HIV Drug Resistance

Impact on ART for the Pregnant WomanElliot Raizes, MD

CDC Division of Global HIV/AIDSJune 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 ARVsARV Significant DRMs

NRTIs3TC/FTC M184 I/V

Zidovudine (AZT)TAM 1 M41L/L210W/T215YTAM 2 D67N/K70R/T215F/T219E/Q

Non-TAM Q151MTenofovir K65R

Q151MNNRTIs

Nevirapine K103N/Y181C/G190AEfavirenz K103N/Y181C/G190A

Wainberg et al, NEJM August 2011

Impact of HIVDR

Impact on outcome of 1st-line ART

Impact on PMTCT 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 NNRTI-resistance detected postpartum– 7 days, 6-8 weeks, or both

1Land et al, Journal of Infectious Diseases 19922Eshleman 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 20022Read et al HIV Med 20083Nolan et al JAIDS 2002

HIVDR and Option A (3)

• Tanzania (2008-9) : 50 women initiating AZT-containing 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 NVP-resistance: 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 20102Lockman 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 20102Lockman 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 20082Ellis 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 peri-

partum?– What is the prevalence of NVP resistance post-

partum?– 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 re-initiating ART after defaulting

• HIVDR incidence survey using a prospective cohort of women initiating ART during pregnancy

Thank you!