Transcript Session 11 - Teaching Slides

ARV Drug Resistance
HAIVN
Harvard Medical School
AIDS Initiative in Vietnam
Learning Objectives
At the end of this lecture, each trainee
should:
• Know how HIV develops resistance
• Know factors increasing the risk for
developing HIV resistance
• Understand genotypic resistance testing
2
Outline of Presentation
• What is resistance?
• How does resistance develop?
• Drug resistance in infants and
children
• Resistance testing
3
What is HIV Drug Resistance?
• Process by which changes (mutations)
in the HIV virus allow the virus to
become tolerant to antiretroviral drugs.
• Resistance is the consequence of
mutations that emerge in the viral
proteins targeted by antiretroviral
agents.
4
Clavel and Hance. N Engl J Med 2004;350:1023-35
How does resistance develop?
• Two important concepts:
HIV has an extremely high rate of
virus replication and production.
The reverse transcription of viral RNA
into DNA is prone to error (i.e
mutations).
On average one mutation is introduced for
each viral genome produced.
5
How does resistance develop?
• Each patient, therefore, develops a
mixture of viral ‘quasi-species’, each
differing by one or more mutations.
• These mutations may confer some
selective advantage to the virus, such as a
decrease in its susceptibility to an
antiretroviral agent.
• Potent combination ART prevents the
development of resistant strains by
maximally suppressing viral replication.
6
How does resistance develop?
• However, administration of
antiretrovirals in an insufficiently potent
manner selects for resistant strains.
Drug resistance emerges when HIV continues
to replicate in the presence of levels of drugs
that are insufficient to block viral replication
but sufficient to exert a positive selective
pressure on variants with decreased drug
susceptibility.
7
How does resistance develop?
8
Reversion to Wild-Type Virus After
Discontinuing ARV
9
Pediatric HIV Drug Resistance
• HIV drug resistance occurs when:
– When an infant acquires a resistant
virus from the mother
or
– When resistance mutations develop
because of ARV exposure for
prophylaxis or treatment.
10
HIV resistance: Perinatal Acquisition
ARV-naive
mother infected
with HIV already
resistant to ARV
Mother exposed
to ARVs before
becoming
pregnant
Mother exposed to
ARVs during
pregnancy (either for
her own health or
PMTCT)
Drug Resistant
Virus
in-utero
intrapartum
Infant
postpartum
during
breastfeeding
11
HIV resistance: ARV Exposure
Infant or child with HIV
Exposure to subtherapeutic
levels of ARVs during
breastfeeding (i.e. from
mothers receiving ART)
Infant ARV prophylaxis of
MTCT intervention (i.e.
single-dose NVP)
Treatment with ARVs
(see next slides)
Drug Resistant
Virus
12
HIV resistance: ARV Exposure
Drug concentration in blood
Changes of drug concentration in blood during treatment
Time
Failed to take
medication
Regular medication
Resistant HIV
Wild-type HIV
Lower limit of effective drug concentration in blood
13
HIV resistance: ARV Exposure
Poor potency
Wrong dose
Social/Caregiver issues
Regimen issues
Toxicities
Poor adherence
Host genetics
Poor absorption
Insufficient drug level
Rapid clearance
Viral replication in the
presence of drug
Poor activation
Drug interactions
Resistant virus
14
Examples: Case 1
• You wish to start an 8 month old infant
male on antiretroviral therapy.
• He was born to a mother who was
diagnosed with HIV infection during
labor.
• The mother received no antiretroviral
therapy for PMTCT.
• The infant received single dose NVP
only.
15
What regimen should you
start?
•
•
•
•
A) d4T / 3TC / NVP
B) AZT / 3TC / NVP
C) AZT / 3TC / ABC
D) AZT / 3TC / LPV-r (Aluvia)
16
Resistance acquired from
infant PMTCT: single dose NVP
17
N Engl J Med 2007; 356: 135-147.
Children less than 12 months
who have been exposed to
NVP during PMTCT
Vietnam MOH Guidelines recommend:
• Preferred regimen: AZT + 3TC + LPV/r
• Alternative regimens:
• a. d4T + 3TC + LPV/r
• b. ABC + 3TC + LPV/r
• c. AZT + 3TC + NVP or
d4T + 3TC + NVP
18
Resistance testing
Types of resistance tests:
• Genotypic testing: look for specific mutations in
the genetic structure of the reverse transcriptase
and protease enzymes that could cause drug
resistance.
• Phenotypic testing: measure the ability of a
patient’s virus to grow in the presence of known
concentrations of ARV. The test is very expensive
and not available in Vietnam.
19
Genotypic Testing
• The genetic code of the sample virus is
compared to the wild type
• The genetic code is a long chain of
molecules called nucleotides
• Each group of 3 nucleotides = “codon”,
defines a particular amino acid used to
build a new virus
Codon
Nucleotide
AAA ATG AGC
Amino acid
Lys Met Ser
20
Genotypic Testing
• Mutations are described by a combination of letters
and numbers, i.e.: M184V = 3TC resistance
– M: Methionine is the name for the amino acid in
the wild type virus
– 184: identifies the position of the codon
– V: Valine is the name for the “changed” amino
acid in the mutant sample
Codon 184
Codon 184 Mutation
Nucleotide
AAA ATG AGC
AAA GTG AGC
Amino acid
Lys Met Ser
Lys
Val
Ser
21
Genotypic Testing:
Mutations Selected by nRTIs
Multi-nRTI Resistance: 69 Insertion Complex (affects all nRTIs currently
approved by the US FDA)
3TC
d4T
AZT
IAS-USA 2007 www.iasusa.org
22
Genotypic Testing:
Mutations Selected by NNRTIs and PI
EFV
NVP
Lopi/r
IAS-USA 2007 www.iasusa.org
23
24
25
Genotypic Testing: Limitations
• The patient must be taking ARV at
the time the test is done.
• The test only detects mutations
present in > 20% of circulating
virus..
• The viral load must be > 1,000
copies/ml.
26
Genotypic Testing: Limitations
• Test is not widely available in
Vietnam
• Expensive (1,200,000 VND per
test)
• Genotype reports can be difficult
to interpret in the setting of
numerous resistance mutations.
27
Resistance Topics: Genetic Barrier
• Genetic barrier is the number of mutations
required to confer resistance to a drug.
• Low genetic barrier: high level resistance
with only one mutation
• NVP, EFV: K103N
• 3TC: M184V
• High genetic barrier: 3 or more mutations
needed to develop high level resistance to
most PI
28
Resistance Topics:
Cross-resistance
• Cross-resistance within classes is common
– Resistance to one NNRTI means resistance
to all available NNRTIs
• NVP and EFV
– Resistance to one NRTI can indicate
resistance to other NRTIs:
• 3TC and FTC
– There is less cross-resistance among PI
• Use the results of resistance testing to choose
second-line drugs with the least risk for
resistance
29
Common mutations in patients with
treatment failure on 1st line ARV
Mutation
Selected by
Effects on ARV
M184V
3TC, FTC
- High resistance to 3TC
- ↓ viral fitness (HIV replicates more slowly)
- Delayed TAMS and ↑ susceptibility to AZT, d4T, TDF
TAMs
AZT, d4T
- M41L, D67N, K70R, L210W, T215Y, K219Q
- Resistance to all NRTIs based on number of TAMs
- More TAMS = more resistance
Q151M,
T69ins
AZT/ddI,
ddI/d4T
- Resistance to all NRTIs
- T69ins: TDF resistance
K65R
TDF, ABC,
ddI
- Variable resistance to TDF, ABC, ddI, 3TC
- ↑ susceptibility to AZT
K103N,
Y181C
NVP, EFV
- High resistance to both NVP and EFV
30
When to do resistance testing
Indications for ordering test in Viet Nam:
(ALL criteria should be met)
• Patient must be currently taking ARV
with good adherence for at least 6
months on the same regimen
• Evidence for treatment failure (by clinical,
immunological, and/or virological criteria)
• Viral load testing done first and result >
1,000
• More than one 2nd Line ARV regimen
available
31
Example: Case #2
• A 3 year old boy whose mother recently died
after a prolonged illness presents to the OPC.
• He has been on ART x 1.5 years with d4T,
3TC, NVP.
• Treatment failure was suspected based on
decreased CD4 counts (immunological) and a
failure to gain weight (clinical).
• A viral load was performed and was 57000
copies/mL.
Example: Case #2
• What are some reasons why he might
have developed treatment failure?
• If you did a genotype what type of
resistance might you expect to see?
• What would you choose for 2nd line
therapy?
Case 2: Genotype
Drug NRTI Mutations
Name
ZDV
3TC/
FTC
ddI
D67N, K70R,
M184V, K219Q
D4T
Conclusion
High-Level Resistance
High-Level Resistance
Low-Level Resistance
High-Level Resistance
ABC
Low-Level Resistance
TDF
Possible Low-Level
Resistance
Case 2: Genotype
NNRTI:
Drug
Name
EFV
NVP
Mutations
Y181C, Y188L
Conclusions
Resistant
Resistant
PI: IDV, SQV/r, NFV, LPV/r, ATV/r, TPV/r, fosAPV/r:
• No mutations detected
• All PI sensitive
Key Points
• Resistance occurs (1) when an infant acquires
a resistant virus from the mother or (2)
develops in the setting of an inadequately
suppressive ARV therapy
• When prescribing an ARV regimen, it is
important to know a child’s prior ARV exposure
(i.e. PMTCT regimen)
• Dose ARVs carefully; remember to switch
formulations as children cross thresholds of
weight or age
• Monitor and optimize adherence; Educating
patients and caregivers about resistance may
promote better adherence
36
Key Points
• Monitor closely for ARV effectiveness and
signs of treatment failure.
• For the patient who is failing therapy: check
adherence issues first
• Testing for HIV resistance to ARVs has
become an important component of clinical
care
• Resistance assays can assist the clinician in
selecting a maximally effective second line
ARV regimen
37
Thank You
Questions?