women are affected differently by HIV and ARVs.
4. Increased rates of certain toxicities in women may be due to differences in
drug metabolism.
5. Issues to consider when starting treatment include: preconception counseling,
teratogenicity of ARVs, drug interactions, efficacy, tolerability, and comorbidities.
6. Patients with AIDS are more likely to suffer from pregnancy-related
complications.
7. Transmission of HIV infection from mother to child can occur during
pregnancy, birth, or breastfeeding.
8. MTCT is the largest source of HIV infection in children under 15.
9. ART can reduce the likelihood of MTCT by 50%.
10. ART to reduce perinatal transmission must be given to the mother and infant.
11. Regardless of treatment strategy, a higher rate of transmission occurs with
breast feeding rather than formula.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-4
Step 1
Step 2
Introductory Case Study (10 minutes)
•
Ask a participant to read the case study on Slide 6.2.
•
Ask participants to silently attempt to answer the question on
Slide 6.3.
•
Explain that the question will be answered and the case
discussed more fully as the unit progresses.
Lecture (90 minutes)
•
•
Step 3
Step 4
This unit will introduce participants to considerations when caring
for HIV positive women and treating pregnant HIV positive
women.
Begin by reviewing slide 6.4 of the PowerPoint presentation,
“Women and HIV & ART in Pregnancy.” Ask the participants if
they have any questions about the objectives before continuing.
•
Present and discuss the PowerPoint presentation, “Women, HIV
& ART in Pregnancy” (Slides 6.5-6.76).
•
Refer to Handout 6.1 Management of Rash and Hepatotoxicity
with Viramune in Participant’s Handbook.
•
Refer to Handout 6.2 FDA Pregnancy Categories in Participant’s
Handbook.
Case study Group Exercise (70 minutes)
•
Case Study Group Exercise: Divide participants into four work
groups. Provide each work group with one of the four Women
and HIV Case Studies (Worksheets 6.1, 6.2, 6.3, 6.4). Ask the
groups to identify a recorder and a presenter, and then spend
twenty minutes discussing the case study together and
answering the related questions on flip-chart paper.
•
Ask each work group to share their decisions and answers.
Discuss each case thoroughly and use this time to answer
questions and clarify misinformation. Review the case studies in
the “Women, HIV & ART in Pregnancy” PowerPoint presentation
(6.77 – 6.93). Spend 15 minutes discussing each case.
•
If time is limited, discuss the case studies as a large group.
Summary (10 minutes)
•
Summarize the presentation, review the Key Points presented in
this Unit (Slides 6.94 - 6.96), and answer final questions.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-5
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes
for reference during the planning and implementation of this course. The
facilitation notes and talking points are included in the “notes” section of the
accompanying PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-6
Unit 6: Women, HIV and ART in Pregnancy
Slide 1
Women, HIV
& ART in Pregnancy
Unit 6
HIV Care & ART: A Course for Pharmacists
•
This unit should take approximately 3 hours to complete.
•
We will be discussing how women are affected by HIV and treatment issues
surrounding the care of HIV infected women.
•
We will also cover the use of ART in Pregnancy.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 2
Introductory Case
■ A 32 year old woman returns to the pharmacy 1month after
starting ART . As she reaches for her prescriptions, you notice
that she is scratching her arms. You know that many ART
medications can cause a rash, so you look to see what she is
taking.
■ Her regimen is as follows: Nevirapine 200 mg bid, lamivudine
150 mg bid and stavudine 40 mg bid.
■ You see a rash on her arms that is blistering. She does not look
well.
■ Which of the following statements is true about nevirapine and
the potential for side effects in women?
Unit 6: Women, HIV & ART in Pregnancy
2
•
Ask a participant to read the case.
•
Ask participants if they have any questions about the information presented.
•
Note: Do not give them further information on the case. Just ask them to consider
the information provided to them.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 3
Introductory Case Question
A. There are no differences between men and women in
regards to nevirapine side effects.
B. Women have a higher risk for developing severe
(grade 3 or 4) skin rashes than men.
C. Women are equally at risk as men for developing
hepatitis from nevirapine.
D. Women are at greater risk of developing lactic
acidosis from nevirapine than men.
Unit 6: Women, HIV & ART in Pregnancy
3
•
Ask participants to silently attempt to answer the question.
•
Explain that the answer to the question will be discussed as the unit progresses.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 4
Unit Learning Objectives
■ Explain the epidemiology of HIV disease in women
■ Describe the natural history of HIV infection in women
■ Recognize the gender differences in ART between
men and women
■ Identify significant toxicities of antiretroviral therapy
that affect women
■ Identify ART that can be used in pregnancy to prevent
PMTCT
Unit 6: Women, HIV & ART in Pregnancy
4
At the completion of the module, the participant will be able to
•
Explain the epidemiology of HIV disease in women
•
Describe the natural history of HIV infection in women
•
Recognize the gender differences in ARVs between men and women
•
Identify significant toxicities of antiretroviral therapy that affect women
•
Identify ART that can be used in pregnancy to prevent PMTCT
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Unit 6: Women, HIV and ART in Pregnancy
Slide 5
Global Facts
■ Of 39.4 million people living with HIV/AIDS, 17.6 are
women (end of 2004)
■ Of 5 million adults infected in 2002, 2 million were
women
■ Of 3.1 million deaths attributed to AIDS in 2001, 1.2
were women
■ Among HIV positive adults, women account for 57% in
sub-Saharan Africa, 30% in southeast Asia, 20% in
Europe, and 20% in the US
Unit 6: Women, HIV & ART in Pregnancy
5
•
HIV infection among women is a growing problem worldwide. In recent years new
data have emerged from ongoing cohort studies focusing on HIV-infected women.
Globally, of 39.4 million people living with HIV/AIDS, 17.6 million are women
(2004)
•
Of 5 million adults infected in 2002, 2 million were women
•
Of 3.1 million deaths attributed to AIDS in 2001, 1.2 were women
•
Among HIV positive adults, women account for 55% in sub-Saharan Africa, 30% in
southeast Asia, 20% in Europe, and 20% in the US
•
Data obtained from Current Status of HIV/AIDS in Ethiopia Source: Dr. Asegid
Woldu, Ethiopian Ministry of Health and MarryAnn Vitiello, HIV/AIDS Update 2003,
HIV Infection in Women, UNAIDS/WHO in December 2004
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Unit 6: Women, HIV and ART in Pregnancy
Slide 6
Prevalence of HIV in Young
Women (Sub-Saharan Africa)
•
Graphics from the "2004 Report on the global AIDS epidemic”
•
The HIV prevalence among young girls in Sub-Saharan Africa is dramatic
•
For example, in Zimbabwe the prevalence of HIV in men is about 5% and about
17% in women
•
Prevalence: percentage of a population that is affected with a particular disease at
a given time
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Unit 6: Women, HIV and ART in Pregnancy
Slide 7
UNAIDS Estimates
■ There are an estimated 3 million people living with
HIV/AIDS in Ethiopia. It is estimated that just over 10% of
the adult population is infected.
■ There were 1.9 million HIV-positive adults, over half of
whom (1.1 million, 57.9%) were women.
■ The group with the highest prevalence in the country is
women ages 15-24
■ Decline in HIV prevalence has been detected among young innercity women in Addis Ababa; infection levels among women 15–24
attending antenatal clinics dropped from 24.2% in 1995 to 15.1%
in 2001
Unit 6: Women, HIV & ART in Pregnancy
7
•
There are an estimated 3 million people living with HIV/AIDS in Ethiopia. It is
estimated that just over 10% of the adult population are infected.
•
There were 1.9 million HIV-positive adults, over half of whom (1.1 million, 57.9%)
were women (2001)
•
According to ANC surveys and from blood donors indicate that he group with the
highest prevalence in the country is women ages 15-24 (12.1.%).
•
A decline in HIV prevalence has been detected among young inner-city
women in Addis Ababa; infection levels among women 15–24 attending
antenatal clinics dropped from 24.2% in 1995 to 15.1% in 2001
•
However, similar trends were not evident in outlying areas of the city,
nor is there yet evidence of them occurring elsewhere in the country.
www.Aidsmap.com
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Unit 6: Women, HIV and ART in Pregnancy
Slide 8
The Plight of Women
“Women are most vulnerable to HIV infection, given
the social and economic disadvantages they face in
their day-to day lives.”
– Dr. Nafis Sadik, Executive Director of the United
Nations Population Fund
Unit 6: Women, HIV & ART in Pregnancy
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HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 9
Natural History of HIV
Disease in Women
■ Heterosexual and MTCT account for almost all HIV
infections in Ethiopia
■ Factors that put women/young girls at particular risk:
■ Biological
■ Economic (lack of health insurance)
■ Social (domestic violence)
■ Cultural (stigma, fear of disclosure)
Unit 6: Women, HIV & ART in Pregnancy
9
•
Data indicate that heterosexual and MTCT account for almost all HIV infections in
Ethiopia. In Ethiopia, women and young girls are disproportionately vulnerable to
HIV.
•
Their physiological susceptibility – is compounded by economic, social and cultural
forms of discrimination.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 10
Biological Factors
4 X at risk for heterosexual transmission than men
Gynecological problems can be early signs of HIV
infection.
■ Bacterial vaginosis increases risk of HIV RNA
expression
■ Candida risk increases 20 fold with CD4 < 100
■ Increased rates of cervical dysplasia
■ STDs increase plasma viremia
Unit 6: Women, HIV & ART in Pregnancy
10
•
NIAID Fact Sheet HIV Infection in women May 2001 / Primary Care Guidelines for HIV CID; 2004:39:
619-621
•
Women are 4 times more susceptible than men to contracting HIV during unprotected heterosexual
intercourse
•
Women with HIV may have gynecologic problems that are associated with HIV infection because of
common risk factors, such as sexual behavior or drug use.
•
HIV infected women get vaginal infections, genital ulcers, pelvic inflammatory disease and genital warts
more often and more severely than uninfected women. Therefore routing gynecologic care is essential.
Gynecological problems can be early signs of HIV infection.
•
Bacterial vaginosis increases risk of HIV RNA expression
•
Recurrent candidiasis (in the US)
•
Problems are more severe and occur more often in HIV infected women
•
Prevalent in 25-30% of women with HIV
•
Risk increases 20-fold with CD4<100. Vaginal candidiasis should be treated with topical
antifungals or if not responsive, oral antifungals can be used on an episodic basis to prevent the
development of resistance. Prophylactic use may be necessary for recurrent candida.
•
IN the US, 66% of HIV-infected women are co-infected with HPV (34% among HIV-negative women)
•
The approach to human papilloma virus (HPV) infection and cervical dysplasia is not defined. HIV
infected women have increased rates of cervical dysplasia and are at risk for cervical cancer. What is not
clear, is whether the improved immune function due to ART translates into reduced rates of cervical
dysplasia in women. Three studies from CROI (Conference on Retrovirus and Opportunistic Infections
2003 demonstrated that ART may improve the prognosis of cervical intraepithelial neoplasia (CIN).
•
STDs (ie. HSV) have been shown to increase genital tract HIV shedding and also increase plasma
viremia
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Unit 6: Women, HIV and ART in Pregnancy
Slide 11
Social/ Cultural Factors
■ Unequal gender relations
■ powerful social, economic, and political dimensions
contribute to the spread of HIV infection
■ gender prevention strategies involve men
■ women disproportionately affected by pandemic
■ Poor access to care
■ Stigma
Unit 6: Women, HIV & ART in Pregnancy
11
Infection in women and girls is fueled by the following factors:
•
Unequal gender relations: Poverty, low status, unequal economic rights and
educational opportunities place women and girls at greater risk of sexual exploitation,
trafficking and abuse. Women are less knowledgeable about HIV prevention.
•
Gender power relations limit women’s ability to negotiate safe sex or refuse unwanted
sex. Condom use is low. Almost 14% of currently married women in Ethiopia are in a
Polygamous union. Older men who often seek younger sexual partners. Even in
marriage this age discrepancy can increase a girl’s risk of infection.
•
Certain gender norms such as those that encourage men and boys to engage in risky,
early or aggressive sexual behavior increase the vulnerability of both men and women.
•
Since women have a low status in society, gender prevention strategies involve men.
All of these factors lead women disproportionately affected by the pandemic.
•
Several studies conducted early in the HIV epidemic that examined whether there is a
survival difference between men and women found that most differences in outcome
were due to differential access to care. Women have poor access to basic health care
and poor reproductive health as evidenced by the country’s high maternal mortality rate
exploitation such as rape and abuse of young women and girls, especially in
emergency and conflict situations. The stigma around HIV prevents women from
accessing care.
Source: UNFPA (2001) Women: Meeting the Challenges of HIV/AIDS
UCSF Country AIDS Policy Analysis Project HIV/AIDS in Ethiopia (2003)
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Unit 6: Women, HIV and ART in Pregnancy
Slide 12
Women Attend an HIV and AIDS
Awareness Session, Chad
Unit 6: Women, HIV & ART in Pregnancy
Credit: UNAIDS/AVECC/H. Vincent
12
•
Women must work together to gain empowerment and learn from each other.
•
Here is a picture of women attending an HIV and AIDS awareness session in Chad.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 13
Gender Differences
■ Viral load/Disease progression
■ ART pharmocokinetics
■ Toxicities (pharmacodynamic)
■ Drug Interactions
■ Oral contraceptives
■ Hormone replacement therapy
■ Adherence
Unit 6: Women, HIV & ART in Pregnancy
13
•
There are subtle gender differences that distinguish how men and women are
affected by the disease and more dramatic differences of how men and women are
affected by ART
•
Differences in viral load and CD4 counts as well as disease presentation i.e:
Women experience less Kaposi sarcoma than men
•
The differences of how women are affected by ARVs involves both
pharmacokinetic parameters (how the body affects the drug) and by
pharmacodynamic parameters (how the drug affects the body)
•
Women are faced with unique challenges around drug-drug interactions and
adherence to therapy.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 14
Viral Load in Women
■ HIV- 1 RNA levels are significantly lower in women than men
early on
■ Viral load early in HIV disease may not have the same
predictive value for women
■ Baseline lower viral loads do not translate into reduced risk of
clinical progression
■ HIV disease proceeds at the same rate as for men
(ALIVE Cohort, Swiss Studies, ICONA)
Unit 6: Women, HIV & ART in Pregnancy
14
•
HIV-1 RNA levels tend to be lower in women than in men. This difference is particularly
evident early in the course of HIV disease, when CD4 cell counts are higher as
described by Sterling and colleague in a study of HIV seroconverters from the ALIVE
Cohort.
•
The ALIVE Cohort demonstrated that the post-seroconversion viral load values were
higher among men who progressed rapidly than among men who were slow
progressors; however, viral load did not distinguish women at risk for rapid progression
from those who were slow progressors. Over time, HIV-1 RNA levels increased more
rapidly in women, and the values for women and men converged after about 4.5 years.
This study provides evidence that viral load early in HIV disease may not have the same
predictive value for women as it does for men. (ICONA and Swiss studies found less
convincing results) Ghandi et. Al Clin Infectious Disease 2002
•
Data reported by Anastos and colleague from the Women's Interagency HIV Study
(WIHS) confirmed that CD4+ cell count, but not viral load, predicts the rate of HIV
disease progression among women.
•
In fact, most studies have demonstrated that there is no difference in rates of
progression to AIDS among men and women.
•
Limited studies in HIV infected adults have indicated that women may have higher CD4
counts than men. Other studies have shown similar rates of disease progression
between men and women matched for CD4 count and/or HIV RNA level. The
immunologic mechanisms that underlie the sex difference in viral load postseroconversion clearly require further careful study.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 15
Drug Pharmacokinetics (PK)
■ Factors that may affect drug disposition, distribution
and metabolism
■ Differences in body weight
■ Hormonal physiology
■ Pregnancy
■ Menstruation
■ Sex differences in concentrations of endogenous plasma
cytokines
Unit 6: Women, HIV & ART in Pregnancy
•
15
A number of factors may in theory have subtle or profound effects on drug disposition,
distribution, and metabolism, including:
•
Differences in weight and body mass. On average, men are larger than women,
resulting in larger distribution volumes and altered clearance. Women have higher
body fat content. Hepatic metabolism differs between men and women.
•
The hormonal physiology associated with sexual maturation, pregnancy, and
menstruation
•
It is likely that any differences in viral and immuonlogic parameters between men and
women are hormonally related. Variations in viral load according to menstrual cycle
have been reported. Additionally PK parameters may vary over the ovulatory cycle;
considerable variations in indinavir PK were found during the menstrual cycle, with a
trend to more drug exposure during the follicular phase.
•
(Considerations for ARV therapy in Women –US Guidelines for the Use of ARVs in HIV_1
Infected Adults and Adolescents March 2004)
•
There are sex differences in concentrations of endogenous plasma cytokines (immunologic
mechanisms)
•
Even though many studies have demonstrated that there are differences in drug interactions
and incidence of adverse events in women compared with men, it is important to realize that
there is a broad clinical consensus that the efficacy of antiretroviral therapy is comparable in
women and men.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 16
Effect of Sex on ART
Pharmacokinetics
■ Predicting the effect of biological sex on PK
parameters is difficult
■ Not enough women in clinical trials
■ Higher levels of efavirenz, nevirapine, zidovudine and
lamivudine triphosphate have been described
■ also saquinavir, indinavir and amprenavir
■ Differences may result in adverse events or variable
response to ART
Unit 6: Women, HIV & ART in Pregnancy
16
•
Predicting the effect of sex on PK parameters is difficult. Schwartz indicated the
difficulty of predicting the effect of sex on PK parameters because of changes in
clearance, ranging from increased to decreased, to no change. (The influence of
sex on pharmacokinetics 2003;42:107-121)
•
There is a need for more research into sex differences in ARV pharmacokinetics.
There are limited PK data since women have been underrepresented in trials to
date.
•
The need for greater attention to PK differences is underscored by the fact that
women have a 1.5-1.7 –fold greater risk of having an adverse drug reaction
compared with men.
•
PK studies have shown that women experience higher drug levels, which may put
them at greater risk for toxicities.
•
Higher levels of efavirenz, nevirapine, zidovudine and lamivudine triphosphate
(concentration of intracellular lamivudine) have been described Also saquinavir,
indinavir and amprenavir.
•
Differences may result in adverse events or variable response to ARVs
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Unit 6: Women, HIV and ART in Pregnancy
Slide 17
ART and Toxicity in Women:
How Do They Differ From Men?
■ Rash
■ Hepatotoxicity
■ Lactic Acidosis/Hepatic Steatosis
■ Mitochondrial toxicity
■ Dysmenorrhea
■ Lipodystrophy / Hyperlipidemia
■ Osteoporosis
■ Renal
Unit 6: Women, HIV & ART in Pregnancy
17
Women are at increased risk of certain ART side effects when compared to men.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 18
ART and Toxicity in Women
NNRTIs
■ Nevirapine (NVP)
■ Incidence of rash: 15%, 1.5% severe, 4% requiring dc
■ Female sex independent risk factor ( 8 X more likely than men)
■ Incidence of hepatotoxicity: 4% symptomatic, 8.8%
asymptomatic
■ Risk greater because female sex (up to 3X more than men)
– Risk is up to 12X (11%) more than men in women with CD4 counts >250
■ Time to onset: risk of rash or hepatotoxicity greatest in the
first 4-6 weeks of therapy
■ NVP first 18 weeks: requires close monitoring
Unit 6: Women, HIV & ART in Pregnancy
•
•
•
•
18
Differences in drug metabolism in women may explain increased rates of certain
toxicities
Refer participants to the workbook. There are two sheets describing time to onset,
incidence, risk factors and the management of NVP related adverse events.
One is titled: Management of hepatic events with viramune and the second is
titled: Management of rash with viramune.
Rash attributed to NVP occurs in roughly 15% of patients overall (men and
women), 1.5% develop severe rash and 4 % require discontinuation
• Women’s risk is 8 X more likely than men ( In a multicenter, retrospective
study of 358 patients (27% women) who received nevirapine over a 5-year
period, women were 8 times more likely to develop grade 3-4 rash
compared with men (9.5% vs 1.1%). Likewise, in another retrospective
review of all patients starting efavirenz or nevirapine during a 3-year period,
female sex was a strong independent risk factor for developing NNRTIrelated rash, while ethnicity and CD4+ cell count were not predictive. )
• Female sex independent risk factor
Hepatotoxicity 4% symptomatic. However there was a range of 2.5-11%
• Overall risk greater because female (up to 3X more than men)
• Risk is up to 12X more than men in women with CD4 counts >250
• Caution in pregnancy when treating women with higher CD4 count (rates
are 11%)
• Risk is greatest for rash and/or hepatotoxicity in the first 6 weeks of therapy.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 19
Introductory Case Answers
■ The statement A): There are no differences
between men and women in regards to
nevirapine side effects is false.
■ Women are at greater risk of developing both
rash and hepatotoxicity from nevirapine than
men. Women who begin nevirapine should be
monitored closely for the first 6 weeks (up to 18
weeks) on therapy.
Unit 6: Women, HIV & ART in Pregnancy
•
19
Let’s think back to the case of the woman who had been taking NVP for 1 month
and review why the statement A): There are no differences between men
and women in regards to nevirapine side effects is false.
•
Women are at greater risk of developing both rash and hepatotoxicity from
nevirapine than men. Women who begin nevirapine should be monitored
closely for the first 6 weeks (up to 18 weeks) on therapy.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 20
Introductory Case
Answers (cont.)
■ The statement C): Women are equally at risk as men
for developing hepatitis from nevirapine is false.
■ Overall (men and women combined) incidence of
symptomatic hepatotoxicity is 4%, asymptomatic hepatitis:
8.8%. Hepatotoxicity generally occurs within first 4-6 weeks
of therapy
■ Overall risk greater because female (up to 3X more than men)
■ Risk is up to 12X (11%) more than men in women with CD4 counts
>250
■ Caution in pregnancy when treating women with higher CD4 count
Unit 6: Women, HIV & ART in Pregnancy
20
•
The incidence of hepatotoxicity associated with nevirapine has also been reported to be
higher in women. In a phase 3 study in which some subjects received nevirapine,
stavudine, and emtricitabine or lamivudine, a statistically significant 2-fold greater
incidence of grade 4 (severe) elevations of liver enzymes during the first 4 weeks of
nevirapine was observed in female subjects.
•
Moreover, an analysis of symptomatic hepatic events in a large cohort comprising 1731
nevirapine-treated patients and 1912 control patients found that the relative risk of rashassociated hepatitis was 3.2 in women compared with men, and 9.8 in women with CD4+
cell counts > 250 cells/mm3 compared with those with lower CD4+ cell counts. This study
confirmed that almost all rash-associated hepatic events occurred within the first 4-6
weeks of therapy.
•
The finding of a nearly 10-fold higher rate of symptomatic hepatitis events in women with
CD4+ cell counts > 250 suggests that caution is required when considering the use of
nevirapine in women with higher CD4+ cell counts. This highlights the importance of
monitoring LFTs when using nevirapine during pregnancy, since CD4+ cell counts tend
to be higher in that setting. The manufacturer reported a 12 fold higher incidence of
symptomatic hepatic events in women (including pregnant women) with CD4 counts > 250
prior to nevirapine initiation. In some cases, these adverse events occurred without prior
clinical signs or symptoms and without prior elevation in hepatic enzymes. Additionally,
hepatic injury may continue to progress despite discontinuation of nevirapine.
•
Therefore it is recommended that if nevirapine is used in women with CD4 counts of
>250, it requires close clinical and laboratory monitoring, especially during the first 18
weeks of therapy.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 21
Nevirapine Rash
•
The rash most commonly appears on the body and arms, usually within the first month
of therapy, although it may start a few weeks later.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 22
Management of NVP
Adverse Events
■ Rash
■ Assess rash and evaluate liver function tests (LFTs)
■ Mild-moderate rash without symptoms or rash with normal LFTs can
continue
■ Severe rash, rash with symptoms or rash with increased LFTs must
permanently discontinue
■ Hepatotoxicity
■ Evaluate pt. clinically and LFTs
■ If symptoms of hepatitis occur must permanently discontinue
Unit 6: Women, HIV & ART in Pregnancy
22
•
Counsel Patients to call their provider or pharmacist or return to clinic if they
develop a rash or have any blistering in the mouth, and if they develop fever,
arthralgias, or myalgias.
•
RASH: In order to reduce the risk of nevirapine-induced rash, the dose should be
escalated over the first 2 weeks – starting at 200mg QD for 2 weeks and then
increasing to 200mg BID. Patients that experience a rash during the 2-week leadin should not increase the dose until the rash has resolved (mean duration of rash
is 14 days). If the patient experiences rash and stops nevirapine on their own,
provider would not reintroduce nevirapine with the dose escalation until the rash
has resolved.
•
Patients that stop their medications for > 7 days should restart their regimen with
the dose escalation: Daily dosing for 2-weeks, then increase to 200mg BID.
•
It is suggested that nevirapine and other medications that often cause rash (e.g.,
abacavir and SMX/TMP) should not be started simultaneously so that the
offending agent can more easily be identified if a rash develops. For example, for
a new patient arriving in clinic that meets criteria for ART and PCP prophylaxis,
start SMX/TMP at first visit and monitor for side effects, then start nevirapine at
least 1 month later as part of ART regimen.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 23
ART and Toxicity in WomenNNRTIs (cont.)
■ Efavirenz
■ RASH: 26%, < 2% requiring discontinuation
– female sex an independent risk factor
■ Teratogenic: causes birth defects including neural tube
defects in newborns:
– should be avoided in pregnancy
– should be avoided in women of childbearing age
– should only be used in women of childbearing age if effective
contraception is absolutely in place
Unit 6: Women, HIV & ART in Pregnancy
23
•
26% of patients may experience rash on efavirenz. Less than 2% require treatment
discontinuation.
•
Female sex has been shown to be an independent risk factor for the development of rash.
Differences in
•
Drug metabolism may account for these differences.
•
Efavirenz is a known teratogen and has been shown to cause birth defects including
neural tube defects in newborns.
•
be avoided in pregnancy, should be avoided in women of childbearing age and should
only be used in women of childbearing age if effective contraception is absolutely in place
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Unit 6: Women, HIV and ART in Pregnancy
Slide 24
Introductory Case
Answers (cont.)
■ The statement B): Women have a higher risk for
developing severe (grade 3 or 4) skin rashes than men is
true.
■ Overall (men and women combined) the incidence of rash is 15%.
■ 1.5% of rashes are severe and 4% require discontinuation.
■ Women are as much as 8 X more likely than men to develop rash
■ Rash generally occurs in the first 6 weeks of therapy
■ Female sex is an independent risk factor
Unit 6: Women, HIV & ART in Pregnancy
24
Women are at greater risk of developing rash from either nevirapine or sustiva.
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Unit 6: Women, HIV and ART in Pregnancy
Slide 25
ART and Toxicity in Women Nucleoside Analogues (NRTIs)
■ Mitochondrial toxicity: class effect > in women
■ Attributed to higher intracellular drug levels
■ Lactic acidosis and hepatic steatosis
■ Symptoms are vague
■ With or without pancreatitis
■ Other risk factors: obesity, female and prolonged use of NRTIs
■ DDI + D4T combination is added risk
■ Must avoid use in pregnancy
Unit 6: Women, HIV & ART in Pregnancy
•
•
•
•
•
•
25
Intracellular concentrations of nucleoside analogues appear to be greater in women than in men
and may account for the stronger antiviral response that is seen as well as the differences in
nucleoside related toxicity.
Earlier studies demonstrated higher rates of mitochondrial toxicity and lactic acidosis in women
receiving nucleoside reverse transcriptase inhibitor (NRTI)-based therapies. In the AIDS Clinical
Trials Group (ACTG) 175 study, which evaluated dual-NRTI combinations of zidovudine plus
didanosine or zalcitabine, women were more likely to change their dose of didanosine earlier in
the study and to report severe symptoms including headaches, nausea, and pain. A recent study
of sex differences in the intracellular accumulation of triphosphate (TP) levels found that NRTIrelated toxicity was associated with higher levels of zidovudine-TP and lamivudine-TP found in
women compared with men (2.3-fold higher for zidovudine-TP and 1.6-fold higher for lamivudineTP). This study also found that women achieved HIV-1 RNA levels < 50 copies/mL more rapidly
than men. The investigators concluded that elevated TP concentrations of zidovudine and
lamivudine may explain the stronger antiviral response and the differences in NRTI-associated
toxicity.
Chronic compensated hyperlactatemia can occur during treatment with NRTIs. Although rare, this
syndrome is associated with a high mortality rate. Other risk factors for experiencing this toxicity
include obesity, being female and prolonged use of NRTIS, although cases have occurred with
risk factors being unknown. Symptoms are vague and include non-specific symptoms: nausea,
vomiting and weight loss. Mean time on ART is about 255 days. However, the combination of DDI
and D4T is not used very often, and it is not one of the recommended nucleoside combinations for
initial or secondary therapy in Ethiopia.
Severe lactic acidosis with or without pancreatitis including three fatal cases were reported during
the later stages of pregnancy or among postpartum women whose ART during pregnancy
included stavudine and didanosine in combination with other ARVs.
Of note, in the US, the FDA reported 60 reports of lactic acidosis associated with dual nucleosides
(does not breakdown which nucleoside combinations): 55% mortality. 83% of the cases were in
women, 50% in women >175 pounds.
Pancreatitis: female sex has been found to be an independent risk factor for pancreatitis. CROI
2001
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 26
Introductory Case
Answers (cont.)
■ The statement D): Women are at greater risk of
developing lactic acidosis from nevirapine than men is
false.
■ Women are at greater risk of developing lactic acidosis
most likely caused by nucleoside analogues than are
men.
■ Nevirapine has not been shown to cause lactic
acidosis.
Unit 6: Women, HIV & ART in Pregnancy
Reference Manual for Trainers
26
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 27
ART and Toxicity in Women Protease Inhibitors (PIs)
■ Hyperglycemia
■ HERS Cohort Study
■ PI use, age and BMI independent predictors of developing diabetes
■ Routine screening for diabetes is essential among patients on PI therapy
■ Older patients
■ Overweight
■ Pregnant
■ Drug interactions
■ Menstrual cycle
■ ART serum levels
Unit 6: Women, HIV & ART in Pregnancy
27
•
HERS Cohort Study: prospectively examined the incidence of diabetes among women
enrolled in the HERS Study. The overall population was predominantly black or Hispanic. In
a multivariate PI use, age and body mass index were independent predictors of developing
diabetes. Rates of diabetes were significantly higher among women receiving PIs 3% vs 1%
for women receiving non-PI based therapy. The low rates of diabetes in this study may be
explained by the reliance of self-report rather than using a specific test such as glucose
tolerance test or fasting glucose. Routine screening for diabetes is essential among patients
on PI therapy, especially those who are older, overweight or pregnant.
•
We will talk about PI specific drug interactions in more detail, just know that PIs can affect
oral contraceptives and hormone replacement therapy.
•
Protease inhibitors may affect or be affected by the menstrual cycle. Indinavir levels taken at
different time points of the menstrual cycle showed a marked variability with a wide range of
concentrations. One report suggested that women taking ritonavir may be at risk of
developing hypermenorrhea. Despite normal pretreatment menstrual cycles and hemoglobin
levels, 4 women developed hypermenorrhea within 2 months of starting ritonavir, and 1
woman required a transfusion because of severe anemia.
•
We know that women seem to have higher levels of certain PIs including saquinavir,
indinavir and amprenavir. In one ACTG study (359) a saquinavir based regimen, women
were reported as having higher blood levels than men, and there was a suggestion of
superior response in women as well. Nelfinavir, when dosed tid had inadequate blood levels
in women compared to when it was dosed bid.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 28
ART and Toxicity in Women:
Lipodystrophy
■ Lipodystrophy
■ Previously thought that there was a greater risk of fat
accumulation and breast enlargement
■ Fat depletion more common in men
■ Recent evidence to challenge previous ideas
■ Body fat changes seem to be comparable among men/women
■ Lipoatrophy is the predominant body shape change in women
■ Lipid abnormalities
■ Elevation of triglycerides and cholesterol (much more common in
men)
Unit 6: Women, HIV & ART in Pregnancy
28
•
Body fat changes seem to be comparable among men/women. Lipoatrophy is the
predominant body shape change in women. New studies demonstrate the need to
compare HIV infected women to non infected women to evaluate metabolic
complications
•
Tien and colleagues from WIHS compared body shape changes in women with
HIV with those of a matched control group of HIV –negative women. Their findings
suggested that the predominant syndrome that separated the HIV positive women
from uninfected controls was the presence of both central and peripheral
lipoatrophy. The rates of central lipohypertrophy did not differ among the two
groups. The FRAM study found similar results in men.
•
A second study demonstrated that women had lower percentages of body fat and
limb fat compared with controls. However, in this study, the percentage of truncal
fat was higher among HIV infected woman than the controls. Black women had
decreased trunk fat compared to all other women. In the multivariate analysis that
included the HIV positive women, stavudine use and non-black race were
independently associated with increased truncal fat and decreased limb fat, but PI
use was not. Therefore, there are possible racial differences in body fat changes
and should be examined in future prospective studies.
•
Lipid abnormalities
•
Elevation of triglycerides and cholesterol were much more common in men.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 29
Lipoatrophy
Notice the thinning of the face through the cheek area.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 30
ART and Toxicity in Women
■ Renal toxicity
■ Limited information
■ Decreased bone mineral density
■ 3 studies found that traditional risk factors and not ART were
associated with decrease BMD
– CROI 2003 (Abstract 102,103,766)
Unit 6: Women, HIV & ART in Pregnancy
30
•
There is limited information about the incidence and prevalence of renal disease
among HIV infected women. The impact of ARVs on the natural history of HIVassociated nephropathy is not well defined. One recent study demonstrated that
renal abnormalities in HIV infected women are associated with increased mortality.
The findings stress the importance of routinely screening women for renal
abnormalities.
•
Decreased bone mineral density
•
3 studies found that traditional risk factors (years since menopause,
smoking, physical activity and weight) and not ARVs were associated with
decrease BMD.
•
Routine screening of HIV infected women using DEXA scans is not
specifically recommended
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 31
Drug Interactions
■ Hormonal contraception
■ Nevirapine, efavirenz, lopinavir, ritonavir, nelfinavir and amprenavir may
lead to subtherapeutic levels of ethinyl estradiol (EE) resulting in
unwanted pregnancy
■ Must use other means of contraception
■ Atazanavir increases EE/norethindrone
■ Hormone replacement therapy
■ Some PIs may decrease estrogen levels
■ May play a role in the onset of early menopause or loss of bone density
■ Indinavir and Efavirenz may increase estrogen levels
Unit 6: Women, HIV & ART in Pregnancy
31
•
Pharmacokinetic interactions between nevirapine and ethinyl
estradiol/norethindrone (EE/NET) were recently reported in a study of 14 women
receiving stable HAART. Coadministration of nevirapine and EE/NET resulted in a
median reduction in EE/NET levels of 29% and a reduced half-life (11.6 hours,
compared with 15.7 hours in the absence of nevirapine) EFV increases EE by
37%. No data on other component. Use alternative method per the guidelines.
•
The protease inhibitors lopinavir, ritonavir, nelfinavir and amprenavir may lead to
subtherapeutic levels of ethinyl estradiol (EE) resulting in unwanted pregnancy
Women must use other means of contraception when taking these PIs.
•
The protease inhibitor atazanavir increases EE by 48% and norethindrone by
110%. Use the lowest effective dose or alternative methods.
•
Must use other methods of birth control. May be able to use depo-provera as it
bypases the interaction, however, condoms should be encouraged to protect
women from other STDs or re-infection.
•
Also, antiretroviral agents may affect estrogen levels in women undergoing
hormone replacement therapy; some PIs may decrease estrogen levels, while
indinavir and efavirenz may result in increased levels. These interactions may
have broader implications: Reductions in natural levels of estrogen may be
associated with other complications, such as the onset of early menopause or loss
of bone density.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 32
Treatment Guidelines
for Women
■ Guidelines are not gender specific
■ Issues to consider when starting treatment
■ Preconception counseling
■ Teratogenicity of ARVs
■ Drug interactions
■ Efficacy
■ Tolerability, side effects
■ Co-morbidities (TB, pregnancy, depression)
Unit 6: Women, HIV & ART in Pregnancy
32
•
Guidelines are not gender specific, the indications for treatment are the same for
women as they are for men.
•
However, there are certain issues to consider when starting treatment in women:
•
Preconception counseling
•
Teratogenicity of ARVs: avoid EFZ in women of childbearing age and in
pregnancy (next slide) Also avoid DDI + D4T which have been shown to
increase the risk of lactic acidosis in pregnancy.
•
Drug interactions:OCs, hormome replacement therapy, others
•
Efficacy
•
Tolerability
•
Comorbidities (TB, pregnancy)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 33
Women of Reproductive Age
■ Regimen selection should account for the possibility of planned
or unplanned pregnancy
■ Sexual activity, reproductive plans and use of effective
contraception, should be discussed with the patients before
initiating therapy and on a routine basis thereafter
■ When evaluating for initiation of therapy, counsel on the
potential risk of efavirenz containing regimen should pregnancy
occur
■ Avoid efavirenz
■ in women who are not using consistent contraception
■ in pregnancy
Unit 6: Women, HIV & ART in Pregnancy
33
•
The most vulnerable period in fetal organogenesis is early in gestation, often
before pregnancy is recognized. Sexual activity, reproductive plans and use of
effective contraception, should be discussed with the patients.
•
As part of the evaluation for initiating therapy, women should be counseled about
he potential risk of efavirenz-containing regimens should pregnancy occur.
•
Efavirenz should be avoided in women who are trying to conceive or are not using
effective and consistent contraception. The counseling should be provided on a
routine basis after initiation of therapy as well.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 34
Women and Adherence
■ Are women less adherent than men?
■ Lack of knowledge about risk for HIV
■ Often don’t disclose HIV status (stigma)
■ May feel isolated, lack of support
■ Caregivers/ family responsibilities
■ Cost of health care
■ Substance abuse, mental health disorders (depression)
■ Challenges in accessing and maintaining care; childcare,
transportation, inexperienced providers, etc.
Unit 6: Women, HIV & ART in Pregnancy
34
•
Are women less adherent than men?
•
What are some of the possible reasons for nonadherence among women? Here
are a few of the obstacles that women face
•
•
Lack of knowledge about risk for HIV
•
Often don’t disclose HIV status (stigma)
•
May feel isolated, lack of support
•
Caregivers/ family responsibilities
•
Cost of health care
•
Substance abuse, mental health disorders (depression
•
Challenges in accessing and maintaining care; childcare, transportation,
inexperienced providers, etc
Depression is common in women and has been reported to adversely affect
adherence. In in analysis by Young et al from the WIHS Cohort, women had a
more rapid decline in CD4 counts and a 150% increase in mortality compared with
women without depression XIV International AIDS Conference
Nauen E. AIDS: A women’s disease The Body Women and AIDS 2002
Cargil V The doctor’s opinion The Body Women and HIV 2002
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 35
Tools for Optimal Adherence
■ Evaluate for mental health, substance abuse and other
barriers to adherence
■ Assess HAART readiness
■ Develop mutually agreeable HAART regimen specific to
lifestyle
■ Prepare plan for side effects
■ Encourage atmosphere of communication and trust
■ Be accessible and available
Unit 6: Women, HIV & ART in Pregnancy
35
•
Evaluate for mental health, substance abuse and other barriers to adherence
•
Assess HAART readiness
•
Develop mutually agreeable HAART regimen specific to lifestyle
•
Prepare plan for side effects
•
Encourage atmosphere of communication and trust
•
Be accessible and available
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 36
ART in Pregnancy
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 37
Objectives for Pharmacists
■ Recognize indications for ART in pregnancy and first
line regimens
■ Identify risk factors for maternal to child transmission
and ways to reduce risk
■ Understand the known toxicities of ART to mothers
and infants
■ Recognize ART to avoid in pregnancy
Unit 6: Women, HIV & ART in Pregnancy
Reference Manual for Trainers
37
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 38
HIV and Pregnancy
■ Pregnancy does not seem to have an effect on
progression of disease to AIDS
■ However, patients with AIDS are more likely to suffer
from pregnancy-related complications
Unit 6: Women, HIV & ART in Pregnancy
38
•
While pregnancy does not appear to hasten HIV progression, it is clearly an
important additional stress on the body in patients with AIDS, above and beyond
the effects of the HIV, possible co-infections and specific ARVs.
•
Pregnancy as an immune suppressor may be a contributing factor that adds stress
on the body
•
In a women with advanced disease, HIV may have an impact on pregnancy:
•
•
Spontaneous abortion
•
Infections (opportunistic, GU, postpartum, post-surgical)
•
Preterm labour
•
Premature rupture of membranes
•
Low birth weight babies
•
Still births
Emphasize that at this point in time, most of the complications appear to be
related to advanced HIV disease.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 39
Pregnant Women Testing
HIV Positive 2001, Urban
Shashemene
13.1
Gambella
14.6
Gonder
15.1
Dire dawa
15.2
Addisava
15.6
Adigrat
16.2
Maichew
16.8
MKELIE
17.2
Nazareth
18.7
Jijiga
19
Bahrdar
23.3
0
5
10
15
20
25
Prevalence (%)
Source: Dr. Asegid Woldu, Ethiopian Ministry of Health, Current Status
of HIV/AIDS in Ethiopia July 2004
•
This slide depicts the prevalence of Pregnant women testing positive in Urban
areas
•
Bahrdar and Jijiga have the highest prevalence.
•
All areas have a prevalence greater than 13%
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 40
Pregnant Women Testing HIV Positive
2001, Rural
1.5
Attat
1.1
Gambo
2.6
Aira
Borena Dadim
1.7
BOREA Gosa
1.7
4.6
Ambo Toke
0
1
2
3
4
5
Prevalence (%)
Source: Dr. Asegid Woldu, Ethiopian Ministry of Health, Current Status
of HIV/AIDS in Ethiopia July 2004
•
The area with the highest prevalence of pregnant women testing HIV positive in
rural areas is Ambo Toke
•
Prevalence rates for all rural areas are <5%
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 41
Antenatal HIV Prevalence Rates
Among Pregnant Women
■ Outside of sub-Saharan Africa: rates > 5% are rare
■ 1999-2002 HIV prevalence among pregnant women in
Ethiopia aged 15-24 outside major urban areas was
12.7%
■ However, in Botswana, Zimbabwe and Swaziland:
rates are over 40%
Source: United Nations Environment Programme – Globalis Ethiopia
Unit 6: Women, HIV & ART in Pregnancy
41
•
Outside of sub-Saharan Africa: rates > 5% are rare
•
Rates among pregnant women >10% in the capital cities of 10 sub-Saharan
countries and >20% in 8 countries
•
1999-2002 HIV prevalence among pregnant women in Ethiopia aged 15-24 outside
major urban areas was 12.7%
•
In Botswana, Zimbabwe and Swaziland: rates over 40%
•
The bold figure was obtained from United Nations Environment Programme –
Globalis Ethiopia
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 42
Estimated & Projected
Number of AIDS Orphans
3
Millions
2
1
0
1984
1989
1994
1999
2004
2009
2014
Source: Dr. Asegid Woldu, Ethiopian Ministry of Health, Current Status
of HIV/AIDS in Ethiopia July 2004
•
The estimated number of AIDS orphans is on the rise. The number of orphans is
thought to double in the next ten years.
•
Effective, safe and affordable methods to reduce transmission rates must be
defined.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 43
Pregnancy Outcomes: Goals
■ Uncomplicated pregnancy
■ Healthy, uninfected infant
■ Prevent transmission from mother to infant during all stages
of pregnancy and through breastfeeding
■ Healthy mother who has not compromised her future
options for HIV therapy
Unit 6: Women, HIV & ART in Pregnancy
43
Pregnancy Outcomes, what are the goals?
•
Uncomplicated pregnancy
•
Healthy, uninfected infant
•
Prevent transmission from mother to infant during all stages of pregnancy
and through breastfeeding
•
Healthy mother who has not compromised her future options for HIV therapy
•
Prevention includes all members of the family.
•
Mothers and fathers have an impact on transmission of HIV to the baby.
•
If a woman becomes infected with HIV when she is pregnant or breastfeeding, the
risk of transmission to the baby increases.
•
Both partners need to be aware of the importance of safer sex throughout
pregnancy and breastfeeding.
•
Whether women are positive or negative:
•
•
all women should recognize the risk of initial infection, super-infection if they
are already infected, STI's which increase the burden on the immune
system.
Discussion question: What are some measures that can help to prevent
transmission of HIV infection from Mother to Child ?
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 44
Current Status of Ethiopia and
Mother-to-Child Transmission
■ Estimates of HIV transmission rates from women to
children are about 20-30%
■ In utero, during labor and delivery and breastfeeding
■ MTCT is by far the largest source of HIV infection in
children under 15
■ The rate of MTCT in Ethiopia has been estimated to be
29-47%
Unit 6: Women, HIV & ART in Pregnancy
•
44
Estimates of HIV transmission rates from women to children are about 20-40%
•
In utero, during labor and delivery and breastfeeding
•
MTCT is by far the largest source of HIV infection in children under 15. In countries
where blood products are regularly screened and clean syringes and needles are
widely available, it is virtually the only source of HIV infection in young children.
•
One study identified an estimate of the rate of MTCT in Ethiopia at 29-47%
•
In 1998, 10% of all new HIV infections were in children, almost all mother-to-child
transmissions (90%) were in Africa.
•
MTCT is a worldwide problem and a particular problem in Africa.
•
The National Guidelines suggest that 90% of HIV/AIDS in children is believed to
be as a result of MTCT.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 45
Risk Mother-to-Infant HIV-1
Transmission
■ ~8% prenatal
■ Primary maternal HIV-1
infection
■ Illicit drug use
■ ~17% breastfeeding
■ Mastitis
■ Primary maternal HIV-1
infection
■ 10-15% peri-natal period
■ Duration of rupture of
membranes
■ Maternal viral load
■ Trauma / exposure to maternal
blood
■ STDs
Unit 6: Women, HIV & ART in Pregnancy
45
•
Risk factors for MTCT are multifactoral A high viral load increases the risk of
vertical transmission as does the acquisition of infection during pregnancy. Women
with advanced disease (low CD4 count) are at increased risk of transmission.
STDs have been shown to increase genital tract HIV shedding and also increase
plasma viremia.
•
Breastfeeding was estimated to have accounted for up to 50% of newly infected
children globally in 1998. Risk of transmission is highest in the earliest months but
increased duration of breastfeeding increases risk.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 46
Unit 6: Women, HIV & ART in Pregnancy
46
Source: Judith Currier, 9th CROI, 2002
•
This graph compares the risk of transmission seen in a variety of studies.
•
The most success has been seen with HAART based regimens, whether with a PI or NNRTI as
seen in the WITS trial and the 316 trial
•
Information from two ACTG trials, protocols 076 and 185, has provided some insight into the
association between maternal viral load and vertical transmission. In ACTG 076, a three-part
AZT protocol reduced the rate of HIV transmission by two-thirds, from about 25% to 8%, (as
was seen in the previous slide) in a group of relatively healthy, mostly treatment-naïve pregnant
women. (The three-part AZT regimen consisted of 100 mg oral AZT five times daily
commenced sometime during the last six months of pregnancy; then IV AZT during labor, and
finally, AZT syrup given to the newborn for six weeks.)
•
ACTG 185 studied a cohort of sicker women, with lower CD4 counts, higher viral loads and
more time on prior antiviral therapy. The group received the 076 regimen plus either HIVIG (an
antibody preparation taken from people who produce high levels of HIV antibodies) or IVIG (a
standard antimicrobial preparation from HIV-negative persons). Researchers had expected the
rate of transmission to be higher in the 185 population and were surprised to find that it was
actually only 4.8% in both treatment arms.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 47
More Potent Antiretroviral Regimens
Associated with Lower Perinatal Transmission
% Transmission
30
21%
20
8%
10
4%
1%
0
None
(N=391)
ZDV
Alone
Less Potent Potent
Combo
Combo
(N=179)
(N=187)
•
Maternal antenatal antiretroviral treatment was associated with risk of perinatal
transmission. Transmission was highest, 21% in women without therapy and also
ZDV monotherapy when administered for maternal HIV disease (prior to 4/94);
these rates were not significantly different. Transmission was significantly lower
with 076 ZDV monotherapy (8%), non-HAART multi-antiretroviral (4%), and lowest
with HAART (1%).
•
FYI: as a reference for the facilitator, not to be discussed
•
In univariate analysis, significant factors associated with transmission was
maternal delivery RNA, low maternal CD4 count, type of antiretroviral therapy,
maternal AIDS-defining illness, duration of membrane rupture, elective cesarean
delivery, maternal antenatal hard drug use, gestational age of infant, low infant
birthweight.
•
In multivariate analysis, independent risk factors for transmission were higher
antenatal delivery RNA, increasing complexity of maternal antiretroviral therapy,
duration of membrane rupture over 4 hours, infant birthweight <2500 grams, and
elective cesarean delivery (the latter borderline significance).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 48
Maternal Delivery HIV RNA Levels and Antiretroviral Use
are Independently Associated With Perinatal
Transmission
Cooper E et al. JAIDS 2002;29:484-94
Percent
Transmission
60
None
ZDV Mono (<4/94)
ZDV Mono (>4/94)
Multi-ART
Antiretroviral
HAART
40
20
0
>4 >1
00 00
00 00
0
-1
>3 000
00
00
040
U
nd
>4 000
et
0
ec
0
ta -30
bl
00
e
(<
40
0)
Therapy
Maternal Plasma HIV1 RNA Copies/ml*
•
Maternal delivery HIV RNA levels and ARV use are independently associated with
perinatal transmission
•
The use of HAART greatly reduces transmission rates at the time of delivery
independent of viral load
•
The bottom line: reduction of viral load with antiretroviral therapy is associated with
reduced risk of perinatal transmission.
•
Antiretroviral therapy is beneficial in reducing risk of transmission even when
maternal baseline viral load is less than 1,000 copies/mL
•
However, there is no viral load threshold below which the risk of transmission is
zero
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 49
ART Clinical Scenarios
■ On ART and become pregnant
■ Pregnant and eligible for ART
■ Pregnant and not requiring ART
■ Pregnant and presenting after 34 weeks
Unit 6: Women, HIV & ART in Pregnancy
49
•
Antiretroviral Therapy, especially HAART, reduces risk of transmission, even in
mothers with low baseline viral loads. There is also a relationship between low
CD4 counts < 200, and increased risk of vertical transmission (National Guidelines
2001)
•
3 drug therapy of HAART reduces the risk of the mother from developing
resistance, thereby preserving future treatment options. There are certain
scenarios where HAART may be appropriate. Here are 4 clinical scenarios which
may present when approaching treatment of the pregnant patient
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 50
Scenario 1: On ART and
became Pregnant
■ Women on efavirenz
■ Counsel about potential
teratogenicity
■ Stop EFV and start NVP if in first
trimester
■ Discuss with ART trained
physician
■ Women on ZDV/DDI/LPV/r
■ Continue treatment
■ Full blood count monthly
■ Monitor blood glucose levels as
appropriate
■ Women on D4T/3TC/nevirapine
■ Continue treatment or change D4T
to ZDV (full blood count monthly if
on ZDV)
■ ALT monthly and when indicated
Unit 6: Women, HIV & ART in Pregnancy
50
•
Some providers may choose to stop therapy in the 1st trimester to avoid toxicities.
All drugs should be restarted in the second trimester unless contraindicated.
•
Women who become pregnant on ARV therapy: can continue their treatment, but
may have to modify their regimen:
•
Women who become pregnant while on EFV must be counseled about potential
teratogenicity.
•
EFV must be stopped and NVP started (in their 1st trimester).
•
Note: Neural tube defects have been described in human babies
•
Women who become pregnant on d4T/3TC/NVP (regimen I) should continue with
same regimen throughout pregnancy. ALT should be performed monthly and as
appropriate. Inclusion of AZT in regimen recommended if Hgb >7.
•
Women who become pregnant on second-line therapy (ZDV, DDI and LPV/r)
should continue their ARV therapy throughout pregnancy. Full blood count should
be done monthly.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 51
Scenario 2: Pregnant and
Eligible for ART
■ WHO stage IV
■ WHO stage III with consideration of CD4 count <350 or
■ WHO stage I or II with CD4 < 200
■ Begin first line therapy:
■ ZDV*300 mg bid or D4T 40 mg every 12 hours (or 30 mg q 12 hours if < 60
kg) +
■ 3TC 150 mg q12 hrs +
■ NVP 200 mg qd for 2 weeks, then 200 mg q12 hrs
■ If unable to use NVP, PI options include NFV, LPV/r or SQV/r
■ ALT q 2 weeks for 1 month, then q month and then as indicated
■ *Preferred
Unit 6: Women, HIV & ART in Pregnancy
51
•
Indication for therapy is the same as in the non-pregnant patient
•
ARV treatment should not be held unless the risk of adverse effects outweigh the benefits for
women
•
Timing of initiation of ARV therapy during pregnancy:
•
For pregnant women it may be desirable to initiate ART after the first trimester although for
such women who are severely ill, the benefit of early therapy clearly outweighs any potential
fetal risks, and therefore should be initiated in these cases.
•
To begin evaluation for ARV therapy, patients must be, at least, < 34 weeks of gestation, by
best dating criteria available.
•
ARV therapy must begin no later than 36 weeks of gestation by best dating criteria available to
ensure maximal viral suppression.
•
Patients greater than 34 weeks of gestation when identified with AIDS or unprepared to start
ARVs by 36 weeks should receive standard PMTCT treatment.
•
ZDV is the preferred nucleoside as is has demonstrated a reduction in vertical transmission
from 25.5% to 8.3 %. IF Hgb is < 7 start with stavudine, not zidovudine.
•
In the case of NVP intolerance, substitute kaletra for nevirapine.
•
If using a PI, monitor blood glucose every 3 months for the 1st year.Avoid the use of D4T and
DDI combination therapy to reduce the risk of lactic acidosis, we’ll talk more about this later
•
Monitor ALT q 2 weeks for 1 month, then q month and then as indicated if on NVP
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 52
Scenario 3: Pregnant and Not
Requiring ART
■ Early stage HIV (WHO Stage 1 or II disease with CD4
>200)
■ Follow the national PMTCT guidelines
Unit 6: Women, HIV & ART in Pregnancy
52
We will discuss the PMTCT guidelines in a moment
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 53
Scenario 4: Pregnant Woman
Presenting after 34 Weeks
■ Defer ART
■ Provide PMTCT
■ Review need for ART after delivery
Unit 6: Women, HIV & ART in Pregnancy
Reference Manual for Trainers
53
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 54
Potentially Competing Issues:
Use of Antiretrovirals in Pregnancy
Safety &
Efficacy for
Mother
Safety
of
Infant
Prevention
of
Transmission
Unit 6: Women, HIV & ART in Pregnancy
54
•
There are potentially competing issues with the use of antiretrovirals in pregnancy
•
Safety and efficacy of ARVs for mother, safety of ARVs for the infant with the goal
of preventing transmission.
•
ARV therapy is often complicated by side effects in relatively healthy HIV infected
nonpregnant adults that could be exacerbated in pregnancy or put the fetus at risk.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 55
Antiretroviral Therapy to Reduce
Perinatal Transmission: Options
■ Four options for PMTCT (Scenarios 3 & 4)
■ Nevirapine monotherapy to mother and infant
■ Zidovudine monotherapy to mother and infant
■ Nevirapine + zidovudine to mother and infant
■ Zidovudine + lamivudine to mother and infant
Unit 6: Women, HIV & ART in Pregnancy
Reference Manual for Trainers
55
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 56
Antiretroviral Treatment to
Prevent MTCT
Drug
Regimen to the Mother
Antepartum
1) Nevirapine
2) Zidovudine
300 mg BID
from 36
weeks
onwards
Regimen to the Baby
Intrapartum
200 mg at onset of
labor
2 mg/kg single dose within
72 hours postpartum
300 mg every 3
hours
4 mg/kg BID for 7 days
beginning at 8-12 hours
postpartum
600 mg at onset of
labor then 300 mg
every 3 hours*
Same as above
3) Combination of zidovudine and nevirapine as above
•
There are four options for PMTCT (when the women presents to delivery not on
ART = Scenarios 3,4). The first three options:
1. Single dose nevirapine to both mother and infant
2. Zidovudine monotherapy to mother beginning at 36 weeks and continued
through delivery or beginning at the onset of labor and continued through
delivery
•
And to the infant for 7 days beginning 8-12 hours postpartum
3. Nevirapine + zidovudine to mother and infant as above
•
If baby has not receive a dose by 72 hours, no nevirapine should be given
•
*This regimen is given if zidovudine is not taken during the antenatal period for any
reason
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 57
Antiretroviral Treatment to
Prevent MTCT (cont.)
Drug
4) Zidovudine
&
Regimen to the Mother
Antepartum
Intrapartum
300 mg BID
600 mg at onset of
labor, then 300 mg
every 3 hours
From 36 weeks
onwards
&
Lamivudine
•
Regimen to the
Baby
150 mg BID from 36
weeks onwards
&
150 mg at onset of
labor then 150 mg
every 12 hours
4 mg/kg BID for 7
days
&
2 mg/kg BID for 7
days, both
beginning within
72 hours
postpartum
The fourth option:
4. Zidovudine + lamivudine to mother and infant
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 58
WHO Recommendations
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 59
Completed Trials: Prevention MTCT HIV-1
Ante-partum
14
wks
28
wks
Post-partum
Intrapartum (baby, mother or both)
36
3d to
6
wks
1 wk
wks
ACTG 076
NonBF
Thai
NonBF
Thai
NonBF
Thai
NonBF
Ivory Coast (ANRS), PETRA, Thai
BF/NonBF
Thai, Ivory Coast
NonBF/BF
PETRA, HIVNET 012, SAINT
BF
PETRA
BF
Refer to enlarged image at end of handout
•
This slide demonstrates a number of completed trials completed on prevention of
MTCT.
•
Many different strategies have been evaluated with differing regimens and course
of therapy in both breastfeeding and non-breastfeeding populations. ACTG 076
was a trial which demonstrated that vertical transmission could be reduced by 2/3
when administering ZDV alone beginning in the 2nd or 3rd trimester, during delivery
and post partum for 6 weeks to the infant.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 60
Single Dose Nevirapine: ART
Prophylaxis for MTCT
■ Nevirapine:
■
■
■
■
Rapid oral absorption
Rapid transplacental passage
Highly potent antiviral
Long half-life, persists for 7-10 days
■ NVP provides prophylaxis to the baby during birth
■ Toxicities rare: severe rash, hepatitis
■ Rapidly selects for drug-resistant mutants
Unit 6: Women, HIV & ART in Pregnancy
•
•
60
Nevirapine: benefits of NVP include:
•
NVP is rapidly absorbed
•
May rapidly reduce mother’s viral load in blood and birth canal
•
NVP crosses the placenta rapidly
•
Highly potent antiviral
•
Long half-life, persists for 7-10 days
•
Maintains therapeutic levels in baby’s blood stream for the first week of life
•
NVP provides prophylaxis to the baby during birth
•
Toxicities with single dose are rare: severe rash, hepatitis
•
Rapidly selects for drug-resistant mutants, with a single point mutation,
whereas other ARVs require multiple mutations to affect the potency of the
drug.
This will be discussed more in detail later.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 61
MTCT with Single-Dose Nevirapine vs UltraShort ZDV: HIVNET 012
Lancet 1999;354:795 and Lancet 2003;362:859
% Transmission
Breastfed Infants
14-16 weeks 18 months
Nevirapine
INTRA POST
200 mg x1
2 mg/kg x1
Ultra-Short INTRA
ZDV
300 mg
POST
versus
q 3 hr
13.1%
15.7%
25.1%
25.8%
4 mg/kg bid
x1 wk
NVP resistance 19% at 6-8 weeks (mothers), 46%
at 6-8 weeks (infants)
•
In a trial comparing single dose NVP with ultra short ZDV, transmission rates were
lower with NVP; however,
•
NVP Resistance postpartum:
•
Mothers: 6-8 weeks= 19%, 21/111; resistance diminished over time , at 1224 months= 0/11 had documented resistance detected
•
Infants: 6-8 weeks= 46%, 11/24. Nearly half of the infants developed
resistance to NVP
Eshleman SH et al. AIDS. 2001;15:1951
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 62
Comparison of IP/PP Regimens: Single-Dose
Nevirapine vs PETRA AZT/3TC - SAINT
Moodley D et al. JID 2003;187:725-35
% Transmission
Nevirapine
(variant of
HIVNET 012)
versus
AZT/3TC
(PETRA)
INTRA
POST
200 mg x1 Mom 200 mg x1
Baby 2 mg/kg x1
INTRA
POST
Q 3 hr
Mom & baby
x1 wk
NVP resistance 6 weeks 67%
moms, 53% infants
Birth
Btn Birth-8 Wks
7.0%
5.7% (2.0-5.3)
Overall, 8 wks: 12.3%
5.9%
3.6% (3.7-7.8)
Overall, 8 wks: 9.3%
(Overall: p=0.11)
•
In a trial by Moodley and investigators: There was no difference between singe
dose NVP and IP,PP combination therapy
•
NVP Resistance at 4-6 weeks and 9-12 months postpartum:
•
Women: 67%, 74/111; 22%, 8/36 (resistant mutations diminish over time)
•
Infants: 53%, 21/40 ZDV/3TC Resistance presumably at 4-6 weeks:
•
Women: 0/37
Sullivan J. XIV Intern AIDS Conf. Barcelona, Spain; 2002
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 63
Higher Transmission with Breast (N=623) than Formula (N=694)
Feeding, Regardless of Treatment
SAINT: Moodley D. JID 2003;187:725-35
% Transmission
25
20
15
10
5
0
Birth
AZT/
3TC
Formula
4 Weeks
Breast NVP
8 Weeks
Formula
Breast
•
Overall there is a higher rate of transmission with breast feeding rather than
formula.
•
Regardless of treatment strategy.
•
For example, the solid blue bars represent NVP therapy in formula fed infants
compared to the blue hashed lines which represent NVP therapy in breastfed
infants. At each time point, there was a higher % of infants who acquired HIV
infection in the breastfed babies compared to the formula fed babies.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 64
Conclusions: Nevirapine
Prophylaxis Regimens
■ When only IP/PP prophylaxis is given
■ single-dose NVP is superior to IP/PP AZT alone and
■ similar to IP/PP AZT/3TC.
Unit 6: Women, HIV & ART in Pregnancy
64
IP= intrapartum, PP= postpartum
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 65
Potentially Competing Issues:
Use of Antiretrovirals in Pregnancy
Safety &
Efficacy for
Mother
Safety for
Infant
HAART?
Prevention
of
Transmission
Unit 6: Women, HIV & ART in Pregnancy
65
There are potentially competing issues in the use of HAART in pregnancy
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 66
PK of ARVs in Pregnancy
■ Few trials have evaluated the clinical significance of
physiologic changes during pregnancy on the PK of
commonly used drugs.
■ Half life of NVP is reduced from 66 hr in non-pregnant
women to 45 hr in pregnant women; this is not likely to
be clinically significant
■ Nelfinavir levels a third lower in pregnancy
■ Pregnancy does not change the PK of ZDV,3TC and
DDI
Unit 6: Women, HIV & ART in Pregnancy
66
•
Although many physiologic changes occur during pregnancy, few trials have
evaluated their clinical significance on the PK of commonly used drugs.
Physiologic changes that may affect drug PK include delayed gastric emptying,
decreased intestinal motility, increased volume of distribution (an average increase
of 8 L), increased renal blood flow by 25-50% and GFR (glomerular filtration rate)
by 50%
•
Now we have data showing altered pharmacokinetics of nevirapine, a substrate for
2B6, in pregnant women.
•
Half life of NVP is reduced from 66 hr in nonpregnant women to 45 hr in pregnant
women; this is not likely to be clinically significant
•
CID, Sept 2004, plasma levels of nelfivnavir were 34% lower in HIV positive
pregnant women than HIV positive women taking the drug that were not pregnant.
Nevertheless, all but one of the pregnant women maintained an undetectable viral
load and none of the women’s babies was infected with HIV.
•
Low concentrations of the drug during pregnancy could be because the liver
metabolizes nelfinavir faster during pregnancy as the production of CYP3A4, which
plays a key role in processing the PI, is increased. Studies of blood levels and
safety during pregnancy in progress for:
Indinavir, ritonavir, saquinavir, nelfinavir, lopinavir/ritonavir
•
Pregnancy does not change the PK of ZDV,3TC and DDI
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 67
Risk of Development of HIV
Resistance: Mother
■ Non-HAART regimens associated with the development of
resistance
■ ZDV-resistant virus not selected by short-course ZDV in therapynaïve pregnant women (however, with longer courses it is
selected)
■ ZDV monotherapy: 0.3 - 14% risk of low-level ZDV resistance
■ ZDV + 3TC: 38% high-level 3TC resistance (ANRS 075)
■ Nevirapine monotherapy: 15% - 18% high level NVP resistance
(PACTG 316; HIVNET 012) (no longer detectable 12 months
postpartum)
■ Risk for future HAART regimens unknown
Unit 6: Women, HIV & ART in Pregnancy
67
•
Use of antiretroviral regimens (particularly singe agents) for the purpose of perinatal prophylaxis has raised
concerns about the induction of resistance mutations. Perinatal transmission of virus with known ZDV
resistant mutations has been described and one study found that maternal ZDV use was associated with more
rapid disease progression in infants who acquired HIV despite maternal ZDV use. WITS study of women who
used ADV in pregnancy found that 25% of 142 maternal isolates had at least one ZDV associated resistance
mutation, a higher vl and lower CD4 count were associated with ZDV mutations at delivery and the presence
of resistance mutations was independently associated with vertical transmission. Mutations due to single dose
of NVP in the Uganda study HIVNET 012 developed in both mom 23% and infected infants (44%) PACTG 316
involved the use of NVP with other ARVs, 12.5% or women developed resistant mutations
•
Non-HAART regimens associated with the development of resistance
•
ZDV-resistant virus not selected by short-course ZDV in therapy-naïve pregnant women (however,
with longer courses it is selected)
•
Overall, AZT monotherapy: 0.3 - 14% risk of low-level AZT resistance
•
AZT + 3TC: 38% high-level 3TC resistance (ANRS 075) after 2 months of therapy
•
Nevirapine monotherapy: 15% - 18% high level NVP resistance (PACTG 316; HIVNET 012)
•
•
No longer detectable 12 months postpartum (67% in study with two NVP doses)
Following single dose intrapartum NVP, some mothers have a decreased response to NVP-based HAART
•
Problem greatest if HAART given within a few months of single dose NVP
•
Risk of NVP resistance appears greatly increased with second maternal dose
•
In contrast to ZDV, development of high-level resistance to 3TC and NVP occurs rapidly based on single point
mutations in the viral genome. Maternal genotypic resistance to 3TC was detected in a substantial proportion
(39%-60%) of pregnant women in both the French Agence Nationale de Recherche Sur le Sida (ANRS) 075
(lamivudine and zidovudine) and PACTG 316 trials who received >4 weeks of prophylaxis. The presence of
detectable 3TC mutant virus among pregnant women at delivery or postpartum did not appear to have a
negative impact on PMTCT, however, because extremely low overall transmission rates (<2%) were observed
in both of these trials.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 68
Risk of Development of HIV
Resistance: Infant
■ ZDV: longer courses (28 weeks) results in
transmission to the infant
■ ~50% of infants develop NVP resistance. The
mutations are often different from their mothers’,
because of de novo selection or emergence of a
mutant with greater fitness.
Unit 6: Women, HIV & ART in Pregnancy
68
•
ZDV: longer courses results in transmission
•
NVP resistance selected in infants. The mutations are often different from their
mothers’, because of de novo selection or emergence of a mutant with greater
fitness.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 69
Safety of NRTIs in Pregnancy
■ Human pregnancy data only for AZT, 3TC, DDI, D4T
■ No increase in birth defects have been observed
■ Lactic acidosis and Hepatic Steatosis
■ Rare, but potentially fatal syndrome
■ Linked to prolonged use of NRTIs, esp DDI, D4T, DDC
(AVOID the use of DDI/D4T combination in pregnancy)
■ Vague symptoms
Unit 6: Women, HIV & ART in Pregnancy
69
•
Substantial human data are available indicating that the risk to the fetus, if any, is
limited when administered to the pregnant mother beyond 14 weeks gestation.
Follow-up for < 6 years for 734 infants who had been born to HIV infected women
and had in utero exposure to ZDV has not demonstrated any tumor development.
Source: Hart, CE, Lennox JL, Pratt-Palmore M et al. Correlation of HIV type1 RNA
levels in blood and the female genital tract J infect Dis 1999, 179:871-872
•
Chronic compensated hyperlactatemia can occur during treatment with NRTIs.
Although rare, this syndrome is associated with a high mortality rate.
•
Severe lactic acidosis with or without pancreatitis including three fatal cases were
reported during the later stages of pregnancy or among postpartum women whose
ART during pregnancy included stavudine and didanosine in combination with
other ARVs. Other risk factors for experiencing this toxicity include obesity, being
female and prolonged use of NRTIS, although cases have occurred with risk
factors being unknown. Symptoms are vague and include non-specific symptoms:
nausea, vomiting, lethargy and in some cases respiratory distress.
•
Etiology: Mitochondrial dysfunction possibly due to inhibition of cellular
mitochondrial by ART
• Similarities to acute fatty liver or pregnancy and HELLP syndrome
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 70
Safety of NNRTIs in Pregnancy
■ Nevirapine single dose has not been associated with
adverse side effects in women and children
■ Nevirapine resistance risk as above
■ Nevirapine elimination may be accelerated in infants whose
mother received chronic nevirapine as part of ART.
■ Pregnancy should be avoided in women receiving
efavirenz
■ No human pregnancy data on long term use of
NNRTIs
Unit 6: Women, HIV & ART in Pregnancy
•
•
70
Single dose nevirapine has not been associated with adverse side effects in
women and children
•
Nevirapine resistance risk as above
•
Nevirapine elimination may be accelerated in infants whose mother
received chronic nevirapine as part of ART. Significance?
Pregnancy should be avoided in women receiving efavirenz
•
No human pregnancy data on long term use of NNRTIs
•
IN the Uganda NIVNET trial: NVP resistance mutations were detected in
44% of infants whose mothers received single dose nevirapine at the onset
of labor
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 71
Safety of PIs In Pregnancy
■ Protease Inhibitors associated with reduced insulin
sensitivity
■ Pregnancy also associated with varying degrees of
insulin resistance
■ Risk of diabetes greater with PI-containing regimen
■ Monitor fasting glucose and 2 hr GTT
■ Avoid indinavir near term and liquid amprenavir
Source: Justman, 6th CROI
Unit 6: Women, HIV & ART in Pregnancy
71
•
Protease Inhibitors associated with reduced insulin sensitivity
•
Pregnancy also associated with varying degrees of insulin resistance
•
In one study, women on PI-containing HAART in pregnancy: higher rate of
diabetes (3.5%) than did HIV-negative women or HIV-positive women on
NRTIs only
•
It is best to avoid the use of indinavir near term in pregnancy because of the
theoretical risk of renal stones in neonates who cannot adequately hydrate
themselves and possible complications associated with exacerbation of
hyperbilirubinemia (especially in premature infants) who are at greater risk for
neonatal jaundice and kernicterus).
•
Avoid the use of liquid amprenavir during pregnancy due to a high amount
of propylene glycol in the preparation.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 72
Data Concerning the Use of
ART During Pregnancy
■ Category B
■ Animal reproduction studies fail to demonstrate a risk to the fetus
and adequate but well controlled studies of pregnant women have
not been conducted
■ Examples: DDI, FTC, TDF, Atazanavir, Nelfinavir, Ritonavir
■ Category C
■ Safety in human pregnancy has not been determined; animal
studies are either positive for fetal risk or have not been conducted
■ Examples: ABC, 3TC, D4T, ZDV, All NNRTIs (avoid EFV),
Amprenavir (fosamprenavir), Indinavir, Lopinavir/r
Unit 6: Women, HIV & ART in Pregnancy
72
•
Refer to handout in workbook titled Preclinical and Clinical Data Concerning the
Use of Antiretrovirals During Pregnancy From the Guidelines for the Use of
Antiretrovirals in HIV-1 Infected Adults and Adolescents Oct 2004
•
These are the FDA pregnancy categories for ARVs:
•
Category B: animal reproduction studies fail to demonstrate a risk to the
fetus and adequate but well controlled studies of pregnant women have not
been conducted
•
Category C: Safety in human pregnancy has not been determined; animal
studies are either positive for fetal risk or have not been conducted, and the
drug should not be used unless the potential benefit outweighs the potential
risk to the fetus. Note that ZDV, NVP are listed as category C, however,
these drugs are used routinely during pregnancy
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 73
ARVs to Avoid in Pregnancy:
Summary
■ Efavirenz containing regimens
■ Teratogenic
■ DDI +D4T combination therapy
■ Lactic acidosis
■ Oral liquid formulation of amprenavir
■ Propylene glycol
■ Indinavir
■ Avoid in late pregnancy
Unit 6: Women, HIV & ART in Pregnancy
73
•
In ARV naïve pregnant women, initiation of ARV therapy may be delayed until after
10-12 weeks gestation to avoid the period greatest vulnerability of the fetus to
potential teratogenic effects and because nausea and vomiting in early pregnancy
may affect optimal adherence and absorption of ARVs. However, if clinical,
virologic or immunologic indications for the initiation of therapy in nonpregnant
individuals exist, many experts would recommend initiating therapy regardless of
gestational age.
•
There are insufficient data to support or to refute teratogenic risk of ARVs when
given to pregnant women in the first trimester. However, efavirenz containing
regimens should be avoided in pregnancy because significant teratogenic effects
were seen in primate studies at drug exposures similar to those representing
human exposure. In addition, single case of myelomeningocele has now been
reported after early human gestational exposure to efavirenz
•
DDI + D4T combination therapy should be avoided as first line therapy during
pregnancy because reports of several maternal deaths due to lactic acidosis after
prolonged use of regimens containing these two drugs in combination. Generally
speaking, this combination should be used only when other nucleoside
combinations have failed or have caused unacceptable toxicity or side effects.
•
The oral liquid formulation of amprenavir contains high level of propylene glycol
and should not be used in pregnant women.
•
The use of indinavir should be avoided late in pregnancy as it may cause an
elevation in bilirubin.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 74
Safety & Efficacy Issues in
Pregnancy: Summary
■ HAART results in the lowest risk of transmission to the infant
■ Use of HAART best preserves mother’s future therapeutic
options
■ Monitor for
■ Lactic acidosis/hepatic steatosis
■ Rash,hepatotoxicity in women with CD4 >250
■ Glucose intolerance
Unit 6: Women, HIV & ART in Pregnancy
74
•
HAART results in the lowest risk of transmission to the infant
•
Use of HAART reduces the risk of the mother developing resistance (best
preserves mother’s future therapeutic options)
•
Beware of signs & symptoms of lactic acidosis/hepatic steatosis
•
Monitor for hepatotoxicity in women with CD4 >250
•
Monitor for glucose intolerance
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 75
A ntiretro viral To xicities to
F et u s/Infa nt: S u m m a ry
■ N o incre ase d risk of birth defects with exp osure to
A R V s overall or for first tri me ster Z D V or 3 TC
e xp o s ures
■ N o p atterns of toxicity associated with antiretrovirals
within 5-10 years
■ Mitoch o n drial toxicity m a y occur rarely
■ L o n g-ter m studies un d er w a y to asc ertain if
carcino g e n ic
U nit 6: W o m en, HI V & A R T in Pregnanc y
75
•
Currently available registry data does not indicate an increased risk of birth defects with exposure to ARVs overall or for first trimester
ZDV or 3TC exposures
•
One example in which the benefit far outweighs the risk of drug administration during pregnancy is evident in the use of zidovudine
(ZDV) in preventing perinatal transmission (ACTG 076) Administration of ADV to the pregnant HIV infected mother after the first trimester,
during labor, after labor and to the newborn reduced the perinatal acquisition of HIV. Follow-up of uninfected infants has not shown a
significant difference in growth, neurologic development or immune status when compared to uninfected infants exposed to placebo. The
use of ZDV has become standard of care in the US.
•
HIVNET 012 compared the administration of one dose of nevirapine given orally to the mother during labor followed by one dose of
nevirapine to the infant within 72 hr after birth with the administration of ADV during labor followed by ZDV to the infant for 7 days. The
14-16 post-delivery data showed that although both regimens were well tolerated, 25.1% of infants in the ZDV arm and 13.1% of infants
in the NVP arm were infected with HIV. (p=.0006) Long term safety data are not currently available for NVP.
•
Possible Mitochondrial Dysfunction and Perinatal Exposure to Nucleoside Analogues (Blanche S, et al. Lancet 1999;354:1084-9)
1.
8 children with possible mitochondrial dysfunction (2 deaths) from a cohort of 1754 children
2.
•
Overall 0.1% mortality, 0.3% morbidity
•
No control group; no mitochondrial DNA depletion; uncertain association with perinatal ARV exposure
French Perinatal Cohort compared ARV exposed/unexposed uninfected children born to HIV-infected women followed 1986-1999:
Mitochondrial Toxicity in HIV-Exposed Infants Delfraissy JF et al. Retrovirus Conf Feb 2001 Abs 625B
•
1,874 unexposed to ARV: no mito toxicity
•
2,209 ARV-exposed:
•
3) Retrospective review of all deaths at <5 years old in children born to HIV+ mothers in U.S. databases
•10 confirmed (includes 8 prior report), 6 strong suspicion
•PACTG, WITS, PACTS, PSD & CDC Surveillance Lack of Death due to Mitochondrial Disease in Children Who Died at
<5 Years in 5 U.S. Cohorts Perinatal Safety Review Working Group. JAIDS 2000;25:261-8
•
Database included 16,313 uninfected children
•>50% ARV-exposed (89% AZT)
•30 deaths reported in cohort
•
•
No death attributable to or following symptoms, signs or laboratory findings suggestive of mitochondrial disease
•
Review of living children ongoing
No patterns of toxicity associated with antiretrovirals within 5-10 years
•
PACTG 219: Long-Term Follow-Up of Uninfected PACTG 076 Infants Culnane M. JAMA 1999;281:151-7
•
Follow-up of 234 uninfected PACTG 076 infants for as long as 6 yrs (median, 4.2 yrs)
•
No significant differences in growth or cognitive functioning, long-term studies are underway to ascertain if treatment is
carcinogenic.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 76
Smiling Mother and Son After Starting
Antiretroviral Treatment, Botswana
Unit 6: Women, HIV & ART in Pregnancy
Reference Manual for Trainers
Credit: WHO/UNAIDS/S. Toffin
76
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 77
Case Studies
Refer participants to Worksheets 6.1-6.4 in their Course Workbooks.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 78
Case 1
■ LG is a 22 year old women with newly diagnosed with HIV
comes who comes to the pharmacy to begin antiretroviral
therapy with nevirapine, 3TC and ZDV. She is ready to
start therapy and wants to be healthy so that she can have
a baby. She has a new prescription for prenatal vitamins
with her that she would like to fill today.
■ She asks you if it is ok to continue taking her antiretrovirals
(ART) should she become pregnant. She has heard that
ART can be harmful to infants. She receives a two week
supply of medication.
■ How would you counsel this patient?
Unit 6: Women, HIV & ART in Pregnancy
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HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 79
Case 1 - Answer #1
■ Women who become pregnant on nevirapine,
ZDV and 3TC should continue the same regimen
throughout pregnancy. This regimen is
appropriate for a pregnant patient.
Unit 6: Women, HIV & ART in Pregnancy
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HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 80
ARVs to Avoid in Pregnancy
■ Efavirenz containing regimens
■ Teratogenic
■ DDI +D4T combination therapy
■ Lactic acidosis
■ Oral liquid formulation of amprenavir
■ Propylene glycol
■ Indinavir
■ Avoid in late pregnancy
Unit 6: Women, HIV & ART in Pregnancy
80
•
In ARV naïve pregnant women, initiation of ARV therapy may be delayed until after
10-12 weeks gestation to avoid the period greatest vulnerability of the fetus to
potential teratogenic effects and because nausea and vomiting in early pregnancy
may affect optimal adherence and absorption of ARVs. However, if clinical,
virologic or immunologic indications for the initiation of therapy in nonpregnant
individuals exist, many experts would recommend initiating therapy regardless of
gestational age.
•
There are insufficient data to support or to refute teratogenic risk of ARVs when
given to pregnant women in the first trimester. However, efavirenz containing
regimens should be avoided in pregnancy because significant teratogenic effects
were seen in primate studies at drug exposures similar to those representing
human exposure. In addition, single case of myelomeningocele has now been
reported after early human gestational exposure to efavirenz
•
DDI + D4T combination therapy should be avoided as first line therapy during
pregnancy because reports of several maternal deaths due to lactic acidosis after
prolonged use of regimens containing these two drugs in combination. Generally
speaking, this combination should be used only when other nucleoside
combinations have failed or have caused unacceptable toxicity or side effects.
•
The oral liquid formulation of amprenavir contains high level of propylene glycol
and should not be used in pregnant women
•
The use of indinavir should be avoided late in pregnancy as it may cause an
elevation in bilirubin
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 81
Case 1 - Answer #2
■ The fetus is at greatest risk of teratogenic effects during the first
trimester. Taking ART during the first trimester may increase the risk
of birth defects in the newborn. However, stopping treatment may
increase the risk of transmission, as viral load would be expected to
rise.
■ It is recommended that women continue ART throughout their
pregnancy
■ To date, children born to mothers exposed to AZT in pregnancy show
no increased risk of birth defects or growth problems. One small study
of pregnant women taking 3TC and ZDV with or without protease
inhibitors found a high rate of premature births and a small number of
abnormalities at birth. Other studies (and 1 large study in the US)
have reported no increase in premature births or abnormalities
Unit 6: Women, HIV & ART in Pregnancy
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HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 82
Case 2
■ MB is a 34 year old woman in her third pregnancy who
delivered a healthy 3.5 kg baby girl an hour after she
arrived at the maternity.
■ After the birth, she told the staff she had a positive HIV
test done in clinic but did not take the tablet given to
her before rushing to the maternity because she did
not want her family to know about her HIV infection.
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HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 83
Case 2 Questions
1. What treatment does MB require now?
2. What treatment does her baby require?
Unit 6: Women, HIV & ART in Pregnancy
Reference Manual for Trainers
83
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 84
Case 2 - Answers Question 1
■ Treating MB so as to reduce the risk of intrapartum
HIV transmission is no longer an option
■ MB needs a follow-up visit to assess her immunologic
status and to determine if she needs any HIV-related
treatment for her own health
■ Needs counseling on disclosure issues
Unit 6: Women, HIV & ART in Pregnancy
84
•
The mother, apparently not on HAART for her own benefit, does not require any
special treatment for HIV infection post-partum.
•
She should follow-up with her clinic where she can be monitored to determine
when she may be eligible for antiretroviral therapy for her own health.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 85
Case 2 - Answers to Question 2
■ The infant has not had any nevirapine exposure as the
mother did not take nevirapine at least 2 hours prior to
delivery
■ The infant requires nevirapine 2 mg/kg:
■ First dose as soon as possible
■ Second dose 48-72 hours post-partum
Unit 6: Women, HIV & ART in Pregnancy
85
•
Nevirapine crosses the placenta; therefore, babies born to women who took
intrapartum nevirapine at least 2 hours prior to delivery will themselves be born
with adequate blood levels of nevirapine.
•
This baby was born to a mother who did not take nevirapine during labor, so has
not yet received any prophylaxis for HIV infection. The baby should receive a dose
of nevirapine syrup (2mg/kg) as soon as possible, and the same dose should be
repeated at 48-72 hours of age. ( From Namibia guidelines)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 86
Case 3
■ A 27-year-old female with a CD4 cell count of 182 cells/mm3
presents to clinic three weeks after starting her new salvage
antiretroviral regimen. She states she has been taking most of
her medications. She admits to not always practicing safe sex
and is concerned about getting pregnant.
■ Her medical provider decides to start her on
norethindrone/ethinyl estradiol 0.5mg / 0.035 mg and reinforces
her need to use condoms.
Unit 6: Women, HIV & ART in Pregnancy
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HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 87
Case 3 (cont.)
■ Current Medications:
■ Didanosine (Videx EC): 400 mg PO qd
■ Lamivudine (Epivir): 300 mg PO qd
■ Nevirapine (Viramune): 200 mg PO bid
■ Trimethoprim-sulfamethoxazole:
■ Bactrim DS (160 mg/800 mg) PO qd
■ Omeprazole: 20 mg PO qd
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HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 88
Case 3 Question
■ Which of the following is TRUE regarding a potential
drug-drug interaction?
A) Nevirapine reduces the plasma levels of ethinyl estradiol.
B) Nevirapine increases the plasma levels of ethinyl estradiol.
C) Nevriapine reduces the plasma levels of norethindrone
D) Nevirapine increases the plasma levels of norethindrone
Unit 6: Women, HIV & ART in Pregnancy
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HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 89
Case 3 Answer:
A and C are correct
The major biotransformation of ethinyl estradiol is
through CYP 3A4. Nevirapine is a known inducer of 3A4.
Decreased plasma levels of ethinyl estradiol and
norethindrone have been demonstrated with concomitant
nevirapine use. The clinical outcomes of this interaction
have not been established. Oral contraceptives are not
recommended as the primary method of birth control in
patients taking nevirapine.
Unit 6: Women, HIV & ART in Pregnancy
89
Oral Contraceptives and NNRTIs
• Among the NNRTIs, nevirapine (Viramune) and efavirenz (Sustiva) both act as inducers of the
CYP3A4 enzyme and thus typically diminish plasma levels of similarly metabolized drugs.
• One study found the concurrent use of nevirapine and oral contraceptives resulted in a
29% decrease in the area under the curve (AUC) of EE, a significant reduction in the halflife of EE, and an 18% reduction in the AUC of norethindrone [2].
• The clinical impact of these interactions was not determined. Nevertheless, for patients
taking nevirapine, oral contraceptives are not recommended as the primary method of birth
control [2].
• Although efavirenz generally acts as a CYP3A4 inducer, it demonstrated an inhibitory
effect on EE. The plasma AUC was increased by 37% after single dose administration of
EE (n=13). The clinical significance of the interaction is unknown [3].
• Moreover, a subsequent study found that efavirenz could interfere with the estradiol ELISA
assay and artificially elevate serum levels of estradiol if an ELISA assay is used [4].
• Because the efavirenz and oral contraceptive drug-drug interaction remains poorly
characterized, it is recommended that women taking efavirenz not use oral contraceptives
as the primary method of birth control.
•
The limited data regarding the interaction between oral contraceptives and antiretrovirals make it
difficult to provide sound clinical recommendations. Oral contraceptives are not recommended as
the primary form of birth control if the patient is taking either an NNRTI or a PI.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 90
Case 4
■ In July 2004, a 31 year old, single HIV positive woman
came to the clinic with pain in her mouth and chest
upon swallowing. She had night sweats and diarrhea
for one month. Her usual weight was 58 kg.
■ On exam she weighed 51 kg, had no palpable lymph
nodes, and had oral candidiasis. She was diagnosed
with presumed esophageal candidiasis and treated
with oral fluconazole for 2 weeks. Her pain subsided
and she began to eat.
Unit 6: Women, HIV & ART in Pregnancy
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90
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 91
Case 4 (cont.)
■ Based on the esophageal candidiasis, she had WHO
Stage IV disease, although no CD4 count was available.
■ In September 2004, she began daily bactrim for PCP
prophylaxis and was started on HAART at the same time
with stavudine 30 mg bid, lamivudine 150 mg bid, and
efavirenz 600 mg qhs.
■ She has been adherent with her medications. The night
sweats and diarrhea have stopped, her appetite has
increased, and she gained 6 kg.
Unit 6: Women, HIV & ART in Pregnancy
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91
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 92
Case 4 Question
■ At her 6-month follow-up visit she reports that her
menstrual period is 2 months late. A pregnancy test
is positive.
1. Should she continue her antiretroviral therapy?
2. If she requires a change in her regimen, what would you
suggest as an alternative?
Unit 6: Women, HIV & ART in Pregnancy
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92
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 93
Case 4 - Answers
■ She must stop taking efavirenz, which is contraindicated in
pregnancy
■ She should be counseled about the potential for
teratogenicity
■ She could continue D4T or change to ZDV
■ A suitable regimen would be: ZDV/3TC/nevirapine.
■ She should have close follow-up and monitoring of ALT q 2
weeks for the first two months then monthly, and a CBC
monthly
Unit 6: Women, HIV & ART in Pregnancy
93
Category C
•
This drug caused birth defects (anencephaly, anophthalmia, and microphthalmia)
in 3 of 20 gravid cynomolgus monkeys. Other antiretroviral drugs have not been
studied for safety in nonhuman primates, and the FDA has assigned FDA
pregnancy category C, which is the same as with AZT, d4T, 3TC, ABC, IDV, APV,
NVP, and DLV. The current recommendation is to avoid EFV during the first
trimester of pregnancy, to warn potentially pregnant women of this complication,
and to ensure adequate contraceptive protection.
•
There has been a single case of myelomeningocele in a newborn child born to a
woman who was taking EFV during conception and early pregnancy (Arch Intern
Med 2002;162:355; AIDS 2002;16:299). Neural tube defects have been
documented as well.
•
Long term studies have not been done for any NNRTIs
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 94
Key Points
■ Women are more susceptible than men to contracting
HIV through heterosexual intercourse.
■ HIV infected women require special care.
■ Women are affected differently by HIV and ARVs.
■ Increased rates of certain toxicities in women may be
due to differences in drug metabolism.
Unit 6: Women, HIV & ART in Pregnancy
94
•
Review Key Points with participants.
•
Ask them if they have further questions about ARVs, women and pregnancy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 95
Key Points (cont.)
■ Issues to consider when starting treatment include:
preconception counseling, teratogenicity of ARVs, drug
interactions, efficacy, tolerability, and co-morbidities.
■ Patients with AIDS are more likely to suffer from
pregnancy-related complications.
■ Transmission of HIV infection from mother to child can
occur during pregnancy, birth, or breastfeeding.
Unit 6: Women, HIV & ART in Pregnancy
Reference Manual for Trainers
95
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 96
Key Points (cont.)
■ MTCT is the largest source of HIV infection in children
under 15.
■ ART can reduce the likelihood of MTCT by 50%.
■ ART to reduce perinatal transmission must be given to
the mother and infant.
■ Regardless of treatment strategy, a higher rate of
transmission occurs with breast feeding rather than
formula.
Unit 6: Women, HIV & ART in Pregnancy
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96
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 97
References
■ Behrens, C. MD, Harborview Medical Center, Seattle, WA,
USA, 2004.
■ Cooper E et al. JAIDS 2002;29:484-94.
■ Currier, J. 9th CROI, 2002.
■ Dabis F et al. 2002 AIDS Conf, Barcelona Abs ThOrD1428.
■ Ethiopia Guidelines, July 2004.
■ Lisa Frenkel, MD, University of Washington and Children's
Hospital, Seattle, WA, USA, 2004.
■ Garcia, NEJM 1999.
Unit 6: Women, HIV & ART in Pregnancy
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97
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 98
References (cont.)
■ Giuliano M et al. 9th CROI; 2002.
■ A Guide to the Clinical Care of Women with HIV, 2001.
■ Guidelines for the Use of Antiretroviral Agents in HIV-1-infected
Adults and Adolescents, March 23, 2004.
■ Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview
Medical Center, Seattle, WA, USA, 2004.
■ HIV/AIDS Annual Update 2003, Proceedings of the 13th Annual
Clinical Care Options for HIV Symposium, May 15-18, 2003;
Scottsdale, AZ
■ Ioannidis, JID 2001.
Unit 6: Women, HIV & ART in Pregnancy
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98
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 99
References (cont.)
■ Justman, 6th CROI.
■ Lallemant M et al. N Engl J Med 2000;343:982-91.
■ Lallemant M et al. 2002 AIDS Conf, Barcelona Abs LBOr22.
■ Lancet 1999;354:795.
■ Lancet 2003;362:859.
■ Moodley D et al. JID 2003;187:725-35.
Unit 6: Women, HIV & ART in Pregnancy
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99
HIV Care and ART: A Course for Pharmacists
Unit 6: Women, HIV and ART in Pregnancy
Slide 100
References (cont.)
■ NIAID Fact Sheet HIV Infection in Women, May 2001.
■ Namibia Ministry of Health and Social Services, Training on the
Use of the Namibia Guidelines for Antiretroviral Therapy (ART),
2004.
■ NIH Prevention of MTCT in the US and Globally.
■ Petra Study Team. Lancet 2002;359:1178-86.
■ Primary Care Guidelines for HIV CID; 2004:39: 619-621 .
■ MaryAnn Vitiello: Women and HIV Physician Curriculum.
■ www.aidsmap.com
Unit 6: Women, HIV & ART in Pregnancy
Reference Manual for Trainers
100
HIV Care and ART: A Course for Pharmacists
Handout 6.1
Management of Rash and Hepatotoxicity with Viramune
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-7
Handout 6.1 (cont.)
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-8
Handout 6.1 (cont.)
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-9
Handout 6.2
Guidelines for the Use of Antiretrovirals in HIV-1 Infected Adults and
Adolescents: FDA Pregnancy Categories-March 2004
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-10
References
Behrens, C. MD, Harborview Medical Center, Seattle, WA, USA, 2004.
Cooper E et al. JAIDS 2002;29:484-94.
Currier, J. 9th CROI, 2002.
Dabis F et al. 2002 AIDS Conf, Barcelona Abs ThOrD1428.
Ethiopia ART Guidelines, July 2004.
Lisa Frenkel, MD, University of Washington and Children's Hospital,
Seattle, WA, USA, 2004.
Garcia, NEJM 1999.
Giuliano M et al. 9th CROI; 2002.
A Guide to the Clinical Care of Women with HIV, 2001.
Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and
Adolescents, March 23, 2004.
Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
HIV/AIDS Annual Update 2003, Proceedings of the 13th Annual Clinical
Care Options for HIV Symposium, May 15-18, 2003; Scottsdale, AZ
Ioannidis, JID 2001.
Justman, 6th CROI.
Lallemant M et al. N Engl J Med 2000;343:982-91.
Lallemant M et al. 2002 AIDS Conf, Barcelona Abs LBOr22.
Lancet 1999;354:795.
Lancet 2003;362:859.
Moodley D et al. JID 2003;187:725-35.
NIAID Fact Sheet HIV Infection in Women, May 2001.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-11
References (cont.)
Namibia Ministry of Health and Social Services, Training on the Use of the
Namibia Guidelines for Antiretroviral Therapy (ART), 2004.
NIH Prevention of MTCT in the US and Globally.
Petra Study Team. Lancet 2002;359:1178-86.
Primary Care Guidelines for HIV, CID; 2004:39: 619-621 .
MaryAnn Vitiello: Women and HIV Physician Curriculum.
www.aidsmap.com
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-12
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Women, HIV & ART in Pregnancy
Unit 6-13
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 7
Importance of Adherence
for ART Success
Unit 7: Importance of Adherence for ART Success
Aim: The aim of this unit is to introduce participants to the importance of adherence
to care and adherence to ART medications.
Learning Objectives: By the end of this unit, participants will be able to:
•
Identify basic adherence principles
•
Review the consequences of ART nonadherence on patient outcomes
•
Identify methods of adherence assessment
•
Identify barriers to adherence
•
Explain strategies to promote adherence
Unit Overview:
1 Hour 45 minutes
Step
Time
Activity/
Method
Resources
Needed
Content
1
10 minutes
Question-Answer
Introductory Case Study and
Question Slides (7.2-7.5)
Overhead or LCD
Projector
2
45 minutes
Lecture
Importance of HAART Adherence for
ART Success (Slides 7.6 - 7.60)
Overhead or LCD
Projector
3
20 minutes
Small Group Exercise
Adherence Exercise #1 (Slide
7.62)
Overhead or LCD
Projector
4
20 minutes
Small Group Exercise
Adherence Exercise #2 (Slide
7.63)
Overhead or LCD
Projector
5*
1 day
Individual Exercise
Practice Taking ARVs Exercise
Worksheet 7.1 (see
workbook)
6
10 minutes
Summary
Presentation of Key Points (Slide
7.64)
Overhead or LCD
Projector
*This exercise is recommended but it is optional.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-3
Resources Needed
•
•
•
•
•
•
Flip Chart and Paper
Markers
Overhead or LCD Projector
Paper
Pens
Sweets (or something similar) to represent antiretrovirals
•
The following enlarged slides can be found in the Participant Handbook:
-Virologic Control Falls Sharply with Dimished Adherence (Slide 7.10)
-Suboptimal Adherence Predisposes to Resistance (Slide 7.15)
-Missed Doses and Development of Drug Resistance (Slide 7.17)
-Development of Drug Resistance (Slide 7.19)
-ART Care Model (Slide 7.50)
•
Worksheet 7.1 for the Individual Exercise can be found in the Course Wookbook
Key Points
1. Antiretroviral (ARV) regimens are complex, have major side effects, and
adherence is challenging.
2. Serious potential consequences can result from non-adherence.
3. Patient/family education and involvement is critical for successful treatment of
HIV infection.
4. The provider and the patient must work together to promote optimal
adherence to both HIV care and ARV regimens.
5. The pharmacist plays a role in promoting adherence.
Step 1
Step 2
Introductory Case Study (10 minutes)
•
Ask a participant to read the case study on Slide 7.2 to 7.4.
•
Ask participants to silently attempt to answer the question on
Slide 7.5.
•
Explain that the question will be answered and the case
discussed more fully as the unit progresses.
Lecture (45 minutes)
•
•
This unit will introduce participants to the importance of
adherence to care and adherence to ART medications.
Begin by reviewing slides 7.1-7.2 of the PowerPoint
presentation, “Importance of Adherence for ART Success.” Ask
the participants if they have any questions about the objectives
before continuing.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-4
•
Step 3
Small Group Exercise #1 (20 minutes)
•
Step 4
Present and discuss the PowerPoint presentation, “Importance
of Adherence for ART Success” (Slides 7.3-7.60).
(Slide 62) Divide participants into small groups. Present the
following questions and give the groups twenty minutes to
review each in turn, asking the groups to identify the most
common problems they think will arise when patients try to take
medication.
o
What are common reasons for nonadherence?
o
How can we as pharmacists or druggists help patients
take their medications regularly as prescribed?
o
How can we track adherence for our patients so that we
can recognize a problem with adherence ?
•
Reform the group and take ten minutes to feedback. Review the
points in previous adherence slides with the group when
receiving feedback.
•
Some examples of problems: The medicine makes them feel
sicker. It’s difficult to adhere to food restrictions. They can’t
remember if they took the dose. When they take so many pills,
they lose their appetite. Their medications give them side
effects, and that may disclose their status to someone who
doesn’t know their status. For example, nevirapine can cause
an upper body drug rash. A medication may need to be taken
with food, and they don’t have access to food at that time. They
go to take a dose and realize they ran out of medicine. Taking
medication regularly is a constant reminder that they have a
chronic disease.
•
This exercise may be most productive if the previous exercise on
pill taking has been done by the group (See Step 4 below).
•
Remember to emphasize the importance of preparing the patient
for treatment.
Group Exercise #2 (20 minutes)
•
(Slide 63) Divide the group into pairs.
•
Each pair should take turns to discuss a past experience of
taking a course of treatment. This may be, for example, a
prescribed course of antibiotics or other medication, or a daily
vitamin or other supplement. Questions to answer:
ο
Describe your own experience of taking medicines to
your partner.
ο
How easy was it to find information about the medicines?
ο
How easy was it to follow the instructions on how to take
the medicines?
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-5
ο
Step 5
What made it easy or hard to take the medicines?
•
Each person should speak for up to three minutes, and then the
listening partner should briefly sum up what they have heard
their partner say.
•
Discussion should focus on participants’ recollection of how easy
it was to find information about how to take the medication,
whether this advice was followed, and what influenced how easy
or hard it was to do so.
•
Remind the group of their confidentiality agreement, and that if
participants share information with their partner which they would
rather not be fed back to the larger group, then they should tell
their partner this at the time.
•
After each person has had a turn (allow about six minutes),
resume the group and invite participants to share some of the
information they had told their partner about themselves. This
should be an open discussion where nobody should feel under
pressure to disclose information.
Individual Exercise (1 day; optional)
•
Refer participants to Worksheet 7.1 in their Course Workbook.
Each participant should make a written pill schedule for an
antiviral drug regimen. Try to use a range of schedules. In
addition, each participant will need a supply of sweets (or
something similar, such as vitamin tablets, nuts, fruit) which will
substitute for the actual drugs in the regimen described on their
pill schedule. There should be enough for several day’s doses.
Use a different sweet for each drug.
•
For example, a regimen of d4T/3TC/efavirenz would require two
orange sweets for d4T (one pill, twice daily); two white sweets
for 3TC (one pill, twice daily); and three yellow sweets for
efavirenz (three pills, once daily).
•
Participants should be advised that they must aim to adhere to
their regimen perfectly, by spacing doses correctly, and by
observing any food or liquid restrictions. The aim is to simulate
taking anti-HIV therapy as accurately as possible (remembering
that some participants may already have done so and may wish
to preserve their confidentiality).
•
Issues such as confidentiality, and therefore who observes your
pill-taking, can be assigned as important for some participants.
The trainer may choose to hand out cards to some participants
instructing them of the need to take pills privately. The trainer
can also determine how much discussion of pill taking is allowed
to take place by setting rules such as: Participants must pretend
that they are a community which is not doing an exercise on pill
taking. Participants must choose who to tell about their
`medication` and what to tell people.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-6
Step 6
•
The trainer should not remind people to take medication unless
discussion arises spontaneously within the group and a reminder
is agreed as a strategy for helping people take medication.
•
If the setting allows, such as within a two or three day training
course, divide participants into small groups to discuss their
experiences. Each group should record which factors acted as
barriers to following their regimen, and which acted as enablers.
Allow 15 minutes and then reform the group for a twenty minute
feedback session.
•
Remember that enablers and barriers vary among individuals,
and that where several different regimens are available, a drug
combination which is easy to manage for one person may be
inappropriate for another.
•
This exercise can still be a useful experiential task when
undertaken outside the group setting, and without the feedback
session. Encourage participants to think for themselves about
barriers and enablers to adherence.
•
In addition, people who are considering beginning an anti-HIV
drug regimen are often encouraged to perform a dummy run
such as this for a longer period. You may like to invite members
of the group to do this where appropriate.
Summary (10 minutes)
•
Summarize the presentation, review the Key Points presented in
this Unit (Slides 7.64), and answer final questions.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-7
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes
for reference during the planning and implementation of this course. The
facilitation notes and talking points are included in the “notes” section of the
accompanying PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-8
Unit 7: Importance of Adherence in ART Success
Slide 1
Importance of Adherence for
ART Success
Unit 7
HIV Care and ART: A Course for Pharmacists
•
This unit should take approximately 1 hour, 45 minutes to complete.
•
Focus on why adherence is important and the consequences of nonadherence
(treatment failure-reducing future options and passing resistance to others)
•
Emphasize ways that pharmacists can help patients take their meds better BEFORE
STARTING THERAPY.
•
Emphasize that published research has shown that pharmacist counseling positively
impacts adherence. Refer participants to Handout 7.1, which provides information on
a set of studies focused on adherence interventions.
•
Tell pharmacists how to counsel patients about the half-way rule to have an easy rule
for patients which can lessen patient stress related to missing doses
•
BID dosing = 12 hours between doses, ½ way is 6 hours.
•
If patient is within 6 hours of a late/missed dose, take that dose when
remembered and then go back to normal schedule.
•
If patient is over 6 hours after late/missed dose, skip that dose and wait till next
dose (to avoid double dosing and added toxicities) then go back to normal
schedule.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 2
Introductory Case
■ SC is an HIV + 30 year old female who presents to the
pharmacy with prescriptions for the following:
■ Lopinavir/r 3 caps bid
■ Zidovudine 300 mg bid
■ Lamivudine 150 mg bid
Unit 7: Adherence for ART Success
2
•
Ask a participant to read the case on Slides 7.2 to 7.4.
•
Ask participants if they have any questions about the information presented.
•
Note: Do not give them further information on the case. Just ask them to consider
the information provided to them.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 3
Introductory Case (cont.)
■ You are a thorough pharmacist and you ask her the
following questions before filling her prescriptions.
■ How are you tolerating your medication?
■ Are you taking any new medication ?
■ Are you able to remember to take all of your doses?
■ How are you taking your doses?
Unit 7: Adherence for ART Success
Reference Manual for Trainers
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HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 4
Introductory Case (cont.)
■ She responds with the following information:
■ She has been taking her medication for 1 month. She gets
occasional diarrhea, which she controls by increasing her
intake of starchy foods
■ She is not taking any new medications
■ She is proud to tell you that she has made her medication last
for 2 months rather than one month because she only takes 1
dose a day, rather than 2 doses per day, to make her pills last
longer. She remembers to take her dose every morning,
except when she is late for work
Unit 7: Adherence for ART Success
Reference Manual for Trainers
4
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 5
Introductory Case Questions
■ Which of the following statements regarding
counseling this patient on adherence is true?
A. Taking less than the prescribed dose is an effective way to
make ART last longer without going to the pharmacy.
B. If any doses of ART are missed, a change in ART regimen
will be necessary.
C. ART must be taken as prescribed to avoid the development
of resistance and possible treatment failure.
D. You have to miss a lot of doses before ART becomes
ineffective.
Unit 7: Adherence for ART Success
•
•
5
Ask participants to silently attempt to answer the question.
Explain that the answer to the question will be discussed as the unit progresses.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 6
Unit Learning Objectives
■ Identify basic adherence principles
■ Review the consequences of ART nonadherence on
patient outcomes
■ Identify barriers to adherence
■ Identify methods of adherence assessment
■ Explain strategies to promote adherence
Unit 7: Adherence for ART Success
•
6
Adherence is a broader term than compliance.
•
It suggests participation of patient in their care plan. It implies understanding,
consent and partnership between patient and providers
•
Includes both adherence to care and adherence to medications. In order for a patient
to be successful with their medication, they must be willing to receive follow-up lab
work to monitor therapy for toxicities as well as virologic success or failure. They
must be willing to follow-up with their provider for clinical evaluation to ensure
continued success on therapy.
•
Pharmacists play an integral part in detecting barriers to adherence, BEFORE a
patient beings therapy. We will talk more about this.
•
Pharmacists can help to monitor adherence for patients over time
•
Pharmacists must help patients to develop strategies that will promote adherence
and therefore long term success on their ART.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 7
Why Is ART Adherence
Important?
■ HAART reduces morbidity, mortality, and overall health
care costs for HIV+ persons.
■ Adherence prevents the development of resistant virus
and treatment failure.
■ As adherence decreases, viral loads and the risk of
progression to AIDS increase linearly.
Unit 7: Adherence for ART Success
Reference Manual for Trainers
7
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 8
Impact of Nonadherence
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 9
Introductory Case - Answers
■ The statement D): You have to miss a lot of doses before ART
becomes ineffective is false. Taking less than 95% of prescribed
doses leads to reduced virologic control. (95% adherence
means missing less than 3 doses per month)
■ Counsel the patient on the need for adherence
■ Taking the medication exactly as prescribed is crucial to prevent the
development of resistance
■ You may give her an example of how decreased drug levels lead to
subsequent drug failure
■ You may help her to devise a plan to remember both doses
■ Recommend that she get a follow-up CD4 or TLC count as
indicated every 3 months to detect drug failure
Unit 7: Adherence for ART Success
Reference Manual for Trainers
9
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 10
Virologic Control Falls Sharply
with Diminished Adherence
Patients with HIV RNA
<400 copies/mL, %
100
80
60
40
20
0
>95
90-95
80–90
70-80
<70
PI adherence, % (electronic bottle caps)
Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.
Unit 7: Adherence for ART Success
10
•
Date of first publication: 2/1/99
•
Keywords: Adherence, antiretroviral therapy, viral load Subject: Degree of
adherence needed for optimal viral suppression Title: “What degree of adherence is
needed?”
•
Discussion and teaching points: How much adherence is needed for optimal viral
load suppression is addressed in the graph from Paterson, which shows that the best
performance was achieved in patients who by self-report and MEMS-caps were
found to have >95% adherence, i.e.
•
Better than 95% of doses were taken during the 3 months of study. Significant
differences were observed between >95%, 90-95%, 80-90%,
•
70-80%, and <70% adherence, as shown. Note that <70% adherence was
associated with only 10% of patients achieving a viral load below detection.
Author(s): Paterson et al. Sources: University of Pittsburgh Sponsors: NA
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 11
Adherence and AIDS-Free Survival
10% Adherence difference = 21% reduction in risk of AIDS
Proportion AIDS-Free
1.00
0.75
0.50
0.25
P = .0012
0.00
0
5
10
15
Months from Entry
Bangsberg D, et al. AIDS. 2001:15:1181
•
20
25
30
Adherence
O 90–100%
O 50–89%
O 0–49%
One study showed that:
•
A 10% increase in ART Adherence resulted in a 21% reduction in risk of the
development of AIDS
•
The difference between 95% and 100% is only 3 doses per month. Therefore if
a patient is missing more than 3 doses per month, they are at great risk of
adherence
Source: Bangsberg D, et al. AIDS. 2001:15:1181
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 12
Why Is ART Adherence
Important? (cont.)
■ Overall, 40% to 60% persons taking HAART are less
than 90% adherent.
■ However, the level of adherence required for success,
is thought to be a staggering 95% or greater.
Unit 7: Adherence for ART Success
Reference Manual for Trainers
12
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 13
Adherence to ARV’s in ResourceLimited Settings*
■ Uganda: 88%
■ Cote d’Ivoire: 75%
■ Haiti: 88%
■ Senegal: 78%, 42%, 88%
■ South Africa: 89%
■ Brazil: 57%, 87%, 69%
■ Botswana: 54%, 53%, 58%
Adherence is as
problematic in
resource-limited
settings as it is in
resource-rich settings.
No evidence shows
that it is more
problematic.
■ Nigeria: 58%
■ Kenya: 59%
Unit 7: Adherence for ART Success
•
Source: MTCT-Plus, Columbia University 2002
*(NB: small studies, differing definitions of adherence)
13
Adherence is as problematic in resource-limited settings as it is in resource-rich
settings. No evidence shows that it is more problematic.
•
Success of antiretroviral therapy hinges on tablet taking behavior.
•
Ideal adherence means a patient must take more than 95% of their doses (i.e.
missing less than 3 doses in a month).
•
If a patient is taking less than 95% of their doses, they are at risk for
developing viral resistance and ultimately virological failure.
•
Note that this data comes from a series of small studies, so the rates of adherence
may underestimate adherence. For example, an adherence study with multivitamins
was conducted in Mombasa, Kenya and documented and documented an average
adherence rate of 80% (Frick PA, Lavreys L, Mandaliya K, Kreiss JK. Impact of an
alarm device on medication compliance in women in Mombasa, Kenya. International
Journal of STD and AIDS. 2001;12:329-333.)
•
There is no reason to think that adherence to ART should be any more problematic in
resource poor settings than in resource rich settings.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 14
Introductory Case - Answers
■ The statement C): ART must be taken as prescribed to
avoid the development of resistance and possible
treatment failure is true.
Unit 7: Adherence for ART Success
•
14
The next slide describes how nonadherence leads to incomplete viral suppression
and the development of drug resistance.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 15
Sub-Optimal Adherence Predisposes
to Resistance
Sub-optimal adherence
Sub-therapeutic drug levels
Incomplete viral suppression
Generation of resistant HIV strains
by selection for mutant viruses
Association between poor adherence and
antiretroviral resistance is well-documented1,2
1. Vanhove G, et al. JAMA. 1996;276:1955-1956.
2. Montaner JS, et al. JAMA. 1998;279:930-937.
•
This depicts the progression from nonadherence to the resultant development of
resistance.
•
When doses are repeatedly missed, drug levels become sub therapeutic. This leads
to incomplete viral suppression and the generation of HIV resistant strains. Not only
is the patient at risk of failing their current regimen, they are at risk of developing
resistance that may reduce the effectiveness of future regimens. This relationship
between poor adherence and ARV resistance is well documented.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 16
What is Resistance?
■ HIV reproduces very quickly, making billions of new viruses
every day.
■ Because the virus often makes errors while copying itself, each
new generation of viruses differs slightly from the one before
■ Some changes to the structure of the virus can improve its ability
to reproduce despite high levels of anti-HIV drugs being present.
■ Viruses which are able to reproduce in the presence of ARVs are
said to be resistant to those drugs.
Unit 7: Adherence for ART Success
16
•
HIV reproduces very quickly, making billions of new viruses every day. Because it
often makes errors while copying itself, each new generation of viruses differs
slightly from the one before.
•
Some of these errors produce viruses which are defective and so can't reproduce
themselves well. Over time these 'less fit' viruses will die off. However, some
changes to the structure of the virus can also improve its ability to reproduce
despite high levels of anti-HIV drugs being present. Viruses which are able to
reproduce in the presence of ARVs are said to be resistant to those drugs.
•
Researchers estimate that every possible error that might appear in HIV's
structure occurs once every day if virus production is not being suppressed. This
means the seeds for a drug resistant crop of viruses are being sown every day,
and these viruses will be the ones which grow best when a patient starts taking
anti-HIV treatment.
.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 17
Missed Doses & Development of
Drug Resistance
•
This diagram shows the effect of missed doses.
•
Anti-HIV drugs are prescribed at doses that will maintain an effective level of drug in
the bloodstream. If a dose is missed, taken late, or with the wrong type of food, the
blood level dips and the virus will be more able to reproduce itself. While the blood
levels of drugs are low, viruses that have some natural resistance to the drugs being
taken will reproduce easily. If these viruses gain a foothold, then even if a person
starts taking drugs regularly again, enough drug-resistant viruses may already have
emerged to cause treatment to fail.
•
Following drug regimens to the letter (taking pills exactly as they were prescribed) is
called adherence (and sometimes also compliance). Unlike treatments used in many
other chronic diseases, anti-HIV drug therapy requires an extremely high level of
adherence if it is not to fail: as stated earlier, we believe that this requires a level of at
least 95%. Increasingly, researchers are recognising that adherence is perhaps the
most important factor in successful HIV treatment, and that people taking anti-HIV
drugs need support in sticking with their treatment in the long-term.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 18
Introductory Case - Answers
■ The statement A): Taking less than the prescribed dose
is an effective way to make ART last longer without
going to the pharmacy is false.
■ Taking less than the prescribed dose will lead to drug
levels that are too low to prevent viral replication. This
will lead to treatment failure. Every effort must be made
to take ART as prescribed to ensure treatment success.
Unit 7: Adherence for ART Success
Reference Manual for Trainers
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HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 19
Unit 7: Adherence for ART Success
•
19
Drug resistance develops when HIV mutants emerge which can reproduce in the
presence of a drug. These mutants form the basis of the new virus population,
because they can reproduce despite the presence of the anti-viral drug. The
resistant population overtakes the drug sensitive population. Resistant virus will
accumulate and will lead to loss of efficacy and treatment failure.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 20
Cross Resistance- NNRTIs
■ Emerges quickly if the virus is not quickly and fully
suppressed
■ Caused by a single mutation
■ Development of resistance to one NNRTI will lead to
resistance of all other NNRTIs
■ Do not sequence if failure has occurred
■ Risk of resistance when stopping an NNRTI
Unit 7: Adherence for ART Success
20
•
Once resistance to one drug has emerged, this virus population may also be resistant to
drugs a patient has not yet taken. This is called cross-resistance.
•
Among people on combinations containing non-nucleoside reverse transcriptase inhibitors
(NNRTIs, e.g. efavirenz, nevirapine, delavirdine), resistance readily emerges to the
NNRTIs if HIV is not quickly and fully suppressed to very low levels.
•
This is because a single mutation can confer high level resistance to an NNRTI.
Consequently, NNRTIs should only be used as part of powerful combinations containing
at least three anti-HIV drugs which can reduce HIV levels below the limits of detection.
•
In the past, concern has been expressed that use of one NNRTI might lead to crossresistance to all other NNRTIs in the future. Current evidence suggests that this is the
case. There is no clinical evidence that people with resistance to one NNRTI will benefit
from second-line NNRTI treatment.
•
Risk of resistance when stopping an NNRTI:
•
The NNRTIs have a long half-life - which means that the body clears these drugs
from the body slowly. This means that if a patinet stops taking all thei drugs at the
same time, low levels of the NNRTIs may remain in your blood after the other
drugs have gone. This can put them at increased risk of NNRTI resistance.
•
When considering stopping a regimen which includes an NNRTI, consider staggering the
discontinuation of the drugs. One expert has recommended that efavirenz and nevirapine
be stopped five or six days before nucleoside analogues are stopped.
•
This is purely for discussion purposes.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 21
Cross Resistance - Nucleoside
Analogues
■ 3TC resistance is caused by a single mutation that is
likely to develop early and may lead to crossresistance against DDC, ABC and DDI
■ However, DDI can still be used as it is less affected by
mutations developed by 3TC, ZDV and D4T
■ DDI has proven to be effective in the presence of multiple
nucleoside analogue mutations
■ ZDV and D4T may still retain activity
■ High level resistance to both ZDV and 3TC =
resistance to abacavir.
Unit 7: Adherence for ART Success
21
•
There is a significant degree of cross-resistance between some nucleoside analogues,
which can lead to problems in selecting pairs of nucleoside analogues for use in
combination therapy for someone who has already received extensive nucleoside
treatment.
•
AZT resistance occurs less frequently when the drugs is paired with 3TC, although there
is wide variation in the frequency of thymidine analogue mutations in patients
experiencing failure of first-line therapy (<1% - 30%).
•
Where nucleoside analogues have been used as the backbone of the first regimen, data
on resistance patterns have the following implications for sequencing of nucleoside
analogues (NRTIs):
•
3TC resistance may lead to cross-resistance against ddC, abacavir and ddI, and vice
versa. Where a 3TC-containing regimen is used as first-line treatment, it is highly likely
that 3TC resistance will emerge if the regimen fails. Resistance to d4T or AZT is far less
likely to emerge (< 10% of patients), and one study suggests no loss of sensitivity to these
drugs in people without genotypic resistance, suggesting that these drugs can be used
again later (Maggiolo).
•
However, DDI can be used after the development of resistance to 3TC (it is not affected
by 3TC resistance), and is not seriously affected by the development of AZT and d4Tassociated mutations (thymidine analogue mutations, or TAMs). It is clear that there is
considerable cross-resistance among the NRTIs. However, multi-nucleoside resistance
mutations may not blunt the effectiveness of all NRTIs. Researchers investigated the
effectiveness of NRTIs against multi-nucleoside resistant virus in the test tube and found
that ddI response was less affected than 3TC, d4T or AZT, suggesting that ddI may be a
more attractive candidate than other NRTIs for `recycling' in a salvage regimen if such
mutations are present.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 22
Cross Resistance- Nucleoside
Analogues (cont.)
■ Cross resistance exists between ZDV and D4T, 3TC
and FTC and between DDI and DDC
■ Susceptibility to ZDV, D4T and TDF is increased when
with 3TC resistance
■ Tenofovir requires the accumulation of a number of
mutations before it’s potency is affected. It is not
associated with cross resistance to nucleosides.
Unit 7: Adherence for ART Success
•
•
•
•
•
22
Resistance to AZT and 3TC may cause resistance to abacavir. Abacavir can probably be used
after the development of resistance to 3TC, providing that three or less TAMs are present (maybe
in the setting of recent failure)
There is now substantial evidence of cross resistance between AZT and d4T, with both drugs
causing ‘AZT-associated’ mutations or TAMs. d4T after AZT, or AZT after d4T, may be less
effective if TAMs have developed. For example, a study which compared 56 individuals who started
therapy with AZT/3TC or d4T/3TC, found there was no significant difference between the groups in
the incidence of mutations associated with AZT resistance after 18 months of therapy (Nicastri).
TAMs reduce the antiviral activity of both d4T and AZT. An analysis of 301 virus isolates from the
Virco database showed that in the presence of five thymidine analogue mutations (41L, 67N, 70R,
210W, 215Y/F and 219Q/E), an average reduction in sensitivity of 2.2-fold was observed (below the
cut-off level previously defined by Virco's phenotypic assay (Craig 2002). In two other studies, HIV
samples from people with lengthy exposure to AZT and 3TC found that 50% of those with AZT and
3TC resistance were no longer susceptible to d4T or had 4-10 fold reductions in sensitivity to the
drug (Ruffault; Izopet). The K70R mutation, often the first mutation to appear during AZT therapy,
does not affect the antiviral activity of d4T but subsequent AZT-associated mutations do limit the
response to d4T (Shulman).
Despite the emergence of resistance to AZT, there is evidence that people who take AZT as part of
their first antiretroviral regimen have a better chance of viral suppression when they switch to a
regimen containing d4T, compared with people who start with d4T and switch to AZT.
There is also high level cross resistance between 3TC and FTC as FTC is the newer version of
3TC.
3TC resistance can reduce resistance associated with AZT or d4T. Susceptibility to AZT, d4T and
tenofovir is increased the primary mutation to 3TC (M184V) is present, even in the presence of
other mutations (TAMS) However, if a patient has multiple TAMS (3) then the 3TC mutation may
not be of benefit to ZDV or D4T. Note that in the US, for patients who have failed a 3TC containing
regimen, they may continue on 3TC as susceptibility to ZDV, D4T and TDF is increased when with
3TC resistance..
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 23
Cross Resistance PIs
■ Some mutations are selected for only by certain protease
inhibitors (Nelfinavir)
■ There is considerable overlap between combinations of
mutations in HIV strains that develop resistance to PIs
■ This explains the wide cross resistance that is observed within this drug
class
■ PIs with activity after failure of an initial PI include lopinaivr/r,
fosamprenavir/r or atazanavir/r
Unit 7: Adherence for ART Success
•
Some mutations are selected for only by certain protease inhibitors For
example:
•
•
23
If Nelfinavir is used as the initial PI, it selects mutations that are not cross
resistant to other PIs. With the acquisition of additional mutations, other Pis
will become less susceptible. The risk of continuation of nelfinavir in a failing
regimen can lead to cross resistance to indinavir, saquinavir and ritonavir.
This highlights the risk of contintuation of a failing regimen, that is, loss of
the opportunity to achieve full viral suppression with future regimens.
There is considerable overlap between combinations of mutations in HIV strains
that develop resistance to PIs
•
This explains the wide cross resistance that is observed within this drug
class. Certain mutations confer cross resistance to saquinavir and
ritonavir.(V82A and L90M) Along with mutations to additional Pis (L10I,
M36I, I 54V, A71V, the afore mentioned mutations are likely to predict poor
response to all currently available Pis. However, lopinavir and amprenavir
often retain activity after failure with other Pis.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 24
Infection with Drug-resistant HIV:
A Public Health Problem
■ Wider use of ART may lead to transmission of
drug-resistant virus.
■ People newly infected with HIV in Europe and
America may have drug-resistant strains.
■ Whether someone HIV-positive can become
infected with a second drug-resistant strain is
less clear.
Unit 7: Adherence for ART Success
24
•
With the widespread use of anti-HIV drugs in many parts of the world and the
accompanying problem of drug resistance, it’s become more common for people who
contract HIV to be infected with a drug-resistant strain. This can happen either
through sexual transmission, through contact with infected blood (for example
through injecting drugs), or from an HIV-positive mother to her baby.
•
Becoming infected with a drug-resistant strain may seriously limit a person’s
treatment options in the same way as developing resistance while taking treatments,
narrowing down the range of drugs that he or she might benefit from.
•
Whether someone who is already HIV-positive can become infected a second time
with a drug-resistant strain is much less clear. Though there is some evidence that it
may occur, it’s difficult to know how great the risk is.
•
In the regions where ART use has been widespread, the transmission of drugresistant HIV is on the increase. With time, and the greater use of multiple classes of
HIV drugs, the transmission of HIV that is multi-drug resistant (resistant to a number
of drugs and therefore more difficult to treat) is becoming more common.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 25
Reasons Why People
May Not Be Adherent
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 26
Published Predictors of Poor
Adherence
■ Active alcohol1 or substance2 abuse
■ Work outside the home for pay1
■ Depressed mood1
■ Lack of perceived efficacy of HAART3
■ Lack of advanced disease4
■ Concern over side effects4
Unit 7: Adherence for ART Success
1. Chesney MA. 37th ICAAC, 1997;
Toronto. Abstract 281.
2. Cheever LW, Curr Infect Dis Rep 1999
Oct;1(4):401-407.
3. Horne R, et al. 39th ICAAC, 1999; San
Francisco. Abstract 588.
4. Wenger N, et al. 6th Conference on
Retroviruses and Opportunistic Infections,
1999; Chicago. Abstract 98.
26
•
What is Predictive of Poor Adherence ?
•
What are some of the factors that can be addressed PRIOR TO STARTING
MEDICATION?
•
Active alcohol or substance abuse (They can work with case workers to get
into rehabilitation programs)
•
Work outside the home for pay (Travel and a schedule that is not routine can
lead to patterns of nonadherence)
•
Depressed mood (This may result in a lack of consistency with the regimen)
•
Lack of perceived efficacy of HAART
•
Lack of advanced disease (if the patient does not “feel sick” they may not feel
the need to or remember to take medication
•
Concern over side effects (Some side effects are very visual (eg. Rash or
lipodystrophy) and patients do not want their family members/friends to know
of their HIV status so they stop taking their medication to avoid the side
effects. Other side effects are very bothersome (eg. Diarrhea or nausea from
the protease inhibitors) which make patients feel sicker than before they went
on medication. Still other patients may never even begin to take their
medication if they are afraid of the side effects or if they do not feel as though
they are prepared to handle them.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 27
Published Predictors of Poor
Adherence (cont.)
■ Non-Caucasian race documented in some studies
conducted in the U.S.1-3 but not others5
■ Association of race with adherence not found in other disease
states
■ Lower literacy rate a confounder?4
■ Inability to fit medications into daily schedule
■ TID dosing, food requirements6
1. Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago, IL. Abstract 92.
2. Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago, IL. Abstract 98.
3. Mar-Tang M, et al. J Gen Intern Med. 1999;14(suppl 2):53.
4. Kalichman SC, et al. J Gen Intern Med. 1999;14:267-273.
5. Stone VE, et al. JAIDS 2001; 28:124-131
6. Stone VE, et al. JAIDS 2001; 28:124-131
Unit 7: Adherence for ART Success
27
•
Some studies have suggest that race other than Caucasian is a predictor of
nonadherence. Other studies have shown that race is not a predictor of
nonadherence.
•
Many patients have difficulties with nonadherence due to the inability to fit
medications into daily schedule. It is crucial to consider the patients lifestyle when
choosing a regimen. A patient has a much better chance at success if the regimen is
designed to fit into their lifestyle, rather than trying to change the patient’s lifestyle to
fit with their regimen. Some of the new ARVs are able to be dosed once daily or twice
daily which makes it much easier for patients to work them into their
•
Schedule versus the previous ARVs that had to be taken three to five times a day.
•
Regimens that require food for absorption may make them more difficult to adhere to
when patients do not have regular access to food.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 28
Published Reasons for
Missed Doses
■ Simply forgot
40%
■ Slept through the dose
37%
■ Away from home
34%
■ Change in routine
27%
■ Busy with other things
22%
■ Too sick
13%
■ Sick from side effects
10%
■ Depressed
9%
Unit 7: Adherence for ART Success
28
•
There are a number of reasons why people stop taking medicines.
•
The reasons that patients miss doses may overlap, meaning that there may be more
than one variable.
•
The majority of the reasons that patients miss doses (as identified in the US by
Chesney et. al., and published in literature) include:
•
They simply forgot, slept through the dose, had a change in their routine or were
away from home.It seems as though, in general,once patients are doing well on
therapy, they are not missing doses because they are sick from the medication or
that or that they do not like taking medicine.
•
Sometimes when people are depressed and isolated they will stop taking
ARVs because they feel that life is no longer worth living, or they do not have
the strength to continue. If patients appear depressed, they should be
questioned for signs of depression and treated accordingly.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 29
Correlates of Nonadherence
■ Patient Characteristics
■ Lack of stable relationship, domestic violence
■ Nondisclosure of HIV status, with accompanying stigma
and isolation
■ General health – if people do not feel ill, may be less
motivated to take meds
■ Psychological impairment and distress – depression, etc.
■ Beliefs – If people believe the meds keep them healthy,
they may take their meds properly
■ Spirituality
Unit 7: Adherence for ART Success
29
•
THE NEXT FEW SLIDES BREAK UP CORRELATES OF ADHERENCE INTO 5
DISTINCT CATEGORIES.
•
Patient Characteristics
•
•
Sociodemographics: age, sex, race/ethnicity, education, income, and
intelligence are NOT predictors
•
Active alcohol and/or drug use IS, but past use is NOT
•
Lack of stable relationship
•
Nondisclosure of HIV status, with accompanying stigma and isolation
•
General health – if people do not feel ill, may be less motivated to take meds
•
Psychological impairment and distress – depression, etc.
•
Beliefs – If people believe the meds keep them healthy, they may take their
meds properly
•
Spirituality
Reference:This information was pulled from the literature and compiled in the “Buddy
Training Manual” for an adherence study in the Bronx, NY and for Project PAL in
Seattle, WA (“Buddy Training Manual” prepared by Jane Simoni, PhD).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 30
Correlates of
Nonadherence (cont.)
■ Aspects of the Provider and Patient-Provider
Relationship
■ Provider belief in medication and how much they convey this
to the patient
■ Provider expertise
■ Knowledge and time spent to implement interventions
■ Openness, consistency, friendliness, genuine interest,
empathy, mutual trust and respect of patient-provider
relationship
Unit 7: Adherence for ART Success
•
30
The provider-patient provider relationship cannot be underscored enough.When providers
convey their belief in the medication, then patients seem to believe in the treatment as
well.Patients look to their providers for their expertise, knowledge and value time spent to
implement interventions. Length openness, consistency, friendliness, genuine interest,
empathy, mutual trust and respect of patient-provider relationship are all important
factors that improve adherence.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 31
Correlates of
Nonadherence (cont.)
■ Variables Related to the Treatment Regimen
■ Complexity of regimen
■ Number of medications, frequent doses, dietary restrictions, various
forms of administration, impact lifestyle
■ Side effect severity
■ Long-term duration
■ Patients are less likely to adhere when their illness is chronic
and there are periods of no symptoms, non-curative treatment
and no immediate effect of nonadherence.
Unit 7: Adherence for ART Success
31
•
Many variables are derived from the choice of treatment regimen.
•
Complexity of regimen: number of medications, frequent doses, dietary restrictions,
side effect severity, various forms of administration, long-term duration.
•
Patients are less likely to adhere when their illness is chronic and there are periods of
no symptoms, non-curative treatment and no immediate effect of nonadherence. This
is where pharmacists need to intervene to educate patients that it is important to
continue to take their medication even though they do not “feel sick”.
•
Patients need to know that the medication is keeping the virus under control and if
the medication is taken away, they will get sick.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 32
Correlates of
Nonadherence (cont.)
■ Contextual Factors
■ Medical clinic is far from the patient’s home, lengthy delays
between clinic contact and appointments, inconvenient
hours of operation, long waiting periods, lack of services
(childcare, poor privacy, inconsiderate staff)
■ Systemic issues include poor access to drugs or inadequate
health insurance coverage
■ Life situation issues include homelessness, lack of steady
income
■ Institutional systems – jail, prison, drug rehabilitation,
hospitalization may not provide adequate access to
medications
Unit 7: Adherence for ART Success
•
32
Other correlates of nonadherence include logistical issue: (cont.)
•
Medical clinic is far from the patient’s home, lengthy delays between clinic
contact and appointments, inconvenient hours of operation, long waiting
periods, lack of services (childcare, poor privacy, inconsiderate staff)Systemic
issues include poor access to drugs or inadequate health insurance coverage
Life situation issues include homelessness, lack of steady income Institutional
systems – jail, prison, drug rehabilitation, hospitalization may not provide
adequate access to medications
Reference:This information was pulled from the literature and compiled in the
“Buddy Training Manual” for an adherence study in the Bronx, NY and for Project
PAL in Seattle, WA (“Buddy Training Manual” prepared by Jane Simoni, PhD).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 33
Factors that do NOT Predict
Nonadherence
■ Sociodemographics
■ Age
- Income
■ Sex
- Intelligence
■ Race/ethnicity
■ Education
■ Past use of alcohol and/or drugs (but active alcohol
and/or drug use IS associated with nonadherence)
Unit 7: Adherence for ART Success
•
33
Research has shown that the sociodemographic factors appear to impact adherence
in some studies and in others they have no impact. So in general, these
sociodemographic factors cannot be used to predict who may or may not be
nonadherent
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 34
Five Different Types of
Nonadherers
■ Consistent Underdoser
■ Who regularly neglects to take a particular one of the
prescribed doses such as the midday dose or who regularly
takes only certain of the prescribed medications
■ Consistent Overdoser
■ Who takes the drug more often or in larger doses than is
prescribed
Unit 7: Adherence for ART Success
•
34
Nonadherence can be seen in many ways, here are a few examples of types of nonadherent
patients:
• Consistent Underdoser
• Who regularly neglects to take a particular one of the prescribed doses such as
the midday dose or who regularly takes only certain of the prescribed
medications. (Some patients think that they can avoid side effects by taking less
of the prescribed dose which puts them at risk of not getting enough medication
which could result in treatment failure)
• Consistent Overdoser
• Who takes the drug more often or in larger doses than is prescribed (they falsely
think that “more is better”), they may be at higher risk for medication toxicity
Reference: This information was pulled from the literature and compiled in the “Buddy Training
Manual” for an adherence study in the Bronx, NY and for Project PAL in Seattle, WA (“Buddy
Training Manual” prepared by Jane Simoni, PhD).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 35
Introductory Case - Answers
■ The statement B): If any doses of ART are missed, a
change in ART regimen will be necessary, is false. A
change in regimen should only be done when
absolutely necessary. Although this patient has been
taking her medication incorrectly ( a consistent
underdoser), this dose not mean that she has failed her
regimen. She should be counseled that she needs to
take her medication as prescribed and should be given
suggestions how to avoid missing her morning dose.
Unit 7: Adherence for ART Success
Reference Manual for Trainers
35
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 36
Five Different Types of
Nonadherers (cont.)
■ Abrupt Overdoser
■ Who does not take medications properly and then takes an
overdose prior to a clinic visit or who doubles up for missed
doses
■ Tourist
■ Who habitually takes “drug holidays” – abruptly stopping all
medications for a few days or weeks or one day off per week .
. All lead to drug resistance
■ Random Doser
■ Takes the medications when she or he thinks of it
Unit 7: Adherence for ART Success
•
•
36
Abrupt Overdoser
• Who does not take medications properly and then takes an overdose prior to a clinic
visit or who doubles up for missed doses (they are at risk for periods of time when
they are not getting enough medication which puts them at risk of developing
resistance and other times when there levels are too high at put them at risk for
toxicity.
Tourist
• Who habitually takes “drug holidays” – abruptly stopping all medications for a few
days or weeks or one day off per week . .
• Random Doser Takes the medications when she or he thinks of it
• All of these lead to drug resistance
Reference: This information was pulled from the literature and compiled in the “Buddy Training
Manual” for an adherence study in the Bronx, NY and for Project PAL in Seattle, WA (“Buddy
Training Manual” prepared by Jane Simoni, PhD).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 37
Factors Associated with
Higher Levels of Adherence
■ Twice-daily or once-daily regimens1,4
■ Belief in own ability to adhere to regimen1
■ Not living alone2
■ Dependent on a significant other for support2
Unit 7: Adherence for ART Success
•
37
The following are some of the factors that have been associated with higher levels of
adherence:
•
Twice-daily or once-daily regimens
•
Belief in own ability to adhere to regimen
•
Not living alone (having a support system)
•
Dependent on a significant other for support
•
History of Opportunistic Infection or Advanced HIV disease
•
Belief in efficacy of antiretroviral therapy
•
Belief that non-adherence will lead to viral resistance
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 38
Factors Associated with
Higher Levels of Adherence (cont.)
■ History of opportunistic infection or advanced HIV
disease3
■ Belief in efficacy of antiretroviral therapy
■ Belief that non-adherence will lead to viral resistance
1. Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117-125.
2. Morse EV et al, Soc Sci Med 1991;32:1161-1167.
3. Singh N, et al, AIDS Care 1996;8:261-269.
4. Stone VE, et al. JAIDS 2001; 28:124-131
5. Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago.
Abstract 98.
Unit 7: Adherence for ART Success
Reference Manual for Trainers
38
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 39
Tools for Improving
ART Adherence
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 40
REMEMBER
ART is NEVER an Emergency
Take Time to Educate the Patient
Before Starting Therapy
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 41
To Help Maximize Adherence
■ Do not start ARVs at first visit.
■ Counseling and education by the pharmacist is very
important and should include discussion of:
■ Adherence
■ Risks and benefits
■ Side effects
■ Drug interactions
■ How nonadherence leads to resistance
■ Lifelong commitment to therapy
■ Follow-up is critical
Unit 7: Adherence for ART Success
41
•
Remember that starting ARVs is not an emergency. It is best to wait to start ARVs
until after the first visit and the patient has had a chance to think about the idea of
starting on medication and the proposed regimen.
•
Pre-therapy counseling should be done by the pharmacist. Information that should
be covered include a discussion around:
Adherence
•
Risks and benefits
•
Side effects
•
Drug interactions
•
Lifelong commitment to therapy
•
Counseling should continue with each follow-up appointment
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 42
Improving Adherence:
Before Initiation of Therapy
■ Make sure that the patient is involved in the decision to
start therapy
■ Take time to educate the patient:
■ Explain the goals of therapy
■ Explain why adherence is important for preventing resistance
■ Provide written schedules, & follow-up education
■ Assess how you the medications can fit their lifestyle
■ Seek help quickly if problems occur in taking pills.
Unit 7: Adherence for ART Success
42
•
Before the patient begins therapy: they must receive pre-treatment information and education
•
Make sure it is the patient’s decision to start therapy. Sometimes the patient may not be ready to start therapy,
but their provider knows that they need the medications clinically and may be pressuring patients to begin
therapy. Determine that they are in fact ready to begin therapy which will be continued life long. The chance for
success is greater if patients agree with starting therapy and are motivated to do so.
•
Involve the patient in the decision making process: ask them questions to determine how to best fit their initial
regimen into their lifestyle. Determine what the best times of day are for them to take their medication.
•
Take time to educate the patient:
•
•
Explain the goals of therapy (to reduce the viral load to undetectable, increase immunologic measures
(CD4 or TLC) and to improve the patient’s quality of life and longevity
•
Explain necessity of adherence to regimen (review the pathway from nonadherence to the development
of drug resistance and treatment failure
•
Provide written schedules to remind them of what times they will take their medication every day.
•
It is important to provide follow-up education to determine that adherence is ongoing, that the patient has
not encountered any new barriers to adherence or side effects that need to be addressed.
Assess how medications fit into patient's lifestyle
•
For example, learn patient's sleeping, eating, and work patterns; amount of time away from home; and
frequency of weekend or overnight trips.
•
For example, say: "Many people find taking HIV medications very difficult. What sort of difficulties have
you had taking your medications?“
•
For example, say: "Tell me what times you take your medications," or "How does this fit into your
lifestyle?“
•
Consider alcohol or drug abuse, depression, and poor coping skills.
Adapted in part from Centers for Disease Control and Prevention. MMWR.
1999.[37] Source: http://hiv.medscape.com/
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 43
Improving Adherence:
Before Initiation of Therapy (cont.)
Assess patient's understanding and
acceptance of the regimens
Determine other medical barriers to
adherence
Manage or refer for management of
adherence-limiting co-morbid conditions
Identify any potential drug interactions
(with other drugs, natural medicines, or
food)
Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.
Unit 7: Adherence for ART Success
•
•
43
Before Initiation of Therapy, also:
•
Assess patient's understanding and acceptance of the regimens
•
Determine other medical barriers to adherence
•
Manage or refer for management of adherence-limiting co-morbid conditions
If these questions are addressed AFTER a patient starts therapy, it may be too late.
This puts them at higher risk of developing resistance and treatment failure.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 44
Improving Adherence:
Before Initiation of Therapy (cont.)
■ Try to use simple regimens
■ Once or twice daily
■ Avoid food restrictions or requirements if possible
■ Use combination tablets where available
■ Clear & simple instructions
Unit 7: Adherence for ART Success
•
44
Before Initiation of Therapy also:
•
Try to use simple regimen (once or twice daily an avoid food restrictions or
requirements if possible) It has been shown that regimens that were three
times daily and those regimens with food restrictions were predictive of
nonadherence
•
Provide Clear & simple instructions. E.g. When patients are to begin
nevirapine and they have to take 1 tablet daily for 14 days, then increase to 1
tablet twice daily, write down the days on a calendar so that they have a visual
reminder of when they should increase their dose. This will help prevent them
from escalating the dose to early, putting them at risk for a rash.
•
Negotiate treatment plan and involve patient in the process. Determine that the
patient is ready to start meds and that they will follow-up for monitoring of
therapy,
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 45
‘I FORGOT’
■ Remember the most common reason for missing doses
is: ‘I forgot’
■ Always try to discover the reason for forgetting
■ If several doses missed, is there a a pattern
Unit 7: Adherence for ART Success
45
•
The most common reason stated by patients for failing to take pill is `I forgot`. Always try to
discover the reason for forgetting. For example, was the patient too busy, or does their work
schedule make it difficult to take the pills at the right time? Did the patient forget to take the
pills once, or several times? Is there a pattern? Is the patient having problems remembering
the plan for pill taking that was agreed before starting treatment?
•
Many people with HIV have learned to find ways around the difficulties of pill taking. Always
remind patients that they are not alone in facing these difficulties, and that membership of a
support group may help in adjusting to taking medication, and maintaining very high
adherence to treatment.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 46
Improving Adherence:
Before Initiation of Therapy (cont.)
■ Inform patient of devices that can assist them in
taking their medications regularly
■ Alarm devices (Watches, Pagers, Cell phones)
■ Pill boxes
■ Associate doses with daily activities
■ Other memory cues
■ Suggest leaving reminders around home or work
■ Leave medications out where they can see them
Unit 7: Adherence for ART Success
•
46
Pill boxes, alarms, pagers and other daily cues can be helpful in reminding patients to take their
medication.
•
Pill boxes can be very beneficial in helping patients to remember if they took their previous dose. For
example, they may become busy and ask themselves if they took there dose from the morning. With a
pill box, they can look in the morning slot and see that the medication is gone. They can fill their pill
box every week. If a patient needs assistance filling their pill box, the pharmacist can help them to fill
the pill box until the patient is able to do so him or herself.
•
Alarms can be set to the times of day that medication should be taken, they are discreet and
are a helpful reminder for many patients.
•
Some patients identify certain daily activities which remind them to take their doses (eg. Just
after getting dressed in the morning and with dinner)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 47
Improving Adherence:
Before Initiation of Therapy (cont.)
■ Develop strategies ahead of time for handling:
■ Side effects
■ Missed doses
■ Change in routine (carry an extra dose of ARVs)
■ Travel (Time zones)
■ Storage of medications
■ Fear of taking medications in front others
■ Encourage patients to talk with others about their
experiences
Unit 7: Adherence for ART Success
•
47
Pharmacists can help patients plan ahead to avoid the risk of nonadherence when away from their
daily routine (e.g., weekends, holidays, visitors in the home, or other changes in routine:
•
They should have a plan of how to handle side effects if away from home. Eg. If a patient
knows that from time to time, they experience headaches on their ARV, they should bring
paracetamol or aspirin to relieve their headache while away from home. They need to think
ahead.
•
An easy rule for a way to handle missed doses is as follows:
• Let’s say that a patient takes her regimen twice daily therefore BID dosing. There are12
hours between doses, ½ way to the next dose is 6 hours. If patient is within 6 hours of a
late/missed dose, they should take that dose when remembered and then go back to
normal schedule. If patient is over 6 hours after late/missed dose, they should skip that
dose and wait till next dose (to avoid double dosing and added toxicities) then go back to
normal schedule. This rule can lessen patient stress related to missing doses.
• Storage of medications: ritonavir, lopinavir/r and saquinavir all require storage in a cold
chain to ensure stability.
• However, lopinavir/r can be at room temperature for 60 days and ritonavir can be at
room temperature for 30 days, saquinavir soft gel caps are stable at room temperature for
up to 3 months, saquinavir hard gel caps are stable at room temperature. All of these
medications should be kept out of hot temperatures.
• Difficulties in taking pills around others – if this is the case, discuss ways of taking pills
privately, or identifying whether it may be necessary to disclose HIV status to a specific
person who is often present when pills must be taken.
•
It is helpful for patients to talk to others about their experiences, this way, they feel less alone in their
struggles with medication. They can get helpful advice from others who have had questions similar to
theirs in the past.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 48
Improving Adherence:
Before Initiation of Therapy (cont.)
■ Let patients practice pill-taking behavior before start
ART with OI prophylaxis medications or candy
■ Short term Directly Observed Therapy (DOT)
■ Encourage social support
■ Improve patient self-efficacy
■ Involve the multidisciplinary team to counsel about
adherence
Unit 7: Adherence for ART Success
•
48
A multidisciplinary approach is best approach for improving adherence. All
disciplines should address adherence with them at every visit in a non-judgemental
fashion. If you as the pharmacist does not have time at that moment, ask them to
come back at a time when the pharmacy may not be as busy or refer them to one of
the other team members to receive counseling
•
Ongoing education with the same messages from pharmacist, nurse,
counselor, provider
•
Published research has shown that pharmacist counseling positively impacts
adherence (refer to Handout 7.1 again).
•
Let patients practice pill-taking behavior before start ART with OI prophylaxis meds or
candy. This can help them to get used to taking medications on a regular schedule
•
Short term DOT. This can be very demanding for staff to coordinate on a large scale
•
Encourage social support. Patients should reach out to friends or family so that they
can offer support or reminders to the patient to take their medications
•
Improve patient self-efficacy (I.e., help them to believe that they can take their
medications according to the schedule and that they will be able to do it well)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 49
The “Adherence Team”
■ A team approach is needed to optimally maximize
adherence
■ Should involve physicians, nurses, pharmacists, other
health care providers, and family/friends of the patient
as possible
■ Do NOT start therapy if the patient is not fully
committed
■ Monitor adherence regularly over time
Unit 7: Adherence for ART Success
49
•
A team approach is needed to optimally maximize adherence
•
Should involve physicians, nurses, pharmacists, other health care providers, and
family/friends of the patient as possible
•
Do NOT start therapy if the patient is not fully committed
•
Monitor adherence regularly
•
DOT may be useful, especially when a patient is starting a new regimen.For
example: side effects may be difficult to handle early on in therapy. It may be difficult
for patients to get used to the idea of taking medication every day.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 50
ART Care Model
(Adherence Protocol)
Multidisciplinary (Team) effort:
Social worker
Physician
Nursing
Patient
Pharmacist
Unit 7: Adherence for ART Success
Nutritionist
TGK/ITECH/9.03
50
The physician, pharmacist, and nurse are intricately connected with the patient and each
other as the decision is being made to start a patient on ART.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 51
Adherence Issues for Health
Care Workers
Don’t make assumptions about patient adherence
Ask questions and discuss solutions.
■ BEFORE TREATMENT:
■ Do you know that the medicines must be taken for the rest of
your life? Your life depends on taking them every day at the
right times.
■ If you stop, you will become ill (not immediately, but after
months or years).
■ Do you know what resistance is?
■ Do you know you should not share these medicines with
family or friends?
Unit 7: Adherence for ART Success
51
•
Don’t make assumptions about patient adherence – ask questions and discuss
solutions. It is not possible for health care providers to reliably predict which
individuals will ultimately be adherent to their treatment plan, as adherence does not
correlate with gender, cultural background, socio-economic or education level, or
language barriers between provider and patient.
•
Before beginning treatment, the health care worker should make sure that the patient
understands the following points:
•
Do you know that the medicines must be taken for the rest of your life? Your life
depends on taking them every day at the right times, the right way. One example: this
means taking medication with food if it needs to be taken with food to increase
absorption.
•
If you stop, you will become ill (not immediately, but after months or years).
•
Do you know what resistance is? Patients need to be aware that ART are different
from any other type of medication. If they miss doses of other medications like a
blood pressure medicine, their blood pressure may go up in the short term, but will
the medication will still work again when they take it. ART on the other hand is less
forgiving and resistance can occur with missed doses which will lead to treatment
failure.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 52
Adherence Issues for Health
Care Workers (cont.)
■ BEFORE TREATMENT (cont.)
■ Have you told anyone that you are HIV-positive? Telling
someone else who can help you take your medicines every
day will help you.
■ Ask about stigma related to taking the pills.
■ Check the patient’s clinic attendance – ask about reasons for
missed appointments.
■ How far do you have to travel to the clinic, and do you think
you can keep regular appointments here?
Unit 7: Adherence for ART Success
52
•
Do you know that you should not share these medicines with family or friends? If you
do not take ART as prescribed, with the right number of pills, the right amount of
times per day, the regimen will ultimately fail.
•
Have you told anyone that you are HIV-positive? Telling someone else who can help
you take your medicines every day will help you.
•
Ask about stigma related to taking the pills.If you discover that the patient is not
taking their ARVs because they will be judged by someone or cannot disclose their
status, you can help them to find a time to take their medication in a private setting.
•
How far do you have to travel to the clinic, and do you think you can keep regular
appointments here?
•
Check if the patient has missed any clinic appointments, and find out the reason for
missed appointments. Poor clinic attendance may be a sign that the patient will also
have difficulty in taking ARVs.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 53
Methods of Monitoring
ART Adherence
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 54
Methods for Monitoring Adherence
■ Track pharmacy medication refills for each patient
■ Pill counts
■ Patients can keep a diary of every dose taken (similar
to monitoring blood sugars for diabetics)
■ Medication punch cards
■ Patient self-report
Unit 7: Adherence for ART Success
•
54
No method of monitoring adherence can be 100% accurate. All methods of
monitoring adherence have limitations, but they can still provide you with some idea
of what the patient is doing. You can use adherence information to direct the need
for potential interventions.
•
Patients can refill medications on time without taking the pills
•
Patients can leave pills at home so that it looks like they are taking them
appropriately
•
Patients can alter their diaries to appear more adherent
•
Patients can remove pills from punch cards
•
Self-report indicators are known to overestimate adherence. If a patient says
they missed any doses, most likely the information is accurate. If they say
they haven’t missed any doses, they could be underestimating their
nonadherence. But,research shows that patient self report seems to be a
better indicator of adherence compared to physician estimates. So, it is
worthwhile to ask.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 55
Tracking HAART Refill History
Med Name
Date
dispense
# Days
supply
given
Date due
for next
fill
#
Days
late
Comment
3tc/d4t/nvp
1/1/04
30
2/1/04
15
Counseled about
adherence, referred to
nurse
3tc/d4t/nvp
15/2/04
30
3/15/04
Patient Name____________________ ID Number: __________
•
If the patient gets their medications filled at your pharmacy, you can also keep a card
for each patient and keep track of every refill they get and monitor their adherence.
Results can be reported back to the provider or nurse as needed.
•
Black ink = filled in on date of 1st fill, blue ink = filled in on date of 2nd fill
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 56
Patient Self-Report of
Missed Doses
■ Ask questions in a respectful and non-judgmental way.
Ask in a way that makes it easier for patients to be
truthful.
■ “Many patients have trouble taking their medications.
What trouble are you having?”
■ “Can you tell me when and how you take each pill?“
■ “When is it most difficult for you to take the pills?“
■ “It is sometimes difficult to take the pills every day and on
time. How many have you missed (yesterday, last 3 days, last
month)?
■ “When was the last time you missed a dose?
Unit 7: Adherence for ART Success
Reference Manual for Trainers
56
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 57
Pill Fatigue…
•
Pill fatigue is often referred to by clinicians to describe how patients become
overwhelmed by their medication regimen.
•
This can develop over time and patients just get tired of taking pills for so long…if a
patient tells you that they are tired of taking pills, they should discuss this with their
provider before stopping their pills on their own.
•
If they are going to stop taking their medication, they should stop all pills at once to
avoid the development of resistance.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 58
Improving Adherence:
After Initiation of Therapy
■ Close follow-up
■ Ask patient to verbalize treatment regimen
■ Education about adherence
■ re-emphasize importance of adherence at each
visit, even in patients with good virologic control
■ review incidence & management of adverse
effects often
Unit 7: Adherence for ART Success
58
•
Ask patient to verbalize treatment regimen (in order to be successful with ARV therapy,
patients need to take action and be responsible for their care
•
Education about adherence
•
re-emphasize importance of adherence at each visit, even in patients with good
virologic control
•
Providers and pharmacists should review incidence & management of adverse effects
often
•
The guidelines recommend that:
•
•
ARV pill-returns count (% doses missed) would be ideal but this would depend on
the clinic load and capacity to undertake this intensive activity. Adherence goal is
> 95% doses taken. Patients with adherence < 80% require increased adherence
support
•
Tablet count may be done before the patient sees the doctor, and the count
reviewed by the doctor during the early/initial visits to evaluate adherence. This
does take up time and might not be possible at all sites all the time,
•
Missed/late clinic visits should trigger concerns about adherence,
•
Routine adherence discussion/education with counselor is of value.
This should be an open-ended discussion, with time for questions and repetition:
•
Feedback from counselor to rest of team is important to get a better profile of the
patient and their environment,
•
Encourage participation in a support group such as on-treatment clubs.
•
Continue monthly visit with counselor for first three months and quarterly
thereafter,
•
Arrange regular community visits by patient advocates
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 59
Improving Adherence:
After Initiation of Therapy (cont.)
■ Education (pharmacist)
■ Plan ahead for travel
■ Pill boxes
■ Let patients practice pill-taking
behavior before start ART with
OI prophylaxis meds or candy
■ Alarm devices
■ Written dosing schedules
■ Coordinate doses with daily
events
■ Short term DOT
■ Social support
■ Leaving reminders around
home or work
■ Improve patient self-efficacy
■ Carry an extra dose of
medication
■ Monitoring – pharmacy refill
records, self-report
Unit 7: Adherence for ART Success
59
•
These interventions are the same as we had listed before starting therapy – since
adherence can change over time for many different reasons, many different
techniques can be tried over time to address the changing individual needs of each
patient.
•
Step-up adherence package for people with reduced adherence or treatment failure
from the Ethiopia Guidelines, July 2004
•
When the adherence assessment is < 80% at any visit, with or without viral or clinical
failure:
•
The therapeutic counselor/nurse or doctor needs to re-educate the patient
(and their buddy) about the importance of adherence. The long-term benefits
need to be re-emphasized.
•
Evaluate the support structures in place. Are they appropriate? How can they
be improved? What alternatives are there?
•
Consider the use of pillboxes and/or daily dosing diary
•
Insist on participation in a support group or link with a patient advocate,
•
Consider doing a psychological profile,
•
Check family situation (through social worker and therapeutic counselor),
•
Do the Cage assessment for alcohol abuse,
•
Arrange home visits by counselor/patient advocates to daily or weekly at a
minimum (spot pill counts to be done at home), and
•
Consider directly observed therapy for an agreed period.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 60
Published Interventions Shown to
Improve Adherence to Antiretrovirals
■ Medication alarms1
■ Education & counseling sessions2,3
■ In particular, counseling provided by pharmacists
■ Directly Observed Therapy (DOT)4,5
1. Samet JH, et al. Am J Med. 1992;92:495-502.
2. Malow RW, et al. Alcohol Drug Abuse 1998;49:1021-4.
3. Tuldra A, et al. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999; Abstract 595.
4. Sorensen JL, et al. AIDS Care. 1998;10:297-312.
5. Wall TL, et al. Drug Alcohol Depend. 1995;37:261-269.
Unit 7: Adherence for ART Success
•
60
These methods have been shown to improve adherence to ARVs
•
The use of medication alarms
•
Education & counseling sessions (In particular, counseling provided by
pharmacists)
•
Directly Observed Therapy (DOT) until patients are comfortable on their own
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 61
Adherence Exercises
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 62
Exercise 1 – Group Discussion
■ What are common reasons for nonadherence?
■ How can we as pharmacists or druggists help patients
take their medications regularly as prescribed?
■ How can we track adherence for our patients so that
we can recognize a problem with adherence ?
Unit 7: Adherence for ART Success
62
Objectives:
•
To review participant understanding of reasons for non-adherence and adherence
difficulties, and what interventions can be offered (or how can patients be counselled) to
help them take their improve their adherence
•
To review potential methods for monitoring adherence over time
•
To develop participants’ skills in discussing adherence with patients and helping patients
to solve adherence problems
Time: 30-40 minutes (20-25 minutes small group work and 10-15 minutes group feedback)
Directions:
1. Divide into smaller groups if the group is too large
2. Present the questions and ask the groups to review each in turn, asking the groups to
identify the most common problems they think will arise when patients try to take
medication.
•
How do we respond to each of the common reasons for missing doses?
•
How can we help patients with future pill taking?
•
How can we track patient adherence over time?
3. Review the points in previous adherence slides with the group when receiving feedback.
4. This exercise may be most productive if the previous exercise on pill taking has been
done by the group.
5. Remember to emphasize the importance of preparing the patient for treatment.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 63
Exercise 2 - Group Discussion
■ Our own experience of taking medicines
1. Describe your own experience of taking medicines to your
partner.
2. How easy was it to find information about the medicines?
3. How easy was it to follow the instructions on how to take the
medicines?
4. What made it easy or hard to take the medicines?
■ Please respect requests for confidentiality.
Unit 7: Adherence for ART Success
63
Objectives
•
To help participants review their own experience of starting a course of treatment
•
To help participants think about the need for preparing patients for treatment
Directions
1. Divide the group into pairs.
2. Each pair should take turns to discuss a past experience of taking a course of
treatment. This may be, for example, a prescribed course of antibiotics or other
medication, or a daily vitamin or other supplement.
3. Each person should speak for up to three minutes, and then the listening partner
should briefly sum up what they have heard their partner say.
4. Discussion should focus on participants’ recollection of how easy it was to find
information about how to take the medication, whether this advice was followed, and
what influenced how easy or hard it was to do so.
5. Remind the group of their confidentiality agreement, and that if participants share
information with their partner which they would rather not be fed back to the larger
group, then they should tell their partner this at the time.
6. After each person has had a turn (allow about six minutes), resume the group and
invite participants to share some of the information they had told their partner about
themselves. This should be an open discussion where nobody should feel under
pressure to disclose information.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 64
Key Points
■ Antiretroviral (ARV) regimens are complex and multiple
barriers to adherence exist
■ Serious potential consequences can result from nonadherence
■ Patient/family education and involvement is critical for
successful treatment of HIV infection
■ The medical team (provider, pharmacist, nurse) and the
patient must work together to promote optimal adherence to
both HIV care and ARV regimens
■ The pharmacist plays a vital role in promoting adherence
and offering techniques for improvement of adherence
Unit 7: Adherence for ART Success
64
•
Review these key points with participants.
•
Ask them questions related to the key points to informally test their knowledge.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 65
References
■ Bangsberg D, et al. AIDS. 2001:15:1181.
■ Centers for Disease Control and Prevention. MMWR. 1999.[37]
http://hiv.medscape.com/
■ Cheever LW, Curr Infect Dis Rep 1999 Oct;1(4):401-407.
■ Chesney MA. 37th ICAAC, 1997; Toronto. Abstract 281.
■ Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference,
1998; Geneva. Lecture 281.
■ Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117125.
■ Ethiopia Guidelines, July 2004.
■ Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
Unit 7: Adherence for ART Success
Reference Manual for Trainers
65
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 66
References (cont.)
■ Fischl et al, 8th CROI, 2001. Abstract 528.
■ Frick, P. PharmD, MPH Clinical Pharmacist, HIV/AIDS Harborview Medical
Center, Seattle, WA, USA, 2004.
■ Horne R, et al. 39th ICAAC, 1999; San Francisco. Abstract 588.
■ Beth Hykes, Pharm.D. Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
■ Kalichman SC, et al. J Gen Intern Med. 1999;14:267-273.
■ Malow RW, et al. Alcohol Drug Abuse 1998;49:1021-4.
■ Mar-Tang M, et al. J Gen Intern Med. 1999;14(suppl 2):53.
■ McGilvray, M, Willis, N. All About Antiretrovirals: A Nurse Training Programme,
Trainer’s Manual, Africaid 2004.
Unit 7: Adherence for ART Success
Reference Manual for Trainers
66
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 67
References (cont.)
■ Miller et al., The AIDS Reader 10(3):177-185, 2000.
■ Montaner JS, et al. JAMA. 1998;279:930-937.
■ Morse EV et al, Soc Sci Med 1991;32:1161-1167.
■ &References
(cont.)
■ MTCT-Plus, Columbia University, 2002.
■ Namibia Minstry of Health and Social Services, Training on the
Use of the Namibia Guidelines for Antiretroviral Therapy (ART),
2004.
■ Paterson, et al. 6th Conference on Retroviruses and
Opportunistic Infections, 1999; Chicago, IL. Abstract 92.
Unit 7: Adherence for ART Success
Reference Manual for Trainers
67
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 68
References (cont.)
■ Samet JH, et al. Am J Med. 1992;92:495-502.
■ Simoni, Jane, Associate Professor, Psychology,
University of Washington, Seattle, WA, USA, 2003.
■ Simoni, Jane. “Buddy Training Manual” UW Physicians.
■ Simoni JM, Frick PA, Pantalone DW, Turner BJ.
Antiretroviral Adherence Interventions: A Review of
Current Literature and Ongoing Studies. Topics in HIV
Medicine. 2003;11(6):185-198.
■ Singh N, et al, AIDS Care 1996;8:261-269.
Unit 7: Adherence for ART Success
Reference Manual for Trainers
68
HIV Care and ART: A Course for Pharmacists
Unit 7: Importance of Adherence in ART Success
Slide 69
References (cont.)
■ Sorensen JL, et al. AIDS Care. 1998;10:297-312.
■ Stone VE, et al. JAIDS 2001; 28:124-131
■ Tuldra A, et al. 39th Interscience Conference on Antimicrobial
Agents and Chemotherapy; 1999; Abstract 595.
■ Vanhove G, et al. JAMA. 1996;276:1955-1956.
■ Vitiello, MA. MSN, CS, ACRN, Senior Technical Consultant,
International Training and Education Center on HIV (I-TECH),
Seattle, WA, USA, 2004.
■ Wall TL, et al. Drug Alcohol Depend. 1995;37:261-269.
■ Wenger N, et al. 6th Conference on Retroviruses and
Opportunistic Infections, 1999; Chicago. Abstract 98.
Unit 7: Adherence for ART Success
Reference Manual for Trainers
69
HIV Care and ART: A Course for Pharmacists
Handout 7.1
Summary of Research on Adherence Interventions
Simoni JM, Frick PA, Pantalone DW, Turner BJ. Antiretroviral Adherence
Interventions: A Review of Current Literature and Ongoing Studies. Topics in
HIV Medicine. 2003; 11(6):185-198.
Article Summary. Ten studies included control or comparison groups, but
only seven of these included the randomization to conditions and control
groups that define RCTs. Of these, only four incorporated a follow-up period
of assessment. Among these four most methodologically rigorous studies,
the most comprehensive intervention employing behavioral and educational
strategies as well as social support, demonstrated no positive intervention
effects. The other three studies reported some encouraging findings but, as
described above, were not without their own methodological limitations.
Individualized Patient Education. The intervention described by Knobel and
colleagues involved a pharmacist who offered a single one-on-one
individualized educational session designed to provide detailed information
about therapy and to help the participant fit the medication regimen into his or
her lifestyle, followed by telephone support. At 24 weeks, participants in the
intervention condition self-reported significantly improved adherence but the
rate of achieving an HIV-1 RNA level below detection in this group was not
statistically significantly better than the control group.
The study by Tuldra and colleagues, based on Bandura’s self-efficacy
theory25, involved a psychologist who provided one-on-one education about
the importance of adherence and managing adherence problems with the
goal of increasing the patient’s self-efficacy. In addition, a daily dosage
schedule was developed. During follow-up visits at 4, 24, and 48 weeks,
adherence was reinforced and any problems addressed. At 48 weeks, 32
patients (94%) in the intervention group, and 25 patients (69%) in the control
group achieved a level of adherence of 95% or greater as measured by selfreport (P = 0.008). In addition, 89% of the intervention group and 66% of the
control group had a plasma HIV-1 RNA level of 400 copies/mL or below (P =
0.026). However, the significant intervention effects with respect to HIV-1
RNA levels of 400 copies/mL or below and the self-reported adherence at
week 48 were from an “as-treated” and not an “intent-to-treat” analysis of only
70 of the original 116 participants.
Cues and Reinforcement. The intervention conducted by Rigsby and
colleagues involved cue-dose training and monetary reinforcement. In 4
weekly sessions, counselors trained patients to time their doses based on
personalized cues such as meal times or other regular daily activities. They
also used feedback from the Medication Event Monitoring System (MEMS®),
which uses electronic monitors that record the date and time of every opening
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-9
of the medication vial. For example, if a particular dose was missed
repeatedly, the counselor would suggest an alternative cue. In a second arm,
cue-dosing was paired with weekly cash incentives for correctly timed
MEMS® bottle openings. Incentives began at $2 per correct dose (within 2
hours of dosing time) and increased with each consecutive correct dose to a
maximum of $10 per day. If doses were missed or not taken within 2 hours of
the specified dosing time, the reinforcement was reset to $2. During the
intervention (weeks 0 to 4), participants who received both strategies (but not
those receiving only cue-dosing) demonstrated enhanced adherence
according to electronic monitoring relative to controls. However, the change
was not sustained at follow up (weeks 5 to 12).
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-10
Slide 7.10
Virologic Control Falls Sharply
with Diminished Adherence
Patients with HIV RNA
<400 copies/mL, %
100
80
60
40
20
0
>95
90-95
80–90
70-80
<70
PI adherence, % (electronic bottle caps)
Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.
Adherence for
11
Slide 7.15
Sub-Optimal Adherence Predisposes to
Resistance
Sub-optimal adherence
Sub-therapeutic drug levels
Incomplete viral suppression
Generation of resistant HIV strains
by selection for mutant viruses
Association between poor adherence and
antiretroviral resistance is well-documented1,2
1. Vanhove G, et al. JAMA. 1996;276:1955-1956.
2. Montaner JS, et al. JAMA. 1998;279:930-937.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-11
Slide 7.17
Missed Doses & Development of
Drug Resistance
Slide 7.18
Adherence for
HIV Care and ART for Pharmacists
Reference Manual for Trainers
21
Adherence for ART Success
Unit 7-12
Slide 7.51
ART Care Model
(Adherence Protocol)
Multidisciplinary (Team) effort:
Social worker
Physician
Nursing
Patient
Pharmacist
Adherence for
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Nutritionist
TGK/ITECH/9.03
52
Adherence for ART Success
Unit 7-13
References
Bangsberg D, et al. AIDS. 2001:15:1181.
Centers for Disease Control and Prevention. MMWR. 1999.[37]
http://hiv.medscape.com/
Cheever LW, Curr Infect Dis Rep 1999 Oct;1(4):401-407.
Chesney MA. 37th ICAAC, 1997; Toronto. Abstract 281.
Chesney M. Adherence to antiretroviral therapy. 12th World AIDS
Conference, 1998; Geneva. Lecture 281.
Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117125.
Ethiopia Guidelines, July 2004.
Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS, Harborview
Medical Center, Seattle, WA, USA, 2004.
Fischl et al, 8th CROI, 2001. Abstract 528.
Frick, P. PharmD, MPH Clinical Pharmacist, HIV/AIDS Harborview Medical
Center, Seattle, WA, USA, 2004.
Horne R, et al. 39th ICAAC, 1999; San Francisco. Abstract 588.
Beth Hykes, Pharm.D. Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
Kalichman SC, et al. J Gen Intern Med. 1999;14:267-273.
Malow RW, et al. Alcohol Drug Abuse 1998;49:1021-4.
Mar-Tang M, et al. J Gen Intern Med. 1999;14(suppl 2):53.
McGilvray, M, Willis, N. All About Antiretrovirals: A Nurse Training
Programme, Trainer’s Manual, Africaid 2004.
Miller et al., The AIDS Reader 10(3):177-185, 2000.
Montaner JS, et al. JAMA. 1998;279:930-937.
Morse EV et al, Soc Sci Med 1991;32:1161-1167.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-14
References (cont.)
MTCT-Plus, Columbia University, 2002.
Namibia Minstry of Health and Social Services, Training on the Use of the
Namibia Guidelines for Antiretroviral Therapy (ART), 2004.
Paterson, et al. 6th Conference on Retroviruses and Opportunistic
Infections, 1999; Chicago, IL. Abstract 92.
Samet JH, et al. Am J Med. 1992;92:495-502.
Simoni, Jane, Associate Professor, Psychology, University of Washington,
Seattle, WA, USA, 2003.
Simoni, Jane. “Buddy Training Manual” UW Physicians.
Simoni JM, Frick PA, Pantalone DW, Turner BJ. Antiretroviral Adherence
Interventions: A Review of Current Literature and Ongoing Studies. Topics
in HIV Medicine. 2003;11(6):185-198.
Singh N, et al, AIDS Care 1996;8:261-269.
Sorensen JL, et al. AIDS Care. 1998;10:297-312.
Stone VE, et al. JAIDS 2001; 28:124-131
Tuldra A, et al. 39th Interscience Conference on Antimicrobial Agents and
Chemotherapy; 1999; Abstract 595.
Vanhove G, et al. JAMA. 1996;276:1955-1956.
Vitiello, MA. MSN, CS, ACRN, Senior Technical Consultant, International
Training and Education Center on HIV (I-TECH), Seattle, WA, USA, 2004.
Wall TL, et al. Drug Alcohol Depend. 1995;37:261-269.
Wenger N, et al. 6th Conference on Retroviruses and Opportunistic
Infections, 1999; Chicago. Abstract 98.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-15
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Adherence for ART Success
Unit 7-16
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 8
Prophylaxis and Treatment
of Opportunistic Infections
Unit 8: Prophylaxis and Treatment of Opportunistic Infections
Aim: The aim of this unit is to provide information to participants on the prevention
and treatment of opportunistic infections in HIV-infected patients.
Learning Objectives: By the end of this unit, participants will be able to:
•
Identify the signs and symptoms of opportunistic infections (OI) in HIV
infected individuals
•
Explain the diagnosis of common OIs associated with HIV
•
Describe the prophylaxis and treatment of the most common OIs associated
with HIV in Ethiopia
Unit Overview:
3 Hours
Step
Time
Activity/
Method
Content
Resources
Needed
1
10 minutes
Question-Answer
Introductory Case Study and
Question Slides (8.2-8.4)
Overhead or LCD
Projector
2
90 minutes
Lecture
Prophylaxis and Treatment of
Opportunistic Infections (Slides 8.5 8.81)
Overhead or LCD
Projector
3
70 minutes
Group Exercise
Case Studies (Slide 8.82-8.100)
Worksheets (8.1, 8.2,
8.3 in the course
workbook. Three flip
chart stands with
paper and markers.
4
10 minutes
Summary
Review of Key Points (Slides 8.101)
Overhead or LCD
Projector
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Prophylaxis & Treatment of OIs
Unit 8-3
Resources Needed
•
•
•
•
Flip Chart and Paper
Markers
Overhead or LCD Projector
The following can be found in the Participant Handbook::
- Immunization Guidelines in the HIV-Infected Individual (Handout 8.1)
- General Principles & Treatment Recommendations for Candidiasis
(Handout 8.2)
- Primary Prevention of Opportunistic Infections (Handout 8.3)
- Prophylaxis and Treatment for Toxoplasmosis (Handout 8.4)
- General Principles/Treatment Recommendations for MAC (Handout 8.5)
- Natural History of HIV Infection in Average Patient Without HAART
from time of transmission to death at 10-11 years (enlarged Slide 8.7)
- Drug Interactions with Fluconazole and Itraconazole (enlarged Slide 8.35)
•
Worksheets 8.1, 8.2 and 8.3 can be found in the Course Workbook:
Key Points
1. Opportunistic infections are those that develop as a result of HIV-inflicted
damage to the immune system.
2. As immunosuppression progresses, the overall incidence of OIs increases.
3. The most common OIs encountered in Ethiopia include oropharyngeal
candida, TB, CNS manifestations, sepsis, herpes zoster, and pneumonia.
4. OIs may be bacterial, viral, fungal or protozoal, or non infectious.
5. The origin of OIs, severity of disease, drug-drug interactions, and drug
toxicities impact choice of therapy.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Prophylaxis & Treatment of OIs
Unit 8-4
Step 1
Step 2
Step 3
Step 4
Introductory Case Study (10 minutes)
•
Ask a participant to read the case study on Slides 8.2 to 8.3.
•
Ask participants to silently attempt to answer the question on
Slide 8.4.
•
Explain that the question will be answered and the case
discussed more fully as the unit progresses.
Lecture (90 minutes)
•
This unit will introduce participants to the prevention and
treatment of opportunistic infections in HIV-infected patients.
•
Begin by reviewing slide 8.5 of the PowerPoint presentation,
“Prophylaxis and Treatment of Opportunistic Infections.” Ask the
participants if they have any questions about the objectives
before continuing.
•
Refer participants to Handouts 8.1 to 8.6 in their Participant
Handbooks. Explain that you will be addressing information in
these handouts during this unit.
•
Present and discuss the PowerPoint presentation, “Prophylaxis
and Treatment of Opportunistic Infections” (Slides 8.6-8.82).
Group Exercise (70 minutes)
•
Case Study Group Exercise: Divide participants into four work
groups. Provide each work group with one of the four Adult ART
Case Studies (Worksheets 8.1, 8.2 and 8.3 in the course
workbook.) Ask the groups to identify a recorder and a
presenter, and then spend twenty minutes discussing the case
study together and answering the related questions on flip-chart
paper.
•
Ask each work group to share their decisions and answers.
Discuss each case thoroughly and use this time to answer
questions and clarify misinformation. Review the case studies in
the “Prophylaxis and Treatment of Opportunistic Infections”
PowerPoint presentation (8.83 – 8.100). Spend 15 minutes
discussing each case.
Summary (10 minutes)
•
Summarize the presentation, review the Key Points presented in
this Unit (Slide 8.101), and answer final questions.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Prophylaxis & Treatment of OIs
Unit 8-5
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes
for reference during the planning and implementation of this course. The
facilitation notes and talking points are included in the “notes” section of the
accompanying PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Prophylaxis & Treatment of OIs
Unit 8-6
Unit 9: Prophylaxis & Treatment of OIs
Slide 1
Prophylaxis and Treatment
of Opportunistic Infections
Unit 8
HIV Care and ART: A Course for Pharmacists
This unit should take approximately 3 hours to complete.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 2
Introductory Case
■ KH is a 45 year old Ethiopian female who has not followed up
with her physician on a regular basis.
■ Over the last month, she has experienced progressive shortness
of breath associated with dry cough. This has gotten to the point
where she is unable to walk across the room without becoming
short of breath. She comes to clinic to be evaluated.
■ She states that she has had a fever but has not actually taken
her temperature.
■ She has diffuse body aches associated with her symptoms. She
occasionally has a headache. She states she has lost
approximately 10 lbs. over the last 1-2 weeks. Her previous
weight was 130 pounds.
Unit 8: Opportunistic Infections
2
•
Ask a participant to read the case on this slide and the next.
•
Ask participants if they have any questions about the information presented.
•
Note: Do not give them further information on the case. Just ask them to consider
the information provided to them.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 3
Introductory Case (cont.)
■ She is diagnosed with severe PCP pneumonia is to
begin therapy.
■ Which of the following statements is true about the
treatment of PCP pneumonia?
Unit 8: Opportunistic Infections
Reference Manual for Trainers
3
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 4
Introductory Case - Questions
A. The treatment of choice for severe PCP is Bactrim 15 mg/kg/day
based on TMP oral or IV divided q6-8h x 21 days + Prednisone
40 mg bid for 5 days, 40 mg qd for 5 days, 20 mg qd for 11 days
B. The treatment of choice for severe PCP is Bactrim (TMP/SMX)
160/800 mg IV divided q6-8h x 21 days + Prednisone 40 mg bid
for 5 days, 40 mg qd for 5 days, 20 mg qd for 11 days
C. The treatment of choice for severe PCP is Bactrim two DS
tablets po TID X 21 days
D. The treatment of choice for severe PCP is Bactrim one DS
tablet po TID X 21 days + prednisone as above
Unit 8: Opportunistic Infections
4
•
Ask participants to silently attempt to answer the question.
•
Explain that the answer to the question will be discussed as the unit progresses.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 5
Unit Learning Objectives
■ Identify the signs and symptoms of opportunistic
infections (OI) in HIV infected individuals
■ Explain the diagnosis of common OIs associated with
HIV
■ Describe the prophylaxis and treatment of the most
common OIs associated with HIV in Ethiopia
Unit 8: Opportunistic Infections
•
5
Review the learning objectives with participants.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 6
Background
■ Opportunistic infections (OIs) occur when a
patients immune system is impaired
■ OIs are leading causes of morbidity and
mortality in HIV-infected persons.
■ Most of the common OIs are preventable as
well as treatable.
■ However, in resource-limited settings, it may
be difficult to manage OIs.
Unit 8: Opportunistic Infections
•
6
Opportunistic infections occur when a patients immune system is
impaired. They are considered opportunists…they cause infections
only when the immune system is weak.
• OIs are leading causes of morbidity and mortality in HIV-infected
persons.
• Most of the common OIs are preventable as well as treatable.
• However, in resource-limited settings, it may be difficult to manage
OIs.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 7
Natural History of HIV Infection in Average Patient Without
HAART from time of transmission to death at 10-11 years
•
This graph depicts the natural history of HIV in an untreated patient. It helps to
demonstrate how the virus progresses and what happens to the immune system
over time. HIV infection follows three clinical phases. The first is acute infection,
when HIV disseminates to lymph nodes, CNS or other organs.
•
The 2nd phase is termed clinical latency which the patient is asymptomatic. This is
when viral replication occurs and steady CD4 depletion occurs.
•
The third phase is symptomatic disease with the development of opportunistic
infections and the development of organ dysfunction.
•
Anywhere along the spectrum, an individual tested positive for HIV may acquire an
AIDS diagnosis
•
By definition, an AIDS diagnosis is given to an individual with a cd4 <200 or having
had and AIDS indicator condition in Stage III or IV (an opportunistic infection).
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 8
CD4 Count as it Correlates with
Selected Diseases & OIs
> 500
Bacterial infections, HIV meningitis, tuberculosis, vaginal
candidiasis
< 500
Herpes zoster, herpes simplex, oral thrush
< 300
Kaposi’s sarcoma, non-Hodgkins lymphoms
< 200
HIV-associated dementia, PCP
< 150
Coccidiodomycosis
< 100
Aspergillosis, cryptococcosis, esophageal candidiasis,
histoplasmosis, PML toxoplasmosis
< 50
Cytomegalovirus (CMV), mycobacterium avium (MAC)
<
Unit 8: Opportunistic Infections
•
8
CD4 data are based on natural history studies in MACS (Multicenter AIDS Cohort
Study). Like we said earlier, CD4 count is predictive of the risk of specific OIs and
other complications. As immunosuppression progresses, the overall incidence of
Ois increases. Routine CD4 cell count determination is critical to detect when a
patient may be at risk of developing an OI. OIs can develop at a CD4 greater than
200, in a patient who is otherwise asymptomatic, ie, KS oral thrush
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 9
Condition
Percentage Decline in Fatal HIV Related
Diseases in 1997-2001 vs 1990-1995
PCP
69
MAC
89
Bacterial Pneumonia
37
Wasting
75
Candida Esophagitis
68
CMV
89
Non Hodgkins
Lymphoma
75
Kaposi's Sarcoma
80
XIV International AIDS Conference- US Data
•
In the US, there has been a dramatic decline in fatal HIV related infections in the
present compared to the pre-HAART era ( prior to 1995). There has been a 37%
decrease in deaths due to bacterial pneumonia. PCP was the most common
clinical manifestation of AIDS in the 80-90s…Notice the 70% decline…it is less
common due to early diagnosis of PCP, prophylaxis and widespread use of
HAART
•
At the 8th Retrovirus conference, several investigators noted that patients seem to
be dying less frequently of "classic" opportunistic infections, and more frequently
without clear etiology consistent with multi-organ failure, or complications of
hepatitis co-infection.
•
OIs remain a concern especially for patients in whom effective HAART cannot be
initiated, if they are failing HAART, non-adherent to meds, or do not have access
to prophylactic meds or treatment for OIs
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 10
Major Diagnostic Categories of HIV-Infected Patients
(TAH 2000) (1)
Diagnosis
•
# of Patients
% Total
Oropharyngeal candidia
136
57.4
TB
131
55.3
CNS manifestations
74
31.2
Sepsis
59
24.9
Herpes Zoster
40
16.9
Pneumocystis pneumonia
34
14.3
Bacterial pneumonia
22
9.3
Kaposi’s Sarcoma
20
8.4
AIDS Dementia Complex
14
5.9
These figures come from Black Lion Hospital in Ethiopia. The most common OIs
encountered (> 10% of total) include oropharyngeal candida or thrush, TB, CNS
manifestations, sepsis, herpes zoster and PCP pneumonia.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 11
Major Diagnostic Categories TAH 2000 (2)
Diagnosis
# of Patients
% of Total
Cryptococcal meningitis
14
5.9
Peripheral neuropathy
11
4.6
Myelopathy
11
4.6
Lymphoma
7
3.0
Others*
82
34.6
•
Other conditions encountered as listed.
•
Of note: Many patients had more than one Dx
•
* others include: hematological problems(17.7%), GI disorders (15.7%),
musculoskeletal and skin problems (11.8%), and miscellaneous (2.9%)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 12
Causes of Hospital Death Among 237 Patients
(TAH 2000)
Causes of Death
# of Patients
% Total
TB
41
56.2
Sepsis
41
56.2
CNS mass lesions
26
35.6
Bacterial pneumonia
10
13.7
Pneumocystis pneumonia
8
11
Cryptococcal meningitis
6
8
Others*
16
21.9
Unknown
4
5.5
•
The most common causes of death included TB, sepsis, CNS mass lesions,
bacterial pneumonia, PCP pneumonia and others
•
Others:
•
Bleeding 6 (8.2%)
•
Acute renal failure 5 (6.9%)
•
Hepatic failure 5 (6.%)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 13
Immunization Guidelines
(General Principles)
■ Avoid use of live-attenuated vaccines
■ Administer single-dose vaccines early in the course of
HIV infection (for optimal response)
■ Routinely recommended
■ Pneumovax, influenza, Td
■ Hepatitis B and A if indicated
■ Transient increases in HIV RNA levels may be
observed with some immunizations
Unit 8: Opportunistic Infections
13
•
Many HIV infected individuals are at increased risk for complications of vaccine-preventable diseases. Vaccines
are generally considered safe to use in HIV patients when you remember these general principles…
•
Avoid live-attenuated vaccines.. (oral typhoid vaccine or oral polio) they may result in severe complications. MMR
is the exception and can be used if CD4 > 200…..killed or inactivated vaccines do not pose danger to HIV
patients …Ie of killed or inactivated virus, influenza,Td, Hep A, Hep B. Pneumo is purified polysacc capsular
antigens
•
See handout 8.1 entitled” immunization recommendations”.
•
Routinely recommend pneumovax, yearly influenza, and Td. (Vaccinate as close to diagnosis as possible when
CD4 counts are highest, both humoral and cellular immunity wane and ability to form spec antibodies after
infection or immunization becomes progressively impaired). Administer early in the course of infection, if pt
present with late disease, may wait to administer until after immune reconstitution occurs.
•
Pneumovax recommended because high incidence of pneumococcal pneumonia and bacteremia assoc with HIV.
May revaccinate every 5 years, revaccinate when CD4 is greater than 200 if first given <200.
•
Influenza is recommended to prevent complications of the Flu :prevention of clinical symptoms that may mimic
more severe OIs or bacterial pneumonia.
•
Hep A and B if indicated (A if gay, IVDU, travel, chronic hep B or C) (B if travel, gay, heterosexual)
•
MMR is only exception…contraindicated if severely immunecompromised < 200
•
In general, symptomatic adults have suboptimal responses to vaccines. The response to both live and killed
antigens may decrease as the HIV progresses, when cd4 < 200.
•
Hep A and B if at risk and susceptible (A if MSM, IVDU, illegal drugs IV and PO, travel, chronic hep B,C, give if
HAV negative serology) (B if travel, MSM, heterosexual. Give if no evidence of prior immunity or prior Hep B
infection-anti Hep B virus neg) HIV individuals are more likely to develop chronic infection.
•
Transient increase in viral RNA can occur for < 6 weeks after pnemovax, influenza and td,however there have
bee no adverse effects and no effect on patient survival in one observational study (influenza). The thought is that
HAART can prevent such VL increases.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 14
Prevention of Exposure
Recommendations
■ Sexual
■ IVDU
■ Environmental and occupational
■ Pet-related
■ Food and Water
■ Travel-related
■ Asplenia
Unit 8: Opportunistic Infections
14
•
HIV patients must be advised on ways to minimize their risk of exposure to
OIs…many potential exposures
•
SEXUAL: Condoms, IVDU clean needles, do not share needles
•
OCCUPATIONAL: Universal Precautions (this will be discussed in another lecture)
ENVIRONMENTAL: avoid exposure to pts with measles or chicken pox
•
Pet related, toxoplasmosis, cats primary host , bartonella: cat scratch fever
•
Food and water: avoid drinking water from lakes or rivers to avoid
cryptosporidiosis and giradiasia. Cook meats thoroughly, avoid unpasturized
cheeses
•
Travel related : HIV infected travelers are at even higher risk for food borne and
water borne illnesses: all patients should carry FQ when traveling if they should
get traveler's diarrhea. Cipro 500 mg BID for 3 to 7 days or DS Bactrim BID. If
blood or shaking chills, or dehydration call MD. Use lomotil no longer than 48
hours,do not use if have fever or blood in stools.
•
Asplenic pts have an increased risk of fulminant bacteremia: HIB, pneumococcal,
meningococcal (Td, influenza)
•
Rubella for childbearing age women, who are not pregnant
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 15
Guidelines For Prophylaxis and
Treatment of OIs
■ Primary Prophylaxis
■ Treatment/Induction
■ Secondary Prophylaxis/Suppressive
Therapy/Maintenance Therapy
Unit 8: Opportunistic Infections
15
•
Before we begin to cover specific OI’s , you must understand certain definitions.
•
Primary prophylaxis: to prevent an initial episode of an infection from occurring
•
•
Treatment/Induction manage active infection
•
•
Let’s use an example that we can all relate to: Stretching is an example of
primary prophylaxis: it prevents muscle injury from occurring
Using that same example to explain treatment, this would be going to the
doctor to treat a pulled muscle
Secondary prophylaxis prevent recurrence of infection
•
Again, using the example: Secondary prophylaxis would be getting into a
regular routine of stretching to avoid another pulled muscle and follow-up to
prevent recurrence
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 16
Opportunistic Infections
■ Bacterial Infections (mycobacterium avium,
mycobacterium tuberculosis, recurrent pneumonia)
■ Fungal Infections (candidiasis, pneumocystis jiroveci
pneumonia, coccidiomycosis, cryptococcosis)
■ Protozoal Infections (cryptosporidiosis, isosporiasis,
toxoplaxmosis)
■ Viral Infections (cytomegalovirus, herpes simplex)
■ Non-infectious (CNS Disease, Malignancies, Wasting)
Unit 8: Opportunistic Infections
16
•
When we talk about OIs, realize that there are many different origins of OIs which
impacts choice of therapy
•
Bacterial Infections (mycobacterium avium, mycobacterium tuberculosis, recurrent
pneumonia)
•
Fungal Infections (candidiasis, pneumocystis jiroveci pneumonia,
coccidiomycosis, cryptococcosis)
•
Protozoal Infections (cryptosporidiosis, isosporiasis, toxoplaxmosis)
•
Viral Infections (cytomegalovirus, herpes simplex)
•
Non-infectious (CNS Disease, Malignancies, Wasting)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 17
Differentiate Between an OI and
Immune Reconstitution Syndrome
Immune Reconstitution syndrome:
■ The worsening of signs and symptoms due to known
infections, or the development of disease due to occult
infections, that results from improvement in immune
function after the initiation of anti-retroviral therapy
■ May occur with certain OIs
■ TB, MAC,PCP, PML, CMV vitritis, mild herpes zoster, cryptococcal
meningitis
Unit 8: Opportunistic Infections
17
•
When detecting OIs, it is necessary to differentiate the development of an
Opportunistic Infection from immune reconstitution syndrome (IRS)
•
IRS is the worsening of signs and symptoms due to known infections, or the
development of disease due to hidden (occult) infections, that results from
improvement in immune function after the initiation of anti-retroviral therapy.
•
IRS will be discussed further in the TB lecture
•
Note: IRS may occur with opportunistic infections (OIs) such as TB,
Mycobacterium avium complex (MAC), pneomocytis jirovecii pneumonia,
cryptococcal meningitis, mild herpes zoster, PML and CMV vitritis.
•
If the OI is presenting with atypical symptoms this may be more likely attributed to
IRS
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 18
Immune Reconstitution Syndrome:
Management
■ Not defined, dependent on disease involved
■ Most agree to maintain HAART and treat
symptomatically (NSAIDs and Steroids).
■ In other cases, the syndrome is treated as an active
infection.
Unit 8: Opportunistic Infections
Reference Manual for Trainers
18
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 19
HIV-Associated TB
■ TB leading infectious disease in HIV-infected patients in
developing countries
■ Extrapulmonary disease is common
■ 50% of HIV infected cases co-infected with TB bacilli
■ 5 - 10% of coinfected persons develop active TB each
year; among HIV negative persons, the lifetime risk is
5%
Unit 8: Opportunistic Infections
19
•
HIV and TB coinfection will be discussed in detail in a separate session. However,
since TB is the leading Infectious Disease in HIV infected patients in developing
countries, the topic will be addressed to highlight the important learning points.
•
50% of HIV infected cases co-infected with TB bacilli
•
5 - 10% of coinfected persons develop active TB each year compared to HIV
negative persons whose lifetime risk is 5%
•
Treatment for TB will be discussed in the following lecture.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 20
Problems of Managing TB/HIV
Co-Infection
■ High incidence of adverse
drug reaction
■ Atypical presentation/EPTB
more common
■ Resistance to anti-TB drugs
■ Resistance to one or more of
the first line drugs in Ethiopia
■ 15% - 33%
■ High pill burden
■ Drug interactions
■ Adherence
■ Immune reconstitution
syndrome
Unit 8: Opportunistic Infections
20
•
In 2000, TB was the leading cause of death at Black Lion Hospital in Addis.
•
Co-infected patients are complex and merit special consideration because comanagement of HIV and TB is complicated by a number of factors including:
•
Overlapping toxicities from HIV meds and TB meds making it difficult to
differentiate the cause
•
Atypical presentations which may lead to underdiagnosing and untreated cases
•
Pill burden is high, leading to adherence issues
•
Resistance to one or more of the first line drugs in Ethiopia 15% - 33%
•
MDR-TB 12% TB center admitted for re-treatment, but 5% among all TB
patients
•
Drug interactions (rifampin with PI and NNRTIs), which require careful dose
adjustment and monitoring
•
Possibility that it is actually IRS
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 21
Candidiasis
■ Oral (thrush)
75% occurrence
■ Esophageal
20-40% occurrence
■ Vulvo-vaginal
30-40% occurrence
■ Recurrence is common
■ Incidence of candida infections has decreased by 6080% with the initiation of HAART in the U.S.
Unit 8: Opportunistic Infections
21
•
In 1981, the first reports of AIDS included pts with PCP and mucosal candida. Since those reports, candida
infection has been found to affect most HIV infected patients at some point in their illness.
•
Candida org are everywhere in the environment.
•
Candida infection in HIV individuals is mostly mucosal, usually caused by Candida albicans, other strains
may occur at later stages, or in patients who have been on azole antifungals for a long time.
•
Diagnosis of oral candida (otherwise known as thrush) is made on appearance alone, and diagnosis of
esophageal thrush is based on presentation and response to empiric treatment. They may require scope if
not responding to treatment.
•
The most common form of candida is oral (referred to as thrush), most pts are colonized with candida in the
oral cavity. What leads to the development of infection is not clear, it may be caused by medication,
antibiotics, smoking, poor hygiene, etc…recurrance is common 30%.
•
Fluconazole can reduce risk of recurrent vaginal, oropharyngeal and esophageal infection
•
However, generally not recommended:
•
potential for resistance, cost, possibility of drug interactions
•
low mortality associated with these infections
•
acute treatment generally effective
•
Other forms of candida infections are esphogeal and vaginal, they are not as common as oral thrush.
•
The clinical manifestations of Candida vulvovaginitis are primarily itching and discharge. Dyspareunia,
dysuria, and vaginal irritation also may be present. Examination shows vulvar erythema and swelling and
vaginal erythema and discharge, which is classically curd-like, but may be watery. Some patients, primarily
those with C. glabrata infection, have little discharge and often only erythema on vaginal examination.The
diagnosis of Candida vulvovaginitis is typically made clinically, but confirmation is easily obtained by
observing budding yeast, with or without pseudohyphae, on a wet mount or KOH preparation of vaginal
secretions.
•
Overall, the incidence candida infections has decreased with the introduction of potent ART.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 22
Oral Candidiasis
Pseudomenbraneous
candidiasis (thrush)
■ Creamy white exudative
(cottage cheese-like) plaque
on the palate, tonsils, or
tongue
■ Usually painless
•
There are 4 types of thrush,
•
Pseudomembranous (thrush), acute atrophic (erethymatous), chornic atropic
(angular chelitis), hyperplastic (leukoplakia)
•
Pseudomembranous thrush can present on the palate, tonsils, tongue (buccal
mucosa). It is usually painless and easy to remove, some patients may experience
pain upon swallowing, or altered taste sensation
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 23
Oral Candidiasis
By Salvatore Marra, from AIDS imaging
http://members.xoom.it/Aidsimaging
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 24
Oral Candidiasis
■ Atrophic (Erythematous)
Candidiasis
■ Appears as flat, red
atrophic plaques
•
Erythematous candida appears as flat, red, atrophic plaques.
•
Candida may be confused with apthous ulcers or herpes, however these are
usually much more painful
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 25
Oral candidiasis: Angular Cheilitis
•
Angular chelitis appears as fissures on corner of mouth
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Unit 9: Prophylaxis & Treatment of OIs
Slide 26
Leukoplakia
•
And leukoplakia appears as white plaques that cannot be scraped away unlike
thrush
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 27
Oropharyngeal Candidiasis
(Treatment Principles)
Mild to moderate disease: Topical Therapy
Nystatin
Clinical response occurs in 90-100% of patients within 7 days
Moderate to severe disease: Systemic Therapies
Fluconazole, Itraconazole
Continue antifungal therapy for two weeks
Reduce colony forming units
Reduce risk factors / increase time to recurrence
Unit 8: Opportunistic Infections
27
•
Many trials looking at therapy for mucocutaneous candidiasis are lacking, not
stratified trials based on CD4, small numbers,
•
In general for mild to moderate disease, initiate with topical therapy
•
Nystatin suspension or clotrimazole troches, if available
•
Clinical response occurs in 90-100% of patients within 7 days
•
Failed topical or moderate to severe disease: systemic fluconazole or itraconazole
•
Refractory oropharyngeal candida generally requires systemic therapy
•
Treatment of Vulvovaginal infections are based on non HIV-infected women
•
Mild mucosal candidiasis (OPC or Vg) respond well to topical antifungal therapy.
Mod to severe typically require systemic therapy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 28
Candidiasis: Episodic vs.
Chronic Suppressive Therapy
■ Episodic therapy is generally preferred
■ Recurrent symptomatic Oropharyngeal Candidiasis
(OPC) may require chronic suppressive therapy
■ Chronic suppressive therapy increases the risk of
developing azole-resistant disease
■ Recurrence risk with esophageal candida is > OPC and
may warrant chronic suppressive therapy
■ May consider discontinuing maintenance therapy with
immune reconstitution from potent ART
Unit 8: Opportunistic Infections
28
•
Although most respond to therapy, relapse is common 20-60% because candida
can still be cultured from oral cavity of many pts.
•
Episodic therapy is generally preferred
•
Chronic suppressive therapy increases the risk of developing azole-resistant
disease, which will eventually require higher doses to treat, increased cost and
drug interactions.
•
Since response rates are high, this is not necessary, unless cases are recurrent,
then consider maintenance.
•
Many require chronic suppressive therapy if recurrent candida is a problem.
Relapse rates are 84% within 1 year in the absence of suppressive therapy for
esophageal thrush. Use suppressive therapy only if needed to avoid toxicity, dev
of drug resistance, additional strains of candida. Ketoconazole requires an acidic
environment for absorption (achlorhydria may affect absorption)
•
May consider discontinuation of maintenance therapy with immune reconstitution
from HAART.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 29
Fluconazole-Resistant
(Refractory) Candidiasis
■ Failure to respond to antifungal therapy
■ Occurs in patients with advanced AIDS (CD4 cell count
< 50/mm3)
■ Occurs with extensive prior treatment with fluconazole
■ Occurs in about 5-7% of patients with advanced HIV
disease.
■ Prevalence has decreased with potent ART
Unit 8: Opportunistic Infections
29
•
Refractory disease is defined as the failure to respond to antifungal therapy with
appropriate doses for a standard duration of time.
•
Pts with OPC who do not respond to flu 200 mg x 2 weeks are unlikely to respond
to higher doses
•
Colonization with a more inherently resistant organism is more common in
advanced HIV infection: CD4 < 50.
•
5-7% of resistance seen in the pre-HAART era.
•
Treatment of fluconazole resistant OPC, try amphotericin B or clotriamzole, get
them on HAART.
•
Resistance may be caused by target enzyme alteration, reduced cell permeability
or active efflux out of cells.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 30
Candidiasis Treatment-OPC
All for 14 days
Topical Therapy
(preferred):
Systemic Therapies:
• Nystatin oral suspension
500,000 units 5X day
• Itraconazole capsule 200mg
daily with food
• Nystatin pastilles 100,000
units:1 to 2 pastilles (200,000
to 400,000 units) 4 to 5 times
daily
• Itraconazole suspension 10
mg/ml 100-200 mg daily
without food
• Clotrimazole 1% cream
• Fluconazole* 100 mg daily
• Ketoconazole tablet 200 mg
daily
• Potent ART
• *Preferred
Unit 8: Opportunistic Infections
30
•
OPC (oropharyngeal thrush) should be treated with topical therapy when able.
•
Topical therapy not absorbed, minimal side effects other than distortion of the sense of taste
•
Nystatin has a bitter taste and has to be taken 5 times a day and is significantly less effective than
fluconazole for rates of response and relapse. Clotrimazole is easier to take and more effective. In
Ethiopia Clotrimazole troches are unavailable. Nystatin may be available in gel.
•
Amphotericin B. oral suspension is difficult to prepare, therefore it is not mentioned here, and is not
used often in the US
•
If systemic therapy is required:
•
Fluconazole is preferred to ketoconazole or itraconazole
•
Fluconazole is more completely absorbed than itraconazole or ketoconazole because it is not
dependant on gastric acidity or food intake. Side effects of fluconazole include headache,
dyspepsia, diarrhea, nausea, vomiting, hepatitis and skin rash.
•
Fluconazole is superior to ketoconazole in terms of efficacy, less drug interactions and more
predictable absorption
•
Itraconazole is less predictably absorbed and has more significant drug interactions than fluconaozle
also
•
Patients who receive potent ART have less episode of recurrent thrush. This is the best treatment:
immune reconstitution with potent ART.
•
Note doses for treatment and maintenance therapy are all listed in the handout.
•
Fluconazole dose requires adjustment for patients with renal dysfunction. The manufacturer
recommends that the daily dose be reduced by 50 percent in patients with a creatinine clearance of
20 to 50 mL/min and by 75 percent in those with a creatinine clearances <20 mL/min.
•
Dose of itraconazole does not need to be adjusted for renal failure
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 31
Candidiasis Treatment - Esophageal
All for 2-3 weeks
Systemic therapy:
• Fluconazole 200-400 mg daily
• Itraconazole capsule 200mg daily with food
• Itraconazole suspension 100-200 mg daily without
food
• Amphotericin B. IV 0.3-0.6 mg/kg/day
Unit 8: Opportunistic Infections
•
31
Esophageal candida always requires oral therapy and may require IV therapy in
severe cases or refractory cases.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 32
Refractory candida
(fluconazole resistant)
■ Higher doses of fluconazole
■ 400-800 mg daily
■ Itraconazole suspension
■ IV Amphotericin 0.3-0.5 mg/kg/day
Unit 8: Opportunistic Infections
Reference Manual for Trainers
32
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 33
Clinically Significant Interactions
with Fluconazole
■ Rifampin
■ Phenytoin
■ Monitor for toxicity
■ Gastrointestinal effects,
hepatitis
■ Protease Inhibitors
■ Coumadin
■ Increased coumadin effect
■ Statins
■ Increased risk of
myopathy, rhabdomyolysis
and acute renal failure
Unit 8: Opportunistic Infections
■ (Monitor for PI toxicity)
■ Nevirapine
■ Increased risk of
hepatotoxicity and rash
33
•
Since fluconazole is the preferred azole, we will focus on significant drug interactions
between fluconazole and other medications.
•
This list is not comprehensive, however, it lists interactions that are clinically significant.
•
Fluconazole may cause an increase in rifampin levels, leading to increased GI effects or
hepatitis.
•
Fluconazole is a potent inhibitor of 2C9 and even at a dose of 100 mg /day can
substantially increase the hypoprothrombinemic response of warfarin. Vaginal miconazole
has also increased warfarin response in isolated cases. Monitor for an increased
response to warfarin
•
Statins: undergo extensive first pass metabolism, azole antifungals increase serum
concentrations of statins leading to an increased risk of myopathy, rhabdomyolysis and
acute renal failure
•
PIs: inhibitors of 3A4 (azole antifungals) may increase the levels of PIs resulting in
increased side effects.
•
Fluconazole appears to be a weaker inhibitor of CYP3A4 then itraconazole or
ketoconazole, but in doses over 200 mg, it also inhibits CYP3A4 and should be used in
caution with PIs. Monitor for PI toxicity
•
Phenytoin: fluconazole inhibits CYP2C9 and can increase phenytoin levels, leading to
phenytoin toxicity.
•
These interactions tend to be gradual and depending on the phenytoin baseline phenytoin
serum concentrations, it may take as long as several weeks for pheytoin toxicity to occur
after starting an inhibitor.
•
NVP, recent evidence demonstrated that fluconazole increases NVP levels and increases
the risk of hepatotoxicity, and rash. Most patients in the study were women which may
have impacted the results. This flags this drug interaction as very significant as NVP is
used in the majority of regimens in Ethiopia, especially among pregnant women.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 34
Unit 8: Opportunistic Infections
34
•
For use with the terms outlined by UP to Date 2004 (a portion only for educational
purposes)
•
Major concerns with the use of itraconzole are the somewhat erratic absorption,
multiple drug interactions and cardiotoxicity (negative inoptropic effects and CHF)
•
Other azole antifungals (itraconazole and ketoconazole) are more potent inhibitors
and can result in more significant interactions. Itraconazole and ketoconazole
should not be used with lovastatin or simvastatin, ritonavir and saquinavir which
could result in increased itraconazole levels. Itraconaozle and ketoconazole
should not be used with buffered DDI, rifampin, phenobarbital, phenytoin,
nevirapine, efavirenz which may result in subtherapeutic levels
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 35
HIV Associated Cryptococcal
Meningitis
■ Clinical presentation:
■ Occurs in advanced immune damage CD4 < 100
■ Characterized by subtle clinical manifestations; headache,
fever, malaise, absent meningeal signs
■ Altered sensorium in 25% cases; and focal signs in 5%
Unit 8: Opportunistic Infections
35
•
HIV Associated Cryptococcal meningitis
•
Clinical presentation:
•
Occurs in advanced immune damage CD4 < 100
•
Characterized by subtle clinical manifestations; headache, fever, malaise,
absent meningeal signs (Symptoms such as stiff neck, photophobia, and
vomiting are only seen in a minority of patients )
•
Altered sensorium in 25% cases; and focal signs in 5%
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 36
HIV Associated Cryptococcal
Meningitis
■ Treatment:
■ Induction: amphotericin B IV 0.6-0.8 mg/kg/day (with or
without flucytosine 100 mg/kg/day) for 2 weeks
■ Consolidation: fluconazole 400 mg daily for 8 weeks
■ Maintenance: fluconazole 200 mg daily, life long
Unit 8: Opportunistic Infections
36
•
Treatment with amphotericin B resulted in sterilization of the CSF faster than
treatment with fluconazole during induction stage. Combination therapy with
amphotericin B and flucytosine is superior to Amphotericin B alone in preventing
relapse but does not improve immediate outcomes.
•
A higher proportion of patients who received fluconazole died within the first two
weeks of therapy.
•
Preferred treatment:
•
Induction: amphotericin B IV 0.6-0.8 mg/kg/day (with or without flucytosine
100 mg/kg/day) for 2 weeks
•
Monitor for renal dysfunction, anemia, chills, fever, headache, vomiting,
diarrhea, cramping, lowered blood pressure and abnormal heartbeat
•
Consolidation: fluconazole 400 mg daily for 8 weeks or until CSF is sterile
•
Maintenance: fluconazole, life long
•
Management of raised intracranial pressure; CSF drainage until CSF
pressure is < 200 mm H2O; repeat LP daily until stable
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 37
Pneumocystis Jirovecii
Pneumonia (PCP)
• Classified as a fungus
• Most people exposed to PCP early in life
• Less common in developing countries
• Disease is likely reactivation of latent infection
• Can be transferred from person to person
• Risk greatly increased at CD4 count < 200
• Symptoms: gradual onset of dyspnea,
fever, non-productive cough
Unit 8: Opportunistic Infections
37
•
PCP recently renamed pneumocystis jirovecii pneumonia after the investigator
who detected the fungus in humans. Still use the acronym PCP. PCP was the
most common clinical manifestation of AIDS in the 80-90s. 80% pts developed
PCP. The incidence has declined greatly with the advent of HAART and the use of
OI prophylaxis. However, PCP remains a leading cause of death in HIV patients
today due to lack of access to care, non-adherence, resistance to HAART, not all
patients benefit from HAART.
•
Many think of PCP as a protozoan, more recently properly defined as a fungus.
Most people in the US exposed to P. carinii early in life. Less common in
developing countries infection is a result of reactivation of latent infection, recnet
evidence suggests that it may be transmitted from person to person.
•
Susceptibiltiy of developing PCP is greatly increased at CD4 < 200.
•
Present PCP, gradual, nonprod cough, may have fever (like a viral resp infection)
prob not seeking med att right away, 3 or 4 weeks may pass, as PCP progresses,
exp SOB, due to low oxygen saturation.
•
Pneumocystis jiroveci (yee-row-vet-zee)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 38
PCP Diagnosis
■ Chest radiograph of HIVinfected patient with
dyspnea
■ Diffuse bilateral interstitial
infiltrates suggestive of
PCP
■ ABG (hypoxemia)
■ Induced sputum
■ BAL
■ Elevated LDH
Unit 8: Opportunistic Infections
38
•
A definitive diagnosis should be made due to a broad differential diagnosis and
prolonged treatment with agents with frequent side effects.
•
Chest radiograph should be performed on all patients with suspected PCP. Diffuse
interstitial infiltrates (honeycomb like appearance) strongly suggest PCP. 1/3 of
pts will have a normal chest x-ray
•
ABG is also recommended. O2 sat < 70 characterizes severe PCP (mild PCP if
>70)
•
Induced sputum is the recommended procedure to detect the organism, use
monoclonal Antibody stain to identify P carinii (monoconal antibody is highly spec
and sensitive, takes 1 hr) Sensitivity of induced sputum generally >80%, specificity
>99%
•
P carinii has been identified 10 to 60 days after initiating therapy, sensitivity of the
induced sputum begins to decrease 2 weeks after therapy is initiated
•
Induced sputum has a low negative predictive value, so if neg, do a BAL
•
BAL sensitivity 95-99%
•
PCP can cause damage to the lungs, a signal that lung damage has occurred is
when LDH > 220
•
Lung biopsy is not often used because induced sputum and BAL are effective
•
Mortality of patients hospitalized with PCP is 15-20%
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 39
PCP Treatment Regimens
(All at least 21 days)
• Bactrim (IV or PO) *preferred
• Trimethoprim (PO/IV) + Dapsone (PO)
• Pentamidine (IV)
• Primaquine (PO) + Clindamycin (IV or PO)
• Atovaquone suspension (PO)
Unit 8: Opportunistic Infections
39
•
TMP/SMX is always the preferred agent, it numerous clinical trials it has been
shown to be equal if not superior to all 2nd line agents.
•
Can use oral if pa02 > 70 improved clinical status, can tolerate oral, no problems
with absorption and not allergic
•
(up to 70% may get rash with bactrim, early on in treatment 1st week)
•
Up to 80 may then get rash with dapsone
•
Next choice for treatment depends on the severity of illness, patient allergy history
•
SEVERE PCP: bactrim, pentamidine (not affordable in Ethiopia)
•
MILD STABLE DISEASE: clinda +primaquine, mepron, dap+ trimethoprim (it does
not appear that the 2nd line options are affordable in Ethiopia)
•
Median time to response is usually 4 to 6 days, monitor response by degree of
dyspnea= shortness of breath, fever, respiratory rate and pao2.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 40
PCP Treatment
Adjunctive Corticosteroids?
Indicated in patients with PaO2 < 70
Prednisone 40 mg bid x5 days, 40 mg qd X 5 days then
20 mg qd x 11 days
Prednisone 40mg po = 32 mg methylprednisone IV
Several studies have established that the addition of
corticosteroids within 72 hrs of beginning PCP therapy
improves outcome and reduces mortality
Concerns with administering corticosteroids to
immunocompromised patients
Unit 8: Opportunistic Infections
40
•
Adjunctive steroids are indicated in patients with PaO2 < 70
•
Mortality is substantially reduced when prednisone is added to therapy within 72
hours of initiation of therapy
•
Prednisone 40 mg bid x 5 days, 40 mg qd X 5 days then 20 mg qd x 11 days
•
If patient cannot tolerate meds by mouth, then
•
Prednisone 40mg po = 32 mg methylpred IV
•
There is no convincing evidence that a 21 day course increases the likelihood that
another OI, KS or Tb with appear,
•
or if present will be exacerbated
•
Dc steroids is PCP is not confirmed within 72 hours.
•
REMEMBER 3 things when treating PCP:
•
Prompt initiation of therapy can improve diagnosis
•
Bactrim is drug of choice for mild, moderate and severe disease
•
Prednisone improves survival for pt with mod-severe disease
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 41
Treatment Regimens for Acute PCP
Drug
Dose
Side Effects/Special
Considerations
Bactrim
15mg/kg/day (based on
TMP component) +
(sulfamethoxazole 75
mg/kg/day )PO or IV
divided q6h to q8h for 21
days (Typical oral dose is
2 DS tablets TID).
Dapsone +
Trimethoprim
Dapsone can cause rash &
TMP 15mg/kg/day PO/IV
hemolytic anemia; Screen
divided q6h to q8h +
Dapsone 100 mg po qd for for G-6PD deficiency
21 days
Rash, neutropenia,
anemia, increased
transaminases, hepatitis,
pancreatitis, GI toxicity;
monitor renal function
•
TMP/SMX is always the preferred agent, it numerous clinical trials it has been
shown to be equal if not superior to all 2nd line agents.
•
The intravenous dose is used for severe PCP and is based on the trimethoprim
component divided every 6 to 8 hours.
•
If the oral fomulation is used, the typical dose is 2 DS tablets TID.
•
Note that if paO2 is < 70 (patient has severe PCP) they should also receive
Prednisone 40 mg bid for 5 days, 40 mg qd for 5 days then 20 mg qd for 11 days
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 42
Treatment Regimens for
Acute PCP (cont.)
Drug
Dose
Side Effects/Special
Considerations
Pentamidine
3-4 mg/kg/day IV
once daily for 21
days
Nephrotoxicity, hypotension, hypoglycemia,
leukopenia, thrombocytopenia, GI
intolerance, pancreatitis; Keep patient
hydrated & closely monitor renal function,
electrolytes, and blood sugar
Clindamycin
+
Primaquine
Clindamycin 300600 mg po q6h
(600-900 mg IV
q6-8h) +
Primaquine base
po 15-30mg per
day for 21 days
Primaquine can cause nausea, vomiting &
epigastric pain which may be limited by
administering with meals.
Screen patients for G-6PD deficiency to
avoid hemolytic anemia.
Clindamycin can cause GI intolerance and
diarrhea.
Unit 8: Opportunistic Infections
Reference Manual for Trainers
42
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 43
Introductory Case - Answers
The statement A): The treatment of choice for severe
PCP is Bactrim 15 mg/kg/day based on TMP oral or IV
divided q6-8h x 21 days + Prednisone 40 mg bid for 5
days, 40 mg qd for 5 days, 20 mg qd for 11 days is true.
■ IV therapy is required for severe PCP
■ IV Bactrim dosing is based on weight
■ Steroids are indicated for severe PCP
Unit 8: Opportunistic Infections
•
43
In order to answer this question, there are multiple factors to consider:
1) How severe is the PCP which will dictate whether or not she needs IV
therapy or if she can take outpatient oral therapy. Oral therapy can only be
used for mild to moderate PCP, pa02 >70
2) Bactrim is the drug of choice, however next you need to determine the
proper dose which is based on her weight
•
She weighs 130 pounds = 60 kg, the dose is 15 mg/kg/day based on
the TMP component of bactrim/75 mg based on the SMX
component: therefore the dose would be 300 mg
3) Since she has severe PCP, she should also receive steroids to prevent
further lung damage. If she can tolerate po meds, she can take oral
prednisone. If she cannot tolerate oral meds, methylprednisone can be
used. The equivalent dose is prednisone 40 mg= 32 mg methylprednisone.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 44
Introductory Case –
Answers (cont.)
■ The statement B): The treatment of choice for severe
PCP is Bactrim (TMP/SMX) 160/800 mg IV divided q68h x 21 days + Prednisone 40 mg bid for 5 days, 40 mg
qd for 5 days, 20 mg qd for 11 days, is false.
■ Bactrim dose is weight based (15 mg/kg/day) based on the
TMP component
Unit 8: Opportunistic Infections
Reference Manual for Trainers
44
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 45
Introductory Case –
Answers (cont.)
The statement C): The treatment of choice for severe
PCP is Bactrim two DS tablets po TID X 21 days, is
false.
Severe PCP requires IV therapy
Oral therapy is appropriate for the treatment of mild to
moderate PCP. The typical oral dose is 2 DS tablets tid
X 21 days.
Steroids are indicated for severe PCP
Unit 8: Opportunistic Infections
Reference Manual for Trainers
45
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 46
Introductory Case –
Answers (cont.)
■ The statement D): The treatment of choice for severe
PCP is Bactrim one DS tablet po TID X 21 days +
Prednisone 40 mg bid for 5 days, 40 mg qd for 5 days,
20 mg qd for 11 days, is false.
Severe PCP requires IV therapy
Oral therapy is appropriate for the treatment of mild to
moderate PCP. The typical oral dose for mild to
moderate PCP is 2 DS tablets tid X 21 days.
Unit 8: Opportunistic Infections
Reference Manual for Trainers
46
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 47
Bactrim Pharmacology
■ Inhibits CYP2C9
■ Requires dose adjustment in renal failure
■ 10- 50 mL/min: half the dose
■ <10 mL recommend avoid use, may use 1/3 dose
■ Mechanism of action
■ Associated with a reduction in bacterial infections
■ Effective prophylaxis for toxoplasmosis
■ Side Effects are dose-related and occur in ~ 50% of
HIV-infected patients
Unit 8: Opportunistic Infections
47
•
PK of bactrim: bioavailiability is >90% with oral administration for each component, Inhibits 2C9
•
Drug interactions: bactrim inhibits 2C9 and can increase the response to warfarin: monitor for
increased brusing or bleeding, may need to adjust warfarin dose
•
Bactrim inhibits 2C9 and may increase phenytoin levels resulting in phenytoin toxicity
•
Half life: trimethoprim 8-15 hours and sulfamethoxzole 7-12 hours
•
Elimination is renal which is why it is necessary to adjust dose in renal dysfunction
•
> 50 mL/min: use standard dose
•
10- 50 mL/min: half the dose
•
< 10 mL: manufacturer recommends avoid use, may use 1/3 dose
•
Mechanism of action of Bactrim:
•
Sulfamethoxazole ( same mechanism as dapsone) inhibits DHPS, blocking formation of folic acid by
competing with PABA
•
TMP (same mechanism as primaquine, pentamidine) block DHFR inhibiting the conversion of folic
acid to tetrahydrofolic acid (FH4) this eventually becomes folinic acid. Pnueumocystis organism does
not have the uptake system necessary to take up folinic acid, which is why it can be given without
disrupting therapy of PCP, in theory.
•
The end result is inhibition of the formation of nucleic acids by the organism.
•
Other benefits of bactrim when used for treatment of PCP include reduction of bacterial infections and
coverage for toxoplasmosis prophylaxis as well.
•
Adverse reactions to TMP/SMX occur more often in patients with HIV (50% compared to 10% in non
HIV infected individuals) and in patients who are receiving treatment doses for PCP.
•
Rash, neutropenia, anemia, increased transaminases, hepatitis, pancreatitis, GI toxicity.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 48
Bactrim
Adverse Effects
• Pruritis/rash
• Bone marrow suppression
• GI toxicity
• Increased LFT’s
• Renal effects
Dosing Strategies If Rash
Occurs
Protocols are for patients with
normal renal function only.
• Desensitization
• Rapid
• Over 8 -15 days
• Gradual dose initiation
Unit 8: Opportunistic Infections
•
48
Potential side effects of bactrim include:
•
Pruritis/rash, Bone marrow suppression, GI toxicity, Increased LFT’s
•
If GI effects are problematic, can pre -medicate to prevent NV (metoclopramide or
promehtazine)
•
If rash occurs, may be able to treat through if mild rash with diphenhydramine
•
May need to Discontinue for neutropenia, thrombocytopenia, or an increase in creatinine
to > 3 mg/dl or an increase in LFTs to 5X ULN and skin rash accompanied by high fever
or mucositis .
•
Hepatic necrosis with cholestatic jaundice has occurred: increase in bilirubin)
•
For a patient who has experienced a rash to Bactrim, if the rash is mild, no fever,not
mucocutaneous, no desquamative reaction:
•
Depending on the clinical situation, some providers have recommended a rapid
desensitization protocol, in the intensive care unit to allow a patient to receive
Bactrim treatment. Preferred strategy is to change to an alternate therapy, if
possible and consider gradual dose introductionof Bactrim once treatment is
completed.
•
Once therapy for PCP is completed, the gradual initiation of bactrim can be attempted and
this results in 50% reduction in adverse reactions including rash and/or fever, suggesting
that it is not a true hypersensitivity reaction. The prevailing opinion is that these side
effects are usually due to toxic metabolites ascribed to altered metabolism of bactrim with
HIV infection. The presumed benefit of gradual initiation or desensitization is to permit
time for enzyme induction. (Med Management of HIV infection 2003)
•
The following slides contain rapid and gradual desensitization protocols.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 49
Bactrim IV
Rapid Desensitization
■ Standing orders:
Epinephrine 1:1000 SQ prn allergic reaction.
■ Diphenhydramine 50 mg IV/PO before starting Bag
#1(see next slide), then q6h thereafter.
■ If the patient has a pO2 < 70 mm Hg begin Prednisone
40 mg bid days 1-5, then 40 mg qd days 6-10, then 20
mg qd days 11-21.
Unit 8: Opportunistic Infections
•
49
Rapid desensitization may be necessary in the critical care setting and the
following protocol may be used when bactrim is the optimal choice for the
treatment of PCP.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 50
Bactrim IV
Rapid Desensitization (cont.)
■ Use incremental doses every 20
minutes (min.) of the following
concentrations:
■ Bag #1:TMP 0.16 mg/SMX 0.8
mg in 50 mL D5W. Infuse over
20 min.
■ Bag #2:TMP 1.44 mg/SMX 7.2
mg in 50 mL D5W. Infuse over
20 min.
■ Bag #3:TMP 8 mg/SMX 40 mg
in 50 mL D5W. Infuse over 20
min.
Unit 8: Opportunistic Infections
•
■ Bag #4:TMP 16 mg/SMX 80 mg in
50 mL D5W. Infuse over 20 min.
■ Bag #5:TMP 80 mg/SMX 400 mg in
100 mL D5W. Infuse over 20 min.
■ Bag #6:TMP 120 mg/SMX 600 mg
in 150 mL D5W. Infuse over 30
min.
■ Bag #7:TMP 240 mg/SMX 1200 mg
in 250 mL D5W. Infuse over 60
min.
■ Follow in 8 hours by 5 mg/kg (TMP
component) dosing every 8 hours
(*unless the patient has renal
dysfunction) for treatment of PCP.
50
Rapid desensitization may be necessary in the critical care setting and the
following protocol may be used when bactrim is the optimal choice for the
treatment of PCP.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 51
Bactrim Oral Rapid
Desensitization Protocol
2003 Medical Management of HIV Infection Bartlett MD
•
Rapid Bactrim desensitization protocol, oral version.
•
Serial 10-fold dilutions of oral suspension (40 mg TMP and 200 mg SMX/5 ml)
given hourly over 4 hours
•
When the use of bactrim is necessary for the treatment of PCP and the patient can
tolerate po medication
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 52
Bactrim Gradual Initiation
■ Days 1-3: TMP 20 mg/SMX
100 mg = 2.5 mL of Bactrim
(TMP/SMX) suspension 8
mg/40 mg per mL.
■ Days 4-6: TMP 40 mg/SMX
200 mg = 5 mL of Bacrim
suspension
■ Days 7-9: TMP 60 mg/SMX
300 mg = 7.5 mL of Bactrim
suspension.
■ Days 10-12:TMP 80 mg/SMX
400 mg = 1 SS tablet (Single
Strength).
■ Days 13-15:TMP 120
mg/SMX 600 mg = 1 & 1/2
tablet (Single Strength).
■ Days 16-22:TMP 160
mg/SMX 800 mg = 1 tablet
(Double Strength).
Unit 8: Opportunistic Infections
52
•
Alternatively, a desensitization protocol over 15 days.
•
Once therapy for PCP is completed, the gradual initiation of bactrim is another
option can be attempted and this results in 50% reduction in adverse reactions.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 53
Bactrim Desensitization Note
■ If a patient who has been desensitized to Bactrim stops
taking Bactrim at some point:
they will need to undergo desensitization over again to
prevent a subsequent allergic reaction before starting
Bactrim therapy again.
Unit 8: Opportunistic Infections
Reference Manual for Trainers
53
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 54
Dapsone
• Adverse Effects
• rash/pruritis
• hepatitis
• neutropenia
• hemolytic anemia/methemoglobinemia
• Screen for G-6PD deficiency
• Consider drug interactions
• antacids
Unit 8: Opportunistic Infections
54
•
Up to 80 % of patients who develop rash with bactrim will be cross sensitive to
dapsone. If mild reaction to bactrim, dapsone is still a reasonable choice.
•
Sulfa (dapsone) inhibits DHPS, blocking formation of folic acid by competing with
PABA
•
TMP (trimetrexate, primaquine, pentamidine) block DHFR
•
Get a g6pd for dapsone or primaquine to prevent hemolytic anemia, o2 del to
tissues is impaired.
•
Symptoms of hem anemia: JAUNDICE, confusion, SOB, headache, weakness
•
Must be taken apart from antacids, absorption is dependant on an acidic pH
•
Dapsone+trimethoprim= effective to TMP/SMX mild to mod disease
•
Sulfa (dapsone) inhibits DHPS, blocking formation of folic acid by competing with
PABA
•
G6PD def most severe in mediteranean pts, less severe in black, Indian, SE
Asian. Sulfa less of a problem.
•
Dapsone has no antibacterial prop and no toxo protection unless taken with
pyrimethamine
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 55
IV Pentamidine
• Often reserved for severe episodes
• (inferior survival rate versus TMP/SMX)
• Most frequent toxicities: nephrotoxicity, hypoglycemia,
hypotension
• Other side effects: hyperkalemia, pancreatitis,
hypomagnesemia, hypocalcemia, bone marrow
suppression, GI intolerance, elevated LFT’s
Unit 8: Opportunistic Infections
55
•
IV pentamidine is restricted to the use in pts with severe PCP who cannot tolerate
TMP/SMX.
•
Hypoglycemia #1 SE ( up to 40%) direct effect on pancreatic b cells may persist
after dc therapy. Monitor patient for reduced consciousness, check blood sugar
twice daily, check renal function daily, nephrotoxicity is result of cumulative drug
effect.
•
Can occur within 1 week.
•
Neprhotoxicity on top of hypoglycemia be with renal impairment, insulin secretion
is impaired resulting in prolonged exposure to insulin.
•
Sulfa (dapsone) inhibits DHPS, blocking formation of folic acid by competing with
PABA.
•
TMP (primaquine, pentamidine) block DHFR.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 56
Primaquine + Clindamycin
(Adverse effects)
Primaquine
Clindamycin
• hemolytic anemia (Screen for
G6-PD)
• diarrhea
• nausea/vomiting
• nausea/vomiting
• rash
• fever
• rash
Unit 8: Opportunistic Infections
56
•
Typically used for mild disease those who cannot tolerate TMP/SMX
•
Screen for g6pr for primauine
•
Clindaymycin diarrhea is major concern
•
Sulfa (dapsone) inhibits DHPS, blocking formation of folic acid by competing with
PABA
•
TMP (trimetrexate, primaquine, pentamidine) block DHFR
•
50S subunit of the bacterial ribosome.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 57
Atovaquone
• Antiprotozoal
• Should be reserved for patients with mild episodes of
PCP or TMP/SMX intolerant
• Poor bioavailability (administer with fatty meal to
enhance absorption)
• Side Effects: Rash, fever, GI intolerance, diarrhea,
fever
Unit 8: Opportunistic Infections
•
57
Mild, stable disease, steady state is not reached for days, absorption requires a
meal with fat 21-28 grams
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 58
PCP Prophylaxis
Who: All HIV-infected patients
When: CD4 count < 200, prior PCP, history of oral
thrush or unexplained fever for > 2 weeks
Consider when:
CD4 <14% or previous AIDS defining illness
Infrequent monitoring of CD4 (CD4 200-250)
Unit 8: Opportunistic Infections
58
•
If no PCP prophylaxis is started after acute PCP therapy is complete, 70-80% will
relapse.
•
Patients with CD4 less than 200 or history of oral thrush should receive PCP
prophylaxis with Bactrim .
•
Consider using prophylaxis if CD4 < 14%, infrequent monitoring, more than every
3 months, prior PCP episode when CD4 >200, wasting, prior AIDS event, CD4
falling rapidly or high VL
•
PCP prophylaxis reduces the risk of PCP 9 fold and patients who get PCP despite
prophylaxis have a low mortality rate. The major reasons for PCP failure include
CD4 < 50 and nonadherence
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 59
PCP Prophylaxis Regimens
Preferred:
TMP/SMX 1 DS QD
TMP/SMX 1 SS QD
Alternatives:
TMP/SMX 1 DS TIW
Dapsone
Aerosolized Pentamidine
Atovaquone
Unit 8: Opportunistic Infections
59
•
Bactrim confers protection against toxoplasmosis at dose of 1 DS daily, as well as
some common respiratory bacterial pathogens …
•
1 ss or 1 tab tiw may provide protection against toxoplasmosis as well
•
If patient had a reaction (rash) to bactrim was not life threatening, treatment should
be continued if clinically feasible.
•
Strongly consider gradual reintroduction of the agent after the adverse event has
resolved as described earlier.
•
Patients who experienced fever and rash, up to 70% may tolerate (gradual
increase in dose ) or desensitization (BI)or as reintroduction at a lower dose or
frequency CIII)
•
Other options not available in Ethiopia.
•
Mepron is as effective as dapsone and aerosolized pentam, but much more
expensive
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 60
Aerosolized Pentamidine
■ Antiprotozoal agent
■ Generally well-tolerated
■ Adverse Effects: bronchospasm (usually in smokers and
asthmatics), cough, unpleasant taste
■ May pose risk of TB to healthcare workers and other patients
■ Disadvantages: high cost, need for a compressed air source,
lack of systemic prophylaxis for extrapulmonary PCP infection
Unit 8: Opportunistic Infections
Reference Manual for Trainers
60
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 61
PCP Prophylaxis Withdrawal
Criteria to
discontinue 1o
prophylaxis
Criteria to
restarting 1o
prophylaxis
Criteria to
initiate 2o
prophylaxis
Criteria to
discontinue 2o
prophylaxis
Criteria to
restart 2o
prophylaxis
CD4+ >200
cells/uL for >3
months
CD4+ < 200
cells/uL
Prior PCP
episode
CD4+ >200
cells/uL for > 3
months
CD4+ <200
cells/uL
Unit 8: Opportunistic Infections
61
PRIMARY PROPHLAXIS
•
Discontinuation of primary prophylaxis is recommended to decrease pill burden,
adds little to disease prevention (toxoplamosis or bacterial),decreases cost,
prevents drug interactions
•
NOTE that patients who discontinues their primary prophylaxi were on HAART
with a PI, many undetectable and median CD4 was >300
•
Median follow-up at discontinuation was at 6-16 months
SECONDARY PROPHYLAXIS
•
Longest follow=up was 13 months
•
Consider prophylaxis for life if patient develops PCP at CD4 > 200
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 62
Toxoplaxmosis
Caused by a protozoan parasite toxoplasma gondii
Source is raw or undercooked meat & cat feces
Disease is likely through reactivation of latent infection
Infection most frequently involves the CNS
Infection occurs when CD4 cells < 100
Unit 8: Opportunistic Infections
62
•
First recognized in the late 60s by pts with cancer, case reports. Later recognized
the the implication in immunompromised atients in the 80s.
•
Frequency is much lower than with PCP.
•
Toxoplasmosis is caused by a protozoan parasite (toxoplasma gondii) that
depends on its host for its supply of purines. The cat is the primary carrier of the
cysts. After ingestion of cysts or oocysts (both contain tachyzoites), they are
released into the bloodstream, diss into tissues causing acute toxo, others encyst
and rupture later
•
Disease is likely through reactivation of latent infection.Prevalence of latent
infection is high (80%)
•
Infection most frequently involves the CNS, other areas affected: lung and eye
•
Humans come into contact with toxoplasmosis from infected undercooked meat
(cysts) cat liter (oocycsts)
•
Infection occurs when CD4 cells < 100
Reference Manual for Trainers
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Unit 9: Prophylaxis & Treatment of OIs
Slide 63
Toxoplasmosis Encephalitis (TE)
CNS is most common clinical presentation: Headache,
confusion, lethargy, low-grade fever, seizures (~25%),
hemiparesis and speech abnormalities
Diagnosis:
Ring-enhancing lesions on CT scan or MRI
Toxoplasma IgG antibodies are usually present but may be
negative in 5-10% patients with TE
Unit 8: Opportunistic Infections
63
•
Most common presentation: is CNS infection hemiparesis and speech
abnormailities, confusion, headaches and seizures. Toxoplasmosis affects basal
ganglia, brain stem and ganglia.
•
Multifocal involvement in the brain therefore you may see a wide spectrum of
clinical findings
•
You will see multiple ring enhancing lesions on CT or MRI scan.
•
Toxoplasma IgG antibodies are usually present but may be negative in 510% patients with TE
•
Brain biopsy only if they fail to improve in 10 days or deteriorate in 7 days and
those without antibody to toxoplasmosis
•
Extracranial sties include retina, myocardium and lung
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 64
Toxoplasmosis Treatment
Treat acute infection for minimum of 6 weeks
Preferable to treat until 3 wks after resolution of lesions
by radiologic scan
After treatment, switch to chronic suppressive therapy
with reduced doses
Best therapy is immune reconstitution with potent ART
Unit 8: Opportunistic Infections
64
•
Treat acute infection for minimum of 6 wks
•
Preferable to treat until 3 wks after resolution of lesions by radiologic scan
•
After treatment, switch to chronic suppressive therapy with reduced doses
•
Best therapy is immune reconstitution with HAART
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 65
Acute Toxoplasmosis Treatment
(all regimens include leucovorin)
Pyrimethamine + sulfadiazine
Pyrimethamine + sulfadoxine
(Fansidar)
■ treatment of choice
■ only available treatment in
Ethiopia
■ synergistic
■ may be effective as PCP
prophylaxis
■ effective as PCP prophylaxis
■ Side effects next slide
Pyrimethamine + clindamycin
■ effective but poorly tolerated
■ alternative treatment for
sulfa-intolerant patients
Unit 8: Opportunistic Infections
■ clindamycin (poor CNS
penetration)
65
•
The only available treatment in Ethiopia is Fansidar (pyrimethamine and
sulfadoxine) Fansidar may be effective as PCP prophylaxis.
•
Use with caution if history of sulfa allergy:
•
Sulfadoxine interferes with bacterial folic acid synthesis and growth via competitive
inhibition of para-aminiobenzoic acid; pyrimethamine inhibits microbial
dihydrofolate reductase, resulting in inhibition of tetrahydrofolic acid synthesis
Highly selective against Toxoplasma gondii.
•
Absorption: Well absorbed
•
Distribution: Sulfadoxine: Well distributed like other sulfonamides; Pyrimethamine:
Widely distributed, mainly in blood cells, kidneys, lungs, liver, and spleen
•
Metabolism: Pyrimethamine: Hepatic; Sulfadoxine: None
•
Pyrimethamine Inhibits CYP2C8/9 (moderate), 2D6 (moderate) (2D6 inhibitor may
increase levels of ritonavir)
•
Half-life elimination: Pyrimethamine: 80-95 hours; Sulfadoxine: 5-8 days
•
Time to peak, serum: 2-8 hours
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 66
Toxoplasmosis Treatment
Side Effects
Pyrimethamine + sulfadoxine
Pyrimethamine + sulfadiazine
■ Stevens-Johnson syndrome,
megaloblastic anemia and other
blood dyscrasias, toxic
nephrosis, hepatitis,
gastrointestinal toxicity, and
kernicterus.
■ Side effects: hypersensitiviry with
rash, drug fever, marrow
suppression, gi intolerance, dose
related ataxia, tremors, seizures,
bone marrow suppression, renal
failure
Pyrimethamine + clindamycin
■ Side effects diarrhea, gi
intolerance, dose related ataxia,
tremors, seizures, bone marrow
suppression
Unit 8: Opportunistic Infections
66
•
Fansidar SIDE EFFECTS Instruct patients to call their doctor right away if they
experience the following side effects: - Extreme tiredness - Painful urination - Skin
rash, hives, or itching - Swollen face, lips, or tongue - Unexplained fever, sore
throat, or cough - Unusual bleeding or bruising - Wheezing or trouble breathing Yellowing of skin and eyes.
•
If they have problems with these less serious side effects, talk with their doctor. Diarrhea - Headache - Irritability, mood changes - Nausea, vomiting, or upset
stomach.
•
Two treatments that are routinely used are not available in Ethiopia.
•
Pyrimethamine + Sulfa is poorly tolerated:
50 to 70% of patients develop dose-limiting SE, including Nausea, leukopenia,
thrombocytopenia, renal failure, fever and rash
•
If nausea becomes very significant, can split the daily dose of pyrimethamine
•
Sulfadiazine can cause crystal-induced reversible renal failure, a serum Cr should
be checked periodically
•
Leucovorin used to minimize leukopenia and thrombocytopenia and the dose
increased as needed to counter these effects.
•
Clindamycin: main side effect is diarrhea
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 67
Acute Toxoplasmosis Treatment
■ Pyrimethamine +Sulfadiazine +Leucovorin
■ Pyrimethamine 100-200mg as loading dose, followed by 50100mg daily (+)Sulfadiazine 1-1.5 gram every 6 hours (+)
Leucovorin 10mg every day
■ Pyrimethamine +Clindamycin +Leucovorin
■ Pyrimethamine (+) leucovorin (as listed above) (+)
Clindamycin 300-600 mg po q6h (600-1200mg IV q6h)
■ Pyrimethamine + sulfadoxine + Leucovorin
■ Pyrimethamine (+) leucovorin (as listed above) (+)
Sulfadoxine (refer to Ethiopia dosing guidelines for sulfadoxine)
Unit 8: Opportunistic Infections
67
•
Maintenance doses (secondary prophylaxis)
•
Pyrimethamine +Sulfadiazine +Leucovorin
•
Pyrimethamine 25-50mg every day (+)Sulfadiazine 0.5-1.0 gm every 6 hours
(+)Leucovorin 10-25 mg every day (preferred)
•
Pyrimethamine +Clindamycin +Leucovorin
•
Pyrimethamine + leucovorin (as listed above) +Clindamycin 300-450mg p.o. every
6 to 8 hours
•
Atovaquone +/-Pyrimethamine+ Leucovorin
•
Atovaquone 750 mg q6-12 hours (+/-) pyrimethamine 25 mg qd (+) leucovorin
10 mg qd
•
Pyrimethamine + sulfadoxine + Leucovorin
•
Pyrimethamine + leucovorin (as listed above) +Sulfadoxine (refer to Ethiopia
dosing guidelines for sulfadoxine)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 68
Toxoplasmosis
Primary Prophylaxis
Indications:
1. Patient who has never had toxoplasmosis (plus)
2. Positive toxoplasma IgG serology (plus)
3. CD4 count less than 100 cells/mm3
Unit 8: Opportunistic Infections
•
68
Indications:
•
Patient who has never had toxoplasmosis (plus)
•
Positive toxoplasma IgG serology
•
CD4 count less than 100 cells/mm3
Reference Manual for Trainers
(plus)
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 69
Toxoplasmosis
Primary Prophylaxis
Preferred Regimens:
TMP/SMX DS daily
TMP/SMX DS three times /week
TMP/SMX SS daily
Alternative Regimens:
Dapsone + pyrimethamine + leucovorin
Atovaquone +/- pyrimethamine + leucovorin
Unit 8: Opportunistic Infections
69
•
Primary prophylaxis for Toxoplasmosis as seen on the slide.
•
Secondary prophylaxis is lifelong maintenance therapy as listed on the handout
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 70
Toxoplasmosis Prophylaxis
Withdrawal
Criteria to
Criteria to
discontinue
restarting 1o
1o prophylaxis prophylaxis
Criteria to
initiate 2o
prophylaxis
Criteria to
discontinue 2o
prophylaxis
(chronic
(chronic
maintenance maintenance
therapy)
therapy)
CD4+ >200
cells/uL for
>3 months
CD4+ < 100- Prior Toxo200 cells/uL plasmosis
encephalitis
Criteria to
restart 2o
prophylaxis
(chronic
maintenance
therapy)
CD4+ >200
CD4+ <200
cells/uL sustained cells/uL
(>6 mos) and
Completed initial
therapy and
asymptomatic for
toxoplasmosis
Unit 8: Opportunistic Infections
70
•
Discontinuation of primary prophylaxis, follow up was 7-22 months mean CD4 was
300, on HAART, undetectable
•
Evidence not as strong to discontinue secondary prophylaxis, probably want to do
a follow-up MRI prior to discontinuing secondary prophylaxis.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 71
Mycobacterium Avium Complex
(MAC)
■ MAC- Mycobacterium avium & M. intracelluare
■ Acid fast Bacteria
■ Ubiquitous in the environment
■ No recommendations for prevention of exposure
■ No person to person transmission
■ Infection is due to recent acquisition
■ Colonization through GI and respiratory tracts
■ Late stage AIDS illness (CD4 cell < 50)
Unit 8: Opportunistic Infections
71
•
MAC-
Mycobacterium avium and Mycobacterium intracelluare
•
Acid fast Bacteria
•
Ubiquitous in the environment
•
Before HIV epidemic, seen only in patients with underlying lung disease
•
No recommendations for prevention of exposure
•
No person to person transmission
•
Infection is due to recent acquisition
•
Colonization through GI and respiratory tracts: results in local and disseminated
disease
•
Incidence has decreased dramatically due to aggressive prophylaxis and HAART
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 72
Mycobacterium Complex (MAC)
Symptoms:
■ Local disease - Fever, lymphadenopathy
■ Disseminated Disease - Late stage AIDS illness. Symptoms:
fatigue, malaise, weight loss, fever, night sweats, abdominal
pain, diarrhea.
MAC Prophylaxis:
■ Who:
all HIV-infected patients
■ When:
CD4<50
■ Drug of Choice: Azithromycin or Clarithromycin
Unit 8: Opportunistic Infections
72
•
Azithromycin can cause GI upset
•
Clarithromycin can cause GI symptoms , 9 LFTs, Metallic taste. Clarithromycin is
a 3A4 inhibitor
•
Clarithroycin levels are increased with concurrent indinavir 50%, RTV 75% and
SQV 177%. Nelfinavir, amprenavir and nevirapine have minimal effect on
clarithromycin. Clarithromycin plus EFV should be given with caution due to high
rate of rash reactions.
•
Therefore the drug of choice is azithromycin
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 73
MAC Treatment Principles
■ Preferred regimen :
■
Azithromycin or
Clarithromycin
plus
Ethambutal
+/-
Rifampin
■ Alternative (3rd) drug or Additional (4th) drug
■ Ciprofloxacin
■ Amikacin
Unit 8: Opportunistic Infections
•
73
Doses in handout 8.5
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 74
Herpes Zoster
■ There is a high incidence of zoster in association with
HIV infection
■ More than 90% of adults have serologic evidence of
infection with varicella-zoster virus
■ Presentation is similar to immunocompetent patient,
duration may be longer and the risk of disseminated
infection is greater in HIV infected individuals
■ Lesions are painful, pruritic, grouped and can be
pustular on an erythematous base
Unit 8: Opportunistic Infections
Reference Manual for Trainers
74
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 75
Herpes Zoster Treatment
■ Dermatomal
■ Acyclovir p.o. 800 mg 5X day for at least 7 days (until lesions
crust) or acyclovir IV 10 mg/kg/day tid
■ Disseminated
■ Acyclovir 30-36 mg/kg/day IV at least 7 days
Unit 8: Opportunistic Infections
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75
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 76
Cytomegalovirus (CMV)
■ Herpes virus
■ High incidence
■ 30 - 40% in general population are Ab+
■ 90% or more in IVDU and MSM are Ab+
■ Able to establish a latent infection which can reactivate
■ Late Stage AIDS illness (CD+4 < 100)
■ Clinical Manifestations■ retinits, esophagitis, colitis
Unit 8: Opportunistic Infections
76
•
There is ophthalmology care in Ethiopia. However, perhaps less than 2% of the
HIV patients can afford it. Cytomegalovirus (CMV) retinitis is the most common
serious ocular complication of AIDS.
•
Prior to the availability of highly active antiretroviral therapy (HAART), CMV retinitis
occurred in 21 to 44 % of patients with AIDS, primarily in those with a CD4 T
lymphocyte count below 50. However, the incidence of CMV retinitis has
decreased by more than 50 % since HAART became available HAART also may
change the setting in which CMV retinitis is seen.
•
CMV retinitis is characterized by full-thickness retinal necrosis and edema that is
subsequently replaced by thin, atrophic scar tissue . Without antiviral treatment or
immune reconstitution, the retinal lesions enlarge centrifugally. The portions of the
retina destroyed by CMV do not regenerate functionally.
•
Thus, the goal of therapy for CMV retinitis is to prevent further retinal necrosis and
loss of vision.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 77
HIV-Associated Wasting
Definition: Involuntary weight loss of greater than 10%
of baseline body weight
plus one of the following:
1) chronic diarrhea
2) chronic weakness and
documented fever
Unit 8: Opportunistic Infections
Reference Manual for Trainers
77
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 78
Wasting
By Salvatore Marra, from
AIDS imaging
http://members.xoom.it/Aidsim
aging
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 79
HIV-Associated Wasting
Factors involved :
1) Inadequate dietary intake
2) Decreased GI absorption
3) Increased energy needs and metabolic rate
4) Alterations in CHO, protein, and lipid
metabolism
5) Alterations in thyroid, adrenal and gonadal
function
Unit 8: Opportunistic Infections
Reference Manual for Trainers
79
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 80
HIV-Associated Wasting:
Treatment
■ Dietary Assessment and Supplementation
■ Oral nutritional supplementation
■ Enteral supplementation
■ TPN
■ Anabolic Steroids
■ testosterone injections
■ Increase in Lean Body Mass, increase energy, libido
Unit 8: Opportunistic Infections
Reference Manual for Trainers
80
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 81
Cryptosporida
■ There is no effective Treatment for crytosporidiosis
■ Immune reconstitution with HAART is the only treatment
that controls cryptospoidiosis
Unit 8: Opportunistic Infections
81
•
Diarrhea: Symptomatic Treatment
•
Loperamide 2 mg
•
Diphenonylate 2.5 mg and atropine 0.025 mg
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HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 82
Opportunistic Infections
Case Studies
•
Refer participants to Worksheets 8.1 to 8.3 in their Course Workbooks.
•
These case studies may be done in small groups and findings reported back to the
larger group, or they may be discussed as a large group when time is limited.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 83
Case 1
■ DH is a 53 year old male who was recently diagnosed with HIV
two months ago. He has developed severe PCP with
concomittant thrush. He experienced a pruritic rash 5 days after
starting therapy with Bactrim for the treatment of his PCP.
■ His physician wants to switch to another agent to treat DH’s
PCP. You recommend the most appropriate option, which is:
A. Clindamycin 600 mg IV q6h + Primaquine 15 mg po qd
B. TMP 220 mg IV q6h + Dapsone 100 mg po qd
C. Pentamidine 240 mg IV QD
D. Rapid bactrim desensitization, followed by 21 days of bactrim IV therapy
Unit 8: Opportunistic Infections
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HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 84
Case 1 - Answers
■ Either C or D are correct answers
■ C: IV Pentamidine is comparable to Bactrim for severe
PCP
■ D: Some may argue to continue T/S for severe PCP
(rapid desensitization) as long as the patient did not
have a severe reaction to Bactrim (SJS or anaphylaxis)
Unit 8: Opportunistic Infections
84
•
Either C or D are correct answers
•
C: If available: IV Pentamidine is comparable to Bactrim for severe PCP. IT must
be monitored closely. Potential side effects are many and include: nephrotoxicity,
hypotension, cardiac, hypoglycemia, leuk/thrombocytopenia, pancreatitis.
•
Patient must be kept well hydrated, monitor renal function and electrolytes closely
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 85
Case 1 - Explanation
■ A is incorrect
■ Clindamycin + primaquine is only indicated for mild to
moderate PCP
■ B is incorrect
■ Dapsone+ trimethoprim is comparable to Bactrim for
moderate PCP
■ would need to monitor for rash
Unit 8: Opportunistic Infections
•
A: is incorrect
•
•
85
Clindamycin + primaquine is only indicated for mild to mod disease.
B: is incorrect
•
Dapsone+ trimethoprim iscomparable to Bactrim for moderate PCP, would
need to monitor for rash
•
The incidence of cross-sensitivity between dapsone and Bactrim may occur
in up to 80% of patients.
•
No risk factors or predictive features for cross-sensitivity have been
identified. Although cross-sensitivity reactions can occur, dapsone is still
considered a reasonable option for patients who experience a mild
hypersensitivity reaction to SMX-TMP
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 86
Case 1 (cont.)
■ During DH’s hospital stay, he is found to have a CD4
count = 110 cells/mm3 and a viral load = 89,503.
■ He tolerated a rapid oral desensitization protocol and is
on day 5 of IV Bactrim
■ His physician would like to begin treatment for his
thrush.
Unit 8: Opportunistic Infections
•
86
Most patients respond slowly to PCP treatment, 5 to 7 days.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 87
Oral Candidiasis
By Salvatore Marra, from AIDS imaging
http://members.xoom.it/Aidsimaging
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 88
Case 1 – Question (cont.)
Which of the following would you recommend?
A. Nystatin oral suspension 500,000 units 5X day
B. Nystatin pastilles 100,000 units:1 to 2 pastilles (200,000 to
400,000 units) 4 to 5 times daily
C. Fluconazole 100 mg daily
D. Itraconazole capsule 200mg daily with food
E. Other ideas?
Unit 8: Opportunistic Infections
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HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 89
Case 1 – Answer (cont.)
■ A or B are correct answers
■ Oropharyngeal thrush should be treated with topical
therapy
■ Systemic therapy is only used if topical therapy has
failed
■ Fluconazole would be drug of choice
■ Potent ART therapy will prevent recurrence of thrush
Unit 8: Opportunistic Infections
89
•
OPC (oropharyngeal thrush) should be treated with topical therapy when able.
•
Topical therapy not absorbed, minimal side effects other than distortion of the
sense of taste
•
Nystatin has a bitter taste and has to be taken 5 times a day and is significantly
less effective than fluconazole for rates of response and relapse. Clotrimazole is
easier to take and more effective. In Ethiopia Clotirmazole troches are unavailable
•
Systemic therapy is only used if topical threrapy has failed
•
Fluconazole is more completely absorbed than itraconazole or ketoconazole
because it is not dependant on gastric acidity or food intake. Side effects of
fluconazole include headache, dyspepsia, diarrhea, NV hepatits, skin rash.
•
Fluconazole is superior to ketoconazole in terms of efficacy, less drug interactions
and more predictable absorption
•
Itraconazole is less predictably absorbed and has more significant drug
interactions than fluconaozle also
•
Patients who receive HAART have less episode of recurrent thrush. This is the
best treatment: immune reconstitution with HAART.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 90
Case 2
■ SC is 24-year-old HIV-infected woman from Jimma who
presents to your pharmacy.
■ She has prescriptions for her current medications:
dapsone (for PCP prophylaxis) and nystatin suspension
(for thrush). At this time she has declined antiretroviral
therapy
■ She just received results from her doctor visit: serologic
testing detects antibodies to Toxoplasma (IgG) and her
current CD4 count is 85 cells/mm3
■ She has a history of rash to bactrim
Unit 8: Opportunistic Infections
•
90
After reading the case, you should consider why this patient does not take bactrim
for PCP prophylaxis
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 91
Case 2 - Question
■ Which of the following statements is most true regarding
Toxoplasmosis prevention for SC?
A.
Since the patient is IgG + to Toxoplasma: that is evidence of
immunity to infection and she does not
need prophylaxis for
Toxoplasmosis
B. The patient does need prophylaxis for Toxoplasmosis. She is taking
dapsone for PCP prophylaxis which will provide protection against
Toxoplasmosis
C.If possible, the patient should be desensitized to and then treated
with bactrim for prophylaxis against both PCP and Toxoplasmosis
D.The patient should be prescribed pyrimethamine in addition to
dapsone which would cover both PCP and Toxoplasmosis.
Unit 8: Opportunistic Infections
Reference Manual for Trainers
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HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 92
Case 2 - Answers
■ A is false: Patients who are IgG + for Toxoplasmosis
and have CD4 <100 require prophylactic therapy
■ B is false: dapsone alone does not prevent
toxoplasmosis
■ D is not the best choice: although dapsone +
pyrimethamine + leucovorin is a reasonable second line
Unit 8: Opportunistic Infections
92
•
An IgG antibody implies previous and likely persistent, latent infection with
Toxoplasma gondii, and this organism can reactivate in the presence of depressed
immunity. All HIV-infected patients who have IgG antibodies against Toxoplasma
and CD4 counts less than 100 cells/mm3 should be prescribed prophylactic
therapy to prevent Toxoplasma encephalitis.
•
Dapsone plus pyrimethamine is an acceptable alternative to trimethoprimsulfamethoxazole for primary prophylaxis against Toxoplasma encephalitis, but it
is not the preferred regimen. In addition, leucovorin must be taken with
pyrimethamine to prevent leukopenia, making this regimen even more complex.
•
Consider the fact that this patient is not using reliable birth control, and the use of
dapsone plus pyrimethamine is not recommended for pregnant women.
Trimethoprim-sulfamethoxazole is the recommended drug for prophylaxis of
Pneumocystis pneumonia and Toxoplasma encephalitis for pregnant women.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 93
Case 2 – Answers (cont.)
■ Bactrim is the drug of choice for PCP and
Toxoplasmosis prophylaxis
■ Patients with a history of allergy to bactrim or other
sulfa drugs can undergo desensitization
■ Unless the reaction was severe
Unit 8: Opportunistic Infections
•
93
The simplest and most effective prophylaxis for both Pneumocystis pneumonia
and Toxoplasma encephalitis is trimethoprim-sulfamethoxazole. Many HIVinfected patients with a history of allergy to “sulfa” drugs can undergo
trimethoprim-sulfamethoxazole desensitization.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 94
Case 3
■ SO is a 50 year old male who is being discharged from
the hospital after having completed treatment for PCP.
■ CD4: 32, VL: 500,000
■ His physician decides SO is ready for HAART therapy.
He is given prescriptions for lamivudine, stavudine and
efavirenz. The physician then asks you to recommend
an appropriate therapy for PCP prophylaxis for SO.
Based on the guidelines, the best option for SO would
be:
Unit 8: Opportunistic Infections
Reference Manual for Trainers
94
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 95
Case 3 - Best choice for PCP
Prophylaxis
A. Aerosolized pentamidine 300mg q month
B. Atovaquone 750 mg po qd
C. Bactrim DS or SS qd
D. Dapsone 100mg po qd
E. Bactrim DS once weekly
Unit 8: Opportunistic Infections
Reference Manual for Trainers
95
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 96
Case 3 - Answer
■ C is the best choice
■ Bactrim is always drug of choice
■ Protection against Toxoplasmosis
■ If unable to tolerate 1 DS tablet daily, lower dose of SS may
be used
■ If unable to take bactrim daily, may consider three times
weekly
■ Other options not likely in Ethiopia
Unit 8: Opportunistic Infections
96
•
Since the patients CD4 count is < 100, you must consider coverage for both PCP
and toxoplasmosis.
•
Bactrim is most likely the only option in Ethiopia:Bactrim is the drug of choice for
treatment and prophylaxis of PCP
•
Bactrim confers protection against toxoplasmosis at dose of 1 DS daily, as well as
some common respiratory bacterial pathogens …
•
1 ss or 1 DS tab three times weekly may provide protection against toxoplasmosis
as well
•
Pentamidine : bactrim is cheaper and very effective, pentamidine does not cover
toxoplasmosis primary prevention
•
Atovaquone dose incorrect and very expensive, does not cover toxoplasmosis
•
Dapsone alone does not cover toxoplasmosis
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 97
Case 4
■ A 37-year-old male is newly diagnosed with both HIV infection
and pulmonary tuberculosis.
■ His laboratory studies show a CD4 count of 6 cells/mm3 and an
HIV RNA greater than 500,000 copies/ml.
■ He is started on four-drug therapy for tuberculosis that consists
of isoniazid, ethambutol, rifampin, and pyrazinamide.
■ The plan is to start antiretroviral therapy after one month of antituberculosis therapy.
■ The antiretroviral therapy regimens that is suggested:
zidovudine plus lamivudine plus lopinavir/ritonavir
Unit 8: Opportunistic Infections
Reference Manual for Trainers
97
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 98
Case 4 - Question
■ Which of the following is true regarding a potential
drug-drug interaction?
A) Isoniazid can decrease lopinavir/r levels
B) Rifampin can significantly lower zidovudine levels
C) Rifampin can significantly lower lopinavir/r levels
D) Ethambutol will lower lopinavir/r levels by at least 50%.
Unit 8: Opportunistic Infections
Reference Manual for Trainers
98
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 99
Case 4 - Answers
■ A is false: Isoniazid does not have a significant
interaction with any of the antiretroviral medications.
■ B is false: Rifampin does not have a significant
interaction with zidovudine
■ D is false: An interaction between ethambutol and
lopinavir/r is not expected.
Unit 8: Opportunistic Infections
99
•
A is false: Isoniazid does not have a significant interaction with any of the
antiretroviral medications.
•
B is false: Rifampin does not have a significant interaction with zidovudine
•
D is false: An interaction between ethambutol and lopinavir/r is not expected.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 100
Case 4 – Answers (cont.)
■ C is correct
■ Rifampin induces CYP3A4 and significantly reduces ritonavir
levels, which in turn lower lopinavir levels (75% lower)
■ Necessary to increase lopinavir/r dose in combination with rifampin
400/400 mg bid or 800/200 mg bid
■ Rifabutin is preferred in combination with lopinavir/r
■ Less impact on CYP3A4 enzymes
■ Requires dose adjustments
■ RIfabutin 150 mg QOD or three times a week
■ Lopinaivr/r dose standard 400/100 mg bid
Unit 8: Opportunistic Infections
100
•
Rifampin is a strong inducer of hepatic cytochrome P-450 isoenzymes, particularly
CYP 3A4, and it will significantly lower ritonavir levels. Lowering ritonavir levels will
then lower lopinavir levels. Overall, the estimated impact is a 75% decrease in
area under the curve (AUC) concentration for lopinavir.
•
Compared with rifampin, rifabutin has significantly less impact on the CYP 3A4
enzymes in the liver. Thus, rifabutin is generally preferred over rifampin when
combining anti-tuberculosis therapy with antiretroviral therapy.
•
Rifabutin has no effect on lopinavir/r levels therefore the dose is standard.
•
Lopinavir, however increases the levels of rifabutin and therefore the dose of
rifabutin must be decreased to 150 mg every other day or three times a week
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 101
Key Points
■ Opportunistic infections are those that develop as a result of HIVinflicted damage to the immune system.
■ As immunosuppression progresses, the overall incidence of OIs
increases.
■ The most common OIs encountered in Ethiopia include
oropharyngeal candida, TB, CNS manifestations, sepsis, herpes
zoster, and pneumonia.
■ OIs may be bacterial, viral, fungal or protozoal, or non infectious.
■ The origin of OIs , severity of disease, drug-drug interactions,
and drug toxicities impact choice of therapy.
Unit 8: Opportunistic Infections
101
•
Summarize these key points.
•
Ask for further questions about content in Unit 8.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: Prophylaxis & Treatment of OIs
Slide 102
References
■ Behrens, C. MD, Harborview Medical Center, Seattle, WA, USA, 2004.Ethiopia
Guidelines on the Use of ART in Co-infected Patients.Faris, J. PharmD, MBA, Clinical
Pharmacist, HIV/AIDS, Harborview Medical Center, Seattle, WA, USA, 2004.
■ HIV Web Study 2004 http://depts.washington.edu/hivaids/index.html
■ Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical Center, Seattle,
WA, USA, 2004.
■ XIV International AIDS Conference - US Data.
■ Jones, T. Madison Clinic HIV Treatment Guidelines, Harborview Medical Center,
Seattle, WA, USA, 2004.
■ Loeffelbein, B., PharmD, Harborview Medical Center, Seattle, WA, 2004.
■ Madison Clinic Desensitization Protocols, Harborview Medical Center, Seattle, WA,
USA, 2004.
■ NWAETC, Opportunistic Infections and Other HIV-Related Conditions: An Overview,
2004.
■ Spach, D. MD, Harborview Medical Center, Seattle, WA, USA, 2004.
Unit 8: Opportunistic Infections
Reference Manual for Trainers
102
HIV Care and ART: A Course for Pharmacists
Handout 8.1
Immunization Guidelines in the HIV-Infected Individual
Adapted from USPHS/IDSA Guidelines; MMWR 42 (RR-4);MMWR 47(RR-8);
MMWR 51 (RR-8) www.cdc.org 2/4/2002
General Principles:
1.
2.
3.
4.
HIV-infected persons should not receive live virus or live bacteria vaccines; Household
contacts should not receive live virus vaccines.
Killed or inactivated vaccines do not pose a danger to immunosuppressed patients.
Symptomatic HIV-infected persons have sub-optimal responses to vaccines. In order to
achieve an optimal immune response, it is preferred to administer single-dose vaccinations
early in the course of HIV infection.
Transient increases in plasma HIV RNA levels (< 6weeks) have been observed with some
immunizations. It s presumed that HAART can prevent such viral load increases.
Immunization Recommendations:
Vaccination
Dose/Frequency
Pneumococcal vaccine
®
(Pneumovax )
Influenza vaccine
Hepatitis B
®
®
(Energix B or Recombivax )
Haemophilus influenzae typeB (Hib) Vaccine
Tetanus-diptheria (Td) vaccine
Measles, mumps, rubella
(MMR) vaccine
BCG
0.5 ml IM deltoid once
(revaccinate in 5 years)
0.5 ml IM deltoid
(revaccinate annually)
3 IM doses at 0, 1, and 6 months
0.5 ml IM deltoid once
0.5 ml IM once
(booster dose every 10 years)
0.5 mL SC at 0& 1 months
Not available (not used)
Oral Polio Vaccine
Inctivated polio vaccine (IPV)
®)
(IPOL
®
Hepatitis A (Havrix )
0.5 ml SC once
•
•
1.0 ml IM deltoid once
(2 weeks prior to travel)
1.0 ml IM deltoid at 0 & 6
months (long term protection)
Varicella-zoster vaccine
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Recommendation
Highly Recommended as Standard of Care
Recommended
Use if Indicated in susceptible patients:
antihepatitis B core Ag neg
(IVDU’s, MSM, sexually active heterosexuals)
Not Recommended
Recommended
Recommended/considered if indicated
(Unless severely immunocompromised)
(primarily with travel)
*Seronegative household contacts of HIV-infected
patients should receive
Contraindicated
(live bacteria vaccine)
Contraindicated in patients & household contacts
(live virus vaccine)
Use if Indicated
(primarily with travel)
Use if indicated, if susceptible: antihepatitis A
virus- neg
(Hemophiliacs, MSM, illegal drug users, or
patients with chronic liver disease (Hep B or C)
Also: community outbreak, travel
Contraindicated
(live virus vaccine)
*Seronegative household contacts of HIV-infected
patients should receive
Prophylaxis & Treatment of OIs
Unit 8-7
Handout 8.2
General Principles & Treatment Recommendations for Candidiasis:
♦
♦
♦
♦
♦
♦
♦
For oral candidiasis, initiate with topical therapy and reserve systemic therapy for
treatment failures or non-compliant patients.
Clinical responses with resolution of symptoms occur in 90-100% of patients within 7 days
of treatment. However, this usually doesn’t correlate with mycologic response since
Candida can still be cultured from the oral cavity in many patients.
FLuconazole is superior to nystatin for the treatment of OPC. Relapse rates are higher
with nystatin.
Patients with refractory oropharyngeal disease require systemic therapy (usually
fluconazole).
Vulvo-vaginal candidiasis can be managed episodically: topical therapy or single-dose
fluconazole.
Treatment of esophageal candidiasis requires systemic therapy (usually fluconazole).
Episodic therapy is generally preferred, but some patients with recurrent candidiasis may
require chronic suppressive therapy.
Candida Infection
Oropharyngeal Episodic
Drug/Formulation
Nystatin oral susp.
Fluconazole tablet
Itraconazole capsule
Itraconazole oral susp.
Dose/Frequency
500,000 units 5 times a day
100 mg every day
200mg daily with food
100-200mg daily without food
Nystatin oral susp.
Fluconazole tablet
Itraconazole capsule
Itraconazole oral susp.
Ketoconazole tablet
500,000 units 5 times a day
100mg daily or 200mg 3 times per week
200mg daily with food
100-200mg daily without food
200mg daily with food
(Treat for 2-3 weeks)
Fluconazole tablet
Itraconazole capsule
Itraconazole oral susp.
Amphotericin B parenteral
200-400mg daily
200mg daily with food
100-200mg daily without food
0.3-0.6 mg/kg/day
Esophageal Maintenance
♦ May consider dc with
immune reconstitution
Fluconazole tablet
Itraconazole capsule
Itraconazole oral susp.
100-200mg daily
200mg daily with food
100-200mg daily without food
Fluconazole-resistant
(Refractory)
♦ Maximize HAART
Fluconazole tablet
Itraconazole oral susp.
400-800mg daily
100-200mg daily without food
Amphotericin B. parenteral
0.3-0.5 mg/kg IV daily for 7-10 days
Miconazole cream
Clotrimazole cream or
vaginal tablet
5 g of 2% cream
5 g 1% cream qhs or 100 mg vag tab qd X7-14
days, 100 mg vag tab bid X 3 nights , 500 mg tab
x1
150 mg single dose
(Treat for 7-14 days, until
symptoms resolve)
Oropharyngeal Maintenance
(for recurrent infections)
♦ May consider
discontinuation (dc)
with immune
reconstitution
Esophageal (Episodic)
Vaginitis
♦ single dose or 3-7
days
Fluconazole tablet
Ketoconazole tablet
HIV Care and ART for Pharmacists
Reference Manual for Trainers
200 mg daily to twice daily X 5-7 days or 200 mg
bid X 3d with food
Prophylaxis & Treatment of OIs
Unit 8-8
Handout 8.3
Primary Prevention of Opportunistic Infections*
Condition
Indication
Pneumocystis
carinii
CD4 <200, or
oropharyngeal candidiasis
Mycobacterium
tuberculosis
PPD reaction >= 5mm OR Prior
PPD + without TX
OR Contact with case of active TB
Toxo IgG (-)
Toxoplasma
gondii
Mycobacterium
Avium complex
Toxo IgG + and
CD4 <100
CD4 <50
Recommendation
First choice: Bactrim 1 DS or SS po q.d.
Alternatives:
Bactrim 1 tab three times weekly
Dapsone 100 mg po q.d.
Aerosolized pentamidine 300 mg q. mo.
Atovaquone 1500 mg po q.d.
INH-sensitive TB:
INH 300mg/d po +pyridoxine 50mg/d x 9mo.
Counsel on prevention, repeat at CD4 <100
First choice: TMP-SMX 1 DS or SS po q.d.
Alternative:
Dapsone 50 g po q.d +
Pyrimethamine 50 mg po q.wk +
Leucovorin 25 mg po q.wk
Azithromycin 1200 mg po q wk OR
Clarithromycin 500 mg po bid
*Consider discontinuing prophylaxis for MAC, PCP and TOXO when CD4 is above
cut-off for >3-6 m.
Reference for Madison Clinic HIV treatment Guidelines, Harborview Medical Center,
University of Washington, Seattle, WA
(prepared by Trudy Jones, ARNP).
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Prophylaxis & Treatment of OIs
Unit 8-9
Handout 8.4
Treatment Regimens for Acute Toxoplasmosis Encephalitis
Drug
Dose
Comments
Pyrimethamine +
Sulfadiazine +
Leucovorin
Pyrimethamine +
Clindamycin +
Leucovorin
Pyrimethamine +
sulfadoxine +
Leucovorin
Pyrimethamine 100-200mg as loading dose, followed
by 50-100mg daily (+)
Sulfadiazine 1-1.5 gram every 6 hours (+)
Leucovorin 10mg every day
Pyrimethamine + leucovorin (as listed above) +
Clindamycin 300-600 mg po q6h (600-1200mg IV
q6h)
Continue treatment for at least six weeks, but
ideally it should be continued until three weeks
after complete resolution of lesions via radiologic
scan. Generally, clinical improvement should be
noticed within one week of starting therapy and
radiologic improvement (CT scan or MRI) within
two weeks. After resolution, switch to
suppressive therapy.
Side Effects/Precautions:
Bone marrow suppression/skin rash with
pyrimethamine, sulfadiazine.
Diarrhea with clindamycin
Pyrimethamine + leucovorin (as listed above) +
Sulfadoxine (refer to Ethiopia dosing guidelines for
sulfadoxine)
Suppressive Therapy (Maintenance Therapy) for Toxoplasmosis
Drug
Dose
Pyrimethamine +
Sulfadiazine +
Leucovorin
Pyrimethamine +
Clindamycin +
Leucovorin
Atovaquone +/Pyrimethamine+
Leucovorin
Pyrimethamine +
sulfadoxine +
Leucovorin
Pyrimethamine 25-50mg every day (+)
Sulfadiazine 0.5-1.0 gm every 6 hours (+)
Leucovorin 10-25 mg every day (preferred)
Pyrimethamine + leucovorin (as listed above) +
Clindamycin 300-450mg p.o. every 6 to 8 hours
Atovaquone 750 mg q6-12 hours (+/-) pyrimethamine 25 mg qd (+) leucovorin 10 mg qd
Pyrimethamine + leucovorin (as listed above) +
Sulfadoxine (refer to Ethiopia dosing guidelines for sulfadoxine)
Toxoplasmosis Prophylaxis
Indications:
1. Positive toxoplasmosis IgG serology (+)
3
2. CD4 count less than 100 cells/mm
Preferred Regimens:
♦
TMP/SMX DS one tablet po qd
Alternative Regimens:
♦
TMP/SMX SS one tablet po qd
♦
Dapsone 50mg daily + pyrimethamine 50mg weekly + leucovorin 25mg weekly
♦
Dapsone 200mg weekly + pyrimethamine 75mg weekly + leucovorin 25mg weekly
♦
Atovaquone suspension 1500 mg once daily with or without pyrimethamine 25 mg po qd + leucovorin 10 mg po qd
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Prophylaxis & Treatment of OIs
Unit 8-10
Handout 8.5
General Principles/Treatment Recommendations for MAC
♦ Treatment consists of a minimum of two drugs.
♦ Treatment of Choice: Macrolide + Ethambutol +/- Rifabutin
♦ Full treatment doses of drugs should be continued for life, unless HAART
associated immune reconstitution occurs.
♦ Clarithromycin doses of > 1000mg/day have been associated with increased
mortality.
♦ Consider drug interactions when using clarithromycin or rifamycins*.
♦ Clofazamine has been associated with adverse clinical outcomes and should not
be used.
Drug
Dose
Macrolides
Clarithromycin
500mg twice daily
Azithromycin
500-600mg daily
Ethambutol
15mg/kg daily
Side Effects/Special Considerations
diarrhea, nausea, vomiting, abdominal
pain, headache, dizziness, elevated LFT’s
Clarithromycin has significant drug
interactions including efavirenz and
atazanavir
optic neuritits, anorexia, nausea, vomiting,
diarrhea, rash
*
Rifamycins*
Rifabutin
300 mg daily
Rifampin
10mg/kg daily (max 600 mg)
Adjust doses for drug interactions
anorexia, nausea, vomiting, diarrhea, rash,
myalgias
leukopenia, thrombocytopenia, rash,
nausea, uveitis
orange-brown discoloration of secretions,
(both)
Fluoroquinolones
Ciprofloxacin
500-750mg twice daily
anorexia, nausea, vomiting, abdominal
pain, diarrhea, rash, joint pain, headache,
anxiety
Aminoglycosides
Amikacin
10-15 mg/kg daily
Nephrotoxicity, ototoxicity
MAC Prophylaxis
Indications:
1. CD4 count nadir less than 50 cells/mm3
Preferred Regimens:
♦ Azithromycin 1200mg given once weekly
♦ Clarithromycin 500mg twice daily
Alternative Regimens:
♦ Rifabutin 300mg daily (less effective and has significant drug interactions)
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Prophylaxis & Treatment of OIs
Unit 8-11
Handout 8.6
Treatment for Cytomegalovirus Retinitis
Drug
Ganciclovir
Induction Therapy
Maintenance
Therapy
5mg/kg IV Q12H for 14-21
days
Side Effects & Special
Considerations
neutropenia, thrombocytopenia
5 mg/kg IV daily
anemia, leukopenia
®
Intraocular device (Vitrasert ) every 6 months (+)
Valganciclovir 900mg BID
Foscarnet
60mg/kg IV Q8H or
90-120mg/kg IV daily
90mg/kg IV Q12H for 14-21
days
nephrotoxicity, serum electrolytes
changes (↓Ca, ↓ phosphate, ↓
Mg,
↓ K), seizures, marrow
suppression
Cidofovir
Valganciclovi
r
5mg/kg IV once weekly for 2
weeks with probenecid and
hydration with NS
5mg/kg IV every other
week)
with probenecid and
hydration with NS
Very specific hydration guidelines
& coadministration with
probenecid
900 mg PO BID for 21 days
900 mg PO daily
neutropenia, thrombocytopenia
nephrotoxicity, neutropenia
anemia, leukopenia
*Intraocular injections of ganciclovir, foscarnet and cidofovir have also been used
Cytomegalovirus Retinitis Prophylaxis -- not generally
recommended
Indications: Positive CMV serology (+)CD4 cell count < 50/mm3
Regimen:
♦ Ganciclovir
1 gm po three times a day with meals
♦ Valganciclovir
role not defined
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Prophylaxis & Treatment of OIs
Unit 8-12
Slide 8.7
Natural History of HIV Infection in Average Patient Without
HAART from time of transmission to death at 10-11 years
Slide 8.35
Opportunistic Infections
HIV Care and ART for Pharmacists
Reference Manual for Trainers
36
Prophylaxis & Treatment of OIs
Unit 8-13
References
Behrens, C. MD, Harborview Medical Center, Seattle, WA, USA, 2004.
Ethiopia Guidelines on the Use of ART in Co-infected Patients.
Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS, Harborview
Medical Center, Seattle, WA, USA, 2004.
HIV Web Study 2004 http://depts.washington.edu/hivaids/index.html
Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
XIV International AIDS Conference - US Data.
Jones, T. Madison Clinic HIV Treatment Guidelines, Harborview Medical
Center, Seattle, WA, USA, 2004.
Loeffelbein, B., PharmD, Harborview Medical Center, Seattle, WA, 2004.
Madison Clinic Desensitization Protocols, Harborview Medical Center,
Seattle, WA, USA, 2004.
NWAETC, Opportunistic Infections and Other HIV-Related Conditions: An
Overview, 2004.
Spach, D. MD, Harborview Medical Center, Seattle, WA, USA, 2004.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Prophylaxis & Treatment of OIs
Unit 8-14
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Prophylaxis & Treatment of OIs
Unit 8-15
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 9
TB and HIV Co-infection
Unit 9: TB and HIV Co-infection
Aim: The aim of this unit is to provide information to participants about the
management of TB and HIV co-infected patients.
Learning Objectives: By the end of this unit, participants will be able to:
•
Describe the relative frequencies of tuberculosis and various clinical
presentations
•
Explain the screening, diagnosis and treatment of TB
•
Differentiate treatment of latent vs active TB
•
Manage potential drug-drug interactions between anti-tubercular and ARV
therapy
•
Cite the overlapping toxicities of ART and anti-tuberculin drugs
Unit Overview:
2 Hours 30 minutes
Step
Time
Activity/
Method
Resources
Needed
Content
1
10 minutes
Question-Answer
Introductory Case Study and
Question Slides (9.2-9.4)
Overhead or LCD
Projector
2
45 minutes
Lecture
TB and HIV Co-infection (Slides 9.5 9.43)
Overhead or LCD
Projector
3
85 minutes
Group Exercise
Case Studies (Slide 9.44-9.66)
Worksheets 9.1, 9.2,
9.3 in workbook. Five
flip chart stands with
paper and markers.
4
10 minutes
Summary
Review of Key Points (Slides 9.67 9.68)
Overhead or LCD
Projector
HIV Care and ART for Pharmacists
Reference Manual for Trainers
TB and HIV Co-infection
Unit 9-3
Resources Needed
•
•
•
Flip Chart and Paper
Markers
Overhead or LCD Projector
•
The following can be found in the Participant Handbook::
- Estimated New Adult Cases of TB (Slide 9.10)
•
Worksheets 9.1, 9.2 and 9.3 can be found in the Course Workbook:
Key Points
1. TB is the leading killer of patients with HIV/AIDS in developing countries.
2. TB is the most common opportunistic infection in Ethiopia, and the incidence
of TB due to HIV is expected to increase.
3. The risk of active TB disease is greatly increased among persons with TB/HIV
infections.
4. Among co-infected patients, extrapulmonary TB is present in up to half: this
rate increases as CD4 cell count diminishes.
5. The treatment of active TB is a priority in co-infected patients.
6. Starting ART and TB therapy together is not always the optimal choice.
7. Patients with TB merit special consideration because co management of HIV
and TB is complicated by drug interactions, pill burden, adherence, Immune
Reconstitution Syndrome, resistance, and drug toxicity.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
TB and HIV Co-infection
Unit 9-4
Step 1
Step 2
Step 3
Step 4
Introductory Case Study (10 minutes)
•
Ask a participant to read the case study on Slides 9.2 to 9.3.
•
Ask participants to silently attempt to answer the question on
Slide 9.4.
•
Explain that the question will be answered and the case
discussed more fully as the unit progresses.
Lecture (45 minutes)
•
This unit will introduce participants to the management of TB and
HIV co-infected patients.
•
Begin by reviewing Slide 9.5 of the PowerPoint presentation, “TB
and HIV Co-infection.” Ask the participants if they have any
questions about the objectives before continuing.
•
Present and discuss the PowerPoint presentation, “TB and HIV
Co-infection” (Slides 9.6-9.43).
Group Exercise (85 minutes)
•
Case Study Group Exercise: Divide participants into five work
groups. Provide each work group with one of the five Adult ART
Case Studies (Worksheets 9.1, 9.2, 9.3, 9.4 in the workbook.)
Ask the groups to identify a recorder and a presenter, and then
spend twenty minutes discussing the case study together and
answering the related questions on flip-chart paper.
•
Ask each work group to share their decisions and answers.
Discuss each case thoroughly and use this time to answer
questions and clarify misinformation. Review the case studies in
the “TB and HIV Co-infection” PowerPoint presentation. Spend
15 minutes discussing each case.
Summary (10 minutes)
•
Summarize the presentation, review the Key Points presented in
this Unit (Slides 9.68), and answer final questions.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
TB and HIV Co-infection
Unit 9-5
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes
for reference during the planning and implementation of this course. The
facilitation notes and talking points are included in the “notes” section of the
accompanying PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
TB and HIV Co-infection
Unit 9-6
Unit 9: TB and HIV Co-infection
Slide 1
TB and HIV
Co-Infection
Unit 9
HIV Care and ART: A Course for Pharmacists
This unit should take approximately 2 hours, 30 minutes to complete.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 2
Introductory Case
■ PF is a HIV + 33 y.o. female who comes in with her
boyfriend for follow-up and medication management.
She and her boyfriend have just been treated for
Chlamydia/ gonorrhea. Today, she has just been
diagnosed with pulmonary TB and is beginning therapy.
■ Her CD4 cell count from 3 months ago is 180.
■ Her current medications include: Bactrim DS daily for
PCP prophylaxis, Nevirapine 200 mg bid, Zidovudine
300 mg bid and Lamivudine 150 mg bid
Session 9: TB & HIV Co-infection
2
•
Ask a participant to read the case.
•
Ask participants if they have any questions about the information presented.
•
Note: Do not give them further information on the case. Just ask them to
consider the information provided to them.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 3
Introductory Case (cont.)
■ PF comes to the pharmacy with the following new
prescriptions for pulmonary TB:
■ Ethambutol 1 gm qd
■ Isoniazid 300 mg qd
■ Pyridoxine 40 mg qd
■ PZA 1750 mg qd
■ Rifampin 600 mg qd
Session 9: TB & HIV Co-infection
•
3
Facilitator: ART = HAART. ART is the familiar term and therefore was used
in the presentations.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 4
Introductory Case Questions
Which of the following statements are true regarding the
drug interaction between this patient’s ART and TB regimens?
A. Rifampin lowers nevirapine levels, therefore the patient should
be monitored for treatment failure.
B. Ethambutol lowers nevirapine levels, therefore the patient
should be monitored for treatment failure.
C. Rifampin lowers nevirapine levels and should not be used in
combination.
D. Nevirapine reduces rifampin levels and should not be used in
combination.
Session 9: TB & HIV Co-infection
4
•
Ask participants to silently attempt to answer the question.
•
Explain that the answer to the question will be discussed as the unit
progresses.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 5
Unit Learning Objectives
■ Describe the relative frequencies of tuberculosis and
various clinical presentations.
■ Understand the screening, diagnosis and treatment of
TB
■ Differentiate treatment of latent vs active TB
■ Anticipate and manage potential drug-drug interactions
between anti-tuberculosis and ART therapy
■ Cite the overlapping toxicities of ART and antituberculosis drugs
Session 9: TB & HIV Co-infection
•
•
5
Review the learning objectives for the unit:
•
Describe the relative frequencies of Tuberculosis and various clinical
presentations.
•
Understand the screening, diagnosis and treatment of TB
•
Differentiate treatment of latent vs active TB
•
Anticipate and manage potential drug-drug interactions between antitubercular and ARV therapy
•
Cite the overlapping toxicities of ART and anti-tuberculin drugs
Ask participants if there are other objectives related to TB and HIV Coinfection they would like to learn about in this unit.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 6
Epidemiology
■ The majority of people living with HIV/AIDS live in countries
where prevalence of TB is high
■ TB is the earliest manifestation in HIV/AIDS in more than half of
the cases in developing countries
■ TB is the leading killer of patients with HIV/AIDS in developing
countries accounting for one-third of all AIDS deaths
Session 9: TB & HIV Co-infection
6
•
The majority of people living with HIV/AIDS live in countries where
prevalence of TB is high
•
TB is the earliest manifestation in HIV/AIDS in more than half of the cases in
developing countries
•
TB is the leading killer of patients with HIV/AIDS in developing countries
accounting for one-third of all AIDS deaths
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 7
Epidemiology (cont.)
■ TB is the most common OI in HIV worldwide
■ 8-9 million cases in 2000, 11% with HIV
■ TB is the most common opportunistic infection in
Ethiopia
■ 42% of adult (15-49) TB cases were HIV–positive in
2000,
■ 50% co-infected in 2004
■ Ethiopia has the sixth-highest number of TB cases in
the world
Sources: WHO, UCSF Report HIV/AIDS in Ethiopia April
2003 CDC MMWR 2003:52:217
Session 9: TB & HIV Co-infection
7
•
TB is the most common OI in HIV worldwide
•
There were 8-9 millions cases in 2000, 11% of those cases were individuals
with HIV
•
TB is the most common opportunistic infection in Ethiopia
•
42 percent of adult (ages 15-49) TB cases were HIV –positive in 2000
•
And that number has increased to 50% in 2004
•
According to WHO, Ethiopia has the sixth-highest number of TB cases in the
world, in the Africa region, it is second only to Nigeria.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 8
1,2 million people have both infections
HIV
Infection
2.2
million
TB
Infection
35 million
The Dual Epidemic in Ethiopia
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
WHO est imat es, 1 997–200
0
8
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 9
Epidemiology (cont.)
■ The risk of TB disease is greatly increased among persons with
TB/HIV infections
■ 10% lifetime risk of active TB among non-immune suppressed individuals
■ 10% risk per year of active TB among HIV+ individuals
■ HIV infected individuals at increased risk of active disease when
newly infected with TB
■ Co-infected patients with active TB often have very high viral
loads and immunosuppression progresses more quickly
■ Impact on survival
Session 9: TB & HIV Co-infection
9
•
The risk of active TB disease is greatly increased among persons with
TB/HIV infections for two reasons
•
1) An HIV infected individual with latent TB is at much higher risk of
reactivation TB.
•
•
10% lifetime risk of active TB among non-immune suppressed
individuals, but there is a 10% risk per year of active TB among HIV+
individuals
2) HIV infected individuals are at an increased risk of active disease when
they are newly infected with TB
•
TB outbreaks in co-infected pts range from 9 to 37 %, in
immunocompetent individuals, the rates are < 2%.
(HIV Manual A Guide to Diagnosis and Treatment D Spach and T Hooton 1998)
•
Active TB is a very potent stimulus to the immune system via cytokine
production. Immune system activation increases the rate of growth of HIV,
leading to high viral loads. In addition, immunosuppression progresses more
quickly and survival may be shorter, among patients with HIV, despite
successful treatment of TB.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 10
Estimated New Adult Cases of TB
300
Thousands
250
200
150
100
50
0
1984
1989
1994
1999
Not Due to HIV
2004
2009
2014
Due to HIV
Source: Dr. Asegid Woldu, Ethiopian Ministry of Health
Session 9: TB & HIV Co-infection
10
•
This graph was taken from the Ministry of Health on the Current HIV/AIDS
Status in Ethiopia
•
The horizontal plane of the graph represents time and the vertical plane
represents estimated thousands newly infected with TB. Back in the mid-80s
not many TB cases were not identified as being due to HIV, over time, the
number of new adult cases of TB has reached nearly 200,000 in 2004, with
half attributed to HIV infection. The numbers are estimated to continue to
increase over the next 10 years.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 11
Clinical Features
■ CD4 < 200 cells/mm3
■ Cough, fever, weight loss
■ Chest radiograph atypical
■ Lower lobe or other atypical
infiltrates
■ Cavitation uncommon
■ Sputum smears often
negative
■ CD4 > 200 cells/mm3
■ Cough, fever, weight loss
■ Chest radiograph typical
■ Upper lobe infiltrates
■ Pulmonary cavities
■ Sputum smears often positive
Session 9: TB & HIV Co-infection
11
•
Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis.
•
The clinical presentation of co-infected patients is correlated with the degree
of immunosupression. Individuals that are healthier, with a CD4 count > 200
tend to present with symptoms and chest radiograph features classic for
reactivation TB. These symptoms and chest radiograph findings include
cough, fever, weight loss, upper lobe infiltrates and pulmonary cavities. Their
expectorated sputum smears are often positive.
•
As the CD4 cell declines, atypical presentations become more common.
Patients with a low CD4 count are more likely to present with hilar
adenopathy:
•
•
Hilar - pit or depression on an organ, giving exit and entrance to
nerves and vessels)
•
Adenopathy, which is enlargement of the glands, esp lymph nodes
(sometimes without the presence of parenchymal (functional tissue)
•
Infiltrates,diffuse pulmonary infiltrates, and
•
Pleural effusions (fluid into the membrane around the lungs). Some
patients have presented with cough and fever, but have a normal
chest radiograph.
(Pulmonary TB is Clinical Stage III in WHO Staging System)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 12
Clinical Features (cont.)
■ Among co-infected patients, extrapulmonary TB is
present in up to half: this rate increases as CD4 cell
count diminishes
■ Common extrapulmonary sites include:
■ Blood, lymph nodes, CNS, genitourinary tract and pleura
Session 9: TB & HIV Co-infection
12
•
Among co-infected patients, extrapulmonary TB is present in up to half: this
rate increases as CD4 cell count diminishes
•
Common extrapulmonary sites include:
•
Blood, lymph nodes, CNS, genitourinary tract and pleura
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 13
Diagnosis: Latent TB
■ All patients should be screened when presenting for
ART therapy
■ Tuberculin Skin Test (PPD or TST) in patients newly diagnosed
with HIV, then yearly due to high prevalence in Africa
■ Three sputum smears for AFB if they fulfill the criteria of “TB
Suspect” of National TB Control program
■ Cough > 3 weeks
■ Other constitutional symptoms
■ Chest X-Ray suggestive of pulmonary TB
Session 9: TB & HIV Co-infection
13
•
PPD Testing: The PPD Tuberculin skin test is a useful test for latent TB in
the HIV infected population, even though the prevalence of anergy increases
as HIV progresses. The PPD is used to test for latent TB infection, not active
disease.
•
Because HIV-infected patients with latent TB have an increased risk of
developing reactivation, all HIV infected patients should have a PPD testing
performed, and if negative, repeated on a yearly basis.
•
HIV infected patients with either a known TB exposure of a history of an
untreated positive PPD test in the past should be assumed to be TB infected
regardless of their current PPD results. Latent TB is not treated. PPD is not
regularly administered. There is no prophylactic program. It is currently being
piloted.
•
Technique for PPD testing: administration of 5 tuberculin units of PPD
tuverculin intradermally. Areas of induration, not erythema, should be
measured 48 to 72 hours after administering PPD. A tuberculin reaction 5
mm of larger is considered positive in HIV infected individuals.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 14
Diagnosis: Active TB
■ Chest radiograph
■ Positive culture for M. tuberculosis from
■ Sputum
■ Bronchoscopy
■ Blood
■ Drug susceptibility testing
■ Reporting
Session 9: TB & HIV Co-infection
14
•
Atypical patterns of chest radiograph are observed with increasing frequency as
CD4 count declines.
•
The standard test for pulmonary TB is AM expectorated sputa X 3 days for smear
and culture. Induced sputum and bronchoscopy are used when there is no sputum
production. Sensitivity of sputum acid fast smears is about 50% is similar for
patients with and without AIDS, and is not better with induced sputum or
bronchoscopy specimens compared with expectorated sputum.
•
Specificity of the smear depends on the prevalence of MAC, but most positive AFB
smears of respiratory specimens in patients with AIDS indicate TB even in areas
where MAC is common.
•
Among sputum smear-negative individuals with active pulmonary TB, smears on
BAL will be positive in 25%, suggesting that bronchoscopy may be moderately
useful for diagnosing pulmonary TB in the occasional pt where rapid diagnosis is
important. A positive smear on bronchoscopy secretions, however, is not specific for
TB and may represent MAC or other non-tubercular mycobacteria.
•
Positive cultures for M tuberculosis approach 100% for sensitivity and 97% for
specificity.
•
However, Blood cultures are positive in about 40% of patients compared to < 5 % in
non-HIV infected pts.
•
Because of the emergence of MDR TB, drug susceptibility testing should be carried
out on the first isolate from all cases and on all isolates associated with treatment
failure or relapse
•
All cases of TB should be reported to the local health department to assess local
patterns of TB transmission and drug resistance
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 15
Abnormal Chest X-Ray in a Patient
with Pulmonary TB
Session 9: TB & HIV Co-infection
15
•
Abnormal chest x-ray. Arrow points to cavity
in patient's right upper lobe. Left lobe is normal.
•
Reference CDC 2001 Self-study modules on Tuberculosis
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 16
Antiretroviral Therapy and TB
■ TB treatment is the priority in co-infected patients
■ ART therapy depends on CD4/TLC and level of
■
immune-suppression
■ Improved immune response to TB with ART
■ Reduction in case rates of TB during ART
■ ART could reduce risk of primary infection, relapse and
re-infection
Session 9: TB & HIV Co-infection
16
•
Once a diagnosis has been made, treatment of TB should be the top priority.
The optimal time to start HAART treatment is not known. Case-fatality rates
in many patients with TB during the first two months of TB treatment are
high, particularly when they present with advanced disease, and ART in this
setting may be life-saving.
•
Starting HAART after the initiation phase of TB therapy is dependant upon
CD4 count/ TLC count (<200) and level of immunesuppression if between
200-350.
•
The era of HAART has proven to provide an improved immune response to
TB with HAART, and a reduction in case rates of TB during HAART.
•
HAART could reduce risk of primary infection, relapse and re-infection
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 17
Antiretroviral Therapy and
TB (cont.)
■ The treatment of active TB is a priority in co-infected
patients
■ ART is recommended for HIV patients
■ with CD4 <200 cells/mm3 OR TLC < 1,200/mm3 OR
■ Extrapulmonary disease (WHO)
■ Patients already on ART may also develop TB
■ This may require a change of medication in the ART regimen
or a change in dose of the ART regimen
Session 9: TB & HIV Co-infection
17
•
Tuberculosis is an entry point for a significant proportion of patients eligible
for ART since about 50% are co-infected. The major issues in clinical
management of patients with HIV and active TB are when to start ART and
which regimen to use in order to avoid drug interactions and added risk of
liver toxicity.
•
ART is recommended for all patients with TB who have CD4 counts below
200 and should be considered after the initiation phase of TB therapy for
patients with CD4 counts 200-350 if severely compromised (WHO
guidelines…scaling up resources in resource limited settings 2003). In the
absence of CD4 counts.
•
Timing of ART initiation should be based on clinical judgment in relation to
other signs of immunodeficiency (ie. WHO stage III or IV disease).
•
Patients may present with TB, already on ART. This may require a change of
medication in the ART regimen or a change in dose. ANY time a patient
begins a new medication, all drugs the patient is taking must be considered
to anticipate and manage potential drug-drug interactions
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 18
Immediate vs Delayed Therapy
■ Arguments to withhold ART until TB is treated
■ HIV is a chronic disease
■ Adherence may be compromised
■ Toxicity management is more complex
■ Complex drug interactions
■ Immune reconstitution syndrome
■ Acceptance of both diseases
Session 9: TB & HIV Co-infection
•
18
There are many reasons why starting ART and TB therapy together may not
be the optimal choice. Arguments for delaying antiretroviral therapy in a
patient with co-infection include:
1) HIV is a chronic disease and ART is never an emergency.
2) Adherence to TB and ART therapy is extremely difficult as the pill
burden is overwhelming for most patients. This may result in the
development of resistance to either the TB medication or the ARV
therapy.
3) Toxicities of ART and TB therapy overlap and can cause significant
distress in a patient who is already sick. It may be difficult to determine
which medication is causing the adverse effect which increases the
complexity of managing the event.
4) Complex drug-drug interactions
5) Starting antiretroviral therapy in a patient with active TB may cause
immune restoration syndrome, which is a paradoxical reaction, a
transient worsening of clinical signs and symptoms after the initial
response to anti-tuberculosis therapy.
6) It may be difficult for a patient to accept both diseases.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 19
Immune Reconstitution
Syndrome
■ The worsening of signs and symptoms due to known
infections, or the development of disease due to occult
infections, that results from improvement in immune
function after the initiation of anti-retroviral therapy
■ May occur in other OIs
■ MAC, PML, CMV vitritis, mild herpes zoster, cryptococcal
meningitis
Session 9: TB & HIV Co-infection
19
•
In summary, IRS is the worsening of signs and symptoms due to known
infections, or the development of disease due to hidden (occult) infections,
that results from improvement in immune function after the initiation of antiretroviral therapy.
•
Note: IRS may occur with other opportunistic infections (OIs) as well, such as
Mycobacterium avium complex (MAC), cryptococcal meningitis, mild herpes
zoster, PML and CMV vitritis.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 20
Immune Reconstitution Syndrome
(IRS) in TB and HIV Co-infection
■ Can occur with any ARV regimen
■ Mean onset of symptoms: 2 weeks
■ Mean duration of symptoms: 3 weeks
■ Most common symptoms include fever, cervical
lymphadenopathy, intrathoracic lymphadenopathy
■ Disease due to a “sterilizing” immune response
■ Associated with restoration of TB reactivity
Session 9: TB & HIV Co-infection
20
•
Patients with advanced disease, particularly those with CD4 count less than
50 cells, my develop IRS during the first few weeks of therapy. TB symptoms
may transiently worsen as part of immune reconstitution syndrome. IRS can
occur with any ARV regimen
•
The mean onset of symptoms is 2 weeks and the mean duration of
symptoms is 3 weeks.
•
Most common symptoms include fever, cervical lymphadenopathy and
intrathoracic lymphadenopathy. IRS is associated with restoration of
Tuberculosis reactivity.
•
IRS has been reported to occur in up to 30% of TB Cases in the developed
world.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 21
Immune Reconstitution
Syndrome: Management
■ Management
■ Continue anti-tuberculosis and anti-retroviral therapy
■ Symptomatic management:
■ NSAIDS or Acetylsalicylic acid
■ For severe symptoms: steroids (40 to 80 mg/d for 5 to 14
weeks
Source: Furrer, Am J Med, 1999])
Session 9: TB & HIV Co-infection
21
•
IRS is not indicative of treatment failure or drug side effects. It is a transient
phenomenon and is not a reason to stop ARV therapy or to change the
regimen.
•
Management
•
Continue anti-tuberculosis and anti-retroviral therapy
•
Provide symptomatic management: ie. NSAIDS, if unavailable, may
use Acetylsalicylic acid
•
For severe symptoms: steroids
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 22
Immediate vs Delayed Therapy
■ Arguments to initiate ART at the onset of TB:
■ TB is associated with immune activation, increased HIV
replication, and HIV disease progression
■ Potent ART therapy can reduce viral load, improve immune
function and slow HIV disease progression
■ Potent ART therapy reduces risk of developing opportunistic
infections
■ including CMV or cryptosporidiosis for which prophylaxis is neither
routinely used nor available
Session 9: TB & HIV Co-infection
22
•
The time to start ART in co-infected patients may be difficult to determine:
•
Arguments to initiate HAART at the onset of TB include:
•
TB is associated with immune activation, increased HIV replication and HIV
disease progression. Potent antiretroviral therapy can reduce HIV RNA
levels, improve immune function and slow HIV disease progression. HIV
therapy also reduces the risk of developing opportunistic infections such as
CMV or cryptosporidiosis, for which prophylaxis is neither routinely used nor
available
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 23
Immediate vs Delayed
Therapy (cont.)
■ Arguments to initiate HAART at the onset of TB:
■ British observational study of 188 HIV+ TB patients at London
HIV centers 1996-99
■ 8.5% died prior to completing TB therapy
■ Mostly not on HAART
■ Fewer further OIs in TB patients on HAART
■ 4% on HAART developed OIs vs 24% not on HAART
■ 66% of those who developed OIs had CD4 count < 100
Source: Dean G, AIDS 2002;16:75
Session 9: TB & HIV Co-infection
23
•
An observational study done in the UK of 188 HIV+ TB patients supports the
idea of initiating HAART early in TB therapy: they found that 8.5% died prior
to completing TB therapy (Most of these patients were not on HAART)
•
Also, there were fewer further OIs in TB patients on HAART:
•
4% of patients on HAART developed OIs vs 24% not on HAART
•
66% of those patients who developed OIs had CD4 count < 100 (they
were sicker patients)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 24
Treatment of Latent TB
■ Any HIV+ patient with a positive PPD of at least 5 mm
induration
■ Any HIV-infected adult in high prevalence area, recent
exposure to active TB or a history of untreated positive
PPD: except those with
■ Suspicion of active TB
■ Previous INH prophylaxis or treatment
■ Contraindication to INH
■ Isoniazid (INH) 300 mg qd for 9 months + pyridoxine
(B6) 40 mg qd for 9 months
Session 9: TB & HIV Co-infection
24
•
PPD screening is not routinely done in Ethiopia and preventative therapy with
INH is not given. A prophylactic program is currently being piloted.
•
Earlier you learned that an HIV infected individual with latent TB is at much
higher risk of reactivation TB. There is a 10% lifetime risk of active TB among
non-immune suppressed individuals, but there is a 10% risk per year of active
TB among HIV+ individuals, also, HIV infected individuals are at an increased
risk of active disease when they are newly infected with TB.
•
INH preventative therapy to persons with latent TB has been shown to reduce
risk of active TB in patients with HIV. There are no standard guidelines for TB
prophylaxis in the protocol of the National TB Control Program except for
children under certain circumstances. Preventative therapy for TB may be
challenging because of the difficulty in excluding active disease. Treatment of
latent TB should be given to any HIV + patient with a positive PPD of at least 5
mm induration, any HIV-infected adult in high prevalence area AND?/OR (ASK
TESFAI) any with a history of untreated positive PPD except those with
•
•
Suspicion of active TB
•
Previous INH prophylaxis or treatment
•
Contraindication to INH
Treatment for latent TB is INH 5 mg/kg/day (max 300 mg)qd for 6 months +
pyridoxine 25-50 mg (B6) tablet strength in Ethiopia is 40 mg for 6 months to
prevent peripheral neuropathy that could be caused by a depletion of B6 by INH.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 25
Treatment of Pulmonary TB
■ Four drug therapy preferred for active TB (for first 2 months only)
■ INH 300 mg qd (with pyridoxine 40 mg qd) +
■ Ethambutol 15-25 mg/kg (max. 2.5 gm) qd +
■ PZA 25 mg/kg (maximum 2 gm) qd +
■ Rifampin 600 mg qd
■ Followed by maintenance phase for 6-9 months (or 3-6 months
after cultures are consistently negative, whichever is longer)
■ INH + Ethambutol (doses as above)
Session 9: TB & HIV Co-infection
•
25
Four drug therapy preferred for active TB with a 2 month induction phase,
followed by a 4 month maintenance phase at a minimum
•
First 2 months 4 drug therapy below until culture susceptibility results
show that the isolate is not drug resistant
•
INH 300 mg qd ( with pyridoxine) +
•
Rifampin 600 mg qd +
•
PZA 25 mg/kg (maximum 2 gm) qd +
•
Ethambutol 15-25 mg/kg (max. 2.5 gm) qd
•
Response: most patients become afebrile within 7-14 days. Sputum
cultures become negative <2 months in 85%
•
Note: Extrapulmonary TB is treated like pulmonary TB
•
Maintenance phase with isoniazid and ethambutol
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 26
Side Effects of Anti-tubercular
Medications
■ Ethambutol (EMB)
■ Dose related ocular toxicity, GI intolerance
■ Pyrazinamide (PZA)
■ Hepatotoxicity, hyperuricemia
■ Isoniazid (INH)
■ Hepatotoxicity, peripheral neuropathy
■ Rifampin (RIF)
■ Orange-brown discoloration, hepatotoxicity
■ Streptomycin (SM)
■ Ototoxicity, vestibular dysfunction, rash
Session 9: TB & HIV Co-infection
26
•
EMB dose related occular toxicity (decreased acuity, restricted fields, and
loss of color discrimination) with 25 mg/kg dose (0.8%), peripheral
neuropathy rare; GI intolerance.
•
PZA: hepatotoxicity up to 15% who receive > 3 gm/day, transient hepatitis,
jaundice. Monitor LFTs, hyperuricemia is common, gout is rare Nongouty
polyarthralgia in up to 40%. Nausea 1-10%.Rare: rash, urticaria, pruritus,
fever, GI intolerance, thrombocytopenia
•
IHH: hepatitis risk varies by age. Incidence is 0.3% in young health adults,
increases to 2.6% in those who drink alcohol daily, have chronic liver
disease, or are elderly. Incidence is 0.15% when used to latent TB. Incidence
is 1% with multiple TB meds. Stop INH if LFT >5XULN PN: due to increased
excretion of pyridoxine, which is dose related and rare with usual doses; give
with B6 10-50 mg/day. Nausea > 10%
•
RIF: orange-brown discoloration of urine, stool, tears (contact lenses), sweat,
skin
•
Infrequent, GI intolerance, hepatitis, usually cholestatic changes in first
month of treatment (no increase risk with INH), jaundice-reversible with dose
reduction or continued use, hypersensitivity, esp pruritis +/- rash (3%), flu-like
illness with intermittent use. Blood dyscrasias are rare
•
SM: overall 8% ototoxicity, vestibular dysfunction (vertigo), paresthesias,
dizziness and nausea (all less in patients receiving doses 3X/week,
nephrotoxicity (rare), allergic skin rashes (4-5%)
•
Dose adjust for renal failure: EMB, SM, IHH and PZA if < 10 mL/min. RIF no
adjustment necessary
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 27
Monitoring TB Therapy
■ Baseline: ALT/AST, sputum, visual acuity and color
discrimination
■ Clinical Monitoring- monthly
■ Symptoms of hepatitis: nausea, vomiting, dark urine, malaise, fever > 3
days
■ Color discrimination
■ Laboratory
■ ALT with symptoms of hepatitis
■ If ALT/AST > 5XULN, discontinue INH, RIF + PZA and give alternative
■ Repeat sputum smear at 2 and 7 months and culture until negative
■ Chest X-Ray at 2 months and end of therapy
Session 9: TB & HIV Co-infection
27
•
Monitoring of TB therapy
•
Baseline: ALT/AST, visual acuity and red-green color discrimination (EMB)
•
Clinical Monitoring
•
•
•
Monthly. Warn of symptoms of hepatitis, seek medical care if nausea,
vomiting, dark urine, malaise, fever > 3 days. Also, monthly color
discrimination should be performed.
Laboratory
•
ALT with symptoms of hepatitis
•
Repeat sputum smear and culture until negative
•
Chest X-Ray at 2 months and end of therapy
Hepatotoxicity
•
If ALT/AST > 5XULN, discontinue INH, RIF + PZA and give alternative
•
When ALT is normal reintroduce primary drugs one at a time
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 28
DOT (Directly Observed Therapy)
■ DOT is always preferred
■ DOT was introduced in 1995
■ At the end of 2001, about 34% of health facilities were
using DOT
■ About 55% of Ethiopians have access to (within 10 km)
general health services, DOT expansion may be very
difficult
Session 9: TB & HIV Co-infection
28
•
Directly observed therapy is always preferred
•
DOT was introduced in 1995
•
At the end of 2001, about 34% of health facilities were using DOTS
•
About 55% of Ethiopians have access to (within 10 km) general health
services, DOT expansion may be very difficult
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 29
Complexity of Management of
Co-infected Patients
■ Immune reconstitution syndrome
■ Toxicity
■ Drug-interactions
■ High pill burden
■ Adherence
■ Resistance
Session 9: TB & HIV Co-infection
29
•
We have reviewed IRS with ART and potential toxicities of ART and
antituberculosis medications when coadministered.
•
Patients with TB merit special consideration because co management of HIV
and TB is also complicated by drug interactions (rifampin with PI and
NNRTIs), pill burden, adherence and drug toxicity. Data supporting specific
treatment recommendations are incomplete and research is urgently needed
in this area.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 30
Drug Interactions
Between ART and TB Yherapy
■ Clinically significant drug interactions exist
between rifampin and PI/ NNRTI therapy
■ Rifabutin based regimens are preferred to rifampin, if
available
■ No interaction between rifampin and NRTI class
Session 9: TB & HIV Co-infection
30
•
There are no clinically significant drug interactions between ARVs and
Ethambutol, Isoniazid or Pyrazinamide.
•
There are clinically significant drug interactions between rifampicin and PI/
NNRTI therapy
•
Rifampicin lowers EFV, NVP levels and lowers most PIs
•
There are no interactions between rifampicin and the NRTI class. This
is because they are metabolized through independent pathways
•
Rifabutin is the preferred rifamycin if available. Rifabutin is not
generally available in Ethiopia, it is used regularly in developed
countries for co-infected patients.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 31
Rifamycin Drug Interactions
■ Rifampin induces CYP3A4
■ Reduces serum levels of PIs and NNRTIs
■ Inadequate drug levels
■ Failure of and resistance to ART (monitor closely)
■ PI or NNRTI may require dose adjustment, may need to avoid
use
■ Rifabutin less potent inducer of CYP3A4
■ Requires dose adjustment when administered with PIs or
NNRTIs to prevent toxicity
■ PI or NNRTI may require dose adjustment
Session 9: TB & HIV Co-infection
31
•
Rifamycin antibacterials are metabolized by the hepatic cytochrome enzyme
3A4 and cause significant drug interactions with protease inhibitors and
NNRTIs
•
Rifampin is a substrate as well as a potent inducer of cytochrome P450
CYP3A4. It reduces serum levels of PIs and NNRTIs which may cause
inadequate drug levels, leading to failure of and resistance to HAART
•
There are a limited number of options for PI or NNRTI therapy given
together with rifampicin.PI and NNRTI therapy used together with ART must
be closely monitored.
•
Rifabutin less potent inducer of CYP3A4. It is the preferred rifamycin for coadministration with PIs and NNRTIs, if available.
•
It also requires dose adjustment when administered with PIs or
NNRTIs
•
PI or NNRTI may require dose adjustment
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 32
Drug Interactions with ART and TB Agents-Non boosted PIs
Rifabutin (RFB)
Antiretroviral
ARV
Dose
Rifampin (RFP)
RFB dose
Details
ATV ↑ RFB conc.
Limited data with RFP
Atazanavir
(ATV)
400mg
QD
Amprenavir
(APV)
150mg QD or
1200mg 300mg 3 times
BID
a week
Indinavir
(IDV)
10001200mg
Q8H
150mg QD
Nelfinavir
(NFV)
1250mg
BID
150mg QD
150mg QOD
APV ↑ RFB by 204%
RFB ↓ APV by 15%
RFP ↓ APV by 82%
Contraindicated IDV ↑ RFB by 60%
IDV ↑ RFP by 73%
RFB ↓ IDV by 32%
RFP ↓ IDV by 89%
NFV ↑ RFB by 200%
RFB ↓ NFV by 32%
RFP ↓ NFV by 82%
•
This is a chart that describes drug interactions between tuberculosis agents
rifabutin and rifampin and unboosted protease inhibitors (without concurrent
dosing with ritonavir)
•
Protease inhibitors alone cannot be given with rifampin due to reduction of PI
levels which may lead to resistance and/ or drug failure.
•
All of the PIs in the chart can be used with rifabutin with appropriate dose
adjustments of either rifabtuin, the PI or both.
•
Ritonavir levels (not shown) are reduced by 35% by rifampin Increased liver
toxicity possible. Coadministration may lead to loss of virologic response if
RTV the sole PI. Should consider using rifabutin instead. Due to intolerance,
ritonavir as a sole PI is rarely used and therefore not included in the table. If
used with rifabtuin, rifabutin levels are increased 4X. Dose of rifabutin muse
be decreased to 150 mg qd or 3X/week. The ritonavir dose remains 600 mg
bid or same dose if used as part of a boosted regimen.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 33
Drug Interactions with ART and TB Agents-NNRTIs
Rifabutin (RFB)
Antiretroviral
Rifampin (RFP)
ARV
Dose
RFB dose
ARV
Dose
RFP
Dose
Efavirenz
(EFV)
600mg
QD
450mg
QD or
600mg 3
times a
week
800mg
QD
600mg
QD
EFV ↓ RFB by 32%
RFB no effect on EFV
RFP ↓ EFV by 26%
Nevirapine
(NVP)
200mg
300mg QD
BID
200mg
BID
600mg
QD
No relevant interaction
with RFB/NVP
RFP ↓ NVP by 31-58%
Caution use
Details
•
When using Efavirenz with Rifampin, the dose of efavirenz must be
increased to 800 mg qd as rifampin decreases EFV levels by 26%. The 800
mg dose achieves higher drug levels than those seen in the absence of
rifampin and thus may reduce the chance of HIV drug resistance. However, it
can also increase the toxicity risk.
•
Nevirapine should only be used with rifampin when there are no other
options. Caution is warranted as the risk of hepatotoxicity is greater with
concurrent administration. Rifampin lowers nevirapine doses and higher
levels of nevirapine have not been evaluated
•
Delavirdine is rarely used anymore. It’s use is contraindicated with all
rifamycins.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 34
Introductory Case Answers
■ The statement, B): Ethambutol lowers nevirapine levels,
therefore the patient should be monitored for treatment
failure, is false. There is no drug interaction between
ethambutol and nevirapine.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
34
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 35
Introductory Case
Answers (cont.)
■ The statement D): Nevirapine reduces rifampin levels
and should not be used in combination, is false.
Rifampin lowers nevirapine levels significantly.
Nevirapine has no effect on rifampin levels.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
35
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 36
Drug Interactions with ART & TB Agents-Boosted PIs
Rifabutin (RFB)
Antiretroviral
LPV/r
SQV/RTV
IDV/RTV
Rifampin (RFP)
RFB dose
ARV Dose
RFP
dose
400mg/100mg
BID
150mg QOD or
3 times a week
(TIW)
400mg/400mg
800mg/200mg
(both BID)
600mg
QD
LPV/r ↑ RFB
RFB no effect on LPV/r
RFP ↓ LPV/r by 75%
400mg/400mg
BID
150mg QOD or
TIW
400mg/400mg
1000mg/100mg
(both BID)
600mg
QD
RFB ↓ SQV by 40%
RFP ↓ SQV by 84%
Limited data with RFP
ARV Dose
800mg/100mg
800mg/200mg
(both BID)
150mg QOD or
TIW
150mg QOD or
TIW
ATV/RTV
300mg/100mg QD
APV/RTV
600mg/100mg
150mg QOD or
BID or
TIW
1200mg/200mg QD
Contraindicated
Details
No data on IDV/RTV with
RFB. RTV may overcome
induction by RFB.
No Data
No formal studies with
ATV/RTV + RFB or RFP
No Data
No Data with RFP
•
The only ritonavir boosted PIs that can be used ( that have some clinical
experience) are
•
SQV/RTV (hard-gel cap is preferred due to increased GI tolerability) and
LPV/RTV in the doses listed in the chart. The rifampin dose remains
unchanged. Problems with drug interactions between ritonavir boosted
regimens with rifampicin include: tolerability, clinical monitoring and risk of
resistance. These drug combinations need further data to support their use.
•
There is no data on the newer PIs, Atazanavir or Amprenavir
•
IDV/RTV, levels are questionable and should not be used together
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 37
ART for TB Co-Infected Patients
Clinical
Situation
Recommendation
Note
On NVP
Change to EFV
Exceptions: intolerance of EFV
or risk of pregnancy
Not on ART
Start TB treatment. Start ART
therapy as soon as TB
treatment tolerated (between 2
weeks to 2 months)
EFV containing is preferred
with monthly ALT monitoring
CD4 < 200 or
TLC < 1200
Not on ART
Start TB treatment. Re-evaluate
patient for ART indications after
CD4 >200 OR completion of intensive phase
(end of 2 months) and end of
TLC >1200
TB therapy. Start ART therapy
if there are indications.
Start ARVT therapy according
to the recommendations for
other HIV patients
•
The following are the recommendations from the Ethiopia Guidelines on the use of ART in
Co-infected patients:
•
In the first clinical situation the preferred option is to switch to EFV, when this is not possible
(risk of pregnancy or patient with intolerance to EFV), NVP may be continued with monthly
ALT monitoring
•
If the patient is not on ART and the CD4 < 200 or TLC < 1200
•
Start TB treatment. Start ARV therapy as soon as TB treatment is tolerated (between
2 weeks to 2 months).
•
EFV containing is preferred with monthly ALT monitoring
•
WHO recommends that treatment with ART be considered if CD4 < 350 in coinfection.
•
If patient is not on ART and CD4 >200 OR TLC >1200
•
•
Start TB treatment. Re-evaluate patient for ART indications after completion of
intensive phase (end of 2 months) and end of TB therapy. Start ARV therapy if there
are indications. Start ARV therapy according to the recommendations for other HIV
patients
In addition, WHO recommends:
•
That in patients with extra pulmonary TB, ART should be started as soon as TB
treatment is tolerate, irrespective of CD4 count
•
If CD4 > 350m defer ART
•
If CD4 unavailable, start TB treatment, consider ART based on clinical judgment in
relation to other signs of immunodeficiency (WHO staging). IF no signs of
immunodeficiency are present, and patient is improving on TB treatment, ART should
be started upon completion of TB treatment.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 38
Introductory Case
Answers (cont.)
■ The true statement is C): Rifampin lowers nevirapine
levels and should not be used in combination.
Nevirapine levels are reduced by 31-58%. This
combination also increases the risk of hepatotoxicity.
■ If a patient is on ART and is to begin therapy for TB, the
NNRTI of choice is efavirenz with an adjusted dose of
800 mg qhs while the patient is on rifampin and for 2
weeks afterwards to account for enzyme induction.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
38
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 39
Possible Regimens for
Administration of Rifampin with ART
■ NNRTI based regimen
■ D4T 40 mg bid (or ZDV 300 mg bid) + 3TC 150 mg bid + EFV-800 mg qhs
■ PI based regimen
■ (D4T 40 mg bid or ZDV 300 mg bid +3TC 150 mg bid) + RTV/SQV 400
mg/400 mg bid, 100/1000 mg bid or LPV/r 400 mg/400 mg bid
■ PI or NNRTI sparing regimen
■ D4T 40 mg bid ( or ZDV 300 mg bid) + 3TC 150 mg bid + ABC 300 mg bid
■ For women of childbearing age (without effective contraception)
or pregnant women
■ (ZDV 30 mg bid or D4T 40 mg bid) + 3TC 150 mg bid + SQV/RTV 400
mg/400 mg bid or ABC 300 mg bid
Session 9: TB & HIV Co-infection
•
39
Treatment of choice for active disease is:
•
Either D4Tor AZT + Efavirenz (which will require a dose increase to
800 mg if given with riampicin). The 800 mg dose achieves higher
drug levels than those seen in the absence of rifampicin and thus may
reduce the chance of HIV drug resistance. However, it can also
increase the toxicity risk. D4T dose is weight based.
•
Data on the use of NVP and rifampicin are limited and conflicting. Rifampicin
decreases NVP levels by 31% and higher NVP doses have not been
evaluated. Although some clinical expericence reports adequate viral and
immunological response and acceptable toxicity, this regimen should only be
considered when no other options are available. Risk of hepatotoxicity is
higher when using NVP with TB medication.
•
The only protease inhibitor regimens that can be given with rifampicin are
ritonavir/saquinavir 400 mg/400 mg bid, 100/1000mg bid or lopinaivr/ritonavir
400 mg/400 mg. Both PI regimens require refrigeration. Tolerability, clinical
monitoring and risk of resistance may be problematic.
•
The disadvantages of triple NRTI therapy are 1) virological potency and 2)
the potential for a patient to stop ART on their own because of suspicion of
hypersensitivity, since there is an overlap with high frequency of immune
reconstitution syndrome that occurs with TB on therapy. If a patient stops
ABC on their own due to suspected hypersensitivity, they can NEVER be
rechallenged.
•
For women of childbearing age (without effective contraception) or pregnant
women (WHO guidelines 2003)(ZDV or D4T) + 3TC + SQV/RTV or ABC
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 40
Introductory Case
Answers (cont.)
■ The statement A): Rifampin lowers nevirapine levels,
therefore the patient should be monitored for treatment
failure is false. The two drugs should not be
coadministered. If TB therapy and ART must be
coadministered, nevirapine should be changed to
adjusted dose efavirenz or to an appropriate ritonavir
boosted protease inhibitor regimen.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
40
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 41
Challenges to Adherence with TB
and ART Therapy Co-administered
■ Involves a large number of pills
(Three drugs for HIV + Four drugs for TB for first 2 months)
■ Poor tolerability
■ Toxicity management is more complex
■ Cost
■ Immune reconstitution syndrome
■ Acceptance of both diseases
Session 9: TB & HIV Co-infection
•
41
Con-current treatment of HIV and TB involves a large number of pills
•
(Three drugs for HIV + Four drug therapy for TB) which may be too
much to bear for a patient who is already sick. It is difficult to
physically take so many pills at once plus the side effects may be
compounded.
•
Side effects of therapy can overlap and make it even more difficult to adhere
to therapy. Also, the dose of PIs and NNRTIS (not NVP) need to be
increased to account for the negative rifamycin drug interaction, which can
make tolerability even more difficult
•
Cost
•
Immune reconstitution syndrome
•
Acceptance of both diseases
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 42
Overlapping Toxicities of ART
and TB Therapy
Side
Effect
Nausea
Hepatitis
ARV
therapy
ZDV,DDI, RTV, NVP, EFV,
SQV
PIs
TB
therapy
Pyrazinamide,
INH
Peripheral Rash
neuropathy
DDI, D4T
Rifampin,
INH
INH,
Pyrizinamide
NVP, EFV
Rifampin,
INH,
Pyrazinamide
Session 9: TB & HIV Co-infection
42
•
There is an increased risk of hepatic toxicity when rifampicin and nevirapine
are used together: avoid this combination if at all possible, otherwise close
monitoring of ALT (monthly) is indicated
•
Nausea: PZA (1-10% gastric irritation, nausea, vomiting or anorexia), INH
>10% (anorexia, nausea, vomiting, stomach pain)
•
Hepatitis: PZA not over 2% if recommended daily dose (2 gm) not exceeded
•
Rifampicin (may cause increased LFTs up to 14%) minor enzyme changes
common and resolve while continuing the drug, alcoholics with pre-existing
liver disease prone to rifampin-induced toxicity
•
INH mild increased LFTs 10-20%, increases with daily alcohol , progressive
liver damage increases with age 2.3% in patients > 50 years of age, acute
liver failure has been reported
•
NVP can cause hypersensitivity reaction in the first 4 weeks
•
Peripheral neuropathy INH < 1% pyridoxine 25 mg qd will decrease incidence
•
Rash: rifampicin (1-5%), PZA < 1%, INH <1%, NVP 15-20%, EFV 5-20%
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 43
Drug Resistant TB
■ Poor adherence to ART and TB medication can lead to
resistance and treatment failure
■ There are two ways an individual can develop multidrug resistant (MDR) TB
■ A strain of MDR TB can be transmitted from person to person
■ Nonadherence leads to resistance of drug susceptible strains
■ Note: immunocompromised patients undergoing therapy for drugsusceptible TB remain at risk of MDR TB if they are exposed to a
resistant strain of TB
Session 9: TB & HIV Co-infection
43
•
Poor adherence to ART and TB medication can lead to resistance and
treatment failure
•
There are two ways an individual can develop multi-drug resistant (MDR) TB
•
A strain of MDR TB can be transmitted from person to person, as
occurs in outbreaks.
•
Alternatively, a strain of a drug-susceptible TB can acquire resistance
to multiple drugs, primarily through nonadherence with medications,
use of inadequate regimens or drug-drug interactions which decrease
the levels of TB medication. Ie. EFV decreases rifabutin levels and
must be increased to 450-600 mg qd when used with efavirenz
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 44
Case Studies
•
Refer participants to Worksheets 9.1, 9.2 and 9.3 in their Course Workbooks.
•
These case studies may be done in small groups and findings reported back
to the larger group or they may be discussed as a large group when time is
limited.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 45
Case 1
■ SM is a 21 year old male who comes to Black Lion Hospital
coughing up blood, complaining of breathlessness and chest
pain. He has had an increase in his temperature in the evening,
which subsides the next morning His weight has gone down by 5
kg.
■ Physical exam reveals swollen lymph nodes in the neck and
groin area
■ Chest X-Ray
■ Upper lobe infiltrates
■ Pulmonary cavities
■ Sputum smear for AFB is positive
■ TLC 1,100
■ Current Medication: none
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
45
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 46
Case 1 Questions
■ SM is started on four drug therapy for his advanced TB. He is
tearful and asks you if he should also take antiretroviral therapy
to help his immune system.
■ Is it appropriate for him to begin on antiretroviral therapy today?
■ How would you counsel him?
■ What are the indications for ART in a co-infected patient?
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
46
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 47
Case 1 - Answer 1
■ No, it is not appropriate to begin SM on therapy today,
although his TLC is < 1,200
■ Although, he should start ART therapy as soon as his
TB treatment is tolerated
■ (between 2 weeks and 2 months)
Session 9: TB & HIV Co-infection
47
•
No, based on the guidelines, it is not appropriate to begin Tesfai on therapy
at this time. Although his TLC is < 1200 and he would require therapy per the
guidelines.
•
It is appropriate to start TB treatment today, this should be the priority. He
should start ART therapy as soon as his TB treatment is tolerated (between 2
weeks and 2 months)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 48
Case 1 - Answer 2
■ Arguments to withhold HAART until TB is treated
■ HIV is a chronic disease
■ Adherence may be compromised
■ Toxicity management is more complex
■ Complex drug interactions
■ Immune reconstitution syndrome
■ Acceptance of both diseases
Session 9: TB & HIV Co-infection
48
There are many reasons why starting ART and TB therapy together may not be the
optimal choice. Arguments for delaying antiretroviral therapy in a patient with coinfection include:
1) HIV is a chronic disease and ART is never an emergency.
2) Adherence to TB and ART therapy is extremely difficult as the pill burden is
overwhelming for most patients. This may result in the development of
resistance to either the TB medication or the ARV therapy.
3) Toxicities of ART and TB therapy overlap and can cause significant
distress in a patient who is already sick. It may be difficult to determine
which medication is causing the adverse effect which increases the
complexity of managing the event.
4) Drug-drug interactions between TB and ARV therapy are complex. It is
essential to take the time to design an optimal ARV regimen that will not
compromise TB therapy or be compromised by TB therapy.
5) Starting antiretroviral therapy in a patient with active TB may cause
immune restoration syndrome, which is a paradoxical reaction, a transient
worsening of clinical signs and symptoms after the initial response to antituberculosis therapy.
6) It can be extremely overwhelming for a patient to accept the dual diagnosis
of HIV and TB. Better wait until he has been able to come to terms and is
ready to begin therapy.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 49
Case 1 - Answer 3
ART for TB Co-Infected Patients
Clinical
Situation
Recommendation
Note
On NVP
Change to EFV
Exceptions: intolerance of EFV
or risk of pregnancy
Not on ART
Start TB treatment. Start ARV
therapy as soon as TB
treatment tolerated (between 2
weeks to 2 months)
EFV containing is preferred
with monthly ALT monitoring
CD4 < 200 or
TLC < 1200
Not on ART
Start TB treatment. Re-evaluate
patient for ART indications after
CD4 >200 OR completion of intensive phase
TLC >1200
(end of 2 months) and end of
TB therapy. Start ARV therapy
if there are indications.
Session 9: TB & HIV Co-infection
Start ARV therapy according to
the recommendations for other
HIV patients
49
•
In the first clinical situation the preferred option is to switch to EFV, when this
is not possible (risk of pregnancy or patient with intolerance to EFV), NVP
may be continued with monthly ALT monitoring, or may switch to a PI
containing regimen either ritonavir/saquinavir or lopinavir/ritonavir
•
OPTION: If not possible to wait until after first 2 months of TB treatment, then
delay for at least one month to avoid reconstitution syndrome (Southern
African Journal of HIV Medicine Oct 2002 p23-33)
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 50
Case 2
■ A 40-year-old man had 4 weeks of fever, cough with
blood-tinged sputum, night sweats, and had lost 7 kg
of weight. He also had pain and numbness in the soles
of both feet.
■ A chest x-ray showed a right lower lobe infiltrate. He
was diagnosed with smear-positive pulmonary
tuberculosis. His HIV test was positive, and his CD4
cell count was 180cells/mm3.
■ He improved during the first two months of treatment
with isoniazid, rifampin, ethambutol, and pyrazinamide,
along with vitamin B6 (pyridoxine).
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
50
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 51
Case 2 (cont.)
■ He also took bactrim for PCP prophylaxis. After two
months, the fever, cough, and night sweats had
stopped and he was gaining weight.
■ He changed to the continuation phase of treatment with
isoniazid and ethambutol, continuing vitamin B6. He
started first line antiretroviral treatment with zidovudine
(because of the peripheral neuropathy), lamivudine and
efavirenz 600 mg qhs.
■ After two weeks he developed fevers, cough, and night
sweats once again.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
51
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 52
Case 2 (cont.)
■ He and his treatment partner report excellent
adherence with both the TB and HIV treatment. Three
sputum smears were negative for acid-fast bacilli.
■ A chest x-ray showed a worsening right lower lobe
infiltrate, a new right-sided pleural effusion, and
enlargement of bilateral hilar lymph nodes. His ALT is
still normal.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
52
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 53
Case 2 Questions
■ What do you think is happening?
■ Should he change his tuberculosis therapy, and if so,
how?
■ Should he change his antiretroviral therapy, and if so,
how?
■ Should he modify his treatment in any other way?
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
53
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 54
Case 2 - Answer 1
■ He probably has immune reconstitution syndrome. He
has partially treated pulmonary tuberculosis, and has
paradoxical worsening despite continuing treatment
after antiretroviral therapy was begun.
■ IRS can occur within weeks among patients with TB
and HIV co-infection. The immune system starts to
improve and an inflammatory reaction against the TB
organisms develops.
■ Previously the immune system was too compromised to
cause an inflammatory response.
Session 9: TB & HIV Co-infection
•
54
Persons with pulmonary TB and a CD4 count under 200 rarely have classical
upper lobe cavitary disease. They often have lower lobe infiltrates that are
not typical of tuberculosis in immunologically normal persons.
Immunosuppressed patients with TB and HIV co-infection are also more
likely to have extra-pulmonary tuberculosis.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 55
Case 2 - Answer 2
■ His sputum smears are negative for AFB, having been
smear positive previously. That makes it less likely that
he has developed drug resistant TB, and he can
continue his same treatment.
■ The history of excellent TB adherence, confirmed by his
treatment support person, is helpful. If he had
resistance testing of his original TB organism, that
could help. Also, send his current sputum for culture
and sensitivity if that is possible.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
55
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 56
Case 2 - Answer 3
■ There is no evidence of antiretroviral toxicity or failure.
An illness occurring within a few weeks of starting ART
may represent disease caused by an opportunistic
organism that was already present when ART began.
■ Pneumocystis carinii is not likely here because it almost
never causes pleural effusions or lymphadenopathy. An
illness occurring within a few weeks of starting ART
may represent Immune Reconstitution Syndrome.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
56
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 57
Case 2 - Answer 4
■ He can be treated for his symptoms while the TB
treatment and ART continue.
■ If there is confidence that the patient does not have
another opportunistic disease, and if the patient is
severely ill, a short course of corticosteroids can be
used while the other treatments continue.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
57
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 58
Case 3
■ KH, an HIV+ 40 year old male was first seen in clinic 10
months ago because of chronic cough and chest pain. At
that time, his CD4 count was 300. A chest x-ray showed left
upper lobe infiltrates.
■ He did not improve on antibiotics, and the infiltrate on chest
x-ray worsened. Three sputum smears were negative. He
was treated empirically for pulmonary tuberculosis and
improved.
■ He completed 2 months of TB treatment. At the two month
visit of his TB, his CD4 count had fallen to 190. He is to
continue on Ethambutol and Isoniazid for 4 months
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
58
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 59
Case 3 Questions
■ Does he fulfill the criteria for antiretroviral therapy?
■ If so, what else would you want to know before
recommending an antiretroviral regimen?
■ What would you recommend?
■ Does he require any additional therapy at this time?
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
59
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 60
Case 3 - Answer 1
■ Yes, at this time he is a candidate for therapy. He has
completed the first two months of his TB therapy. Now,
his CD4 count has dropped to 190.
■ According to the guidelines, he should begin ART
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
60
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 61
Case 3 Gathering
Information - Answer 2
■ Does he have any other co-morbidites?
■ You discover that he has a history of severe depression with suicidal
ideation for which he is not currently receiving treatment.
■ Does he have any drug allergies?
■ Penicillin= rash
■ What other medications does he take?
■ Acetylsalicylic acid 500 mg as needed for pain
■ Baseline labs
■ ALT 27, SCr 0.7, Hgb 15/45
■ What ART are available in his area for the management of his HIV?
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
61
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 62
Case 3 - Answer 3
■ He should start ARV therapy according to the recommendations
for other HIV patients
■ He should avoid taking efavirenz with a history of severe
depression for which he is not being treated as efavirenz may
worsen underlying depression
■ The only PIs available in his area at this time are nelfinavir and
ritonavir
■ He could begin on nevirapine with the appropriate dose
escalation + zidovudine and lamivudine, with monthly LFT
monitoring and monitoring for zidovudine as routinely indicated
Session 9: TB & HIV Co-infection
•
62
Since the only PIs available in his area are nelfinavir and ritonavir, he cannot
use a protease inhibitor based regimen. He should not receive efavirenz as
he has a history of severe depression which could be worsened by efavirenz.
He could begin on nevirapine with the appropriate dose escalation +
zidovudine and lamivudine, with monthly LFT monitoring and monitoring for
ZDV as routinely indicated.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 63
Case 3 - Answer 4
■ Since his CD4 count has dropped below 200, he is a
candidate for bactrim DS daily to prevent PCP
pneumonia
■ He does not have a sulfa allergy and therefore it is an
appropriate choice
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
63
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 64
Case 4
■ A 35-year-old HIV-infected woman with a CD4 count of
300 cells/mm3 and an undetectable viral load presents
for routine follow-up. She is currently asymptomatic and
is taking ART.
■ She states that her sister was recently diagnosed with
active pulmonary tuberculosis (TB) and is currently
receiving treatment.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
64
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 65
Case 4 Question
■
Regarding the exposure to her sister, which of the following
statements describes appropriate subsequent management of
this 35-year-old HIV-infected woman?
A. After excluding active TB, she should be treated with 9 months
of isoniazid (INH) and pyridoxine 40 mg qd
B. If active TB is ruled out in this patient, she does not require
further treatment.
C. She should discontinue her ART and be started on four-drug TB
treatment.
D. She should be tested for latent TB infection with a tuberculin
skin test If, 50 hours later, she has 0 mm of induration for the
test, she does not require further treatment
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
65
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 66
Case 4 – Answer (C is correct)
■ Prior to giving isoniazid (INH) for latent TB infection, active TB
should be excluded by symptom review and by chest radiograph.
■ If this patient has no evidence of active TB, she should be
treated for latent TB infection. This patient is presumed to have
latent TB infection based on the close exposure to her sister with
active pulmonary TB.
■ In this situation, the patient is considered to have latent TB
infection regardless of her tuberculin skin test result. For HIVinfected persons, 9 months of INH with pyridoxine is appropriate
therapy for latent TB infection.
Session 9: TB & HIV Co-infection
•
66
Facilitators: this case is for educational purposes only. Latent TB is not
treated in Ethiopia. PPD screening is not routinely done.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 67
Key Points
■ TB is the leading killer of patients with HIV/AIDS in
developing countries
■ TB is the most common opportunistic infection in
Ethiopia, and the incidence of TB due to HIV is
expected to increase
■ The risk of active TB disease is greatly increased
among persons with TB/HIV infections
■ Among co-infected patients, extrapulmonary TB is
present in up to 50% (this rate increases as CD4 cell
count diminishes)
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
67
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 68
Key Points (cont.)
■ The treatment of active TB is a priority in co-infected
patients.
■ Starting ART and TB therapy together is not always the
optimal choice.
■ Patients with TB merit special consideration because
co- management of HIV and TB is complicated by drug
interactions, high pill burden, adherence issues,
immune reconstitution syndrome, resistance, and drug
toxicity.
Session 9: TB & HIV Co-infection
•
68
Review key points with participants and ask them if they have any questions
about Unit 9 on TB and HIV co-infection.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 69
References
■ Barlett, MD, Gallant, MD, Medical Management of HIV Infection, 2003.
■ Behrens, C. MD, Harborview Medical Center, Seattle, WA, USA, 2004.
■ Benedek I, Joshi A, Fiske WD, et al. Pharmacokinetic interaction
between efavirenz and rifampicin healthy volunteers. 12th World AIDS
Conference, 1998, abstract 42280.
■ Binswanger, I. MD, MS, University of Washington School of Medicine,
Seattle, WA, USA, 2004.
■ CDC MMWR 2003:52:217.
■ Colbers EPH, Bertz R, et al. 42nd Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Diego, September 2002.
■ Dean G, AIDS 2002;16:75.
■ Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS, Harborview
Medical Center, Seattle, WA, USA, 2004.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
69
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 70
References (cont.)
■ Furrer, Am J Med, 1999.
■ Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
■ Justesen US, et al. 10th Retroconference, February 10-14, 2003.
Boston, MA. Abstract 542.
■ Kosel. B. Madison Clinic Pharmacy Drug Interaction Table, 2004.
■ La Porte CJL Pharmacokinetics of two adjusted dose regimens of
lopinavir/ritonavir in combination with rifampicin in healthy volunteers.
■ Lee, Autran, Lancet, 1998.
■ Namibia Ministry of Health and Social Services, Training on the Use of
the Namibia Guidelines for Antiretroviral Therapy (ART), 2004.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
70
HIV Care and ART: A Course for Pharmacists
Unit 9: TB and HIV Co-infection
Slide 71
References (cont.)
■ Pharmacokinetic Interaction betweem Rifampin and the Twice-Daily
Combination of Indinavir and Low Dose Ritonavir in HIV-Infected
Patients.
■ Ribera E, Pou L, Lopez RM, et al. Pharmacokinetic interaction between
nevirapine and rifampicin in HIV-infected patients with tuberculosis. J
Acquir Immune Defic Syndr, 2001, 28:450-453.
■ Rifabutin Given Twice Weekly With Ritonavir-Boosted Amprenavir in a
Once-Daily HAART Regimen May Result in Sub-Therapeutic Levels of
■ Rifabutin Despite Directly Observed Treatment. [Abstract 58] 4th
International Workshop on the Clinical Pharmacology of HIV Therapy,
Cannes, France March 27-29, 2003.
■ UCSF April 2003 HIV/AIDS in Ethiopia.
■ Woldu, A. Current HIV/AIDS Status in Ethiopia, Ethiopian Ministry of
Health, 2004.
Session 9: TB & HIV Co-infection
Reference Manual for Trainers
71
HIV Care and ART: A Course for Pharmacists
Slide 9.10 Estimated New Adult Cases of TB
Estimated New Adult Cases of TB
300
Thousands
250
200
150
100
50
0
1984
1989
1994
1999
Not Due to HIV
2004
2009
2014
Due to HIV
Source: Dr. Asegid Woldu, Ethiopian Ministry of Health
TB & HIV Co-infection
HIV Care and ART for Pharmacists
Reference Manual for Trainers
11
TB and HIV Co-infection
Unit 9-7
References
Barlett, MD, Gallant, MD, Medical Management of HIV Infection, 2003.
Behrens, C. MD, Harborview Medical Center, Seattle, WA, USA, 2004.
Benedek I, Joshi A, Fiske WD, et al. Pharmacokinetic interaction between
efavirenz and rifampicin healthy volunteers. 12th World AIDS Conference,
1998, abstract 42280.
Binswanger, I. MD, MS, University of Washington School of Medicine,
Seattle, WA, USA, 2004.
CDC MMWR 2003:52:217.
Colbers EPH, Bertz R, et al. 42nd Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Diego, September 2002,
Abstract A-1821.
Dean G, AIDS 2002;16:75.
Faris, J. PharmD, MBA, Clinical Pharmacist, HIV/AIDS, Harborview
Medical Center, Seattle, WA, USA, 2004.
Furrer, Am J Med, 1999.
Hykes, B. PharmD, Clinical Pharmacist, HIV/AIDS, Harborview Medical
Center, Seattle, WA, USA, 2004.
Justesen US, et al. 10th Retroconference, February 10-14, 2003. Boston,
MA. Abstract 542.
Kosel. B. Madison Clinic Pharmacy Drug Interaction Table, 2004.
La Porte CJL Pharmacokinetics of two adjusted dose regimens of
lopinavir/ritonavir in combination with rifampicin in healthy volunteers.
Pharmacokinetic Interaction betweem Rifampin and the Twice-Daily
Combination of Indinavir and Low Dose Ritonavir in HIV-Infected
Patients.
Lee, Autran, Lancet, 1998.
Namibia Ministry of Health and Social Services, Training on the Use of the
Namibia Guidelines for Antiretroviral Therapy (ART), 2004.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
TB and HIV Co-infection
Unit 9-8
Ribera E, Pou L, Lopez RM, et al. Pharmacokinetic interaction between
nevirapine and rifampicin in HIV-infected patients with tuberculosis. J
Acquir Immune Defic Syndr, 2001, 28:450-453.
Rifabutin Given Twice Weekly With Ritonavir-Boosted Amprenavir in a
Once-Daily HAART Regimen May Result in Sub-Therapeutic Levels of
Rifabutin Despite Directly Observed Treatment. [Abstract 58] 4th
International Workshop on the Clinical Pharmacology of HIV Therapy,
Cannes, France March 27-29, 2003.
UCSF April 2003 HIV/AIDS in Ethiopia.
Woldu, A. Current HIV/AIDS Status in Ethiopia, Ethiopian Ministry of
Health, 2004.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
TB and HIV Co-infection
Unit 9-9
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
TB and HIV Co-infection
Unit 9-10
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 10
ART in Children
Unit 10: ART in Children
Aim: The aim of this unit is to introduce participants to the special considerations
necessary when administering ART to children
Learning Objectives: By the end of this unit, participants will be able to:
•
Describe the guidelines for ART treatment in pediatric patients
•
Describe and understand the special challenges of diagnosing infants for HIV
in resource limited settings
•
Anticipate the unique considerations required for follow up and management
of the pediatric HIV patient
•
Determine the effectiveness of ART in children
Unit Overview:
1 Hour
Step
Time
Activity/
Method
Content
Resources
Needed
1
10 minutes
Question-Answer
Introductory Case Study and
Question Slides (10.2-10.3)
Overhead or LCD
Projector
2
30 minutes
Lecture
ART in Children (Slide 10.4-10.33)
Overhead or LCD
Projector
3
15 minutes
Group Exercise
Case Studies (Slide 10.34-10.36)
Worksheet 10.1, 10.2
in workbook, flip chart
stands with paper and
markers.
4
5 minutes
Summary
Presentation of Key Points (Slide
10.37)
Overhead or LCD
Projector
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART in Children
Unit 10-2
Resources Needed
•
•
•
•
Flip Chart and Paper
Markers
Overhead or LCD Projector
Worksheets 10.1 and 10.2 in the Course Workbook
Key Points
1. An increasing number of children are becoming infected with HIV/AIDS.
2. Only a small percentage of HIV/AIDS infected children have access to
ART in developing countries.
3. In working with pediatric patients, special considerations (see WHO
guidelines) for treatment and diagnosis must be taken into account.
4. Adherence to treatment presents a special challenge within the
pediatric population.
Step 1
Step 2
Step 3
Introductory Case Study (10 minutes)
•
Ask a participant to read the case study on Slides 10.2.
•
Ask participants to silently attempt to answer the question on Slide
10.3.
•
Explain that the question will be answered and the case discussed
more fully as the unit progresses.
Lecture (30 minutes)
•
Present “ART in Children” (Slides 10.4 – 10. 33) in the PowerPoint
presentation.
•
Ask participants if they have any questions about the objectives
before moving forward with the lesson.
Group Exercise (15 minutes)
•
Step 4
Case Study Group Exercise (Slides 10.34-36): Participants have 2
Case Studies (Worksheets 10.1, 10.2) in the workbook. Ask the
groups to identify a recorder and a presenter, and then spend
twenty minutes discussing the case study together and answering
the related questions on flip-chart paper.
Summary (5 minutes)
•
Summarize the presentation, review the Key Points presented in
this Unit (Slides 10.37), and answer final questions.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART in Children
Unit 10-3
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes for
reference during the planning and implementation of this course. The facilitation
notes and talking points are included in the “notes” section of the accompanying
PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART in Children
Unit 10-4
Unit 10: ART in Children
Slide 1
ART in Children
Unit 3
HIV Care and ART: A Course for Pharmacists
This unit should take approximately 1 hour to complete.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 2
Introductory Case
■ A 5 year old child was diagnosed as HIV+ at 1 year
of age. He has not had any symptoms of HIV and
has not required ART up to this point.
■ Today his lab work indicates that he is in need of
ART. He is to begin a regimen of nevirapine,
lamivudine and zidovudine twice daily. The child
lives with his elderly grandmother. She is anxious
that the child will be able to take his medication
properly.
Unit 10: ART in Children
2
•
Ask a participant to read the case.
•
Ask participants if they have any questions about the information presented.
•
Note: Do not give them further information on the case. Just ask them to consider
the information provided to them.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 3
Introductory Case Question
■ Which of the following statements are true
regarding adherence in the pediatric population?
A. There are many strategies to assist with
adherence in the pediatric population.
B. Adherence is generally not a problem for
children.
C. It is easy to assess adherence accurately.
D. Treatment options are very limited for pediatric
patients, so they have to get used to the
regimen that is chosen for them.
Unit 10: ART in Children
3
•
Ask participants to silently attempt to answer the question.
•
Explain that the answer to the question will be discussed as the unit progresses.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 4
Unit Learning Objectives
■ Become familiar with the guidelines for ART
treatment in pediatric patients
■ Describe and understand the special challenges of
diagnosing infants for HIV in resource limited
settings
■ Anticipate the unique considerations required for
follow up and management of the pediatric HIV
patient
■ To ascertain the effectiveness of ART in children
Unit 10: ART in Children
Reference Manual for Trainers
4
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 5
Introduction
■ In 2003, number of children <15 yrs living with
HIV/AIDS = 2.5 million
■ No of New infections=700,000
■ No of AIDS deaths =500,000
■ Vertical transmission is responsible for 90% of
childhood infection
■ Rate of MTCT in breast feeding population is 2045%
Unit 10: ART in Children
Reference Manual for Trainers
5
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 6
Introduction (cont.)
■ Significance of effective PMTCT program and
primary prevention of HIV in adults
■ ART has dramatically reduced mortality and
morbidity in children
■ Cohort study of 1028 HIV Infected children in US
on combined therapy documented decline in
mortality:1996 5.3%, 1997 2.1%,1998 o.9%, 1999
0.7%
■ In developing countries only 5% have access to
ART
Unit 10: ART in Children
Reference Manual for Trainers
6
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 7
Special Considerations in
Pediatric Patients
■ Route of HIV acquisition
■ In utero exposure to
Antiretrovirals
■ Evaluation of HIV status
during infancy
■ Impact of immunological
immaturity
■ Adherence to treatment
■ Differences in
immunologic markers
■ Changes in
pharmacokintics with age
Unit 10: ART in Children
Reference Manual for Trainers
7
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 8
Diagnosis of HIV in Infancy
■ Is possible in most infants by the age one month
■ Possible virtually in all infected infants at the age of
six months
■ At least two isolated positive results are required to
make a diagnosis in infants
■ DNAPCR, RNAPCR,P24 antigen, viral culture
■ Need to set up testing schedule
Unit 10: ART in Children
Reference Manual for Trainers
8
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 9
Diagnosis of HIV in
Infancy (cont.)
■ Antibody tests are not diagnostic in those
<18months
■ Umbilical cord blood sample should not be used
■ Positive virology test before age of 48hrs indicates
intrauterine infection
■ Infants with +ve result after a week are considered
to have intrapartum infection
Unit 10: ART in Children
Reference Manual for Trainers
9
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 10
Diagnosis of HIV: CD4 Count
■ CD4 count: consider age as variable
■ Counts are higher in infants
■ CD4 percentage is not age variable
■ CD4 count declines to adult level by the age 6 yrs
■ Intrapatient variation in CD4 count
Unit 10: ART in Children
Reference Manual for Trainers
10
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 11
Total Lymphocyte Count (TLC)
■ Like adults significantly correlates with risk of
mortality
■ The 12month risk of mortality >20% in those<18
months if TLC<2500
■ For those>=18 months if TLC<1500
■ Can substitute CD4 count for Rx indication in
presence of symptomatic diseases(stage2&3)
Unit 10: ART in Children
Reference Manual for Trainers
11
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 12
HIV Diagnosis: Excluding HIV
■ HIV can reasonably be excluded if 2 –ve pcr both
performed at >1month and one at >4 months
■ Two or more negative antibody tests performed at
age 6 to 18 months can reasonably exclude HIV
■ One negative EIA after 18 months can definitely
exclude HIV
■ Testing in breastfeeding infant
Unit 10: ART in Children
Reference Manual for Trainers
12
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 13
WHO Staging System
■ Simple but lacks specificity
■ Revision planned in 2004
■ Clinical stage 1: asymptomatic:
■ Gen. Lymphadenopathy
■ Clinical stage 2: unexplained chronic diarrhea:
severe persistent and recurrent oral candidiasis: wt
loss or failure to thrive: persistent fever:recurrent
severe bacterial infections
Unit 10: ART in Children
Reference Manual for Trainers
13
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 14
Clinical Diagnostic…
■ Stage 3: AIDS defining opportunistic infections,
severe failure to thrive, progressive
encephalopathy, malignancy, recurrent septicemia
and meningitis
■ CDC clinical diagnostic criteria are complex &
sophisticated lab is required
Unit 10: ART in Children
Reference Manual for Trainers
14
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 15
Introductory Case - Answers
■ The statement B): Adherence is generally not a
problem for children, is false. Many times it is
difficult to explain to a child why they have to take
medication. The timing of medication may be
difficult or the child may simply refuse to take the
medication. All of these situations increase the
need for adherence interventions by a pharmacist.
■ Assisting pediatric patients with adherence will
help to preserve treatment options in the future.
Unit 10: ART in Children
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15
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 16
Introductory Case –
Answers (cont.)
■ The statement C): It is easy to assess adherence
accurately, is false. Many young children cannot
express themselves. When determining whether a
child is adherent to their ART regimen may depend
on gathering information from the care giver.
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 17
Adherence
■ Is a complex health behavior that is influenced by
the regimen prescribed, patient factors and
character of healthcare provider
■ Is fundamental for successful ART
■ Adherence problems frequently occur in children
■ Is difficult to assess accurately
■ Evaluation of caregiver for the very young is
important
Unit 10: ART in Children
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17
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 18
Introductory Case –
Answers (cont.)
■ The statement A): There are many strategies to
assist with adherence in the pediatric population, is
true.
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 19
Adherence
■ Strategies to improve adherence
■ Regimen related strategy
■ Should be simplified: number of pills, volume of liquid, frequency
of therapy, side effects & drug interactions
■ Child/family strategy
■ Provide information and adherence tools
■ Written and visual materials
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 20
Adherence (cont.)
■ Schedule illustrating time and doses of medication
■ Demonstration of the use of syringes, cups & pill boxes
■ Use of small incentives for children
■ Healthcare provider strategy
■ Engage in open communication
■ Ability to foster trusting relationship
Unit 10: ART in Children
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20
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 21
Principles of Management of
Pediatric HIV Patient
■ Assess and treat common illnesses
■ Completing the immunization schedule
■ Dietary advice and nutritional support
■ Monitor growth & development
■ Cotrimoxazole prophylaxis
■ Vitamin A supplementation
Unit 10: ART in Children
Reference Manual for Trainers
21
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 22
WHO Recommendations for
Initiating ART
■ <18moths if CD4 test is available and virologic test
is +ve
■ WHO stage3 irrespective of cd4 percentage
■ Stage1&2 if CD4 percentage is<20%
■ Stage2 with TLC<2500/mm
■ <18 months if virologic test not available
■ Stage 2 & 3 with CD4<20%
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 23
Recommendations
■ Rx is not recommended for stage1 if no CD4
capability
■ If a child has AIDS defining OIs like cryptococcal
meningitis Rx is indicated
■ >18 months HIV antibody seropositive
■ Stage 3 irrespective of cd4% or TLC
■ Stage 2 with CD4<15% or TLC<1500
■ Stage 1 with CD4 <15%
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 24
Recommendations (cont.)
■ Children >8 yrs can be managed like adults
■ Antiretrovirals for pediatric use:
■ As of January 2004, 22 drugs are approved for adult
use. Only 12 are recommended for pediatric use
■ The list includes zidovudine, lamivudine, stavudine,
didanosine, zalcitabine ,abacavir & emticitabine
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 25
Recommendations (cont.)
■ NNRTI: The list includes three drugs nevirapine,
efavirenz & delavirdine
■ Protease inhibitors: nelfinavir, lopinavir, ritonavir,
indinavir, amprenavir, atazanavir, fasamprenavir,
saquinavir
■ Fusion inhibitors: enfuvirtide(T-20)
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 26
First Line ART for Children
in Ethiopia
■ ZDV/3TC or 3TC/D4T plus NNRTI
■ Use nevirapine for those < 3yrs & <10Kgs
■ Use nevirapine or efavirenz > 3yrs & >10Kgs
■ ZDV/3TC plus ABC
■ Implication of nevirapine resistance after PMTCT
use
■ Increase the dose of ART as the child grows
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 27
Second Line Treatment
■ 2NRTI plus protease inhibitor:
■ ABC/DDI plus lopinavir/ritonavir
■ ABC/DDI plus nelfinavir
■ ABC/DDI plus saquinavir if wt>25kgs
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 28
Introductory Case –
Answers (cont.)
■ The statement D): Treatment options are very
limited for pediatric patients, so they have to get
used to the regimen that is chosen for them, is
false.
■ As you can see, there are options available, even
for pediatric patients. As with adults, an ART
regimen may need to be tailored to a particular
child who has unique circumstances.
Unit 10: ART in Children
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28
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 29
Monitoring Response to
Therapy
■ Should be guided by immunolgic, clinical and
virologic parameters
■ Detailed clinical evaluation is important
■ Basic recommended lab tests
■ Assess adherence & drug tolerance
■ Clinical signs of positive response, improvement in
growth, improvement in neurological symptoms,
decrease in frequency of infections
Unit 10: ART in Children
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29
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 30
Monitoring Response (cont.)
■ If available CD4 count and percentage are the
most useful and reliable way in assessing
effectiveness of ART
■ Monitoring plasma RNA level
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 31
Indications to Change ART
■ Three conditions
■ 1-Treatment failure with evidence of disease progression
based on virological, clinical, and immunological parameters
■ Virological:
a) repeated detection of HIV RNA in children who had
undetectable level
b) HIV RNA not suppressed to undetectable after 4-6 months
of ART
c) less than a minimally acceptable response after 8-12
weeks of Rx (a less than 10 fold decrease from baseline)
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 32
Indications to Change
ART (cont.)
■ Clinical
a) progressive neurodevelopmental deterioration
b) growth failure
c) disease progression
■ Immunological
a) significant change in cd4 percentage i.e. a drop from
15%-10%
b) rapid and substantial decline in CD4 count
(i.e.>30%drop in<6months). Before decision repeat test
is required a week after initial result
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 33
Indications to Change
ART (cont.)
■ Toxicity and intolerance to the current regimen
■ New data demonstrating that a new drug or
regimen is superior to the current regimen
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 34
Case 1 and Questions
■ An eight months old infant presented with a Hx of oral
lesions of two months duration. On evaluation oral
candidiasis was noted. Three months back the baby was
admitted to TAH hospital for management of severe
pneumonia. Anthropometrical data showed no abnormality.
His HIV antibody test was HIV positive but virologic and cd4
test was not done.
■ How would you classify this child using the WHO staging system?
■ Would you recommend ART?
■ How would you treat the opportunistic infections?
■ What prophylaxis would you recommend?
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 35
Case 2
■ A seven months old child presented with a Hx of
high grade fever & neck stiffness of two days.
There was no Hx of seizure. The child was
recently hospitalized for Mx of pyogenic meningitis.
PE revealed nuchal rigidity & temp of 39.
Anthropometric data indicated failure to thrive. CSF
analysis showed pleocytosis and culture grew
Strept. pnuemoniae. HIV antibody test was
positive
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 36
Case 2 - Questions
■ Using the WHO classification system, what stage is
this child in?
■ What lab tests would you suggest?
■ What ART regimen do you suggest?
■ What PCP prophylaxis would you recommend?
■ What follow-up would you recommend for this
child?
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 37
Key Points
■ An increasing number of children are becoming infected
with HIV/AIDS.
■ Only a small percentage of HIV/AIDS infected children have
access to ART in developing countries.
■ In working with pediatric patients, special considerations
(see WHO guidelines) for treatment and diagnosis must be
taken into account.
■ Adherence to treatment presents a special challenge within
the pediatric population.
Unit 10: ART in Children
37
•
Review Key Points with participants
•
Ask for further questions about the unit.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 38
References
■ Frenkel, L., M.D. Children’s Hospital and Regional Medical
Center, Seattle, WA, USA, September, 2004.
■ Frick, P., PharmD, MPH, Clinical Pharmacist, HIV/AIDS,
Harborview Medical Center, Seattle, WA, USA, 2004.
■ Guidelines for use of Antiretroviral Drugs in Ethiopia,
August 2004
■ McGilvray, M., & Willis, N., All about Antiretrovirals: A Nurse
Training Programme, Trainer’s Manual, Africaid, 2004.
Available online at: www.aidsmap.org
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
Unit 10: ART in Children
Slide 39
References (cont.)
■ Mok, J., and Newell, M-L., (1995) HIV Inf in Children.
■ Moss, V. HIV: Clinical Presentations in Children. The
Mildmay Center, Kampala, Uganda.
■ Saloojee, H., & Violari, A., HIV Inf in children. BMJ 2001;
323:670-4
■ UNAIDS (September 2002) Pediatric HIV Infection and
AIDS.
■ WHO World Health Organization (2002) Scaling up
Antiretroviral Therapy in Resource Limited Settings:
Guidelines for a Public Health Approach.
Unit 10: ART in Children
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HIV Care and ART: A Course for Pharmacists
References
Frenkel, L., M.D. Children’s Hospital and Regional Medical Center, Seattle, WA,
USA, September, 2004.
Frick, P., PharmD, MPH, Clinical Pharmacist, HIV/AIDS, Harborview Medical Center,
Seattle, WA, USA, 2004.
Guidelines for use of Antiretroviral Drugs in Ethiopia, August 2004
McGilvray, M., & Willis, N., All about Antiretrovirals: A Nurse Training Programme,
Trainer’s Manual, Africaid, 2004. Available online at: www.aidsmap.org
Mok, J., and Newell, M-L., (1995) HIV Inf in Children.
Moss, V. HIV: Clinical Presentations in Children. The Mildmay Center, Kampala,
Uganda.
Saloojee, H., & Violari, A., HIV Inf in children. BMJ 2001; 323:670-4
UNAIDS (September 2002) Pediatric HIV Infection and AIDS.
WHO World Health Organization (2002) Scaling up Antiretroviral Therapy in
Resource Limited Settings: Guidelines for a Public Health Approach.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART in Children
Unit 10-5
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 11
Communicating with Patients and Providers
Unit 11: Communicating with Patients and Providers
Aim: The aim of this unit is to assist pharmacists in developing communications skills
for counseling patients and interacting with providers.
Learning Objectives: By the end of this unit, participants will be able to:
•
Describe the team approach to ART care and treatment
•
Explain basic principles and behaviors of ART counseling
•
Describe essential steps in communicating with an HIV positive patient
•
Demonstrate effective communication with patients and providers
Unit Overview:
1 Hour 50 minutes
Step
Activity/
Method
Time
Content
Resources
Needed
1
20 minutes
Lecture
Communicating with Patients and
Providers (Slides 11.2-11.11)
Overhead or LCD
Projector
2
80 minutes
Group Exercise
Role Play Exercises (Slides 11.1211.24)
Flip chart stand with
paper and markers.
3
10 minutes
Summary
Presentation of Key Points (Slide
11.25)
Overhead or LCD
Projector
Resources Needed
•
•
•
Flip Chart and Paper
Markers
Overhead or LCD Projector
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Communicating with Patients and Providers
Unit 11-2
Key Points
1. A team approach to HIV care and treatment is an effective way to care for HIV
positive patients.
2. Good communication with providers and patients is essential for successful
HIV care and treatment.
3. Pharmacists need to counsel patients on ART readiness, ART information,
and the importance of adherence and ongoing monitoring.
Step 1
Lecture (20 minutes)
•
•
•
Step 2
Step 3
This unit will encourage participants to develop communication skills
for counseling patients and interacting with providers.
Begin by reviewing the learning objectives on Slide 11.2 of the
PowerPoint presentation, “Communicating with Patients and
Providers.” Ask the participants if they have any questions about the
objectives before continuing.
Present and discuss Slides 11.3-11.11.
Group Exercise (80 minutes)
•
Role Play Group Exercise: (Slides 11.12-11.24) Divide participants
into small groups (5-8 per group). Select 2 participants to do the
Role Play for each group. 1 person will be the pharmacist/druggist.
1 person will be the patient OR the physician/nurse.
•
Select 1 participant to provide feedback to the pharmacist about
how the counseling session went (e.g., language, professionalism,
information provided, empathy, etc.) Spend 10 minutes on each
role play.
Summary (10 minutes)
•
Summarize the presentation, review the Key Points presented in
this Unit (Slide 11.25), and answer final questions.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Communicating with Patients and Providers
Unit 11-3
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes for
reference during the planning and implementation of this course. The facilitation
notes and talking points are included in the “notes” section of the accompanying
PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Communicating with Patients and Providers
Unit 11-4
Unit 11: Communicating with Patients and Providers
Slide 1
Communicating with
Patients and Providers
Unit 11
HIV Care and ART: A Course for Pharmacists
This unit should take approximately 1 hour, 50 minutes to complete.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 2
Unit Learning Objectives
■ Describe the team approach to ART care and
treatment
■ Explain basic principles and behaviors of ART
counseling
■ Describe essential steps in communicating with an
HIV positive patient
■ Demonstrate effective communication with patients
and providers
Unit 11: Communicating with Patients and Providers
2
•
Review learning objectives of the unit with participants.
•
To begin a discussion on communicating with patients and providers, ask participants:
•
What challenges do you face when you talk with patients about their medications?
•
What challenges do you face when you communicate with physicians and nurses
about medications and drug regimens of any kind?
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 3
Team Approach in ART
■ Involves pharmacist or druggist, physician and
nurse working together towards comprehensive
patient care
■ Involves information sharing between providers
and patients
■ Ensures patient confidentiality
■ May involve others (family members) as patient chooses
Unit 11: Communicating with Patients and Providers
•
3
Ask participants to discuss why a team approach to ART is the best way to provide
effective care and treatment to patients with HIV.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 4
Objective of ART Counseling
To be able to effectively work with both patients
and physicians/nurses, pharmacists and druggists
need to be able to share information
On a professional level with physicians and nurses
Ie. “The combination of DDI and D4T increases the risk of
pancreatitis and peripheral neuropathy, therefore it is not
recommended that they be used together.”
With an individual patient on a level that he/she can
understand
Ie. “ D4T may cause peripheral neuropathy, this would feel like
tingling in your hands and or feet. It may be painful.”
Unit 11: Communicating with Patients and Providers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 5
Communication Skills for
Physician/Nurse Interaction
■ Begin by identifying yourself
■ Identify the patient whom you are to discuss
■ Present the issue that you have identified or your concern
■ Never use judgment
■ Use your professional report to gain respect
■ Be prepared to discuss the issue on a professional level
■ Propose a solution
■ Await feedback
Unit 11: Communicating with Patients and Providers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 6
Communication Skills for
Physician/Nurse Interaction (cont.)
■ You may not always have all of the answers to the
questions that follow.
■ Be comfortable saying that you do not know the answer at
the moment, that you will look into it and get back to the
provider as soon as you can.
■ The provider will respect that you will only give them
information that you are confident with.
■ Over time you will build a working relationship with the
physicians and nurses that you work with.
Unit 11: Communicating with Patients and Providers
6
•
Ask participants to share their positive or negative interactions with other health care
workers.
•
Why did they think it was positive? Why negative?
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 7
Essential Counseling Points
when Communicating with Patients
■ Assess readiness to start therapy
■ Identify barriers to success with ART
■ ie. financial concerns, sustainability, fears of side effects,
nonadherence
■ Correct the barriers before starting therapy
■ Every patient will have unique barriers to success
■ Provide specific ART information
■ Dosing, schedule, meal requirements, early and late side
effects, side effect management, drug interactions,
storage requirements, efficacy
Unit 11: Communicating with Patients and Providers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 8
Counseling Points when
Communicating with Patients (cont.)
■ Review need for strict adherence
■ > 95% adherence necessary for treatment success ( < 3
missed doses per month)
■ Prevent resistance and treatment failure
■ May limit future treatment options
■ Give the patient examples of how to remember to take
their doses
■ i.e., When they brush their teeth or when they wake up their
children
■ Assist patients in preparing for changes in their routine
■ i.e., Vacation or visiting family
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 9
Counseling Points when
Communicating with Patients (cont.)
■ Review need for ongoing clinical and laboratory
monitoring
■ Success of ART regimen
■ Toxicities
■ Detect ART side effects that the patient may not feel
■ Evaluate symptoms
Unit 11: Communicating with Patients and Providers
•
9
When assessing adherence at the follow-up visits, it is better to ask when a patient last
missed a dose, rather than asking have you missed a dose.
•
If you phrase the question, “when did you last miss a dose,” you can tell the
patient, that it is realistic that patients will miss doses from time to time.
•
If you ask the patient, “have you missed any doses,” they may tell you no because
they want to please their health care worker.
•
If they can tell you when they last missed a dose, you can help them to identify the
cause and provide a solution to avoid missing more doses in the future.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 10
Counseling Points when
Communicating with Patients (cont.)
■ Assess adherence each time patients refill their
ART
■ Ask “When did you last miss a dose?” rather than, “Have
you missed any doses?”
■ Congratulate the adherent patient
■ Identify the reason for missed doses and provide possible
solutions to avoid missing doses in the future
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 11
Counseling Points when
Communicating with Patients (cont.)
■ If written information is provided
■ Identify if the patient has any learning barriers: ie. low literacy
■ Pictures can be a helpful way of communicating information
■ Indicate colors of the pills to familiarize patients with their
regimen
■ Ensure written information is provided in patients native language
■ Show patients their regimen before they start ART
■ Familiarize them with the medication and allow them to express
any concerns ie. tablet or capsule size.
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 12
Practice Through Role Play
■ What is Role Play?
■ It is where you “Play the Role” of the pharmacist, for
example, in a practice setting.
■ You pretend to have a conversation with a health
professional or patient about a particular issue.
■ Role Playing allows you to see how you might react in a
certain situation before it arises.
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 13
Why Do We use Role Play
in Training?
■ Allows you to make improvements in your clinical
skills in a non-judgmental setting
■ Helps to improve interactions with physicians and nurses
■ Demonstrates effective patient counseling and helps to
identify areas of improvement
Unit 11: Communicating with Patients and Providers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 14
Format for Role Plays
■ Divide into small groups (5-8 per group)
■ Select 2 participants to do the Role Play for each
group
■ 1 person will be the pharmacist/druggist
■ 1 person will be the patient OR the physician/nurse
■ Select 1 participant to provide feedback to the
pharmacist about how the counseling session went
(e.g., language, professionalism, information
provided, empathy, etc.)
Unit 11: Communicating with Patients and Providers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 15
The Feedback “Sandwich”
■ Begin with a positive comment
■ Ie. “ I liked the way you approached the problem.”
■ Follow with suggestions for improvement
■ Ie. “ Next time, you might try to slow down your speech.”
■ End with a positive comment
■ Ie. “ You identified a potentially negative drug interaction
and corrected the problem.”
Unit 11: Communicating with Patients and Providers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 16
Providing Feedback on
Role Plays
■ Avoid negative feedback that the individual cannot
change (ie. the tone of their voice)
■ Instead, provide constructive criticism that can help
them improve on their skills
■ You may share an experience that you have had to
demonstrate your point
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 17
Role Play Scenarios - 1
■ A patient brings a prescription to the pharmacist for
stavudine + zidovudine + nevirapine
■ Contact the patient’s physician to alert them to the
drug interaction between stavudine and zidovudine
and recommend an alternative regimen
Unit 11: Communicating with Patients and Providers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 18
Role Play Scenarios - 2
■ A patient comes to your pharmacy and through your
conversation with him you discover that he meets criteria
for starting PCP prophylaxis (he has lost > 10% of body
weight and had TB last year). He is not currently taking
Bactrim for PCP prophylaxis.
■ Ask the patient if he has ever had Bactrim in the past and
try to find out if he has any drug allergies. Then, contact the
patient’s nurse/physician to suggest that the patient be
started on Bactrim DS daily for PCP prophylaxis if
appropriate
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
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HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 19
Role Play Scenarios - 3
■ A patient that you have gotten to know over the
past few months lets you know that they have been
losing weight lately. They have lost 5 kg so, they
now weigh 55 kg. You look at his medication
record and notice that he is taking Stavudine +
Lamivudine + Nevirapine.
■ Contact the patient’s physician or nurse and ask
them to reduce the dose of stavudine from 40mg to
30mg BID
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
19
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 20
Role Play Scenarios - 4
■ A patient comes to your pharmacy with new
prescriptions for:
■ Stavudine
■ Lamivudine
■ Nevirapine
■ He or she has never taken these medications
before
■ Counsel the patient about these medications
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
20
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 21
Role Play Scenarios - 5
■ A patient comes to the pharmacy and tells you that
he have been feeling itchy. He pulls up his shirt
and shows you a rash on his skin.
■ You look at their medication profile and can see
that he started the following regimen 3 weeks ago:
Stavudine + Lamivudine + Nevirapine.
■ You need to gather more information from the
patient to determine if the patient is having a mild
rash or a serious rash. Talk with the patient and
try to determine if the rash is mild or severe.
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
21
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 22
Role Play Scenarios - 6
■ Take the same patient discussed in Role Play
Scenario (5). You identify that the patient is having
a mild rash.
■ Contact the patient’s nurse or physician and pass
on the information about the nevirapine drug
reaction
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
22
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 23
Role Play Scenarios - 7
■ A patient comes to your pharmacy with a prescription for:
Nevirapine
Rifampin
Stavudine
Isoniazid & Pyridoxine
Lamivudine
Pyrazinamide
Ethambutol
■ You notice the drug interaction between nevirapine and
rifampin and recognize that these 2 drugs should not be
combined together.
■ Contact the patient’s physician/nurse and pass on the
information to them. Recommend an alternative regimen as
well.
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
23
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 24
Role Play Scenarios - 8
■ A woman comes to your pharmacy to refill her
prescriptions for stavudine + lamivudine +
nevirapine. She also has a new prescription with
her for oral contraceptives
■ You notice the drug interaction between the oral
contraceptives and nevirapine. Counsel her that
she needs to use an alternate form of birth control
to prevent becoming pregnant
Unit 11: Communicating with Patients and Providers
Reference Manual for Trainers
24
HIV Care and ART: A Course for Pharmacists
Unit 11: Communicating with Patients and Providers
Slide 25
Key Points
■ A team approach to HIV care and treatment is an
effective way to care for HIV positive patients.
■ Good communication with providers and patients
is essential for successful HIV care and
treatment.
■ Pharmacists need to counsel patients on ART
readiness, ART information, and the importance
of adherence and ongoing monitoring.
Unit 11: Communicating with Patients and Providers
•
25
Review key points with participants and ask for questions.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Communicating with Patients and Providers
Unit 11-5
Notes
HIV Care and ART for Pharmacists
Reference Manual for Trainers
ART in Children
Unit 10-6
HIV Care and ART:
A Course for Pharmacists
Reference Manual for Trainers
Unit 12
Universal Precautions (UP) and
Post Exposure Prophylaxis (PEP)
Unit 12: Universal Precautions (UP) and Post Exposure
Prophylaxis (PEP)
Aim: The aim of this unit is to identify universal precautions and post exposure
prophylaxis procedures to use when working with HIV patients and providers.
Learning Objectives: By the end of this unit, participants will be able to:
•
Describe proper standards for infection control, commonly understood as
Universal Precautions
•
Identify the risks, clinical management issues, and treatment methods for
exposures to HIV
•
Describe measures to maximize the effectiveness of PEP
Unit Overview:
Approximately 4 hours (includes end-of course tasks)
Step
1
2
3
Time
5 minutes
15 minutes
20 minutes
Activity/
Method
Content
Lecture
Review learning objectives (Slide
12.2)
Lecture
Universal Precautions (Slides 12.312.7)
Lecture
Post-Exposure Prophylaxis (Slides
12.8-12.25)
Resources
Needed
Overhead or LCD
Projector
Overhead or LCD
Projector
Flip chart stand with
paper and markers
Overhead or LCD
Projector
Overhead or LCD
Projector
4
60 minutes
Group Exercise
Case Studies (Slides 12.26-12.54)
Flip chart stand with
paper and markers.
5
6
10 minutes
90-120
minutes
Summary
End of Course Tasks
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Presentation of Key Points and
questions (Slides 12.55-12.56)
Overhead or LCD
Projector
Jeopardy! Review Game
Post-Assessment
Course Evaluation
Presentation of Certificates
-Overhead or LCD
Projector
-Jeopardy trainer
handouts 19.1 and
19.2
-Post Assessment in
Workbook
-Course Eval in
Workbook
-Certificates
Universal Precautions and PEP
Unit 12-2
Resources Needed
•
•
•
Flip Chart and Paper
Markers
Overhead or LCD Projector
•
Handouts in Workbook:
-Post Assessment
-Course Evaluation
•
Handouts for Jeopardy! Review game in this unit of the Reference Manual:
-Instructions
-Answers to game
•
Jeopardy PowerPoint slide set
Key Points
1. UPs should be implemented and practiced at all times by all health care
providers and caregivers in all settings (hospital, clinic, community settings,
and patient homes).
2. PEP is the use of therapeutic agents to prevent infection following exposure to
a pathogen
3. Risk factors for seroconversion vary according to the type of injury, viral load
of source patient, glove use, type of needle, and drying conditions.
4. PEP should be initiated as soon as possible (within hours).
5. Basic PEP regimen involves 2 NRTIs.
6. The most effective infection control measure that can be performed by health
care workers is handwashing with soap and water before and after patient
contact.
Step 1
Brief Lecture (5 minutes)
•
•
Step 2
This unit will identify universal precautions and post exposure
prophylaxis procedures to use when working with HIV patients and
providers.
Begin by reviewing the learning objectives on Slide 12.2 of the
PowerPoint presentation, “Universal Precautions and Post Exposure
Prophylaxis.” Ask the participants if they have any questions about
the objectives before continuing.
Lecture and Discussion (15 minutes)
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Universal Precautions and PEP
Unit 12-3
•
•
Step 3
•
Step 5
•
What would they list as basic universal precautions?
•
Have they seen instances in hospitals and clinics where
universal precautions were not used extensively?
After this short discussion, begin the lecture on universal
precautions using Slides 12.3 to 12.7.
Post-Exposure Prophylaxis (20 minutes)
•
Step 4
Before beginning the lecture on universal precautions, ask
participants what they understand by the term.
Before beginning this lesson, ask participants what they know about
post-exposure prophylaxis.
•
When do they believe PEP procedures should be carried out?
•
Have they seen PEP carried out?
Use Slides 12.8 to 12.25 to discuss post-exposure prophylaxis with
participants.
Case Study Exercise (60 minutes)
•
There are two case studies. For Case 1, use Slides 12.27 to 12.36
and for Case 2, use Slides 12.37 to 12.54.
•
Do not separate participants into groups. Review the case studies
as a large group.
•
These case studies provide information about each case on the
slides. Questions for these cases studies are on Slides 28, 37, 41,
44 and 46. Discuss the information provided after each question
slide that will help to answer the questions and provide important
information on PEP.
Summary (10 minutes)
•
Review the Key Points on Slides 12.55 and 12.56.
•
Ask participants for questions about UP and PEP before ending the
session.
•
End the session by asking participants about changes they may
need to make in their clinic or dispensary that will meet the
necessary guidelines and safety precautions outlined by the
universal precautions and PEP guidelines.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Universal Precautions and PEP
Unit 12-4
Step 6 End of Course Tasks
Allow at least 90 minutes (two hours is better) for these end-of course tasks on
the last day.
Review Content with Jeopardy
•
Jeopardy! Is a television game show popular in the United States
and elsewhere in the world. It is a test of knowledge and
contestants try to answer questions so that they can win as much
money as possible.
•
Read more about this game adapted for pharmacist ART training in
Handout 12.1 in this Reference Manual. There are also copies of
slides used to play this Jeopardy review game. You will need the
electronic copy of these slides to play the game.
•
The answers to each of the questions is provided in Handout 12.2.
•
If there is time, this review game can take 30 minutes. You can
also do a shortened version and not answer all the questions.
Post-Assessment
•
Refer participant to the Post-Assessment in their Course
Workbooks.
•
Make sure they have at least 20 minutes to answer the questions.
They should put the same code number on their post-assessment
that they used for the pre-assessment.
•
After you have collected all of the post-assessments, share the
answers to the assessment. They are located in Section One of
your Reference Manual.
Course Evaluation
•
Refer participants to their Course Workbook again. Ask them to
complete the Course Evaluation on the last two pages.
•
Collect the evaluations after approximately 15 minutes.
Course Certificates
•
Present a certificate of completion to each participant. This is the
last task to complete in the course.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Universal Precautions and PEP
Unit 12-5
Handout 12.1 Pharmacists Jeopardy Game
Are your students tired of sitting in class and listening to lectures for hours?
Would you like to make your teaching more interactive and entertaining? Well,
it’s time for Jeopardy! Jeopardy is a question and answer game that can test your
knowledge, as well as teach you new information.
How does it work?
You need to divide your class into two to four teams and each team will be
playing for points. The team with the most points at the end of the game will be
the winner. The game is somewhat different from a typical quiz where you are
asked questions and need to provide answers. In Jeopardy the participants will
be given answers and their task will be to provide questions to these answers.
The game is a Power Point document. You will need to start the slide
presentation to begin the game. The main slide (home) is a table with links to all
the questions in the game. The questions are grouped in columns with categories
(NRTI’s, HIV and Women, Drug Interaction, etc). The questions are worth
different number of points based on how difficult they are.
The first team of students will select a question (the category and the number of
points it is worth). You will need to click on the question on the screen in order to
see it. Another mouse click will initiate a countdown and the team will have to
answer the question (in the form of a question!) in 8 seconds or so. If the team
doesn’t know the answer or the answer is incorrect, the next team can try to
answer that same questions and win the points.
There is a penalty for incorrect answer – a team will actually lose the number of
points the question was worth if the answer they give is incorrect. You will need
to click again in order for the correct answer to appear on the screen. This is a
good time to discuss the question and make sure the whole class understands
the problem and knows how it applies to clinical practice.
Now you need to click on the “home button” in the right lower corner of the
screen and this will take you to the home slide and allow the next team to select
next question. Write down the number of points each team is winning or losing
after each round. You will need to keep track of all the points throughout the
game.
The game ends when all the questions in the table are answered and the team
with most points is the winner.
Jeopardy game created by Jeff Faris, PharmD, Harborview Medical Center, Seattle, WA.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Universal Precautions and PEP
Unit 12-6
Handout 12.2 Answers for Pharmacists’ Jeopardy
NRTI’s
NNRTI’s
PI’s
Managing
Side Effects
Drug
Interactions
- Peripheral
neuropathy is a
possible side effect of
these 3 nucleoside
reverse transcriptase
inhibitors.
- These NNRTI’s are
associated with the
development of rash.
- This medication is
seldom administered
as a sole PI, but is
frequently combined
with other PI’s to
enhance their
pharmacokinetics.
- Loperamide
(Immodium),
increasing dietary fiber,
and calcium carbonate
(Tums) are possible
remedies commonly
used with this
medication.
- Relating to drug
interactions, the
following (nevirapine,
efavirenz, rifampin,
rifabutin,
antiepileptics
(phenytoin,
carbamazepine,
phenobarbital)
are examples of CYP
__________________.
- What are efavirenz,
nevirapine, and
delavirdine?
- What are didanosine
(DDI), stavudine
(D4T), and zalcitabine
(DDC)?
- A hypersensitivity
reaction occurring in
approximately 5% of
patients and associated
with the following
symptoms is the result
of this drug.
Hypersensitivity
reaction: fever, skin
rash, fatigue,
gastrointestinal
symptoms such as
nausea, vomiting,
diarrhea, or abdominal
pain; respiratory
symptoms such as
pharyngitis, dyspnea, or
cough.
- What is abacavir (also
found in Trizivir)?
- These two drugs have
a reduced dose for
patients weighing less
than 60 Kg.
- What are didanosine
(DDI) and stavudine
(D4T)?
- What is ritonavir?
- What is nelfinavir?
- Commonly used as a
part of a PI-sparing
regimen, these two
NNRTI’s cause
induction of
cytochrome P450 3A4
enzymes, leading to
numerous drug
interactions.
- Of the PI’s, this
medication is the only
one that contains a
combination of two
different PI’s in one
capsule.
-If this drug causes
insomnia and/or
daytime drowsiness,
patients can try to take
their dose a few hours
before bedtime.
- What is
lopinavir/ritonavir?
-What is efavirenz?
- What are efavirenz
and nevirapine?
- What are Cytochrome
P450 enzyme
inhibitors?
- This NNRTI is likely
to cause inhibition of
cytochrome P450 3A4
enzymes.
- What is delavirdine?
- This PI is known to
caused nephrolithiasis –
to prevent this, it is
recommended that
patients drink at least
1.5 Liters of water
daily!
- What is indinavir?
- This NRTI should not
be used in a patient
with a hemoglobin less
than 7 mg/dL.
- What is zidovudine?
- What are Cytochrome
P450 enzyme inducers?
- Relating to drug
interactions, the
following are examples
of CYP_______.
(protease inhibitors,
ketoconazole >
itraconzole >
fluconazole,
delavirdine, efavirenz,
macrolide antibiotics
(erythromycin >
clarithromycin))
- This NNRTI must be
dosed at 200mg once
daily for 14 days and
then increased to
200mg twice daily
thereafter.
•Of the PIs, this
medication is the most
likely to cause diarrhea
as a side effect.
- Increases in
cholesterol and
triglycerides are
associated with this
group of antiretroviral
medications.
- What are Protease
Inhibitors (with the
possible exception of
atazanavir)?
- Dose reduction for
weight less than 60 Kg
is necessary to avoid
peripheral neuropathy
that can occur with
these drugs.
- What is nelfinavir?
- What is nevirapine?
HIV Care and ART for Pharmacists
Reference Manual for Trainers
- What are stavudine
(D4T) and didanosine
(DDI)?
- This anticonvulsant
can be safely used in
patients on protease
inhibitors
- What is sodium
valproate?
- These protease
inhibitors and NNRTIs,
when appropriately
dose adjusted can safely
be used with rifampin
- What are efavirenz
800 mg qhs,
lopinavir/ritonavir
400/400 mg bid,
saquinavir/ritonavir
400/400 mg bid?
Universal Precautions and PEP
Unit 12-7
NRTI’s
NNRTI’s
PI’s
- This drug is taken
once daily and should
be taken on an empty
stomach. However, it
can be taken without
regard to meals when
taken with tenofovir.
- Of the NNRTI’s, this
medication is
commonly associated
with abnormal dreams,
impaired concentration,
dizziness, and
drowsiness or insomnia.
- This medication is
most potent inhibitor of
cytochrome P450 3A4
among the protease
inhibitors.
- Women are more
likely than men to
experience these side
effects due to
nevirapine.
- What are rash and
hepatotoxicity?
- What is didanosine
(DDI)?
(Didanosine Cmax dec.
by 46% and AUC dec.
by 19% with food)
- What is efavirenz ?
- What is ritonavir?
(ritonavir >>
amprenavir, indinavir,
nelfinavir > saquinavir)
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Managing
Side Effects
Drug
Interactions
-This term refers to the
use of small doses of
ritonavir along with
another protease
inhibitor
- What is
pharmacokinetic
enhancement?
–Increase drug
exposure
–Compensate for
induction effect of other
drugs
–Decrease number of
daily doses
–Decrease pill count
–Possibly overcome
resistant species
–Activity primarily via
inhibition of CYP450
3A4
–May also inhibit
MDR-PGP cellular
efflux pumps
Universal Precautions and PEP
Unit 12-8
PowerPoint Slides & Facilitator Notes
The following pages contain copies of PowerPoint slides and facilitator notes for
reference during the planning and implementation of this course. The facilitation
notes and talking points are included in the “notes” section of the accompanying
PowerPoint slide set.
HIV Care and ART for Pharmacists
Reference Manual for Trainers
Universal Precautions and PEP
Unit 12-9
Unit 12: Universal Precautions and PEP
Slide 1
Universal Precautions (UP) &
Post-Exposure Prophylaxis (PEP)
Unit 12
HIV Care and ART: A Course for Pharmacists
•
This unit should take approximately 1 hour, 50 minutes to implement.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 2
Unit Learning Objectives
■ Describe proper standards for infection control,
commonly understood as Universal Precautions
■ Identify the risks, clinical management issues, and
treatment methods for exposures to HIV
■ Describe measures to maximize the effectiveness
of PEP
Session 12: Universal Precautions and PEP
2
•
Begin by reviewing the session aim and objectives. The aim of this session is
to provide an overview of Universal Precaution and Post-Exposure
prophylaxis (PEP) for occupational exposure to HIV.
•
Ask the participants if they have any questions before continuing.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 3
Importance of
Universal Precautions
■ Standards of infection control were developed to
prevent exposure and transmission of blood-borne
pathogens (HIV, HBV, HCV).
■ Should be implemented and practiced at all times
by all health care providers and caregivers in all
settings (hospital, clinic, community settings, and
patient homes).
Session 12: Universal Precautions and PEP
3
•
Most patient care does not involve any risk of HIV transmission. Therefore,
routine HIV testing of all health care workers or patients is NOT
recommended.
•
Most HIV-infected health care workers are infected through sexual contact,
and, to a lesser degree, through intravenous drug use, blood transfusions
and invasive surgical procedures, including organ transplantation.
•
Occupational exposure is rare. To minimize the risk of occupational
transmission of HIV (as well as other infectious diseases), all health care
workers should adopt appropriate infection, risk assessment and accident
prevention procedures.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 4
Principles of Universal
Precautions
■ Increased attention for the correct handling of
sharps and all infected materials
■ Safe disposal of waste contaminated with blood or
body fluids and proper handling of soiled linen
■ Hand washing with soap and water before and
after all procedures
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
4
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 5
Principles of Universal
Precautions (cont.)
■ Use of protective barriers, such as gloves, gowns,
masks, goggles when in direct contact with
potentially infected body fluids
■ Proper disinfection of instruments and other
contaminated equipment
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
5
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 6
Basic Universal
Precautions
■ Everyone is considered infectious; therefore, glove
before touching:
■ Non-intact skin
■ Mucus membrane
■ Blood & body fluids
■ Wash before and after gloving & in between
patients
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
6
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 7
Basic Universal
Precautions (cont.)
■ Use appropriate PEP
■ Use approved sharps disposal containers
■ Immunize when appropriate
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
7
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 8
Post-Exposure Prophylaxis
(PEP)
■ The use of therapeutic agents to prevent infection
following exposure to a pathogen
■ Types of exposures include percutaneous
(needlestick), splash, bite, sexual
■ For health-care workers, PEP commonly
considered for exposures to HIV and Hepatitis B
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
8
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 9
Post-Exposure Prophylaxis:
Core Principles
■ Evidence is limited
■ Balancing of risks vs benefits
■ Timing: the sooner the better, but interval beyond
which there is no benefit is unclear
■ Optimal duration unclear, 28 days is recommended
■ Decision making can become very complex when
resistance in SP suspected
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
9
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 10
Country PEP Policy
■ Current
■ Practice “universal precautions”
■ PEP will be made available as resources allow
■ Recommended revision – free PEP for:
■ HCW
■ Emergency personnel
■ Rape victims:
■ documented in adults
■ ASAP in minors
Session 12: Universal Precautions and PEP
10
•
The government of Ethiopia believes that PEP would be unnecessary if all
HCW were to observe and practice universal precautions.
•
The HIV core team working on ART implementation guideline has
recommended that PEP would be required even after the max universal
precautions have been observed.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 11
PEP Risk
Risk of viral transmission with sharp injury from
infected source:
Source
Risk (%)
HBeAg+
37 – 62
HBeAg-
23 – 37
HCV
1.8
HIV
0.3
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
11
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 12
HIV PEP
■ Exposures common
■ 56 documented cases of health care workers
contracting HIV from exposures; 138 other
possible cases
■ Area of considerable concern but little data
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
12
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 13
Occupational Exposure to HIV
■ Contaminated sharp injuries
■ Body fluid in contact with mucosa (splashes in eye)
■ Transmission estimated at 0.3% per exposure
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
13
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 14
Risk of BB
diseases
High
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
14
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 15
PEP: Non-immuned Employee
Stat HBsAg, patient &
employee blood
Employee Negative
Employee positive
Employee negative
Patient Negative
Patient negative
Patient positive
Test employee for HCV at:
HBiG stat, HBV series
6 weeks, 3 mos, 6 mos, 12mos
HCV FU at 6 w, 3m, 6m, 12 m
T. Gabre-Kidan, MD, I-TECH, September, 2003
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 16
Timing of PEP:
What’s the Evidence?
■ Animal PEP studies: suggest substantially less
effective beyond 24 - 36 hours
■ Case-control study: most subjects in each group
received PEP within 4 hours
■ Analysis of PEP failures does not suggest a clear
cut-off
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
16
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 17
Timing of PEP:
CDC Guidelines
■ Initiate as soon as possible (within hours)
■ Interval after which there is no benefit for humans
is undefined
■ “If appropriate for the exposure, PEP should be
started even when the interval since exposure
exceeds 36 hours”
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
17
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 18
Exposure to HIV-1
•
Following initial exposure weather through skin or sub-mucosal the virus is
taken by denderetic cell where it starts to multiply locally.
•
This process of local multiplication can last 2 to 3 days before reaching to a
regional lymph-node.
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 19
Step 1: Type of Exposure –
Determine Exposure Code (EC)
Exposure on
Mucous
membrane or
broken skin
Exposure on
Intact Skin
Determine
Volume
Few drops, short duration,
SMALL = EC 1
Several drops/long
duration/major blood splash
LARGE = EC 2
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
No PEP
Percutaneous
Exposure
Determine Severity
Solid, superficial
Scratch
LESS SEVERE = EC 2
Hollow needle, deep
Puncture
MORE SEVERE = EC
19
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 20
Step 2: Determine HIV Status
Code of Source (HIV SC)
HIV negative
HIV positive
Asymptomatic/high
CD4
HIV SC 1
No PEP
Advanced disease,
Primary Infection or
low CD4 count
HIV status
unknown or
source unknown
=
HIV SC
UNKNOWN
HIV SC 2
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
20
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 21
Step 3: Determine PEP
Recommendation from EC and HIV SC
HIV SC
EC
PEP Recommendation
1
1
PEP may not be warranted
2
1
Consider basic regimen
1
2
Recommend basic regimen
2
2
Expanded regimen recommended
1 or 2
3
Expanded regimen recommended
Unknown
Reference Manual for Trainers
Where EC is 2 or 3 and a risk exists,
consider PEP basic regimen
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 22
PEP Regimens: Basic
■ Two NRTIs
■ Simple dosing, fewer side effects
■ Common basic regimens:
■ zidovudine + lamivudine (Combivir)
■ stavudine + lamivudine
■ tenofovir + lamivudine?
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
22
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 23
Adverse Effects:
Basic vs Expanded Regimens
% of individuals
60
2 NRTI
2 NRTI + 1 PI
50
40
30
20
10
0
General
Lower GI Upper GI
Session 12: Universal Precautions and PEP
•
elevated
TG
hyperbilirubinemia
2x ALT
Puro V et al. 9th CROI, February 2002, Abstract 478-M
23
Trend towards higher rates of discontinuation in the expanded PEP regimen
group also
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 24
Tolerability of HIV PEP
in HCWs
Side Effects of PEP Regimens
6
Myalgias
14
Diarrhea
Vomiting
16
18
Headache
38
Fatigue
57
Nausea
0
20
40
60
80
100
Percent
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
24
HIV Care and ART: A Course for Pharmacists
1
Unit 12: Universal Precautions and PEP
Slide 25
Session 12: Universal Precautions and PEP
Reference Manual for Trainers
25
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 26
PEP Case Studies
Reference Manual for Trainers
HIV Care and ART: A Course for Pharmacists
Unit 12: Universal Precautions and PEP
Slide 27
Case 1
■ 27 yo female nurse presents to OPD for evaluation
of needle stick 2 days ago from a diabetic lancet.
■ Source patient (SP): 35 yo male known HIV+
(wasn’t known at the time)
Session 12: Universal Precautions and PEP
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Prese
