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Jorge Sánchez MD MPH XVII International AIDS conference Mexico City August 7 th , 2008

Incidence of Genital Ulcers and HSV + genital ulcers in trial of HSV-2 suppression to prevent HIV acquisition. Jorge Sánchez MD MPH XVII International AIDS conference Mexico City August 7 th , 2008. Effect of HIV on HSV-2 Alters clinical presentation & frequency of HSV-2 shedding

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Jorge Sánchez MD MPH XVII International AIDS conference Mexico City August 7 th , 2008

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  1. Incidence of Genital Ulcers and HSV + genital ulcers in trial of HSV-2 suppression to prevent HIV acquisition Jorge Sánchez MD MPH XVII International AIDS conference Mexico City August 7th, 2008

  2. Effect of HIV on HSV-2 Alters clinical presentation & frequency of HSV-2 shedding Longer duration of lesions (CD4 <200)  HSV-2 acquisition & transmission Effect of HSV-2 on HIV  HIV acquisition  HIV levels in plasma & genital tract  HIV transmission HIV HSV-2 Interactions: HSV-2 and HIV

  3. HSV-2 increases HIV susceptibility Epidemiologic Data Longitudinal studies which adjusted for age & sexual behavior (n=18) Prevalent HSV-2 infection and HIV acquisition: Men RR 2.7(95% CI 1.9-3.9) WomenRR 3.1(95% 1.7-5.6) MSM RR 1.7(95% CI 1.2-2.4) 38-69% of new HIV infections in ♀ & 8-49% in ♂ due to prevalent HSV-2 (Freeman AIDS 2006) Biologic Plausibility HSV-2 causes macro- & microscopic ulcerations HSV-2 reactivation is frequent: 20% of days HSV PCR+ in HIV-negative persons (Mark ISSTDR 2007)  cervical CD4 T cells & immature dendritic cells in HSV-2 seropositive women (Rebbapragada AIDS 2007)

  4. Translating epidemiology and biology to Proof of Concept trials • Use antiviral therapy as a ‘probe’ to evaluate: • HSV-2 and Increased HIV Susceptibility • London School of Hygiene & Trop Medicine Trial in Tanzania • HIV Prevention Trials Network (HPTN 039) trial in US, Peru, & Africa • HSV-2 and Increased HIV Infectiousness • 6 pilot studies • 1 large multi-center trial (Partners in Prevention) in Africa • HSV-2 and HIV Disease Progression • Partners in Prevention trial • Rakai, Uganda trial • Ultimately best intervention is to prevent HSV-2 acquisition through an HSV vaccine

  5. HPTN 039: HSV-2 suppressive therapy to prevent HIV acquisition Harare, Zimbabwe Lusaka, Zambia Johannesburg, So Africa HIV- HSV-2+ heterosexual women and HIV- HSV-2+ MSM Lima, Iquitos, Pucallpa: Peru Seattle, San Francisco, NYC Randomize Acyclovir 400 mg bid Matching Placebo bid Both arms received episodic ACV for GUD & risk reduction counseling 1° endpoint: HIV infection

  6. HPTN 039Assumptions & Analyses Sample size assumptions: 50% effect size;90% power; 3.5% HIV incidence in placebo arm Primary analysis: Intent-to-treat Risk estimates adjust for gender, age, GUD at enrollment & # of sex partner in last 12 months at entry Additional analyses adjust for sexual behavior during the study as time-dependent covariates Adherence measured by monthly pill count (& used self-report, when pill bottles not returned) GUD definition based on exam (enrollment, quarterly in all pts, and monthly if report symptoms)

  7. HPTN 039Study Design 11731 assessed for eligibility 8454 ineligible 3277 randomized 1637 assigned to intervention 1640 assigned to control 8 HIV + 3 duplicate 45 HSV-2 - 13 HIV + 2 duplicate 34 HSV-2 - 1581 included in analysis 1591 included in analysis

  8. HPTN 039 Entry criteria Age of informed consent (>18 yrs all but Zambia, >16 yrs) HIV negative HSV-2 seropositive Focus EIA index value > 3.4; confirmed with UW HSV Western blot Behavioral criteria Women from southern Africa: >1 episode of unprotected vaginal sex in past 6 months MSM from U.S. and Peru: > 1 episode of anal intercourse in past 6 months & not mutually monogamous with HIV- man

  9. HPTN 039 Study Drug Adherence Based on Pill Count & Self-Report *87% ‘true adherence’ for ITT analysis where each randomized participant counts

  10. HPTN 039: Demographic & behavioral characteristics at enrollment, N=3172

  11. HPTN 039: Time to HIV by study arm Overall HR 1.16 (95% CI 0.83-1.62); p=0.39

  12. Riesgo Relativo de Ulceras Genitales, Aciclovir vs. Placebo, p<0.001 para todas las sedes Riesgo Relativo de ulcera genital AFRICA GENERAL PERU US Sedes de Estudio En general, 37% de reducción en la incidencia de ulcera genital en el grupo de Aciclovir Diferencias significativas en la reducción de las ulceras genitales por región (p=0.01)

  13. Episodios de ulceras genitales por brazo Ulcera Genital durante el estudio N° de personas Porcentaje de participante con ulcera genital Aciclovir Placebo Numero de recurrencias de ulceras genitales durante el estudio

  14. Association between self-report GUD and GUD on exam

  15. Frecuency of HSV 2 detection in Genital Ulcers Solo 2 muestras positivas para VHS-1 ADN ** p <0.001

  16. Cantidad de VHS DNA detectado (log10) entre episodios positivos de ulceras genitales herpéticas por región Porcentaje Numero de copias de VHS DNA PCR (log10)

  17. RR for Aggregate GUD as a function of quarterly adherence

  18. RR for HSV 2 + GUD as a function of quarterly adherence RR for Aggregate GUD as a function of quarterly adherence

  19. Conclusions Acyclovir 400 mg bid did not reduce risk of HIV acquisition among high-risk HSV-2 seropositive MSM and women. Acyclovir 400 mg bid was safe and well-tolerated; largest trial ever of HSV-2 suppression Adherence to study drug was excellent 94% of dispensed doses taken, 87% expected doses taken Suppressive acyclovir led to a significant reduction in incidence of genital ulcers  47% overall GUD,  63% HSV+ GUD Higher than expected prevalence, non-specificity and site variability in GUD diagnosis among women

  20. Possible Interpretations HSV-2 is a risk marker, not a risk factor for HIV Unlikely to be only confounding, given plethora of epidemiologic data Concept is right but intervention isn’t potent enough HSV in Africa responds less well to acyclovir; less effect on HSV+ GUD than in prior trials Acyclovir pharmacokinetics or susceptibility a factor? Adherence overestimated? Different natural history of HSV in African women? Other etiologies of GUD in African women? We have underestimated HSV-2 More frequent reactivation, persistent genital immune response Need better virologic and/or immunologic tools

  21. Acknowledgements • Study Participants • HPTN 039 Protocol team and staff • HIV Prevention Trials Network (HPTN) • Sponsored by NIAID, NIDA, NIMH, NICHD, and OAR under Cooperative Agreement # U01 AI068619

  22. Association between Perianal or Penile ulcers and circumcision

  23. Effect of sexual role on association between penile ulcer and circumcision

  24. Acyclovir as a ‘probe’ for HSV-HIV synergy Targets an enzyme only present in herpes viruses (thymidine kinase), not in human cells or other viruses Shortens duration of genital ulcers in episodic therapy If taken daily (eg acyclovir 400 mg twice daily), reduces shedding of herpes virus (HSV-2 ) by 80-90% Does not have specific activity against HIV virus Very safe and well-tolerated; rare to have any side effects Resistance is rare (3%) and only occurs in the setting of ‘drug pressure’ in immunocompromised persons Related antivirals (valacyclovir & famciclovir) have similar spectrum of activity, modestly longer half-life, not yet generic

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