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HIV Drug Resistance

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

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HIV Drug Resistance

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  1. HIV Drug Resistance Impact on ART for the Pregnant Woman Elliot Raizes, MD CDC Division of Global HIV/AIDS June 18, 2012

  2. 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

  3. 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

  4. 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

  5. Global Distribution of HIV Subtypes Wainberg et al, NEJM August 2011

  6. 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

  7. DRMs: relationship to ARVs Wainberg et al, NEJM August 2011

  8. Impact of HIVDR

  9. Prevalence of HIVDR in ART-naïve patients (“transmitted HIVDR”) Hamers et al Lancet Infectious Diseases, July 2011

  10. Prevalence and patterns of HIVDR in patients failing ART after 12 months Hamers et al, Clinical Infectious Diseases, June 2012

  11. Prevalence and patterns of HIVDR in patients failing ART after 12 months Hamers et al, Clinical Infectious Diseases, June 2012

  12. PMTCT regimens and the impact of HIVDR on the pregnant woman

  13. 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 1992 2Eshleman et al, AIDS Res and Hum Retroviruses 2004

  14. 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

  15. 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

  16. HIVDR after complex PMTCT regimens in Tanzania Hauser et al, PLOS One2012

  17. 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

  18. 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

  19. 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

  20. 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

  21. HIVDR in Octane • NVP resistance detected (13%) • NVP arm: 73% failure • LPVr arm: 6% failure • NVP resistance not detected • NVP arm: 19% failure • LPVrarm: 9% failure Boltz et al, PNAS 2011

  22. 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

  23. 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

  24. 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

  25. Prevalence and patterns of HIVDR in patients failing ART after 12 months Hamers et al, Clinical Infectious Diseases, June 2012

  26. Option B+ Resistance after failure (Gilead 934) Margot et al, JAIDS 2009

  27. 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)?

  28. 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)?

  29. 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?

  30. 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

  31. 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

  32. Thank you!

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