HIV-prevention scientists evaluate unexpected results of VOICE HIV prevention trial

Continued FEM-PrEP and VOICE analyses may yield important clues

September 28, 2011

RESEARCH TRIANGLE PARK, NC — The Microbicides Trial Network (MTN) announced today that its HIV-prevention study, VOICE (Vaginal and Oral Interventions to Control the Epidemic), will continue. However, researchers made an unanticipated decision to discontinue the daily, oral tenofovir arm of the trial.

On September 16, 2011, the VOICE Data and Safety Monitoring Board (DSMB) reviewed study data for the period between Sept. 9, 2009 (when the study began) and July 1, 2011. Based on this interim review, the DSMB determined that it was not possible to show whether oral tenofovir tablets were any better than a placebo for preventing HIV in the women assigned to that study group. The DSMB therefore recommended that the women randomized to the oral tenofovir tablet group discontinue their use of the study product. This recommendation does not apply to the women in the groups using either the tenofovir gel or oral Truvada® tablets, or the corresponding placebos; the DSMB recommended that these four study groups continue in VOICE.

All VOICE participants will be informed about the decision to modify the study. Because the DSMB had no concerns about the safety of oral tenofovir, the process of discontinuing its use among the participants in that study group can proceed in an orderly fashion. Each of these participants will stop using the oral tenofovir tablets at their next scheduled clinic appointment. They will then return eight weeks later for a last set of tests and procedures before exiting the study.

The VOICE trial will continue to evaluate the safety and HIV-prevention effectiveness of tenofovir gel, applied vaginally, and the oral tablet Truvada, an HIV treatment product that contains a combination of the antiretroviral drugs tenofovir disoproxil fumarate (TDF, 300 mg) and emtricitabine (FTC, 200 mg) in a single pill. The DSMB recommended that these two study arms continue as originally planned. Final results are expected in early 2013.

The FEM-PrEP team commends the MTN and the VOICE researchers for their dedication to a rigorous scientific process and the trial participants for their important contribution to ending the HIV epidemic. VOICE remains a critically important study that will advance HIV prevention.

The VOICE Trial: VOICE is a Phase IIB HIV prevention trial involving 5,029 women from Uganda, South Africa and Zimbabwe. It is being conducted by MTN, which is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID). The trial is testing whether antiretroviral (ARV) medicines commonly used to treat people with HIV are safe and effective for preventing sexual transmission of HIV in women. In VOICE, the safety and effectiveness of two different ARV-based approaches are being tested: daily use of an ARV tablet – an approach called oral pre-exposure prophylaxis (PrEP) – and daily use of a vaginal microbicide containing an ARV in gel form.

VOICE is the first effectiveness study on an ARV-based, topical microbicide that women use once daily and the only trial evaluating both an oral tablet and a vaginal gel in the same study. This approach is important for determining how each product works compared to its control (placebo gel or placebo tablet) and which approach women prefer.

The FEM-PrEP Trial: FHI 360 is closing its PrEP trial, FEM-PrEP, which is a Phase III, randomized, placebo-controlled clinical trial designed to assess the safety and effectiveness of a daily oral dose of Truvada for HIV prevention among women in sub-Saharan Africa.

Following a scheduled interim review of the FEM-PrEP study data in April 2011, the trial's Independent Data Monitoring Committee advised that the FEM-PrEP study will be highly unlikely to demonstrate Truvada's effectiveness in preventing HIV infection in the study population, even if it continued to its originally planned conclusion. FHI 360 subsequently concurred and initiated an orderly closure of the study over the subsequent few months.

When screening and enrollment stopped on April 18, 2011, a total of 4,054 women had been screened for the FEM-PrEP trial, and 2,119 had been enrolled. We previously reported that, as of February 18, 2011, a total of 56 new HIV infections had occurred; an equal number of infections occurred in participants assigned to Truvada and those assigned to a placebo pill. Follow-up of the HIV-negative cohort ended on August 12, 2011. The total number of HIV infections to be included in the primary analysis of the trial will be determined after confirmatory testing is completed.

FEM-PrEP Next Steps: Closing of the FEM-PrEP trial was initiated in April 2011, and the follow-up the HIV-negative participants was completed in August 2011. Follow-up of women who became HIV-infected during the trial will continue until one year after their seroconversion, as per protocol, and they are referred for appropriate medical care and treatment in their community.

Data analyses from FEM-PrEP are not yet complete. Ongoing data cleaning will be completed by the end of October 2011. Confirmation of all HIV infections, antiretroviral resistance testing and tenofovir and emtricitabine drug level testing is ongoing. The primary statistical analysis will be conducted in November 2011.

Publication of the main findings, along with dissemination of final results to site communities, is expected between late 2011 and early 2012. Secondary analyses and associated paper writing will occur in 2012.

Comparison of PrEP trial results is crucial: The decision to drop the tenofovir arm from the VOICE trial comes only two months after researchers from the University of Washington (who conducted the Partners PrEP Study in Kenya and Uganda) and the U.S. Centers for Disease Control and Prevention (CDC) (who conducted the TDF2 study in Botswana) provided the first evidence that HIV infection among heterosexuals can be prevented by taking oral, once-daily Truvada or tenofovir tablets.

With the closing of the tenofovir arm of VOICE, there is now an even more critical need to explore why VOICE, FEM-PrEP and the other PrEP trials had seemingly different findings. In addition to possible differences in adherence to the study pills, there may have been important differences in the study populations related to sexual activity, other sexually transmitted infections or levels of inflammation that can affect HIV susceptibility. FHI360 will be working with scientists from MTN, the University of Washington and the CDC to compare data from the studies to better understand differences and similarities.