VOICE – Vaginal and Oral Interventions to Control the Epidemic – is a major HIV prevention trial designed to evaluate whether antiretroviral (ARV) medicines commonly used to treat people with HIV are safe and effective for preventing sexual transmission of HIV in women. The study focused on two ARV-based approaches: daily use of an ARV tablet – an approach called oral pre-exposure prophylaxis, or PrEP; and daily use of a vaginal microbicide containing an ARV in gel form. Specifically, VOICE sought to determine the safety and effectiveness of three different products: an oral tablet containing tenofovir (known by the brand name Viread®); an oral tablet that contains both tenofovir and emtricitabine (known as Truvada®); and tenofovir gel, a vaginal microbicide with the same active ingredient as the oral tenofovir tablet.
The study, which began in September 2009, enrolled a total of 5,029 sexually active women at 15 sites in Uganda, South Africa and Zimbabwe, encompassing a region where HIV incidence is among the highest in the world. Follow-up of all participants was completed in August 2012 and the study’s results are expected to be reported in March 2013.
VOICE was conducted by a team of researchers working in the Microbicide Trials Network (MTN), an HIV/AIDS clinical trials network established and funded in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all components of the U.S. National Institutes of Health (NIH). Leading the study were Zvavahera Mike Chirenje, M.D., from the University of Zimbabwe in Harare; and Jeanne Marrazzo, M.D., M.P.H., from the University of Washington in Seattle.
VOICE has already answered two key questions it was designed to ask, finding that while both oral tenofovir tablets and tenofovir gel were safe, neither was effective in preventing HIV among the women in the study, who were asked to use their assigned product daily. The study’s final results will help in understanding why these products were not effective in VOICE as well as determine whether daily use of Truvada can prevent HIV in these women.
Why the VOICE Study is Important
The participants in VOICE were predominately women in their 20’s, many were single, and those who were married or in a committed relationship, did not necessarily know the HIV status of their partners. These are the very women who are the face of the epidemic in Africa, where unprotected heterosexual intercourse is primarily to blame for the region’s heavy HIV burden. Women account for 60 percent of adults with HIV in sub-Saharan Africa. Women are twice as likely as their male partners to acquire HIV during sex, and young women are especially vulnerable. Efforts to promote abstinence, monogamy and the use of male condoms have not been enough to stop the HIV epidemic nor are these practical methods in most settings. There is an urgent need for effective prevention strategies that women can control themselves. As a large study that included women from diverse cultural settings in Africa, VOICE is important for helping to understand what will be safe, effective and practical for preventing HIV in these women.
Although VOICE already found both oral tenofovir tablets and tenofovir gel were safe but not effective in preventing HIV among the women in the study, the study’s final results will be critical for helping to understand why these products were not effective in VOICE. The field is particularly in want of understanding why tenofovir gel did not protect women in VOICE against HIV when in the CAPRISA 004 study tenofovir gel used before and after sex reduced HIV risk by 39 percent. While it was hoped that VOICE would provide the strength of evidence needed to support possible licensure of tenofovir gel, the study’s final results could have important implications for ongoing trials, particularly FACTS 001, a Phase III trial testing the same regimen as CAPRISA 004 (before and after sex), and the product’s further development as a vaginal or rectal microbicide.
Results of VOICE also will be important for determining whether daily use of Truvada can prevent HIV in women. While Truvada, which had already been approved for the treatment of HIV, is also now approved by the U.S. Food and Drug Administration (FDA) for use in preventing HIV, information from VOICE will still carry substantial weight. The FDA’s decision to approve Truvada for HIV prevention was based on strong evidence from two studies in specific populations – one in heterosexual men and women in committed relationships with an HIV-infected partner, and the other in men who have sex with men. Results of VOICE will enhance the base of understanding about Truvada for preventing HIV, and, importantly, contribute critical information about its use in different populations and settings. The FDA’s approval of Truvada for HIV prevention applies only to the United States. On the global stage, WHO has issued guidance on PrEP only for serodiscordant couples and men who have sex with men, recommending its use initially in the context of demonstration projects. VOICE results could suggest the need for revisions of the current guidance. Because VOICE will help to understand Truvada’s safety and effectiveness in protecting against HIV in a diverse yet vastly representative population of at-risk African women, its results will be essential as WHO develops formal PrEP implementation guidelines, which are anticipated to be released in 2015.
The VOICE Study at a Glance
VOICE was designed as a large Phase IIb (proof of concept) trial to evaluate two ARV-based approaches for preventing the sexual transmission of HIV in women – daily use of an ARV tablet (tenofovir or Truvada) or a vaginal gel (tenofovir gel). Learning about the safety and effectiveness of each approach required the kind of trial in which participants were randomly assigned by chance to different study groups, including groups that used a placebo, which has no active drug. Moreover, neither participants nor researchers knew who was in which group while the study was ongoing because it was “blinded.” As with other HIV prevention trials, all participants in VOICE received ongoing HIV risk reduction counseling, condoms and diagnosis and treatment of sexually transmitted infections – standard methods for preventing HIV – throughout their participation.
VOICE originally had five study groups – two gel groups (tenofovir gel and an inactive placebo gel) and three tablet groups (tenofovir, Truvada and an inactive placebo tablet) – with about 1,000 women in each group who were instructed to use their assigned study product every day. VOICE stopped testing oral tenofovir and tenofovir gel, however, after routine reviews of study data by the trial’s independent data safety and monitoring board (DSMB) determined that while each was safe, neither was effective in preventing HIV compared to its matched placebo.
VOICE included numerous measures to monitor and protect the safety and wellbeing of participants, beginning with the clinical research teams at the trial sites who performed thorough checks on the health, safety and welfare of participants at each study visit. In addition, the study teams worked actively to decrease participants’ risk of HIV infection by providing free condoms, regular counseling about preventing HIV and other STIs, and STI testing and treatment. Safety was also monitored by a team at the MTN statistical and data management center that assessed incoming reports on a daily basis; and a VOICE protocol safety review team that provided regular monthly oversight. An independent group of clinical research experts, bioethicists and statisticians called a data safety monitory board, or DSMB, also conducted regular reviews of blinded data while VOICE was in progress. The DSMB conducted four
routine reviews of safety data and three reviews for efficacy – an assessment of the number of HIV infections that occurred in each of the different study groups since the study began. At no time did the DSMB have any major concerns about the safety of the products.
The Products Studied
The Vaginal Gel: The active ingredient in tenofovir gel belongs to a class of ARVs called nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). In its oral form, tenofovir disoproxil fumarate (TDF), known by the brand name Viread®, is approved as a treatment for HIV infection in combination with other medications. Laboratory and nonclinical studies have demonstrated that tenofovir gel acts on certain cells of the vagina and cervix that are the primary targets for HIV infection. Clinical safety studies performed to date have found it is well-tolerated and safe. In July 2010, a study called CAPRISA 004 found tenofovir gel was safe and reduced the risk of HIV by 39 percent among women who used it before and after vaginal sex compared to women who used a placebo gel. CAPRISA 004 involved 889 women at two sites in South Africa. A Phase III trial, called FACTS-001, is evaluating the same regimen used in CAPRISA 004 and plans to enroll at least 2,700 women at nine sites in South Africa, with results expected in 2015.
The ARVs: Tenofovir and Truvada, the brand name for a combination drug consisting of tenofovir and emtricitabine (FTC), are NRTIs that are approved for and widely used for the treatment of HIV. In July 2012, the U.S. FDA approved the use of Truvada also for prevention of HIV based primarily on the results of two studies. The iPrEx Study of 2,500 men who have sex with men, there were 42 percent fewer HIV infections among participants assigned to daily use of Truvada compared to the placebo group. The Partners PrEP Study evaluated the safety and effectiveness of both tenofovir and Truvada among 4,758 heterosexual couples in whom one of the partners is HIV-positive. There were 67 percent fewer HIV infections among participants assigned to take tenofovir daily compared to participants who took a placebo tablet, and 75 percent fewer infections among those who took Truvada. In a smaller trial of 1,200 heterosexual men and women in Botswana, researchers from the U.S. Centers for Disease Control and Prevention found 62.6 percent fewer HIV infections occurred in the group assigned to take Truvada than in the placebo group. Yet, the FEM-PrEP Study was unable to demonstrate that daily use of Truvada was effective among 2,119 higher-risk women between the ages of 18 to 35 in Kenya, South Africa and Tanzania. To date, of the more than 8,000 participants involved in previous trials, drug resistance has been detected in only a handful of cases and concerns about safety have been few and minimal. In a minority of participants, side effects such as mild nausea and diarrhea were experienced in the first few weeks of starting study product.
Viread and Truvada are registered trademarks of Gilead Sciences, Inc., of Foster City, Calif., U.S. Gilead assigned a royalty-free license for tenofovir gel to CONRAD, of Arlington, Virginia, and the International Partnership for Microbicides of Silver Spring, Maryland, in 2006. For VOICE, Gilead is providing the oral products free of charge, and CONRAD is providing both the gel and gel applicators at no cost.
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About the MTN
The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health (NIH). The MTN brings together international investigators and community and industry partners who are devoted to reducing the sexual transmission of HIV through the development and evaluation of products applied topically or administered orally, working within a unique infrastructure specifically designed to facilitate the research required to support licensure of these products for widespread use.
Based at the University of Pittsburgh and Magee-Womens Research Institute in Pittsburgh, Pennsylvania, USA, MTN’s core operations are supported by a network laboratory at the University of Pittsburgh, a statistical and data management center housed within the Statistical Center for HIV/AIDS Research & Prevention (SCHARP) at the Fred Hutchinson Cancer Research Center, and FHl 360, a global organization with expertise conducting clinical protocols. MTN conducts its trials at clinical research sites located in seven countries and spanning three continents. MTN receives its funding from three NIH institutes: NIAID, the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Among the groups developing and evaluating microbicides for HIV prevention globally, the MTN is the only one funded by NIH. More information about the VOICE Study and other MTN studies can be found at http://www.mtnstopshiv.org/news/studies/mtn003
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