Hopeful that some of the same antiretroviral (ARV) drugs used to treat HIV infection also can prevent it, researchers from a network funded by the U.S. National Institutes of Health have enrolled the first participants into a new, large-scale clinical trial testing two approaches of the strategy in women.

The trial, named the Vagina and Oral Interventions to Control the Epidemic (VOICE), will help determine whether applying a vaginal microbicide gel containing an ARV every day or taking an oral ARV tablet once a day can reduce a woman's risk of acquiring HIV.

While the study's primary aim is to evaluate the safety and effectiveness of the two regimens, an important question VOICE also will address is which of the two—the tablet or the gel—women will be more inclined to use. Researchers claim it's the first HIV prevention trial testing these two different approaches in the same study and the first effectiveness trial of a microbicide in which women use the gel every day instead of only at the time of sex.

Up to 5,000 women will be enrolled in VOICE at clinical trial sites in Uganda, South Africa, Zambia, and Zimbabwe. Pending government approval, the study also may be conducted in Malawi. The Spilhaus Clinical Research Site, located at the University of Zimbabwe-University of California-San Francisco (UZ-UCSF) Clinical Trials Unit in Harare, began enrolling trial participants last month.

VOICE is being conducted under the leadership of the National Institutes of Health (NIH)-funded Microbicide Trials Network, which is based at the University of Pittsburgh and Magee-Womens Research Institute.

"The HIV prevention field has not been without its share of disappointments. So, naturally we are excited that in VOICE we have not just one, but two promising approaches to evaluate," says Dr. Mike Chirenje, associate professor and consultant gynecologist in the department of obstetrics and gynecology at the University of Zimbabwe in Harare and co-chair of the VOICE Study. "Hopefully, we'll find that ARVs, which helped turn the tide in the treatment of HIV, can be a prevention powerhouse, too."

Women represent nearly 60 percent of adults living with HIV in sub-Saharan Africa, and in several southern African countries young women are at least three times more likely to be HIV-positive than young men. In most cases, women acquire HIV through sexual intercourse with an infected male partner.

Although correct and consistent use of male condoms has been shown to prevent HIV infection, women often cannot control if or when condoms are used by their male partners. Moreover, women are twice as likely as their male partners to acquire HIV during unprotected sex, due in part to biological factors that make them more susceptible to infection.

Dr. Jeanne Marrazzo, associate professor of medicine in the division of allergy and infectious diseases at the University of Washington, in Seattle, and VOICE study co-chair, says, "Women need safe and effective methods for preventing HIV that they can control themselves. Importantly, women need methods that they are willing and able to use, because no approach can be truly effective if she leaves it in her purse or hidden in a drawer."

Two ARV tablets are being tested in VOICE: tenofovir and Truvada. Tenofovir, short for tenofovir disoproxil fumarate, also is known by the brand name Viread, while Truvada is the brand name for a combination drug that contains tenofovir and another active ingredient called emtricitabine. Both are approved for treating HIV as part of antiretroviral therapy. While at least three ARVs typically are used for such therapy, a single ARV tablet taken once a day—an approach called pre-exposure prophylaxis—is the regimen being tested for HIV prevention in current trials, including VOICE.

The vaginal microbicide being evaluated in VOICE, tenofovir topical gel, contains the activated form of the same ingredient in the tenofovir oral tablet. It is among a newer class of candidate microbicides—substances intended to reduce or prevent the sexual transmission of HIV and other sexually transmitted infections when applied topically inside the vagina or rectum—specifically targeting HIV.

Women in VOICE are randomly assigned to one of five study groups. Two groups will apply gel every day—either tenofovir gel or a placebo gel with no active ingredient. Three groups will be assigned to daily tablet regimens, taking either tenofovir, Truvada, or a placebo tablet. The study is "blinded," so neither the participants nor the researchers will know who is in which gel or tablet group. Women will use the same product every day the entire time they are in the study, which is expected to be an average of 22.5 months.

All participants will receive regular HIV testing and risk-reduction counseling, condoms, and testing for sexually transmitted infections (STIs). Staff will refer any participant who acquires HIV or other sexually transmitted infections during the study to appropriate treatment and care in her community.

Researchers at the Uganda and Zimbabwe sites also are conducting a companion study called VOICE B, or the Bone Mineral Density Sub-study. VOICE B will involve about 300 women who have been randomized to the oral tablet groups to determine the potential effects, if any, that the oral ARVs may have on bone health in HIV-negative women.

Both studies were designed to meet rigorous international medical practice and ethical standards and include numerous measures, beginning at the site level, intended to protect the safety and well-being of participants, researchers say. All women participating in VOICE and VOICE B will provide written informed consent through a process that ensures they understand the procedures, as well as possible risks and benefits of the study.

The VOICE Study is being funded by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all of which are affiliated with NIH.