Transcript Elliot Raizes

HIV Drug Resistance
Impact on ART for the Pregnant Woman
Elliot Raizes, MD
CDC Division of Global HIV/AIDS
June 18, 2012
HIV Drug Resistance (HIVDR):
Impact on ART for the Pregnant Woman
• Outline:
– HIVDR: the basics
– PMTCT regimens and the impact of HIVDR
on the pregnant woman
– Important unanswered questions and the
role of HIVDR surveillance
HIVDR: the basics (1)
• Rapid turnover of virus = higher mutation rate
• Stability of drug-resistance mutations (DRMs) vary
but typically more stable in presence of drug
pressure
– Mutations can have other phenotypic effects
besides drug resistance
• Viral fitness
• Hypersusceptibility
• Transmission efficiency
• Resistance may require single mutations or multiple
mutations to confer phenotypic resistance
HIVDR: the basics (2)
• Detection by standard genotype requires >20% of
virus to have DRMs
– “Minor variants”-when detection requires
hypersensitive methodology
• Genetic barrier to DRMs vary by drug and also by HIV
subtype
• Adherence-resistance relationship dependent on:
– Drug potency
– Viral Fitness
– Genetic barrier
Global Distribution of HIV Subtypes
Wainberg et al, NEJM August 2011
Adherence-resistance relationship
(in order of likelihood of acquired resistance)
• NVP, EFV: highest risk at low adherence
• 3TC/FTC: highest risk at moderate-to-high
adherence
• TDF, AZT, d4T: highest risk at moderate
adherence
• Boosted Protease Inhibitors (bPIs): highest risk
at moderate-to-high adherence
Adapted from Gardner et al, AIDS 2009
DRMs: relationship to ARVs
ARV
Significant DRMs
NRTIs
3TC/FTC
Zidovudine (AZT)
M184 I/V
TAM 1 M41L/L210W/T215Y
TAM 2 D67N/K70R/T215F/T219E/Q
Non-TAM Q151M
Tenofovir
K65R
Q151M
NNRTIs
Nevirapine
K103N/Y181C/G190A
Efavirenz
K103N/Y181C/G190A
Wainberg et al, NEJM August 2011
Impact of HIVDR
Impact on
Impact on
outcome of 1st- PMTCT
line ART
effectiveness
Impact on
Outcome of
2nd-line ART
Potential for
HIVDR
transmission
Transmitted
HIVDR (recent
infection)
?
X
X
Baseline HIVDR
(at ART start)
X
X
X
Acquired
HIVDR (on ART)
X
X
X
Prevalence of HIVDR in ART-naïve
patients (“transmitted HIVDR”)
Hamers et al Lancet Infectious Diseases, July 2011
Prevalence and patterns of HIVDR in
patients failing ART after 12 months
Hamers et al, Clinical Infectious Diseases, June 2012
Prevalence and patterns of HIVDR in
patients failing ART after 12 months
Hamers et al, Clinical Infectious Diseases, June 2012
PMTCT REGIMENS AND THE IMPACT OF
HIVDR ON THE PREGNANT WOMAN
HIVDR and Option A (1)
• 19921: AZT monotherapy led to AZT-resistance
in 93% of patients after 36 months
– all with low CD4 at initiation
• HIVNet 012 (2004)2: 32% of women receiving
peripartum single-dose NVP had NNRTIresistance detected postpartum
– 7 days, 6-8 weeks, or both
1Land
et al, Journal of Infectious Diseases 1992
2Eshleman et al, AIDS Res and Hum Retroviruses 2004
HIVDR and Option A (2)
• Cote d’Ivoire (1996-8)1: 20 women on 2-6 weeks
of AZT pre-partum tested for ZDV-resistance at
delivery with no resistance detected
• UK 20082: Women with low viral loads and high
CD4 counts failed to develop AZT-resistance after
median 11 weeks of AZT monotherapy
• Review in 2002 showed wide range of prevalence
for AZT resistance mutations (0-25%) but much
lower levels of AZT phenotypic resistance3
– Most studies in US
1Ekpini
et al, AIDS 2002
2Read et al HIV Med 2008
3Nolan et al JAIDS 2002
HIVDR and Option A (3)
• Tanzania (2008-9) : 50 women initiating AZTcontaining complex PMTCT regimens (with
sdNVP) and tested for minor variants of DRMs
– Median duration pre-partum: 53 days
– 40% had DRMs
• AZT-resistance: 11/50
• NVP-resistance: 9/50
• 3TC-resistance: 4/50
Hauser et al, PLOS One 2012
HIVDR after complex PMTCT regimens
in Tanzania
Hauser et al, PLOS One 2012
Short-course AZT/3TC to reduce NVPresistance: the Tail
• South Africa 2003-7: randomized 3-arm trial
– Arm 1: sdNVP (71 women)
• 59.2% acquired resistance
– Arm 2: sdNVP + 4 days of AZT/3TC (154 women)
• 9.7% acquired resistance
– Arm 3: sdNVP + 7 days of AZT/3TC (151 women)
• 7.3% acquired resistance
– CD4 count <200 cells/µl at baseline a risk factor
(21% of women in study)
McIntyre et al PLOS medicine 2009
Impact of HIVDR on maternal ART
outcomes
• NNRTI response study1: 24 or 48 week virologic
failure rate of NNRTI-based ART after sdNVP
– NVP unexposed: 25%
– NVP exposed: 32%
• 0-6 months post-exposure: 41% (p < 0.001)
• 6-12 months post-exposure: 37% (p = 0.04)
• >12 months post-exposure: 24% (p = 0.82)
• Octane2: two randomized, open-label trials
comparing TDF/FTC/LPVr to TDF/FTC/NVP
– Trial 1: sdNVP exposed
– Trial 2: sdNVP unexposed
1Stringer
et al, PLOS medicine 2010
2Lockman et al, NEJM 2010
Impact of HIVDR on maternal ART
outcomes
• NNRTI response study1: 24 or 48 week virologic
failure rate of NNRTI-based ART after sdNVP
– NVP unexposed: 25%
– NVP exposed: 32%
• 0-6 months post-exposure: 41% (p < 0.001)
• 6-12 months post-exposure: 37% (p = 0.04)
• >12 months post-exposure: 24% (p = 0.82)
• Octane2: two randomized, open-label trials
comparing TDF/FTC/LPVr to TDF/FTC/NVP
– Trial 1: sdNVP exposed
– Trial 2: sdNVP unexposed
1Stringer
et al, PLOS medicine 2010
2Lockman et al, NEJM 2010
Octane trial results
• Trial 1 (NVP-exposed):
– LPVr superior efficacy
• Trial 2 (no NVP exposure): no difference in
regimen efficacy
Lockman et al, NEJM 2010
HIVDR in Octane
• NVP resistance detected (13%)
– NVP arm: 73% failure
– LPVr arm: 6% failure
• NVP resistance not detected
– NVP arm: 19% failure
– LPVr arm: 9% failure
Boltz et al, PNAS 2011
HIVDR in Octane
• NVP resistance detected (13%)
– NVP arm: 73% failure
– LPVr arm: 6% failure
• NVP resistance not detected
– NVP arm: 19% failure
• 60% of these had minor variants for NNRTI-resistance
– LPVr arm: 9% failure
• 33% of these had minor variants for NNRTI-resistance
Boltz et al, PNAS 2011
Option B: HIVDR risk associated with
drug interruption
• SMART study1
– HIVDR within 2 months after treatment interruption
(SMART)
• Simultaneous interruption: 16.4%
• Staggered interruption (tail): 12.5%
• Switched interruption (bPI): 4.2%
– Virologic suppression after NNRTI restart in SMART study
• 69.2% with HIVDR (p=0.05)
• 86.7% with HIVDR
• HIVDR after suspension of PMTCT regimens (PACTG
1022)2
• NVP resistance in 4/8 stopping NVP regimens
1Fox
et al, AIDS 2008
2Ellis et al, JAIDS 2011
HIVDR and Option B+
• What is the risk of acquired HIVDR with
Option B+ compared to all ART-eligible
patients?
– Greater risk: if adherence worse
– Lesser risk: if factors mitigating against HIVDR are
present in women presenting with high CD4
counts
• such as viral fitness and host immunity
– Risk comparable: prevalence and pattern of HIVDR
can be assessed from studies among ART eligible
Prevalence and patterns of HIVDR in
patients failing ART after 12 months
Hamers et al, Clinical Infectious Diseases, June 2012
Option B+
Resistance after failure (Gilead 934)
Margot et al, JAIDS 2009
ART in pregnancy and the Impact of
HIVDR: unanswered questions (1)
• Option A
– What is the prevalence of AZT-resistance peripartum?
– What is the prevalence of NVP resistance postpartum?
– What are the effects of exposure to Option A on
resistance patterns and outcomes when ART
reinitiated (either for mother’s health or
subsequent pregnancy)?
ART in pregnancy and the Impact of
HIVDR: unanswered questions (2)
• Option B
– What is the prevalence of HIVDR at or after
discontinuation of Option B+ regimens?
– Can HIVDR at discontinuation be reduced by
staggered discontinuation (i.e., a tail)?
– What are the effects of exposure to Option B on
resistance patterns and outcomes when ART is
reinitiated (either for mother’s health or
subsequent pregnancy)?
ART in pregnancy and the Impact of
HIVDR: unanswered questions (3)
• Option B+
– What are the long term adherence and retention
rates and subsequent impact on HIVDR?
– Should these women be targeted for viral load
monitoring to prevent resistance?
HIVDR surveillance: updated WHO
strategy (2012)
• Cross-sectional surveys of HIVDR in adults and
children on ART >12 months
• Cross-sectional surveys of HIVDR in adults
initiating ART
• Surveys for HIVDR in newly diagnosed children
<18 months old
• Surveys for transmitted resistance in pregnant
women believed to be recently infected with
HIV
Targeted HIVDR Surveillance for
Pregnant Women?
• Cross-sectional survey of baseline HIVDR in
pregnant women initiating ART
• Cross-sectional survey of acquired HIVDR in
women initiated on ART during pregnancy
• Cross-sectional survey of HIVDR in women reinitiating ART after defaulting
• HIVDR incidence survey using a prospective
cohort of women initiating ART during
pregnancy
Thank you!