Herpes Simplex Virus Type 2 (HSV-2) Suppression to Prevent HIV Transmission

Study Overview
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Brief Summary
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The University of Washington has received funding to conduct a proof-of-concept trial to assess the impact of suppression of genital herpes on HIV infectiousness. This study (the Partners in Prevention Study) will enroll HIV discordant heterosexual couples in which the HIV-infected partner is co-infected with herpes simplex virus type 2 (HSV-2) to test the efficacy of twice daily (bid) acyclovir (400 mg) given to the HIV-infected partner to prevent transmission to his/her HIV negative partner(s). This randomized, double-blind, placebo-controlled proof-of-concept trial will provide evidence for the efficacy of HSV-2 suppression with daily acyclovir on HIV transmission among HIV-discordant couples among whom the HIV-positive partner is also HSV-2 seropositive with CD4 >250. The researchers hypothesis is that, by decreasing the frequency and amount of genital HIV shedding, standard doses of daily acyclovir 400 mg bid will reduce the rate of HIV transmission by 50% in HIV-discordant couples among whom the HIV-infected partner is HSV-2 positive. Under the study protocol version 4.1.1, 3000 HIV-discordant heterosexual couples in which the HIV-positive partner is HSV-2 positive and has a CD4 count >250 will be recruited; participants will be followed for up to 2 years. A 4% per year HIV incidence in the placebo arm is assumed. The first study site began enrolling participants on 17 November 2005. As of September 2006, 14 sites in Eastern and Southern Africa had participated in recruiting the 2300 HIV-discordant couples enrolled to date.

Detailed Description
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Herpes simplex virus type-2 (HSV-2) is the primary cause of genital ulcers and one of the most prevalent sexually transmitted diseases worldwide. Consistently, over 30 studies have found HSV-2 infection to be a risk factor for HIV acquisition with an overall relative risk of 2.1 in the studies that demonstrated HSV-2 preceded HIV infection. A recent study of HIV-discordant couples from Rakai, Uganda, has shown that at all levels of HIV viral load in the HIV-positive partner, HSV-2 infection in the susceptible partner increased the per-contact risk of acquisition of HIV five-fold, and GUD in the HIV-source partner increased the per-contact risk of HIV transmission five-fold. As strong as these epidemiological data are, an intervention trial is required to define the clinical and public health significance of these findings. This trial will directly answer the extent to which HSV-2 infection increases infectiousness of HIV/HSV-2 co-infected persons and the relative reduction in HIV transmission among HSV-2 seropositive persons treated with daily suppressive antiviral therapy. Acyclovir has an acceptable safety profile for widespread STD treatment and is inexpensive, well-tolerated, and episodic and long-term suppressive therapy has not been associated with increased acyclovir resistance. Given high HSV-2 seroprevalence in HIV-infected persons (70-80%) and high HIV incidence in populations with high prevalence of HSV-2 infection worldwide, this approach could have great public health importance by providing a safe, acceptable, and cost-effective method to reduce HIV transmission among HIV-infected persons who are also HSV-2 seropositive. Sites that have enrolled couples in this study include: Johannesburg (2 sites) and Cape Town, South Africa; Gaborone, Botswana; Kitwe/Ndola and Lusaka, Zambia; Nairobi, Kisumu, Eldoret and Thika, Kenya; Moshi, Tanzania; Kampala, Uganda; and Kigali, Rwanda.

Official Title
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Phase III Randomized Placebo-Controlled Trial of HSV-2 Suppression to Prevent HIV Transmission Among HIV-Discordant Couples

Conditions
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HIV Infection, Herpes Simplex, Genital, Sexually Transmitted Diseases

Intervention / Treatment
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* Drug: Generic acyclovir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Potential index (HIV-infected) participants must meet the following criteria (by self-report, unless otherwise indicated) in order to be eligible for inclusion in the study: Of legal age to provide independent informed consent for research per local regulations and guidelines. Able and willing to provide written informed consent to be screened for and to take part in the study. (Note: Index participants who are not willing to provide genital tract specimens for HIV viral load quantitation, but are willing to undergo all other study procedures, will be considered eligible for inclusion in the study.) Part of a heterosexual couple in which one partner meets the study eligibility criteria for index participants and the other partner meets the study eligibility criteria for partner participants. Couples are defined as partners who are sexually active and plan to remain in the relationship for at least one year. Each site will develop appropriate criteria for determining whether a couple is likely to remain in the relationship (i.e., married, duration of partnership, cohabitation, have children). Has had vaginal intercourse with the partner participant at least three times in the last three months. Plans to maintain his/her relationship with the partner participant for the next 24 months. HIV-infected based on positive EIA. HSV-2-seropositive based on the Focus HSV-2 EIA (performed by study staff) with an index ratio of at least 3.5 or if Focus EIA IN 1.1-3.4, confirmed by HSV-2 WB dot-blot performed at the UW. CD4 cell count (performed by study staff) of at least 250 cells/mm3. No history of any clinical AIDS-defining diagnoses. Able and willing to provide adequate locator information for study retention purposes, as defined by local standard operating procedures. Potential partner (HIV-uninfected at enrollment) participants must meet the following criteria (by self-report, unless otherwise indicated) in order to be eligible for inclusion in the study: Of legal age to provide independent informed consent for research per local regulations and guidelines. Able and willing to provide written informed consent to be screened for and to take part in the study. Part of a heterosexual couple in which one partner meets the study eligibility criteria for index participants and the other partner meets the study eligibility criteria for partner participants. Has had vaginal intercourse with the study partner at least three times in the last three months. Plans to maintain his/her relationship with the index participant for the next 24 months. HIV-uninfected based on negative HIV EIA tests. Able and willing to provide adequate locator information for study retention purposes, as defined by local standard operating procedures. Exclusion Criteria: Potential index (HIV-infected) participants who meet any of the following criteria (by self-report, unless otherwise indicated) will be excluded from the study: Current use of combination antiretroviral therapy Known history of adverse reaction to acyclovir. Known history of persistent genital ulcers unresponsive to episodic acyclovir therapy. Known plans to re-locate or travel away from the study site for more than two consecutive months during the next 24 months. Pregnant, based on participant self-report or urine testing performed by study staff. (Note: Self-reported pregnancy is adequate for exclusion from the study. A documented negative test performed by study staff is required for inclusion.) Potential partner participants who meet any of the following criteria (by self-report, unless otherwise indicated) will be excluded from the study: Has had sexual intercourse with a partner other than the index participant in the last two months. Known plans to re-locate or travel away from the study site for more than two consecutive months during the next 24 months.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Acyclovir<br> | Drug: Generic acyclovir<br>* 400 mg twice-daily oral<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* twice-daily oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sequence-verified HIV-transmission from index to partner participant |  | March 2009 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure effect of viral load, gender and other factors on HIV transmission |  | March 2009 | 
| Assess adherence to acyclovir suppressive therapy |  | March 2009 | 
| Assess effect of twice daily acyclovir on the frequency of genital ulcers |  | March 2009 | 
| Assess effect of twice daily acyclovir on plasma HIV viral load |  | March 2009 | 
| Assess effects of twice daily acyclovir on the sexual behaviors |  | March 2009 | 
| Assess host immunologic and virologic determinants of HIV transmission |  | March 2009 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV infection, HIV transmission, genital herpes, sexual intercourse, sexual transmitted infection, acyclovir, HIV Seronegativity, Treatment Naive, HIV-discordant couples, HIV serodiagnosis