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This section provides information on how suppression of genital herpes or herpes simplex virus type 2 (HSV-2) infection has been tested as part of the effort to identify additional tools to reduce the risk of HIV transmission.

What is HSV-2 suppression for HIV prevention?

Genital herpes is an infection caused by herpes simplex virus 2 (HSV-2). Genital herpes cannot be cured, but it can be treated and controlled. There are two main treatment strategies: symptomatic treatment involves medications when there are signs of an outbreak such as genital lesions; suppressive treatment is treatment with drugs (such as twice-daily acyclovir) that are taken whether or not the person has symptoms. HSV-2 suppressive treatment has been evaluated as an HIV prevention strategy in both HIV-positive and HIV-negative people. It was tested in HIV-positive people who were also infected with HSV-2, to see if suppressive treatment reduced the risk of transmitting HIV to HIV-negative partners. Suppressive treatment was tested in HIV-negative individuals with HSV-2 to see whether effective management of HSV-2 symptoms reduced the risk of acquiring HIV. Neither strategy was found to have an HIV risk-reduction benefit.

Why was HSV-2 suppression studied as an HIV risk-reduction tool?

Data from observational studies of people with HIV have shown a link between HSV-2 infection and risk of HIV transmission. In some of these studies, people who had both viruses (HIV and HSV-2) were observed to be more likely to transmit HIV to sexual partners than were people with HIV alone. There are several possible explanations. One explanation is that co-infection (being infected with both HSV-2 and HIV) can be associated with higher HIV viral load. Higher HIV viral load has been connected with infectiousness. The open lesions caused by HSV-2 may also make it easier to transmit HIV.

The observational data from HSV-2 and HIV in HIV-positive people led scientists to design trials to determine whether ongoing suppressive therapy for an HIV-positive, HSV-2 infected individual would reduce the chance of transmitting HIV to the person's primary sexual partner.

There are also observational data on HSV-2 infection in HIV-negative people. These data suggest that being infected with HSV-2 increases an individual's risk of HIV infection. This could be because HSV-2 sores and lesions permit HIV to enter the body more easily. It could also be because the immune cells being sent to the genital tract to combat HSV-2 infection are targets for HIV.

These observational data led scientists to design trials to determine whether ongoing suppressive therapy for an HIV-negative, HSV-2 infected individual would reduce his/her risk of acquiring HIV.

How was HSV-2 suppression for HIV prevention tested?

The drugs tested against HSV-2 for HIV prevention trials have been approved and used safely and effectively in HSV-2 treatment for many years. This meant that researchers looking at HSV-2 as an HIV risk-reduction strategy could move ahead with efficacy trials with already licensed drugs.

The details of these large-scale efficacy studies vary, but the design of the HSV-2 suppression efficacy trials was similar to that of most HIV prevention trials. Each participant received a basic prevention package including treatment for sexually transmitted infections, condoms, and behavior change counseling. Some of the participants were randomly assigned to receive ongoing suppressive HSV-2 treatment (twice-daily acyclovir), while the other participants received a placebo, a pill that had no effect on the body and looked exactly like acyclovir. No participant knew whether he or she received acyclovir or a placebo. All participants were counseled at every study visit. Participants did not know whether they had received acyclovir or the placebo and therefore couldn't assume they would be protected.

Over the course of the trial period, some participants got infected even though they were being counseled and receiving prevention services. This is consistent with what we know about the AIDS epidemic: even with information and services, not everyone can protect himself or herself all the time.

At the end of a trial, researchers compared the rates of new infections in the participants who received acyclovir and in those who received a placebo. By comparing the rates of infections in these two groups, researchers could get an indication of whether HSV-2 suppressive treatment provided an additional HIV risk-reduction benefit beyond standard prevention services. Neither trial showed a benefit.

Where did trials of HSV-2 suppression as an HIV risk-reduction strategy take place?

The Partners in Prevention trial was conducted in seven African countries: Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia. Another large-scale trial of HSV-2 suppression, HPTN 039, was conducted in Peru, the United States, South Africa, Zambia, and Zimbabwe. Visit the HSV-2 Clinical Trials page for additional trial details, including the reported results, are detailed below.

Who participated in trials of HSV-2 suppression as an HIV risk-reduction strategy?

Like other HIV prevention strategies, these trials were conducted among different populations including gay men and other men who have sex with men, heterosexual men and women, HIV-serodiscordant couples, and sex workers.

When were results announced?

There have been a number of observational studies and randomized controlled trials looking at the relationship between HSV-2 suppression and HIV transmission and acquisition. The two studies described below are the largest randomized controlled studies of HSV-2 treatment to date. Both studies tested a drug regimen of twice-daily acyclovir. One trial examined the effect of HSV-2 suppressive therapy on HIV transmission, and the other on the effect of HSV-2 suppressive therapy on HIV acquisition.

In May 2009, results were reported from the Partners in Prevention trial. This trial enrolled 3,400 HIV-serodiscordant couples across 14 sites in seven African countries and looked at whether ongoing HSV-2 suppressive therapy in HSV-2 infected HIV-positive people reduced their risk of transmitting HIV to their HIV-negative partners. Suppressive therapy means daily treatment whether or not the person with HSV-2 has herpes ulcers or symptoms. In this study, the treatment was acyclovir twice a day. The Partners in Prevention trial also looked at the effect of suppressive HSV-2 treatment on the HIV-positive person's viral load, rate of genital ulcers, and disease progression.

The trial found that suppressive treatment of HSV-2 with twice-daily acyclovir didn't reduce HIV-positive people's risk of transmitting HIV to their sexual partners but that twice-daily acyclovir suppressive treatment in the HIV-positive and HSV-2 infected individuals led to a decrease in genital ulcer disease, a decrease in viral load, and slower disease progression. For more details, read our update describing the results from the trial.

In February 2008, results were reported from HPTN 039. This trial enrolled 3,172 HSV-2 infected individuals, including heterosexual women as well as men who have sex with men, across nine sites in Peru, South Africa, the United States, Zambia, and Zimbabwe. The trial looked at whether ongoing HSV-2 suppressive therapy could reduce an HSV-2 infected person's risk of HIV infection. Suppressive therapy means daily treatment whether or not the person with HSV-2 has herpes ulcers or symptoms. In this study, the treatment was acyclovir twice a day. The trial also looked at the effect of suppressive HSV-2 treatment on the rate of genital ulcers among HIV-negative HSV-2 infected participants.

The trial found that suppressive treatment of HSV-2 with twice-daily acyclovir didn't reduce HIV-negative people's risk of HIV infection. It did find that in those who received acyclovir, there was a decreased rate of genital ulcers.

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Visit the HIV prevention research timeline and trials map for details on other ongoing biomedical HIV prevention research trials. 

Click here for more information on HSV-2 trials.

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