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

A multi-site trial funded by the Bill & Melinda Gates Foundation, conducted by the University of Washington, Partners in Prevention.

The problem of interest:

The University of Washington has received funding to conduct a clinical trial to assess the impact of suppression of genital herpes on HIV transmission. Four of the sites selected (the cities of Ndola, Kitwe, and Lusaka, in Zambia; and Kigali in Rwanda) are directed by Dr. Susan Allen, Professor of Global Health at Emory University.

Herpes simplex virus type-2 (HSV-2) is the primary cause of genital ulcer disease (GUD) and one of the most common sexually transmitted diseases worldwide. Consistently, over 30 studies have found HSV-2 infection to be a risk factor for HIV acquisition, when HSV-2 infection preceded HIV infection. A recent study of HIV-discordant couples (one partner is HIV positive and the other partner is HIV negative) from Rakai, Uganda, has shown that HSV-2 infection in the negative partner increased the per-contact risk of acquisition of HIV, and GUD in the HIV positive partner increased the per-contact risk of HIV transmission. An intervention trial is required to define the clinical and public health significance of these findings.

This study will be the first ever to evaluate whether it is possible to reduce transmission of HIV-1 by treating genital herpes with acyclovir, a widely used and generically available medication. Acyclovir has an acceptable safety profile for widespread STD treatment and is inexpensive and well-tolerated; episodic and long-term suppressive therapy has not been associated with increased HSV-2 resistance to acyclovir. Researchers theorize that the treatment could reduce HIV transmission by 50 percent. If successful, the study could lead to an important new approach to HIV prevention in the developing world.

The person at highest risk for HIV is the regular partner of an HIV+ person. It is estimated that 60-70% of new HIV infections in Africa occur between spouses where one partner is HIV negative and the other partner is HIV positive. Given that HSV-2 seroprevalence is high among HIV-infected persons (70-80%), this study could have great public health impact by providing a safe, acceptable, and cost-effective method to reduce HIV transmission among HIV-infected persons who are also HSV-2 seropositive.

(A separate study, not conducted by Dr. Susan Allen, is currently underway to evaluate whether acyclovir treatment of HSV-2 in the HIV negative partner can reduce their susceptibility to HIV infection from their HIV positive spouse.)

How the problem will be studied:

The study is a Phase III clinical trial, to test the efficacy of daily suppressive therapy of genital herpes in reducing the transmission of HIV between HIV-discordant couples. All couples will have received their HIV test results and counseling jointly, prior to screening for possible inclusion in the clinical trial. Discordant couples are counseled regarding the implications of their HIV status, and provided with condoms and instruction/demonstration on how to use condoms.

Participants will be randomized to receive either daily acyclovir or daily placebo. Only the partner who is both HIV and HSV-2 positive will receive study drug/placebo, although the HIV-negative spouse will also participate in study visits per the protocol. The HIV+/HSV+ spouse must be healthy, as evidenced through laboratory tests of immune system capacity. Neither the participants nor the study coordinators/directors/staff will know who receives acyclovir and who receives placebo.

Couples in both randomization groups will continue to receive condoms, and counselors will reinforce the message that condoms are the only prevention method proven to reduce HIV transmission within discordant couples.

How the research will advance scientific knowledge and human health:

This trial will directly measure the extent to which daily suppressive acyclovir therapy given to HIV/HSV-2 seropositive persons can reduce HIV transmission to their HIV-seronegative partners. Our hypothesis is that suppression of HSV-2 in the HIV-positive partner through standard daily doses of acyclovir will reduce HIV transmission in these couples by 50%. This is important, because condoms alone do not reduce the transmission of HIV within discordant couples by 100%; a residual transmission rate of 7-9% per year remains after CVCT. Research is clearly needed to investigate other medical and/or behavioral interventions which will further reduce HIV transmission between spouses.