Hopes for a female-controlled HIV prevention tool have been dealt a blow by the termination of one part of a large African trial after it failed to show effectiveness.
The Vaginal and Oral Interventions to Control the Epidemic (VOICE) study - involving more than 5,000 HIV-negative women in South Africa, Uganda and Zimbabwe - aimed to test the safety, effectiveness and acceptability of three HIV prevention methods: a vaginal gel containing antiretroviral drug tenofovir; daily use of oral tablets containing tenofovir, and daily use of oral Truvada, a combination of tenofovir and another ARV, emtricitabine.
But the independent Data and Safety Monitoring Board (DSMB) last week recommended that women assigned to the tenofovir tablet should discontinue use because the study would be unable to show a difference in effectiveness between the drug and a placebo. The trial's remaining two parts will continue as planned.
"Although the findings are disappointing, this is the way research happens. By no means does it mean PrEP [pre-exposure prophylaxis] doesn't work; it just means there are many more questions to be answered, and research will continue until we get the answers," Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition (AVAC), told IRIN/PlusNews. "This is not the end of the road, nor is it a dead end, but it is a big bump in the road."
For the investigators, the termination of the tenofovir arm is deeply disappointing, and could create challenges for the remaining two.
“The fact that Truvada contains tenofovir and the gel also has the same agent means that we must work hard to communicate to our teams and participants that both arms are still viable and we are still hopeful about them,” Jeanne Marrazzo, one of the trial’s investigators, told IRIN/PlusNews, adding that information was being collated to ensure the trial participants were fully informed of the new developments and understood the distinction between oral tenofovir and the other two arms. The DSMB found no safety concerns with oral tenofovir.
“We do not know why the oral tenofovir proved ineffective – whether it was an adherence issue, or the absorbance of oral tenofovir did not produce high enough levels of the drug in the vagina, or a high viral load among participants’ partners; we need to wait till the end of the trial to analyze all the data,” she added. “We need to be careful about offering information until we have all the facts.”
The women on the oral tenofovir arm will all stop taking it within the next week, Marrazzo said, and they will be followed for two months to ensure there is no delayed effect.
Uncertainty
The modification of the trial will add to the uncertainty already surrounding the efficacy of ARV-based HIV prevention, with recent research yielding both promising and disappointing results. In April 2011, a three-country study known as FemPrEP was halted after daily doses of Truvada failed to prevent HIV infection in the women participating, while the iPrEx study of men who have sex with men and transgender people found that daily oral Truvada reduced HIV infection risk among participants by an average 43.8 percent.
In July 2011, scientists announced that the Partners PrEP trial had ended a year early because it found overwhelming evidence of the effectiveness of oral tenofovir and Truvada in preventing HIV infection among discordant couples; earlier in the year, a major randomized clinical trial – HPTN 052 – found that treating an HIV-infected individual reduced the risk of sexual transmission of HIV to an uninfected partner by as much as 96 percent. In 2010, the Centre for the AIDS Programme of Research in South Africa (CAPRISA) found that a vaginal gel containing tenofovir was 39 percent effective in reducing a woman's HIV risk.
Marrazzo said she hoped the VOICE trial – due for completion in June 2012 – would reflect the results of the CAPRISA trial.
Sheryl Zwerski, acting director of the prevention science programme of the department of AIDS at the US National Institute of Allergy and Infectious Diseases – the trial’s main sponsor – said the DSMB would meet in the next two months to review the trial and possibly offer further recommendations.
She noted that the setback would not affect the US government’s commitment to HIV prevention. “We are taking one step at a time and remain committed to funding HIV prevention to the point where there is an effective prevention method that women can control,” she told IRIN/PlusNews.
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The Vaginal and Oral Interventions to Control the Epidemic (VOICE) study - involving more than 5,000 HIV-negative women in South Africa, Uganda and Zimbabwe - aimed to test the safety, effectiveness and acceptability of three HIV prevention methods: a vaginal gel containing antiretroviral drug tenofovir; daily use of oral tablets containing tenofovir, and daily use of oral Truvada, a combination of tenofovir and another ARV, emtricitabine.
But the independent Data and Safety Monitoring Board (DSMB) last week recommended that women assigned to the tenofovir tablet should discontinue use because the study would be unable to show a difference in effectiveness between the drug and a placebo. The trial's remaining two parts will continue as planned.
"Although the findings are disappointing, this is the way research happens. By no means does it mean PrEP [pre-exposure prophylaxis] doesn't work; it just means there are many more questions to be answered, and research will continue until we get the answers," Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition (AVAC), told IRIN/PlusNews. "This is not the end of the road, nor is it a dead end, but it is a big bump in the road."
For the investigators, the termination of the tenofovir arm is deeply disappointing, and could create challenges for the remaining two.
“The fact that Truvada contains tenofovir and the gel also has the same agent means that we must work hard to communicate to our teams and participants that both arms are still viable and we are still hopeful about them,” Jeanne Marrazzo, one of the trial’s investigators, told IRIN/PlusNews, adding that information was being collated to ensure the trial participants were fully informed of the new developments and understood the distinction between oral tenofovir and the other two arms. The DSMB found no safety concerns with oral tenofovir.
“We do not know why the oral tenofovir proved ineffective – whether it was an adherence issue, or the absorbance of oral tenofovir did not produce high enough levels of the drug in the vagina, or a high viral load among participants’ partners; we need to wait till the end of the trial to analyze all the data,” she added. “We need to be careful about offering information until we have all the facts.”
The women on the oral tenofovir arm will all stop taking it within the next week, Marrazzo said, and they will be followed for two months to ensure there is no delayed effect.
Uncertainty
The modification of the trial will add to the uncertainty already surrounding the efficacy of ARV-based HIV prevention, with recent research yielding both promising and disappointing results. In April 2011, a three-country study known as FemPrEP was halted after daily doses of Truvada failed to prevent HIV infection in the women participating, while the iPrEx study of men who have sex with men and transgender people found that daily oral Truvada reduced HIV infection risk among participants by an average 43.8 percent.
In July 2011, scientists announced that the Partners PrEP trial had ended a year early because it found overwhelming evidence of the effectiveness of oral tenofovir and Truvada in preventing HIV infection among discordant couples; earlier in the year, a major randomized clinical trial – HPTN 052 – found that treating an HIV-infected individual reduced the risk of sexual transmission of HIV to an uninfected partner by as much as 96 percent. In 2010, the Centre for the AIDS Programme of Research in South Africa (CAPRISA) found that a vaginal gel containing tenofovir was 39 percent effective in reducing a woman's HIV risk.
Marrazzo said she hoped the VOICE trial – due for completion in June 2012 – would reflect the results of the CAPRISA trial.
Sheryl Zwerski, acting director of the prevention science programme of the department of AIDS at the US National Institute of Allergy and Infectious Diseases – the trial’s main sponsor – said the DSMB would meet in the next two months to review the trial and possibly offer further recommendations.
She noted that the setback would not affect the US government’s commitment to HIV prevention. “We are taking one step at a time and remain committed to funding HIV prevention to the point where there is an effective prevention method that women can control,” she told IRIN/PlusNews.
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