HIV prevention in a pill?

Drugs that treat herpes may help reduce HIV transmission

If ongoing clinical trials pan out, it's possible that one day people could be cutting their risk of HIV infection simply by popping a couple of pills per day. The pills are cheap, safe, and have been around for years. The catch? These drugs don't target HIV, they fight off herpes.

Simply suppressing genital herpes could be enough to substantially reduce an individual's risk of acquiring and transmitting HIV. Researchers have long known that sexually transmitted infections (STIs) play a role in HIV transmission. Now nearly a dozen clinical trials are investigating whether drugs that suppress a type of herpes virus (herpes simplex virus-2 or HSV-2) that causes genital herpes can reduce HIV transmission.

Approaches to HIV prevention that aim to modify behavior are yielding only modest gains against HIV transmission, so many researchers are now looking into strategies that focus on biology rather than behavior. For example, earlier this year a clinical trial in South Africa found that male circumcision could reduce the risk of men acquiring HIV.

Ideally strategies that combine biology and behavior may provide greater gains in prevention than either would alone. "Aside from individual behavior change, we don't really have ways to prevent HIV transmission," says Anna Wald, an epidemiologist at the University of Washington School of Public Health and Community Medicine in Seattle. "That is the starting point of why we are looking at herpes."

The current trials will test whether drugs to suppress herpes can actually reduce HIV transmission in real world settings, says Jairam Lingappa, medical director of one of the studies organized by the University of Washington. "While epidemiologic studies show a relationship between HIV and genital herpes," he says, "we don't yet have a clear demonstration of the public health benefit."

Partners in crime

Herpes is a lifelong infection that causes recurring outbreaks of painful ulcers at the surface tissues (or mucosae) of the genitals. During the course of infection the virus moves between periods of latency and reactivation, when the ulcers appear. Numerous studies have found a strong association between herpes or other genital ulcer diseases and an increased risk of HIV transmission. An analysis of previously completed studies conducted by Esther Freeman and colleagues at the London School of Hygiene and Tropical Medicine (LSHTM) found that men and women with genital herpes are at three times greater risk of acquiring HIV.

Genital ulcers can help HIV establish an infection by disrupting the physical barrier of the skin and enabling the virus to more easily enter the body. Genital herpes also causes inflammation of the genital tissues, which in turn recruits activated CD4+ T cells, the primary cells infected by HIV, to the site. Dendritic cells are also recruited and can entrap HIV particles and carry them to CD4+ T cells in other areas of the body.

The elevated risk of acquiring HIV may be greatest in the first few months following infection with HSV-2 when severe outbreaks of genital ulcers are most common. So controlling these ulcers should reduce HIV transmission, especially in sub-Saharan Africa where genital herpes is the most widespread STI. In some regions of Africa about 80% of the population has acquired HSV-2 by age 35.

There are also other ways that herpes could increase the risk of becoming HIV infected. Even if actual genital sores are not present, HSV-2 can increase the risk of HIV transmission because the two viruses can interact in complicated ways that aggravate the effects of both diseases.

People infected with HIV and HSV-2 will often have frequent and prolonged outbreaks of genital ulcers because herpes takes advantage of HIV's ability to weaken the immune system. This increased expression of the herpes virus in turn allows for an increase in HIV replication. This vicious cycle between HIV and HSV-2 means that suppressing herpes could reduce both the risk of acquiring HIV (acquisition) and the risk of transmitting it to a sexual partner (infectiousness).

Herpes suppression on trial

To demonstrate the possible public health benefit of knocking down herpes, researchers are running a number of clinical trials to evaluate if two types of treatments can reduce HIV transmission. One type will assess the benefit of giving a drug to treat HSV-2 only during outbreaks of genital herpes when genital ulcers are present. The other will evaluate the benefits of suppressing the herpes virus by continuous administration of the drug in order to keep it latent. All of these trials are using the drug acyclovir, an affordable, safe, and proven anti-herpes medication efficient at blocking HSV-2.

Some researchers, including Philippe Mayaud of the LSHTM, think providing acyclovir just when herpes flares up and ulcers appear could have a significant effect on HIV transmission. He is currently involved in three studies, one of which is looking at HIV transmission after acyclovir is given to women in Ghana and the Central African Republic who come to clinics seeking treatment for genital herpes. Women who consent to be in the study are HIV tested and offered acyclovir three times a day for five days or an inactive substance called placebo. Mayaud and his colleagues will take genital samples from all women and will monitor the interactions between the two viruses in women that are HIV infected.

Mayaud and other research teams are also exploring providing volunteers with a continuous, suppressive regimen of acyclovir therapy. One study is testing this concept in female bar- and hotel-workers in Tanzania. Either acyclovir or placebo is being given to 1,000 HIV-infected and uninfected women in a trial led by Debby Watson-Jones at the LSHTM. The women that are HIV uninfected at the start of the trial are being monitored for HIV infection, while the HIV-infected women are being monitored to see if the suppressive acyclovir regimen decreases the amounts of HSV and HIV present at the genital mucosae.

But researchers also want to know is giving acyclovir to people with HSV-2 can reduce HIV acquisition. A large scale study to answer that question is being conducted by Wald and Connie Celum, also of the University of Washington. The study is following women in three African nations (South Africa, Zambia and Zimbabwe) and men who have sex with men (MSM) in the US and Peru to see if acyclovir can reduce their risk of becoming HIV infected. The researchers will also be looking at how well the drug controls the occurrence and frequency of genital ulcers and whether the participants can adhere to the regimen of two pills daily. "The trial of 3,200 women and men is over 80% enrolled with excellent retention and adherence, so we are optimistic that we will get an answer about the degree to which genital herpes increases HIV susceptibility," says Celum.

Stopping transmission

Researchers are also interested in studying how HSV suppression can limit the risk of an HIV-infected person transmitting the virus to their sexual partners. This question is being studied in a cohort of "HIV discordant" couples, where one partner is infected with both HIV and HSV-2 and the other partner is not infected with HIV. Nearly 3,000 HIV discordant couples will participate in such a study at twelve sites in seven African countries. The HIV-infected, HSV-2-infected partner will be given either acyclovir or a placebo to see if they are at reduced risk of passing HIV to their non-infected partner, in the context of couples' counseling (see October 2005 Primer on Understanding Couples Voluntary Counseling and Testing), treatment of bacterial STIs, and condom provision.

If acyclovir proves capable of reducing HIV transmission, the trial results will benefit everyone—but none so much as the discordant couples themselves. HSV-2 is the leading cause of genital ulcers in married couples, says Susan Allen, a professor at Emory University's Rollins School of Public Health and a pioneer in studying HIV-discordant couples. "This time period [when one partner is infected and the other is not] is a critical window in which to implement a public health strategy to reduce transmission," says Lingappa. "If we can enhance the number of families that maintain one healthy parent or adult," he says, "that is one of the things we should promote."

While well-designed, no study can answer every question about HSV suppression. The couples study is meant to examine acyclovir's role in preventing HIV transmission to the non-infected partner, but it does not test whether a greater reduction in intra-couple transmission could result if both members of the couple took acyclovir. By studying acquisition and transmission of HIV in two separate trials, the researchers run the risk of finding only weak associations in both. But Celum says the team carefully considered combining the trials and decided it would be better to separate the studies to determine the relative impact of acyclovir.

A medicine for the masses?

If Mayaud's trials are successful, he hopes that acyclovir will be offered as a standard treatment for genital ulcers when people seek treatment at a clinic. But providing a suppressive therapy regimen—that is, a 400 mg pill of acyclovir twice a day for years—will be expensive and may be difficult to distribute. Although a year's course of generically–produced acyclovir could cost as little as US$40 per year in Africa, it could still be prohibitive in most settings. Valacyclovir, the newer form of the drug that can be taken just once a day is not yet manufactured generically.

Despite these concerns most researchers argue that if there is a remedy on the shelf that can be used to reduce HIV transmission it should be made available. "Until the day comes when an effective AIDS vaccine is developed," says Pat Fast, medical director at the International AIDS Vaccine Initiative, "researchers must try everything they can to stem the spread of HIV."