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MDP301 HIV prevention trial results published

21 September 2010

PRO2000 vaginal gel does not protect African women from HIV infection.

The results of a randomised trial show that the vaginal gel PRO2000 does not prevent HIV infection in African women. The findings are published in an article online first and in an upcoming Lancet, written by Dr Sheena McCormack, MRC Clinical Trials Unit, London, UK, and colleagues.

Innovative prevention strategies for HIV-1 transmission are urgently needed. PRO2000 vaginal gel was efficacious against HIV-1 transmission in studies in macaques. In this study, the authors assessed the efficacy and safety of 2% and 0·5% PRO2000 gels against vaginal HIV-1 transmission in women in sub-Saharan Africa.

The Microbicides Development Programme 301 study was a phase 3, randomised, double-blind, parallel-group trial, undertaken at 13 clinics in South Africa, Tanzania, Uganda, and Zambia. Sexually active women aged 18 years or older (≥16 years in Tanzania and Uganda) without HIV-1 infection were randomised in a 1:1:1 ratio to 2% PRO2000, 0·5% PRO2000, or placebo gel groups for 52 weeks (up to 104 weeks in Uganda).  The primary efficacy outcome was incidence of HIV-1 infection before week 52, which was censored for pregnancy and excluded participants without HIV-1 follow-up data or with HIV-1 infection at enrolment. HIV-1 status was established by rapid or local lab tests  at screening at 12 weeks, 24 weeks, 40 weeks, and 52 weeks, and confirmed in a central reference laboratory. The primary safety endpoint was an adverse event of grade 3 or worse.

Use of 2% PRO2000 gel was discontinued on Feb 14, 2008, on the recommendation of the Independent Data Monitoring Committee because of low probability of benefit. The researchers enrolled 9385 of 15 818 women screened. 2591 (95%) of 2734 participants enrolled to the 2% PRO2000 group, 3156 (95%) of 3326 in the 0·5% PRO2000 group, and 3112 (94%) of 3325 in the placebo group were included in the primary efficacy analysis.

Mean reported gel use at last sex act was 89%. HIV-1 incidence was much the same between groups at study end (incidence per 100 woman-years was 4·5 for 0·5% PRO2000 vs 4·3 for placebo,  and at discontinuation 4·7 for 2% PRO2000 gel, 3·9 for 0·5% PRO2000 gel, and 3·9 for placebo gel). Safety related events were rare and at similar rates in all three groups.

They discuss possibilities for the failure of  PRO2000, saying that in early human studies, active drug was recoverable from cervicovaginal lavage several hours after insertion, suggesting that it was released from the formulation and not overly diluted by vaginal secretions. However, in a study in which cervicovaginal lavage samples were obtained from ten women who inserted 0·5% PRO2000 gel, significantly lower concentrations of PRO2000 were recovered after sex without a condom than were reported in the absence of sex. The authors say: "This difference could result from drug redistribution, binding to semen, loss from leakage, or difficulty in assaying drug because of physical changes after interaction with semen." They add that unprotected anal sex could also have been a source of  some HIV infections, though they believe this unlikely based on low rates of reported anal sex.

The authors conclude: "Despite high rates of reported adherence, 0·5% PRO2000 and 2% PRO2000 were not effective for prevention of vaginally acquired HIV-1 infection or other sexually transmitted infections."

In a linked comment, Dr Sandra I McCoy, Institute of Business and Economic Research, University of California, Berkeley, CA, USA, and colleagues discuss other options for cutting down transmission of sexually transmitted infections, including the RESPECT study in Tanzania. This examined the effect of conditional cash transfers as an incentive for young people to stay free of sexually transmitted infections. Participants in the cash group were eligible to receive a payment (US$20) every 4 months if they had negative laboratory tests for curable sexually transmitted infections. Preliminary results indicated the prevalence of sexually transmitted infections declined in the cash group compared with the control group. These results contrast with a study in Malawi (with a different incentive structure), which found that a one-time cash reward for maintaining a negative HIV-infection status for 1 year had no effect.

McCoy and colleagues conclude: "Although neither tenofovir microbicide gel nor conditional cash transfers will be an immediate prevention panacea, these promising approaches have the potential to greatly expand prevention options for women in sub-Saharan Africa. Along with further research on tenofovir gel and conditional cash transfers, serious investment in upstream, economic prevention approaches that respond to the realities faced by adolescent girls and women is still needed."

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