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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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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

interactions hsv 2 and hiv
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
hsv 2 increases hiv susceptibility
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)

translating epidemiology and biology to proof of concept trials
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
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
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)

hptn 039 study design
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

hptn 039 entry criteria
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
HPTN 039 Study Drug Adherence Based on Pill Count & Self-Report

*87% ‘true adherence’ for ITT analysis where each randomized participant counts

hptn 039 time to hiv by study arm
HPTN 039: Time to HIV by study arm

Overall HR 1.16 (95% CI 0.83-1.62); p=0.39

riesgo relativo de ulceras genitales aciclovir vs placebo p 0 001 para todas las sedes
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)

episodios de ulceras genitales por brazo
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

frecuency of hsv 2 detection in genital ulcers
Frecuency of HSV 2 detection in Genital Ulcers

Solo 2 muestras positivas para VHS-1 ADN

** p <0.001

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Cantidad de VHS DNA detectado (log10) entre episodios positivos de ulceras genitales herpéticas por región

Porcentaje

Numero de copias de VHS DNA PCR (log10)

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

RR for Aggregate GUD as a function of quarterly adherence

conclusions
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

possible interpretations
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

acknowledgements
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
acyclovir as a probe for hsv hiv synergy
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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