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Changing Antiretroviral
Therapy
Unit 9
HIV Care and ART:
A Course for Physicians
Learning Objectives
 Explain the different reasons for changing
therapy.
 List important drug toxicities that necessitate
changing therapy.
 Describe the clinical, immunologic, and virologic
indicators of ART failure.
 Describe the principles of changing therapy in
the event of drug toxicity and treatment failure.
 List factors to consider when changing ART.
2
Reasons to Change Therapy
 Toxicity
 Treatment Failure
 Clinical failure
 Immunologic failure
 Virologic failure
 Pregnancy
 Treatment of active tuberculosis
 Non-adherence
3
Changing Therapy Due to Toxicity
 Toxicity: Organ dysfunction and/or intolerable
side effects of a medication.
 Detected as a result of patient report, physical
exam, and laboratory tests.
 Approximately 50 percent of patients treated for
years with good viral suppression will require a
change in therapy due to an adverse reaction
4
Principles of Managing Adverse Events
 Establish whether the adverse event is due to
ARV drugs, other drugs, or diseases.
 Try to identify the responsible ARV drug.
 Assess the severity using ACTG (AIDS Clinical
Trial Group) grading system
5
Lab Grading of Adverse Events in Adults
and Adolescents (ACTG)
Item
Grade 1
Grade 2
Grade 3
Grade 4
Hgb (g/dl)
8 - 9.4
7 – 7.9
6.5 - 6.9
< 6.5
ANC(/mm3)
10001500
750 -990
500 - 749
<500
<49,000
--
Platelets(/mm3)
ALT (×ULN)*
-1.25-2.5
-2.5-5
5-10
>10
Bilirubin((×ULN)
--
--
3-7.5
>7.5
Creatinine(mg/dl)
--
--
1.2-1.5
>1.5
* “ULN” = Upper limit of normal value
6
Clinical Grading of Adverse Events in Adults
and Adolescents (ACTG)
Item
Grade 1
Grade 2
Grade 3
Grade 4
Peripheral
neuropathy
Mild
discomfort
&/or
impairment
Moderate
discomfort
&/or
impairment
Severe
discomfort &/or
impairment;
sensory loss to
knee and wrist
Incapacitating
or not
responsive to
narcotics;
sensory loss
involves limb
& trunk
Rash
Erythema,
prurius
Diffuse
maculopapular rash or
dry desquamation
Vesiculation,
moist
desquamation
or ulceration
Erythema
multiforme,
SJS, or TEN
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Changing Therapy Due to ToxicitySpecific Exchanges
 d4T induced neuropathy or pancreatitis: switch
to AZT
 AZT induced anemia: switch to d4T
 EFV induced persistent CNS toxicity: switch to
NVP
 NVP induced hepatotoxicity or non-life
threatening severe rash: switch to EFV
 NVP induced life threatening rash like SJS:
switch to PI
8
Discontinuation for Severe Toxicity
 If severe toxicity identified, need to stop ALL HIV
drugs
 Do not reinitiate ART until toxic effect has
resolved
 When stopping NVP, do not re-challenge
 Substitute new HIV drug for the drug that caused
the toxicity, if known (e.g., if NVP hepatotoxicity,
substitute EFV)
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Stopping Drugs with Different Half
Lives
Last Dose
Day 1
Drug concentration
Day 2
MONOTHERAPY
IC90
Zone of potential replication
IC50
0
12
24
Time (hours)
36
48 10
Source: S. Taylor et al. 11th CROI Abs 131
Introductory Case: Abebe
 Abebe, a 30-year- old HIV positive woman has
been taking d4T+3TC+NVP for the last 2 months
 Her baseline CD4 count was 150/mm3
 Gained weight and strength in the first 6 weeks
of starting ART
 Developed anorexia, nausea and vomiting with
jaundice in the last 2 weeks
 Became weak and confused in the last 2 days
 On exam, she has deep icterus and tender liver;
confused, with flapping tremor
11
Introductory Case: Abebe (2)
 What are the likely differential diagnosis?
 What tests would you request?
12
Introductory Case: Abebe (3)
 Lab tests revealed:
 ALT: 800 IU/L ( normal value = upto 40)
 Bilirubin( total): 12mg/dl ( normal upto 1mg/dl)
 HBs Ag and anti HCV Ab: negative
 How would you manage her?
13
Causes of ART Failure
Preexisting Resistance
Limited Potency of Regimen
Host Immune Failure
Poor Absorption
Rapid Elimination
Drug-Drug Interactions
Imperfect Adherence
Persistent Viral Replication
Drug Failure
14
Treatment Failure
 Treatment failure can be classified as:
 Clinical failure
 Immunologic failure
 Virologic failure
15
Clinical Failure
 Clinical Failure: clinical disease progression
despite HAART given for a sufficient time to
allow immune restoration, or clinical disease
following a period of HAART-induced immune
restoration.
 Development of an OI or symptomatic disease
 Development of an HIV-related malignancy
 Should be differentiated from Immune
Reconstitution Inflammatory Syndrome
16
Immune Reconstitution
Inflammatory Syndrome (IRIS)
 Different from clinical failure
 IRIS is the clinical manifestation of a sub-clinical
infection that was already present at baseline,
brought about by HAART-induced reconstitution
of the immune system
 Typically seen within the first several weeks after
initiating HAART
17
Immunologic Failure
 Fall in CD4 counts more than 30% from peak
value or
 A return of CD4 count to, or below, the pretreatment baseline
 Not usually not seen for several months or
maybe years after starting successful ART.
 CD4 count can take a long time to come back up
even on effective ART, and may never reach a normal
level if initially significantly suppressed
18
Virologic Failure
 Failure of viral load to become undetectable
after 24 weeks of ART (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 6-8 weeks of HAART
 Need to ensure that failure is not due to lack of
adherence.
19
Virologic Failure with non-initial Suppression
Courtesy of David H. Spach, MD; NW AETC, University of Washington
20
Virologic Failure after Initial Response
Medications Started
50
50
Courtesy of David H. Spach, MD; NW AETC, University of Washington
21
Causes of Failure of Therapy
 Poor adherence – most common and important reason
 Viral resistance
 Diminished efficacy of ARVs
 Decreased absorption of ARVs
• Drug-food interactions (eating/not-eating with meds 
malabsorption)
• Drug-drug interactions
• Other disease processes in GI tract
• Colitis, gastritis, diarrhea lead to rapid transit times in intestines
 Inadequate dosage
 Increased metabolism
22
Time
Clinical Failure
E
f
f
e
c
t
Immunologic Failure
A
n
t
i
v
i
r
a
l
Virologic Failure
Time Course of Treatment Failure
.
23
Which Measure of Treatment Failure
Should be Used?
 Virologic failure precedes immunologic & clinical
failure
 Periodic viral load screening therefore offers
advantage of detecting treatment failure earlier,
when more options may exist for subsequent
treatment regimens
 However, viral load testing is also very
expensive: Is the benefit of earlier detection
worth the cost?
24
Introductory Case: Abebe (4)
 Abebe continued to take d4T+3TC+EFV for the
last 2 years
 Has been doing well clinically until 3 months
back
 CD4 count was 220/ mm3 6 months back
 In the last 3 months, she started to have
recurrent diarrhea and lost weight
 On exam, she has oral thrush
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Introductory Case: Abebe (5)
A. What is wrong with Abebe?
B. What additional information would you like to
know?
C. What lab tests are important for managing this
patient?
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Introductory Case: Abebe (6)

Abebe claims that she misses only 1 or 2
doses of ARV drugs in 3 months
 CD4 count: 142/mm3
 Viral load and resistance testing not available
A. What is your assessment?
B. How would you manage her?
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Treatment Failure Approach
 Adherence! Adherence! Adherence!
 Revisit co-morbid conditions that might be
interfering, e.g. mental health; substance abuse
 Inquire about side effects that may have
contributed to poor adherence
 Before moving on to the next regimen, try to
identify and correct the cause of treatment
failure with the initial regimen
28
Changing Therapy in the Setting
of Treatment Failure
 In the setting of treatment failure, resistance
should be suspected once complete nonadherence (“drug holiday”) is ruled out
 A completely new regimen that includes a new
class of agents is ideal
 Resistance testing, if available, can help to guide
the selection of the new regimen
 Without resistance testing, empiric decision
making based on clinical history is indicated
29
Case Study: Management
 Management
 Strong adherence counseling
 Start her with 3 new drugs; preferably 1 of which is
from a new class of drugs
 ABC or TDF or AZT
and
 ddI
and
 LPV/r or SQV/r or NFV
30
Second Line Regimens- Ethiopian Guideline
First-line Regimen
Second-line Regimen
d4T or ZDV
and
3TC
and
NVP/EFV
ABC or TDF or ZDV (if not taken)
and
ddI a
and
LPV/r b or SQV/r b or NFV
31
Group Discussion
 Would it be better to change to a second
regimen sooner or later after ART failure and the
development of viral resistance?
 Ideally, we want to change from a failing regimen
as soon as possible
32
CNA3005: Slow Stepwise Appearance of
Mutations in Patient With Virologic Failure
Plasma HIV-1 RNA log
4.5
4
WT
5000 c/mL
28 weeks of
M184V only
M184V
D67N/D, K70R/K, M184V
M184V, Y215T/Y
M41L/M, M184V, Y215Y
M41L, M184V, Y215Y
M41L, M184V, L210L/W, Y215Y
3.5
ABC=6.2,
ZDV=12.2-fold
3
400 c/mL
2.5
2
ABC=5.9, ZDV=4.1-fold
50 c/mL
1.5
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
Study week
33
Source: Melby T, et al. 8th CROI; February 4-8, 2001; Chicago, IL. Poster 448.
Antiretroviral Resistance Testing
 Goal of resistance testing is to identify these resistanceconferring mutations in order to design a ‘salvage’
regimen intelligently
 Studies have documented clinical benefit of resistance
testing
 Expert advice on interpretation of the genotype is vital
 Two types:
 Genotyping (less expensive; can be completed in 1-2 weeks)
 Phenotyping (more expensive; generally takes 2-3 weeks)
34
Factors to Consider When
Changing Regimen









Prior antiretroviral history (assessment of adherence)
Ability to follow-up in clinic
Side effects
Antiretroviral resistance
Barriers to adherence
Patient life-style and preferences
Drug interactions
Cost and sustainability
Ethiopian ARV Guidelines
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Summary Guidelines for Changing ARV
Regimens





Utilize caution when considering ARV change
Assess adherence
At least 2 new drugs
Preferably 1 new drug class
Don’t add one drug to a failing regimen
36
Summary Guidelines for Changing ARV
Regimens (2)





Consider resistance & cross resistance
Quality of life in end stage disease
Get advice from experienced clinicians
Consider resistance testing if available
Premature changing in ARV can limit future
options
37
Case Study
Handout 9.1
Key Points
 If drug toxicity (grade 3 or 4) occurs, replace the
offending agent with a drug which doesn’t cause
the specific side effect.
 If there is a life threatening toxicity, stop all drugs
until patient’s condition is stabilized
 In case of treatment failure, first check patient’s
adherence and then change all 3 drugs
39
Key Points (2)
 The main reasons for changing ART are
treatment failure and drug toxicity. Treatment
failure may be clinical, immunologic, or virologic.
 Other reasons include problems with adherence
or other medical conditions, or illnesses that may
impact choice of therapy such as pregnancy or
TB.
 Regular clinical and laboratory monitoring is
necessary to detect side effects and to monitor
success/failure of therapy.
40