Transcript HIVART_9 - I-TECH

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.
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Reasons to Change Therapy
 Toxicity
 Treatment Failure
 Clinical failure
 Immunologic failure
 Virologic failure
 Pregnancy
 Treatment of active tuberculosis
 Non-adherence
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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
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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
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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
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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
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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
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Introductory Case: Abebe (2)
 What are the likely differential diagnosis?
 What tests would you request?
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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?
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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
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Treatment Failure
 Treatment failure can be classified as:
 Clinical failure
 Immunologic failure
 Virologic failure
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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
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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
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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
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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.
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Virologic Failure with non-initial Suppression
Courtesy of David H. Spach, MD; NW AETC, University of Washington
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Virologic Failure after Initial Response
Medications Started
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Courtesy of David H. Spach, MD; NW AETC, University of Washington
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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
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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
.
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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?
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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
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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
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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
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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
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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
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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
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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)
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Factors to Consider When
Changing Regimen
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





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
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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
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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
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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.
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