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Women's HIV Prevention Trial Halts Oral Tenofovir Arm

Researchers will discontinue one arm of the VOICE study testing oral tenofovir (Viread) pills after an interim analysis by an independent monitoring board showed that the trial would be unlikely to show that the drug works better than placebo for pre-exposure prophylaxis (PrEP) to prevent HIV infection. Other study arms testing the tenofovir/emtricitabine combination pill (Truvada) and a tenofovir vaginal gel will continue. No safety concerns were identified.

The large study, being conducted in South Africa, Uganda, and Zimbabwe, remains blinded, and details of the findings have not yet been released. But the announcement was unexpected because other tenofovir PrEP studies have recently produced promising results.

The iPrEX trial showed that Truvada reduced the risk of new infections by 44% among high-risk men who have sex with men, rising to more than 90% for those with measurable levels of the drug in their blood.

Two other studies presented this summer's International AIDS Society meeting in Rome showed that PrEP with tenofovir or tenofovir/emtricitabine reduces the risk of HIV infection among heterosexuals and serodiscordant couples.

However, another study, called FEM-PrEP, found no prevention benefit for women using the tenofovir/emtricitabine regimen, and that trial was also stopped ahead of schedule this past April.

The reason for the disparity across studies -- and even within the VOICE study, since the combination tenofovir/emtricitabine arm is being allowed to continue -- are far from clear, and call into question efforts to rapidly roll out PrEP programs.

"The data are trying to tell us something very important," Microbicide Trials Networkdirector Sharon Hillier told Science magazine. "People thought [antiretrovirals] were going to be magic, and you could sprinkle them out there and people would use them all the time and they'd prevent all infections. These studies are teaching us loud and clear that how and when they'll work raises very nuanced questions."

The Microbicide Trials Network, which is conducting the study, has prepared a Frequently Asked Questions document about the modification of VOICE trial modification, available athttp://www.mtnstopshiv.org/node/3622.

Below is an edited excerpt from a press release issued this week by the National Institutes of Health, which is funding the VOICE trial, providing more details about the study and its modification.

NIH Modifies ‘VOICE’ HIV Prevention Study in Women

Oral tenofovir discontinued in clinical trial

A large-scale clinical trial evaluating whether daily use of an oral tablet or vaginal gel containing antiretroviral drugs can prevent HIV infection in women is being modified because an interim review found that the study cannot show that one of the study products, oral tenofovir, marketed under the trade name Viread, is effective.

An independent data and safety monitoring board (DSMB) recommended that the Vaginal and Oral Interventions to Control the Epidemic (VOICE) (http://www.niaid.nih.gov/news/newsreleases/2009/Pages/VOICE.aspx) study discontinue evaluating tenofovir tablets because the study will be unable to show a difference in effect between tenofovir tablets and placebo tablets. The DSMB found no safety concerns with oral tenofovir, which is currently used to treat HIV, or with the other products that will continue to be investigated as the VOICE study proceeds.

As the trial's primary sponsor, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, concurred with the DSMB's recommendation and will modify the study. Because the trial is continuing, the study data remain confidential and restricted to DSMB analysis. Given that data are unavailable, NIAID cannot speculate about why oral tenofovir did not show an effect among VOICE study participants.

Begun in September 2009, the VOICE study, or MTN-003, involves more than 5,000 HIV-uninfected women in South Africa, Uganda and Zimbabwe. The trial was designed to test the safety, effectiveness and acceptability of two different HIV prevention strategies: an investigational microbicide gel containing tenofovir, and oral tablets containing tenofovir either alone or co-formulated with the drug emtricitabine. The tablets, known by the brand names Viread (tenofovir) and Truvada (tenofovir plus emtricitabine), have been taken daily in an approach known as pre-exposure prophylaxis, or PrEP.

After its routine review of the study data on Sept. 16, the DSMB recommended that the investigators stop evaluating oral tenofovir because the study would be unable to show that tenofovir tablets have a different effect than placebo tablets at preventing HIV infection among the study participants. The DSMB therefore recommended that the roughly 1,000 women in the oral tenofovir group stop taking the study product. Further, the DSMB recommended that the VOICE study continue as designed to evaluate tenofovir gel and oral Truvada.

The study team will immediately begin to inform all VOICE participants of this new development and will soon begin the orderly discontinuation of the tenofovir tablets. Participants who were taking oral tenofovir will stop using the product at their next scheduled clinical site visit. They will then return eight weeks later for a final set of tests and procedures before exiting the study. At that visit, they will be provided information about where they can continue to receive HIV testing and counseling, contraception and other medical and support services.

NIAID is pleased that the trial will continue to examine the question of whether tenofovir gel and oral Truvada are safe and effective HIV prevention measures for women and thanks all participants in the VOICE study for their significant contribution to furthering HIV prevention research. This study is an important component of NIH’s comprehensive HIV prevention research program articulated in the HHS National HIV/AIDS Strategy Operational Plan (http://www.aids.gov/federal-resources/policies/national-hiv-aids-strategy/whats-next/agency-operational-plans.html).

NIAID remains committed to supporting research to develop HIV prevention tools that women can implement. Slightly more than half of all new HIV infections globally occur in women, mostly through unprotected sex with HIV-infected men. A safe and effective microbicide or oral PrEP regimen would be particularly helpful to women when it is difficult or impossible for them to refuse sex or negotiate condom use with their male partners.

NIAID is sponsoring and 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 NIH. 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.

For additional information about the VOICE study, see the Microbicide Trials Network site at http://www.mtnstopshiv.org/node/3619.

9/30/11

Sources

National Institutes of Health. NIH Modifies ‘VOICE’ HIV Prevention Study in Women. Press release. September 28, 2011.

Microbicide Trials Network. MTN Statement on Decision to Discontinue Use of Oral Tenofovir Tablets in VOICE, a Major HIV Prevention Study in Women. Press release. September 28, 2011.

J Cohen. A Dizzying Second Twist in Trial of Anti-HIV Drugs as Preventives. Science. September 28, 2011.