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ARV Drug Use in
Management of
HIV/AIDS in a
Resource Poor
Setting
Henry Njuguna,
MBChB IV
Contents
1 Introduction
3
2
3
4
4
5
6
6
7
7
8
9
5
6
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ARV drugs currently available for use
Life cycle of HIV and sites of drug action
Treatment of HIV in adolescents and adults
 Diagnostic tests
 When to start treatment
 W.H.O. staging of HIV/AIDS disease
 When to start treatment
 Recommended drug regimen
Long term adverse effects of HAART
Monitoring
Adherence
11
13
13
INTRODUCTION.
HIV/AIDS has caused and is still causing immense losses both socially and economically. Over 700
lives are being lost daily in Kenya to AIDS and millions of children being left as orphans.
Patients suffering from AIDS related opportunistic infections occupy more than 60% of our
hospitals’ bed capacity. It is not only expensive to treat this infections but treatment is often
ineffective as most patients have low immunity.
The developed countries have managed to control this pandemic with the use of anti-retroviral
(ARV) drugs, in a treatment protocol now referred to as the highly active anti-retroviral therapy
(HAART). They have less patients succumbing to AIDS and are able to prolong and give quality life
to HIV/AIDS patients.
Some developing countries too have been able to successfully manage HIV/AIDS using ARV drugs;
in Guatemala, Thailand, Malawi and other developing countries, hundreds of people who would
have died are instead living normal productive lives. Credit goes to the wide use of these ARV
drugs.
With the availability of cheaper generic drugs and pressure to drug companies to lower costs of
these drugs, it is expected that these drugs will soon be available to the average citizen. We should
therefore not lose hope but arm ourselves with the necessary skills that will enable us use these
drugs effectively.
Despite the fact that ARV drugs have the benefit of prolonging life, their use is associated with
numerous side effects and threat of emerging resistance. Health care personnel will play a pivotal
role in deciding who to treat, when to treat and the most suitable regimen of drugs to use.
It is therefore necessary that health care personnel concerned with management of HIV/AIDS
understand the ARV drugs available, the recommended regimens and their side effects and ensure
that patients know the importance of adherence to treatment. This will help reduce resistant strains
to the available drugs.
ARV DRUGS CURRENTLY AVAILABLE FOR USE.
These are grouped into four categories based on their mechanisms of action:
1.
2.
3.
4.
NRTIs
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Protease Inhibitors (PIs)
Fusion Inhibitors (FIs)
They compete with the hosts’ nucleotides to be incorporated into the viral DNA. Once incorporated,
they cause termination of the viral DNA chain. To be activated, they are first phosphorylated by
cellular kinases into the active triphosphate form. They include:
Common names
Other names
Abacavir
Ziagen
Didanosine
Videx, ddI
Emtricibine
Emtriva,
Lamivudine
Epivir, 3TC
Stavudine
Zerit, d4T
Tenofovir*
Zalcitabine
HIVID, ddC
Zidovudine
Retrovir, AZT, ZDV
*Nucleotide reverse transcriptase inhibitor
Combined drugs:
Trizivir: Abacavir+Zidovudine+Lamivudine
Combivir: Lamivudine+Zidovudine
NNRTIs
They do not require phosphorylation to be activated. They directly block the reverse transcriptase
enzyme and are not incorporated into the viral DNA. They include:
Common names
Other names
Delavirdine
Rescriptor
Efavirenz
Sustiva
Nevirapine
Viramune
PIs
They interfere with viral maturation process by blocking viral enzyme protease. They include:
Common names
Other names
Amprenavir
Agenerase
Atazanavir
Reyataz
Indinavir
Crixivan
Nelfinavir
Viracept
Ritonavir
Norvir
Saquinavir
Fortovase, Invirase
FIs
They work by preventing HIV from entering healthy T cells, proteins on outer surface of HIV i.e.
Gp140 and gp 41 must interact with cellular proteins and receptors on T cells i.e. CD4, CCR5,
CXCR4. Fusion inhibitors target these proteins and receptors to prevent the virus from infecting new
cells. Only one drug is available for clinical use:
-
Fuzeon (T20).
LIFECYCLE OF HIV AND SITES OF DRUG ACTION
The diagram shown below illustrates the lifecycle of HIV and the sites of drug action.
See explanation below
1: Fusion stage
The viral envelope proteins; gp120 and gp41 bind to host T cells containing CD4 receptors, CCR5
andCXCR4 co receptors. Fusion takes place and the virus is able to penetrate into the cell.
FIs attack this stage of the HIV lifecycle.
2: Reverse transcription stage
Reverse transcriptase a viral enzyme, translates the viral genetic material, RNA into DNA.
NRTIs and NNRTIs attack this stage by inhibiting the viral enzyme.
3: Integration
The translated viral DNA is incorporated into the host cell DNA by the viral enzyme integrase. This
programs the host cell to produce more HIV.
Integrase inhibitors are currently being developed.
4: Transcription
The two strands of DNA separate, a molecule known as messenger RNA (mRNA) is formed. This is
a step in the synthesis of new viruses.
Antisense nucleotides are being developed to attack this stage.
5: Translation
Protein building blocks are assembled according to the information contained by the mRNA to form
new viral particles
6: Viral assembly
Protein building blocks are cut into smaller pieces by viral enzyme protease. These pieces form the
structure of the new HIV particle including enzymes and proteins needed to repeat the reproductive
process. Once this has occurred, the new virus particle buds off the human cell and may infect new
cells.
Protease inhibitors attack this stage.
TREATMENT OF HIV/AIDS IN ADOLESCENTS AND
ADULTS
DIAGNOSTIC TESTS
Tests for diagnosis and monitoring HIV infection can broadly be divided into two:
1. Those that detect immunoglobulin antibodies (IgG) specific for HIV. (Antibody detection
tests).
2. Those that identify viral material.
1. Antibody detection tests.
These tests identify virus specific antibodies in serum. It takes about three months from the point of
infection for the antibodies to be produced in sufficient quantities for the tests to detect them. This is
known as the window period and it is important to keep it in mind when testing patients.
IgGs are able to pass through the placenta into the fetus and therefore infants of HIV positive
mothers may test positive when antibody detection tests are used. These maternal IgGs are cleared
from the fetal circulation after a period of about eighteen months and the infant may test negative
after this period has elapsed.
Some of the antigen detection tests available include:
 Antibody sensitive enzyme linked immunosorbent assay (ELISA). It requires expensive
equipment and skilled manpower and therefore is not widely used.
 Western blot. It is usually used to confirm positive results where two ELISA or rapid tests
are discordant. It is expensive and requires skilled personnel.
 Rapid antibody detection tests which include brands like: Determine, Unigold, Capillus,
Immunocomb etc that are locally available. They are cheap and simple to use and
interpret. They are widely used in voluntary counseling and testing (VCT) centers.
2. Tests that identify viral material.
Most of these tests require expensive equipment and skilled manpower and therefore are used in
special circumstances. They include:
 Polymerase Chain Reaction tests (PCR). This tests is used to determine the viral load in
HIV positive individuals in order to determine whether to initiate treatment or to note
how effective the treatment is.


P24 antigen test.
Viral culture
WHEN TO START TREATMENT,
This is based on:  Patient’s clinical as well as laboratory staging of the disease
 Patients acceptance as well as willingness to adhere to treatment
WHO STAGING OF HIV/AIDS
There are several classifications of HIV/AIDS staging. In this article W.H.O. classification, which is
recommended for resource poor settings, is shown below: WHO classification is based on clinical manifestations of HIV/AIDS and is categorized into the
following stages:
Stage 1
1. Asymptomatic infection
2. Persistent generalized lymphadenopathy
3. Acute retroviral infection
Patient’s performance: Asymptomatic with normal activity.
Stage 2
1. Unintentional weight loss < 10% body weight
2. Minor mucocutaneous manifestations e.g. Dermatitis, fungal nail infection, angular cheilitis
3. Herpes zoster within previous 5 years
4. Recurrent upper respiratory tract infections
Patient’s performance: Symptoms but nearly fully ambulatory.
Stage 3
1. Unintentional weight loss > 10% body weight
2. Chronic diarrhea > 1 month
3. Prolonged fever:>1 month
4. Oral candidiasis
5. Oral hairy leukoplakia
6. Pulmonary TB
7. Severe bacterial infections
8. Vulvovaginal candidiasis
Patient’s performance: in bed more than normal but <50% of normal day time during the previous
month
Stage 4
1. HIV wasting syndrome
2. Pneumocystis jiroveci pneumonia (pcp)
3. Toxoplasmosis of the brain
4. Cryptosporidiosis with diarrhea > 1 month
5. Isosporiasis with diarrhea > 1 month
6. CMV disease in any organ other than liver spleen or lymph nodes
7. Herpes simplex virus infection , mucocutanious
8. Disseminated mycosis
9. Candidiasis of the esophagus, trachea, bronchi or lungs
10. Disseminated atypical mycobacteria
11. Extra pulmonary TB
12. Lymphomas
13. Kaposi’s sarcoma
14. HIV encephalopathy
15. Non typhoid salmonella septicemia
WHEN TO START ARV THERAPY
If CD4 testing is unavailable:
 WHO stage IV disease irrespective of total lymphocyte count
 WHO stage II or III disease with a total lymphocyte count below 1200/mm3
If CD4 testing is available:
 WHO stage IV disease irrespective of CD4 count
 WHO stage I,II or III with CD4 counts below 200/mm3
RECOMMENDED DRUG REGIMEN
The table below is a guide to treatment regimens for patients who have no previous experience with
HIV therapy. Regimens should be individualized based on the advantages and disadvantages of each
combination such as pill burden, dosing frequency, toxicities, and drug-drug interactions, and
patient variables, such as pregnancy.
Preferred regimens are in bold type; these regimens have been selected by experts based on the
totality of virologic, immunologic, and toxicity data.
NNRTI-Based
Regimens
perday
Preferred Regimens
Efavirenz + lamivudine + (zidovudine or tenofovir DF or stavudine) – except for
pregnant women or women with pregnancy potential
Alternative Regimens
Efavirenz + lamivudine + didanosine - except for pregnant women or women with
pregnancy potential
Nevirapine + lamivudine + (zidovudine or stavudine or didanosine)
PI-Based
Regimens
of pills per day
Preferred Regimens
Kaletra® (lopinavir+ ritonavir) + lamivudine + (zidovudine or stavudine)
Alternative Regimens
Amprenavir + ritonavir + lamivudine + (zidovudine or stavudine)
Indinavir + lamivudine + (zidovudine or stavudine)
Indinavir + ritonavir + lamivudine + (zidovudine or stavudine)
Nelfinavir + lamivudine + (zidovudine or stavudine)
Saquinavir (sgc or hgc) + ritonavir + lamivudine + (zidovudine or stavudine)
Triple NRTI Regimen – As Alternative to PI- or NNRTI-based regimens
# of pills per day
Alternative Regimens
Abacavir + lamivudine + zidovudine
Abacavir + lamivudine + stavudine

Preliminary 96-week data comparing stavudine + lamivudine vs. tenofovir +
lamivudine revealed higher incidence of lipodystrophy and lipid abnormalities in the
stavudine group
sgc = soft gel capsule; hgc = hard gel capsule
LONG-TERM ADVERSE EFFECTS OF HAART
Long-term use of ARV drugs has been associated with the following adverse effects;



Hyperlipidemia especially due to efavirenz
Lipodystrphy and
Lactic acidosis both associated with stavudine
Immune reconstitution syndrome refers to the flaring up of dormant infection as a result of
immune restoration following HAART. Dormant infections such as TB, CMV, hepatitis B&C,
herpes etc may start manifesting again or get worse. This occurs in the early days of treatment and is
attributed to the ability of the restored immunity to fight the infection.
The table below shows Antiretroviral Regimens or Components That Should Not Be Offered
Rationale
Antiretroviral Regimens Not Recommended
Exception
Monotherapy


Two-agents drug
combinations


Rapid development of
resistance
Inferior antiretroviral
activity when compared to
combination with three or
more antiretrovirals

Pregnant women with
HIV-RNA < 1,000
copies/mL using
zidovudine
monotherapy for
prevention of
perinatal HIV
transmission
Rapid development of
resistance
Inferior antiretroviral
activity when compared to
combination with three or
more antiretrovirals

For patients currently
on this treatment, it is
reasonable to
continue if virologic
goals are achieved
Antiretroviral Components Not Recommended As Part of Antiretroviral Regimen
 No exception
Saquinavir hard gel
capsule (Invirase®) as
single protease
inhibitor

d4T + ddI in pregnancy
Reports of serious, even fatal,
cases of lactic acidosis with
hepatic steatosis with or without
pancreatitis in pregnant women
When no other
antiretroviral options are
available and potential
benefits outweigh the risks
Efavirenz in pregnancy

Teratogenic in nonhuman
primate
 When no other
antiretroviral options are
available and potential
benefits outweigh the risks
Amprenavir oral
solution in:

Oral liquid contains large
amount of the excipient
propylene glycol, which may
be toxic in the patients at
risk
 No exception




pregnant
women;
children <4 yr
old;
patients with
renal or hepatic
failure; and
patients treated

Poor oral bioavailability
(4%)
Inferior antiretroviral
activity when compared to
other protease inhibitors
with
metronidazole
or disulfiram
d4T + ZDV

Antagonistic
 No exception
ddC + d4T

Additive peripheral
neuropathy
 No exception
ddC + ddI

Additive peripheral
neuropathy
 No exception
Hydroxyurea


↓ CD4 count
↑ ddI-associated side effects
– such as pancreatitis &
peripheral neuropathy
Inconsistent evidence of
improved viral suppression
Contraindicated in
pregnancy
 No exception


MONITORING
Patients on HIV treatment should be assessed regularly. Thorough physical examination should be
done to check for signs listed in the WHO clinical staging of HIV/AIDS. Laboratory work up where
possible can be done. This will help a great deal to determine whether the treatment is effective and
assess any adverse drug reactions.
Although progress is being made in the search for more affordable testing methods for use in
resource-poor regions, it is important that lack of technology does not prevent the introduction of
treatment. For instance, most successful tuberculosis programs in resource-poor countries do not
monitor liver enzyme levels. As Joep Lange said, "There is actually very little evidence that
laboratory monitoring prevents mortality due to drug toxicity, but there is an awful lot of evidence
that not treating symptomatic HIV infection is lethal, and usually not in a nice way; why are we
always more concerned about doing harm than about not doing good?"
ADHERENCE
Adherence refers to the patient ability to take the prescribed drugs at the right dosages, at the right
time and in the right way without missing any dose. This enables the drugs to work effectively and
more so prevents resistance.
It is important to counsel patients on the need of adherence. They should also be made aware of
expected side effects of the drugs used.
References
Bertram G. Katzung: Basic and clinical pharmacology 8th edition
Ministry of Health: Guidelines to Antiretroviral Drug Therapy in Kenya
http://AIDSinfo.nih.gov
Harrison’s textbook of medicine
New England journal of medicine 2002, 347:1203-4
MY ELECTIVE TERM AT SEATTLE WASHINGTON
I must say that I am fortunate to have represented our medical school in an exchange program with
the University of Washington during my elective term. It’s practically impossible for me to put
down my two and a half month experience in Seattle but I’ll summarize some of my experiences in
this article.
Brief history of the program
This program was organized by the International Health Group (IHG) in collaboration with the
International AIDS Research and Training Program (IARTP).Four students from the University of
Washington visited our University in the middle of the year 2003. Unfortunately they were hardly
noticed by most of our students owing to their busy schedules in various research programs. Two
students from our university were chosen to represent our university as part of the exchange
program. We are the pioneer students in this newly started exchange program and we hope it is
going to continue.
Our university paid for our visa fees and promised to give us some stipend. The IHG working
together with other donors paid for our traveling expenses, accommodation expenses as well as a
small stipend for our upkeep. IARTP led by Dr Carey Farquhar played a pivotal role in coordinating
our learning activities during our stay in Washington, Seattle.
The flight to Seattle
We took off at exactly 1020pm. It was very exiting but a bit scaring being my first flight. I was
amazed, mesmerized and tantalized, though quietly in order not to elicit any unnecessary attention. I
settled down after saying a short prayer and I was able to appreciate this enormous vessel that was
taking us up right into the skies. I could not help imagine the weight it was caring and yet it was able
to keep afloat. There were also some funny contraptions that I had to get myself acquainted to, this I
successively did after reading the manuals and carefully stealing glances at passengers already using
them. The journey was however long and tiring.
We took a connecting flight from Amsterdam after going through some rigorous security checks.
We finally arrived at SeaTac airport after nineteen hours of flying; we again went through security
checks as well as document verification.
At the airport we were paged by one of the students and a member of the I HG. She took us to our
hosting family who were very welcoming.
We were led to our room and shown the necessary facilities we would need to use. After taking a
warm refreshing shower which I badly needed, we had dinner and later on went to sleep.
Learning continues
The following morning, we were taken to the university district and its environs. Everything looked
strange; the huge skyscrapers the big roads with gigantic vehicle riding on them. The streets were
amazingly quiet and well organized compared to the big city I knew before i.e. Nairobi. At first I
thought I was dreaming and I had to pinch myself on several occasions just to confirm.
Learning continued on the third day and serious business began though suffering from jet lag. It
was amazing how we managed to attend wardrounds, conferences and clinics with so much
enthusiasm. It was so exciting, learning new things especially in the wardrounds and conferences.
Well, Americans are well endowed in terns of financial facilities as well as technology. Their
medical practice is thus based on investigations. They are able to routinely order for what we
consider very expensive investigations such as MRIs. Their laboratories are also very efficient and
results are timely for proper management of patients.
They are also very strict on infection control systems. There are taps and soap in every ward and
medical personnel have to wash their hands after attending to each and every patient. In the
infectious diseases wards, one has to wear sterile gowns into each room.
It is also important to note how much they respect their patients and take their time to address their
concerns. They explain each procedure to the patient and request for his/her consent and respect it.
Drug therapy and procedures done are usually based on recent research. A doctor will often quote a
certain research to justify his choice of management. Students too are introduced to research quite
early and have to carry our one during his/her formative years in medical school i.e. end of their first
year. This I came to understand was what the four exchange students who had come to Kenya were
doing. This probably explains why they are very particular about research findings.
Their lectures are well conducted; reading material is first loaded into the departments’ website for
student access. Before attending a given lecture, the students ought to have read the material and
answered some given questions. This makes the lectures very interactive. The lecturers also
prepare slides, which are accompanied with audiovisual aids to explain the concepts better.
The libraries are well equipped with numerous computers, audiovisual aids i.e. TVs and Videos,
latest journals and textbooks as well as photocopy machines. Videotapes demonstrating clinical
examination techniques of different systems are available.
Despite all these seemingly good things, I did not like how medicine is practiced due to the fear of
being sued. After seeing a patient a doctor spends a considerably long period of time documenting
all he/she has done to the patient. Approximately; for every ten minutes spent in seeing one patient,
twenty minutes or even more is spent documenting. Due to this the students don’t have much ‘hands
on’ experience with their patients.
Social experience
We had a very interesting and enlightening moments with our host Dr Hunt who is a professor in
psychiatry and also the vice dean in the school of medicine. Note, he prefers being addressed to as
Doctor rather than Professor despite having a superior title.
He used to drop us at the university and return us back home in his gigantic truck. One question he
used to ask and was very motivating was, “without thinking much, what did you learn today?” One
had to think fast come up with an interesting learning experience. This made me very observant on
things I encountered the following day.
He also gave us insights on how to tackle life challenges. One interesting teaching was on how to
approach and answer questions. Mrs. Hunt, his wife is very motherly; she would cook for us and
ensure we were comfortable. She also gave us a chance to experiment on our cooking skills on
Saturdays.
The last 6 weeks of my 10 week stay at Seattle was spent with another family.
Elizabeth a final year medical student and her husband Bill Hutchinson is a very lovely young
couple. I was able to appreciate how good love can be for a young couple. I admired how mature
they conducted themselves, full of love and respect for each other.
In their house, I learned some cooking skills which were fun. By the time I was returning home, I
had added on three kilograms. Through them, I made many friends including Mr. & Mrs. George
Kerchney who will be visiting Kenya soon.
I was fortunate to get an invitation by some family friends who stay at the Eastern Coast of US in
Boston. Here I was able to visit great educational institutions including; Harvard University and
MIT amongst other landmarks.
I can summarise the whole trip as an eye opener. I believe we too can be able to improve our health
delivery system and society as a whole despite our limited resources. We should also appreciate and
respect the freedom we have when attending to our patients and not take advantage of this. Finally
the most important thing we need is determination and hard work, with the changes we are
experiencing in our country now, the future is bright. Let us support and encourage one another in
building our great Nation.
Henry Njenga Njuguna
MBChB IV
The following is a draft copy of what we intend to do in rehabilitating the health center.
Wangige Health Center Rehabilitation Project
Introduction
Wangige Health center opened its doors to serve the public on ---- by the late founding father Mzee
Jomo Kenyatta. Then, while still new, it was able to serve the community surrounding it with the
much needed vital health services. People were proud of it and benefited very much from it. There
was a sense of ownership as the community was deeply involved in its running and management.
It was well equipped with the following facilities;
 A general out patient clinic
 Maternal and family planning clinic
 Maternity ward
 Child welfare clinic
 A well stocked pharmacy
 Minor theatre
 A laboratory
 An ambulance for referral cases
 In addition it had staff quotas as well as room for future expansion
Today we talk of a different story and a sad story indeed. The facility has been grossly neglected.
Most of the facility’s services are not running as they were supposed to. Some of the services e.g.
maternity have actually been withdrawn. All this can be attributed to lack of community
involvement in running the facility. Most people now seek health services in private clinics which
are actually business entities with an aim of making profit. Those who cannot afford remain at home
suffering.
Problem statement
The aim of this proposal is to create awareness amongst the community on the need to have
ownership of the facility. This by extension will lead to long term improvement of the facility’s
services as the community will scrutinize its running and this will help restore its lost glory.
Methodology
Friends of Wangige have come up with various activities that will greatly involve the community in
rehabilitating the facility. These activities will be carried out during the Easter holidays as
scheduled;
Friday 9th April
 Cutting grass and clearing bushes
 Planting flowers and trees
 Repairing fences
Saturday 10th April
 Cleaning the rooms; removing cobwebs etc
 Repainting the health center’s buildings
 Repairing leaking roofs and damaged ceiling boards.
Monday 12th April
 Health education facilitated by medical students
 Free medical check up
 Laying down long term activities e.g. fixing water source, purchase of sterilizers, surgical
equipment
Target group
We are targeting the local community through churches and schools surrounding the facility. We
will also target companies and individuals who are in a position to donate items listed below:
 --liters of oil paint
 --numbers of paint brushes
 --rolls of barbed wire
 --numbers of fencing poles
 --kg of nails
 --numbers of ceiling soft boards
 --blankets and bed sheets for the maternity ward
 Suction pump
 Surgical kit
 Two sterilizers, one for the maternity ward and another for the minor surgery theatre a fridge
Justification
Wangige health center serves a population of --- people. The out patient clinic serves an average of-- per month. Monthly postnatal as well as child welfare clinic visits averagely total ----while
monthly antenatal visits --- unfortunately none of these mothers get to deliver in this facility. Most
of them deliver in hospitals far away from their homes while others deliver at home. This is not only
inconveniencing but can be a risk to the pregnant mother as well as her child.
The facility is not able to provide basic surgical services such as wound dressing. Emergency cases
e.g. road traffic accidents, severe dehydration etc that may benefit from basic first aid, may not
benefit much from this facility.
Background of friends of Wangige
Friends of Wangige was established six years ago, it is a group of young people drawn from the
neighborhoods of Wangige. It organizes Christmas parties for destitute children at the Nairobi
children’s home in Kabete every year for the last six years. During these parties, it mobilizes people
to donate foodstuffs, clothing, drugs as well as their services to brighten up the lives of these
children.
Our humble appeal
Finally we appeal to you as an individual or company to kindly assist us with the above items. We
would appreciate if you give as physical items instead of cash. Your ideas on how to improve it will
also be appreciated.
Yours truly,
Friends of Wangige