Incidence of Genital Ulcers and HSV genital ulcers

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Incidence of Genital Ulcers and HSV + genital ulcers in trial of HSV-2 suppression

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

Interactions: HSV-2 and HIV HSV-2 Effect of HIV on HSV-2 Effect of HSV-2 on

Interactions: HSV-2 and HIV HSV-2 Effect of HIV on HSV-2 Effect of HSV-2 on HIV • Alters clinical presentation & frequency of HSV-2 shedding • Longer duration of lesions (CD 4 <200) • HSV-2 acquisition & transmission • HIV acquisition • HIV levels in plasma & genital tract • HIV transmission

HSV-2 increases HIV susceptibility • Epidemiologic Data • Longitudinal studies which adjusted for age

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 • Women • MSM RR 2. 7 (95% CI 1. 9 -3. 9) RR 3. 1 (95% 1. 7 -5. 6) 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 CD 4 T cells & immature dendritic cells in HSV-2 seropositive women (Rebbapragada AIDS 2007)

Translating epidemiology and biology to Proof of Concept trials • Use antiviral therapy as

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

HPTN 039: HSV-2 suppressive therapy to prevent HIV acquisition Harare, Zimbabwe Lusaka, Zambia Johannesburg,

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

HPTN 039 Assumptions & Analyses • Sample size assumptions: 50% effect size; 90% power;

HPTN 039 Assumptions & 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 timedependent 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)

HPTN 039 Study Design 11731 assessed for eligibility 8454 ineligible 3277 randomized 1637 assigned

HPTN 039 Study 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

HPTN 039 Entry criteria • Age of informed consent (>18 yrs all but Zambia,

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

HPTN 039 Study Drug Adherence Based on Pill Count & Self-Report % doses taken

HPTN 039 Study Drug Adherence Based on Pill Count & Self-Report % doses taken of doses dispensed (by pill count) 94%* Maximum doses missed in a row ≥ 6 doses 4. 4% % bottles not dispensed due to pregnancy 4. 8% Open label episodic HSV treatment since last visit 3. 2% *87% ‘true adherence’ for ITT analysis where each randomized participant counts

HPTN 039: Demographic & behavioral characteristics at enrollment, N=3172 Women N =1358 Peru MSM

HPTN 039: Demographic & behavioral characteristics at enrollment, N=3172 Women N =1358 Peru MSM N =1355 U. S. MSM N = 459 31 28 40 76% 61% 16% # SP, past year (median) 1 10 6 # SP, past month (median) 1 2 1 # sex acts past 3 months 24 6 6 Any unprotected vaginal sex, past 3 months 90% - - Any unprotected receptive anal sex, past 3 months - 56% 33% Any unprotected insertive anal sex, past 3 months - 21% 40% Age (median) Secondary education or less

HPTN 039: Time to HIV by study arm Overall HR 1. 16 (95% CI

HPTN 039: Time to HIV by study arm Overall HR 1. 16 (95% CI 0. 83 -1. 62); p=0. 39

Riesgo Relativo de ulcera genital Riesgo Relativo de Ulceras Genitales, Aciclovir vs. Placebo, p<0.

Riesgo Relativo de ulcera genital Riesgo Relativo de Ulceras Genitales, Aciclovir vs. Placebo, p<0. 001 para todas las sedes GENERAL US PERU AFRICA 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)

Episodios de ulceras genitales por brazo N° de personas Porcentaje de participante con ulcera

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

Association between self-report GUD and GUD on exam Self-report No GUD Yes Total No

Association between self-report GUD and GUD on exam Self-report No GUD Yes Total No 14965 (97. 66%) 359 (2. 34%) 15324 (89. 05%) Yes 749 1136 (60. 27%) 1885 (10. 95%) Total 15714 * P < 0. 001 Based on GEE model (39. 73%) 1885 OR [95% CI] 62. 4 [52. 95, 73. 58] *

Frecuency of HSV 2 detection in Genital Ulcers Aciclovir Placebo N = 729 hisopos

Frecuency of HSV 2 detection in Genital Ulcers Aciclovir Placebo N = 729 hisopos N=1258 hisopos VHS-2* PCR + 246 (33. 7%) 688 (54. 7%)** Negativo 473 (64. 9%) 552 (43. 9%) Inhibido 8 (1. 1%) 16 (1. 2%) Solo 2 muestras positivas para VHS-1 ADN ** p <0. 001

Porcentaje Cantidad de VHS DNA detectado (log 10) entre episodios positivos de ulceras genitales

Porcentaje Cantidad de VHS DNA detectado (log 10) entre episodios positivos de ulceras genitales herpéticas por región Numero de copias de VHS DNA PCR (log 10)

RR for Aggregate GUD as a function of quarterly adherence AFRICA RR CI 95%

RR for Aggregate GUD as a function of quarterly adherence AFRICA RR CI 95% PERU OR CI 95% US OR CI 95% OVERALL OR CI 95% Adherence Low adherence : Acyclovir vs Placebo 0. 63 [0. 37, 1. 08] ** 0. 37 [0. 18, 0. 74] 0. 18 [0. 07, 0. 44]* 0. 41 [0. 27, 0. 62] * Adherence High adherence: Acyclovir vs Placebo 0. 401 [0. 3, 0. 53] * 0. 30 [0. 19, 0. 45] * 0. 36 [0. 21, 0. 60] * 0. 33 [0. 26, 0. 42] * Age increase 1 yr 0. 97 [0. 95, 0. 99] * 0. 97[0. 96, 0. 98] * * P < 0. 001 Based on GEE model ** P > 0. 05 Low adherence=90 -105%, High adherence=>105% test for effect modification by level of adherence is not significant

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

RR for HSV 2 + GUD as a function of quarterly adherence RR for Aggregate GUD as a function of quarterly adherence AFRICA RR CI 95% PERU OR CI 95% US OR CI 95% OVERALL OR CI 95% Adherence Low adherence : Acyclovir vs Placebo 0. 63 [0. 37, 1. 08] ** 0. 37 [0. 18, 0. 74] 0. 18 [0. 07, 0. 44]* 0. 41 [0. 27, 0. 62] * Adherence High adherence: Acyclovir vs Placebo 0. 401 [0. 3, 0. 53] * 0. 30 [0. 19, 0. 45] * 0. 36 [0. 21, 0. 60] * 0. 33 [0. 26, 0. 42] * Age increase 1 yr 0. 97 [0. 95, 0. 99] * 0. 97[0. 96, 0. 98] * * P < 0. 001 Based on GEE model ** P > 0. 05 Low adherence %, High adherence=90 -105% Test for effect modification by level of adherence is not significant

Conclusions • Acyclovir 400 mg bid did not reduce risk of HIV acquisition among

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 welltolerated; largest trial ever of HSV-2 suppression • Adherence to study drug was excellent o 94% of dispensed doses taken, 87% expected doses taken • Suppressive acyclovir led to a significant reduction in incidence of genital ulcers o 47% overall GUD, 63% HSV+ GUD • Higher than expected prevalence, non-specificity and site variability in GUD diagnosis among women

Possible Interpretations • HSV-2 is a risk marker, not a risk factor for HIV

Possible Interpretations • HSV-2 is a risk marker, not a risk factor for HIV o 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 o Acyclovir pharmacokinetics or susceptibility a factor? o Adherence overestimated? o Different natural history of HSV in African women? o Other etiologies of GUD in African women? • We have underestimated HSV-2 – More frequent reactivation, persistent genital immune response o Need better virologic and/or immunologic tools

Acknowledgements ♦ ♦ Study Participants HPTN 039 Protocol team and staff HIV Prevention Trials

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 # U 01 AI 068619

Association between Perianal or Penile ulcers and circumcision Compare Perianal Ulcer/ Circumcision OR CI

Association between Perianal or Penile ulcers and circumcision Compare Perianal Ulcer/ Circumcision OR CI 95% P value Penile Ulcer / Circumcision OR CI 95% P value Circumcision: 0. 62 [0. 33, 1. 16] 0. 134 0. 80 [0. 38, 1. 69] 0. 561 Age increase 1 yr 0. 97 [0. 95, 0. 99] 0. 003 0. 96 [0. 95, 0. 98] < 0. 001 Based on GEE model, adjusted for region and time in study

Effect of sexual role on association between penile ulcer and circumcision Compare OR CI

Effect of sexual role on association between penile ulcer and circumcision Compare OR CI 95% P-value Acyclovir vs Placebo 0. 417 [0. 29, 0. 59 < 0. 001 Receptive: Circumcision yes vs no 2. 87 [1. 23, 6. 66] 0. 0014 Versatile: Circumcision yes vs no 1. 14 [0. 46, 2. 81] 0. 779 Insertive: Circumcision yes vs no 0. 55 [0. 28, 1. 07] 0. 079 Unknown: Circumcision yes vs no 0. 23 [0. 07, 0. 67] 0. 007 Age increase 1 yr 0. 97 [0. 95, 0. 98] < 0. 001 Time increase 1 yr 0. 93 [0. 91, 0. 96] < 0. 001 Based on GEE model, adjusted for region and time in study

Acyclovir as a ‘probe’ for HSV-HIV synergy • Targets an enzyme only present in

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