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Tenofovir Gel & Tablets PrEP Study: Clinical Trial of Antiretroviral-based HIV Prevention Strategies for Women Now Under Way (study in 5,000 women)
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Sept 16 2009
NIH Announcement
A new, large-scale clinical trial is examining whether antiretroviral medications normally used to treat HIV infection can also prevent HIV infection in women when applied as a vaginal gel or taken as oral tablets once daily.
The study, called Vaginal and Oral Interventions to Control the Epidemic (VOICE) or MTN-003, will involve up to 5,000 HIV-uninfected women at risk for HIV infection in four African countries. The trial will test the safety and efficacy of two different HIV prevention strategies: an investigational microbicide gel containing the antiretroviral drug tenofovir, and oral tablets containing tenofovir or a combination of tenofovir and emtricitabine known by the brand name Truvada. The tablets would be taken prior to exposure in an approach known as pre-exposure prophylaxis, or PrEP. Testing a microbicide and PrEP in the same trial will enable scientists to directly compare the two strategies in terms of their safety and acceptability.
Notably, the VOICE study is the first efficacy study of an investigational microbicide in which participants apply the gel once daily rather than shortly before sexual intercourse. If found effective, this approach would allow participants to choose whether to use the gel in association with sexual activity or at another time of day, permitting greater privacy and convenience of use.
"We need multiple, scientifically proven HIV prevention strategies acceptable to different populations to effectively combat the spread of the virus, and PrEP and microbicides are two promising approaches that we are actively pursuing," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID). "The VOICE study is designed to answer multiple crucial questions about these experimental interventions, with an emphasis on protecting women from HIV."
NIAID is sponsoring and funding the trial with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the National Institutes of Health. Co-sponsors are Gilead Sciences Inc. of Foster City, Calif., and CONRAD of Arlington, Va. The NIH-funded Microbicide Trials Network is conducting the study.
Women make up half of all people worldwide living with HIV, and in sub-Saharan Africa, women represent nearly 60 percent of adults living with the virus. In most cases, women become infected with HIV through sexual intercourse with an infected male partner. An effective microbicide or PrEP regimen could give women an HIV prevention method they control. This would be particularly helpful in situations where it is difficult or impossible for women to refuse sex or negotiate condom use with their male partners.
The VOICE study is being conducted at 14 sites in South Africa, Uganda, Zambia and Zimbabwe. The Phase IIb study, which will last approximately three and a half years, is being led by Zvavahera Mike Chirenje, M.D., of the University of Zimbabwe in Harare, and Jeanne Marrazzo, M.D., M.P.H., of the University of Washington in Seattle. The sexually active, HIV-uninfected women ages 18 to 45 participating in the study will be randomly assigned to one of five regimens, each performed once daily:
- Applying tenofovir gel vaginally
- Applying a placebo gel vaginally
- Taking a tenofovir pill and a placebo pill
- Taking a tenofovir/emtricitabine pill and a placebo pill
- Taking two placebo pills
Neither the investigators nor the participants will know who receives the active gel or tablets and who receives the placebos. Gilead Sciences is providing tenofovir and tenofovir/emtricitabine tablets at no cost, and CONRAD is providing tenofovir gel and gel applicators free of charge.
Study staff will follow the participants for 14 to 35 months. The investigators will compare the number of women in each group who acquire HIV during the study to determine whether the microbicide or either PrEP regimen is markedly more effective than the corresponding placebo in preventing HIV infection.
Safety will be monitored closely throughout the study. Designed according to the most rigorous standards of international medical practice and ethics, the VOICE study contains numerous measures, beginning at the site level, intended to protect the safety and well-being of participants. This includes a multi-tiered safety review process with strict U.S. and international procedures for monitoring and reporting of adverse events. Also, all participants will receive regular HIV testing and risk-reduction counseling; condoms; and testing for sexually transmitted infections. Staff will refer any participant who acquires HIV or a sexually transmitted infection during the study to appropriate treatment and care in her community.
In addition to testing tenofovir gel and PrEP for safety and efficacy, the VOICE study aims to determine which regimen-pill or gel-women are likely to follow more consistently, and whether either intervention influences participants' risk-taking behavior. The study also will assess how frequently participants who acquire HIV during the trial develop resistance to tenofovir or tenofovir/emtricitabine.
The premise behind PrEP is that taking an antiretroviral drug before exposure to HIV could potentially inhibit HIV replication immediately after exposure to the virus, thwarting permanent infection. This strategy is used globally to successfully prevent the transmission of HIV from mother to infant.
A companion study at the Uganda and Zimbabwe clinical trial sites involving 300 women assigned to the tablet groups will examine the potential effects, if any, of oral tenofovir on bone density in HIV-uninfected women. A second companion study will examine household and community-level factors associated with adherence to the VOICE study products.
QUESTIONS AND ANSWERS
The VOICE HIV Prevention Study
1. What is the VOICE study?
VOICE stands for "Vaginal and Oral Interventions to Control the Epidemic." The VOICE study, also known as MTN-003, is a large, Phase IIb clinical trial among HIV-negative women in four African countries designed to determine whether antiretroviral drugs used to treat HIV infection can also prevent male-to-female HIV transmission. The study is testing the safety and efficacy of two HIV prevention strategies: an investigational vaginal microbicide containing the antiretroviral drug tenofovir, and oral tablets containing tenofovir or a combination of tenofovir and emtricitabine. The tablets would be taken prior to potential exposure in an approach known as pre-exposure prophylaxis, or PrEP.
2. What is PrEP?
PrEP is an investigational strategy to prevent HIV infection by giving a daily dose of one or two antiretroviral drugs to HIV-negative people who are at high risk for acquiring the virus. Scientists theorize that taking an antiretroviral drug before exposure to HIV could potentially inhibit HIV replication immediately after exposure to the virus, thereby thwarting the establishment of permanent infection.
3. What is a microbicide?
A microbicide is a vaginal gel, foam, cream or ring designed to prevent transmission of HIV when applied topically inside the vagina or the rectum. No microbicide has been approved yet for use outside of research studies.
4. Who will participate in the VOICE study, and where is the study being conducted?
The study team plans to enroll up to 5,000 sexually active, HIV-uninfected women ages 18 to 45 into the VOICE study. The clinical trial is taking place at 14 sites in six cities in four countries, specifically:
* Durban, South Africa (seven sites)
* Harare, Zimbabwe (three sites)
* Johannesburg, South Africa
* Kampala, Uganda
* Klerksdorp, South Africa
* Lusaka, Zambia
5. Who is funding, sponsoring and conducting the VOICE study?
The National Institute of Allergy and Infectious Diseases (NIAID) is funding the VOICE study with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all part of the National Institutes of Health. NIAID is the study's primary sponsor; the co-sponsors are CONRAD of Arlington, Va., and Gilead Sciences Inc. of Foster City, Calif.
The NIH-funded Microbicide Trials Network (MTN) is conducting the VOICE study under the leadership of protocol co-chairs Zvavahera Mike Chirenje, M.D., F.C.R.O.G., of the University of Zimbabwe in Harare, and Jeanne Marrazzo, M.D., M.P.H., of the University of Washington in Seattle.
Gilead Sciences is providing tenofovir and tenofovir/emtricitabine tablets to the VOICE study team free of charge, and CONRAD is providing tenofovir gel and gel applicators at no cost. Co-formulated tenofovir/emtricitabine is known by the brand name Truvada.
6. Which PrEP regimens and microbicide are being tested in the VOICE study?
The VOICE study is testing the safety and efficacy of two PrEP regimens: a daily dose of 300 mg tenofovir, and a daily dose of 300 mg tenofovir plus 200 mg emtricitabine combined into one pill.
The study also is testing the safety and efficacy of an investigational microbicide gel containing the antiretroviral drug tenofovir at a concentration of 1 percent.
7. Why is the VOICE study important?
The VOICE study is important for several reasons. First, an effective microbicide or PrEP regimen could give women an HIV prevention method they control. This would be particularly helpful in situations where it is difficult or impossible for women to refuse sex or negotiate condom use with their male partners. Women make up half of all people worldwide living with HIV, and in sub-Saharan Africa, women represent nearly 60 percent of adults living with the virus. In most cases, women become infected with HIV through sexual intercourse with an infected male partner.
In addition, if PrEP or the tenofovir-based microbicide under study in VOICE is found to be effective, it could expand the number of HIV prevention tools available to curb the HIV/AIDS pandemic. The best offense against HIV/AIDS is a comprehensive prevention toolkit that can be tailored to meet the needs of specific populations.
8. How does the VOICE study differ from other clinical trials of microbicides or PrEP?
The VOICE study is the first to test the efficacy of a microbicide gel that women apply once daily rather than shortly before they have sexual intercourse, which may enable women to use the microbicide more privately and conveniently. It is also one of the first large-scale clinical trials of the newer class of microbicides that contain an antiretroviral drug and thus act specifically against HIV.
The VOICE study also is the first to test a microbicide and PrEP in the same clinical trial. This will enable researchers to directly compare the acceptability of the two experimental HIV prevention strategies in adult heterosexual women. The study also will examine whether the antiretroviral-containing prevention strategies generate drug resistance, and if so, to what extent.
9. What is the study design?
VOICE is a Phase IIb, five-arm, multi-site, placebo-controlled trial. Participants will be assigned at random to one of five regimens, each performed once daily:
* Applying tenofovir gel vaginally
* Applying a placebo gel vaginally
* Taking a tenofovir pill and a placebo pill
* Taking a tenofovir/emtricitabine (Truvada) pill and a placebo pill
* Taking two placebo pills
Neither the investigators nor the participants will know who receives the active products and who receives the placebos.
In addition to testing tenofovir gel and PrEP for safety and efficacy, the VOICE study aims to determine which regimen-pill or gel-women are likely to follow more consistently and whether either intervention influences the risk-taking behavior of participants. The study also will assess how frequently participants who acquire HIV during the trial develop resistance to tenofovir or tenofovir/emtricitabine (Truvada).
Study staff will follow the participants for 14 to 35 months. All participants will receive regular HIV testing and risk-reduction counseling; condoms; and testing for sexually transmitted infections. Staff will refer any participant who acquires HIV or a sexually transmitted infection during the study to appropriate treatment and care in her community.
Safety will be monitored closely throughout the study. Designed according to the most rigorous standards of international medical practice and ethics, the VOICE study contains numerous measures, beginning at the site level, intended to protect the safety and well-being of participants. This includes a multi-tiered safety review process with strict U.S. and international procedures for monitoring and reporting of adverse events.
10. How will the investigators know whether the microbicide or PrEP strategy is effective?
The investigators will compare the number of women in each group who acquire HIV through exposure in their environment during the study to determine whether the microbicide or either PrEP regimen is markedly more effective than the corresponding placebo in preventing HIV infection. Neither the investigational microbicide nor PrEP can cause HIV infection.
11. How and why will bone density be studied in VOICE?
In previous animal studies of tenofovir, very high doses of the drug (many times higher than the dose given to humans) were found to have an adverse effect on the animals' bone health. In addition, an ongoing clinical study of HIV-infected men and women taking tenofovir as part of an antiretroviral drug treatment regimen has found measurable decreases in the density of spine and hip bones, although these decreases have not adversely affected the individuals' health. Thus, the VOICE study investigators want to learn what effects, if any, tenofovir has on the bone density of healthy, HIV-uninfected women.
The study team will monitor the bone density of all clinical trial participants. In addition, about 300 study participants taking the oral tenofovir or tenofovir/emtricitabine (Truvada) tablets at sites in Uganda and Zimbabwe will enroll in a sub-study called VOICE B. The VOICE B participants will periodically undergo specialized testing of bone-mineral density so investigators can monitor bone health even more closely.
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