Large Trial Finds PRO 2000 Microbicide Is Ineffective in Preventing HIV Infection in Women

		SUMMARY: The experimental vaginal microbicide gel PRO 2000 -- which appeared promising in earlier studies -- did not protect women from becoming infected with HIV in a large clinical trial known as MDP 301, which included more than 9000 participants in Africa, investigators announced on December 14.

By Liz Highleyman

"The largest international clinical trial to date into a preventative HIV gel has found no evidence that the vaginal microbicide PRO 2000 reduces the risk of HIV infection in women," according to a press release issued by the U.K. Medical Research Council, one of the study sponsors.

PRO 2000 is a 0.5% microbicidal (germ-killing) gel applied in the vagina prior to sexual intercourse. An earlier study of more than 3000 African women (HPTN 035), sponsored by the U.S. National Institutes of Health (NIH) and presented at the Conference on Retroviruses and Opportunistic Infections this past February, was the first human clinical trial to suggest that a microbicide might prevent male-to-female sexual transmission of HIV. In that study, PRO 2000 demonstrated 30% effectiveness, falling just short of the 33% threshold for statistical significance.

The MDP 301 trial was about 3 times larger than HTPN 035, involving 9385 women at 6 research sites in 4 African countries with high HIV prevalence rates. It was conduced by the Microbicides Development Programme (MDP), a not-for-profit partnership of 16 African and European research institutions. Enrollment started in September 2005 and the trial ran through September 2009.

Participants were randomly assigned to use PRO 2000 gel or a placebo gel before each act of sexual intercourse. They also received free condoms, which they were instructed to use along with the gel. The women were followed for 12 months at most study sites, or up to 24 months in Uganda.

"[T]he risk of HIV infection in women who were supplied with PRO 2000 gel was not significantly different than in women supplied with placebo gel," according to the MRC statement. "To date, no microbicide has been shown to be effective against HIV infection. This trial shows conclusively that PRO 2000 gel is of no added benefit, ending scientific speculation about its clinical importance."

In the PRO 2000 group, 130 new HIV infections occurred among 3156 women, compared with 123 infections among 3112 women in the placebo group. This translates to 4.5 infections per 100 person-years in the PRO 2000 group versus 4.3 in the placebo group, not a statistically significant difference. PRO 2000 gel was safe, however, with no serious adverse side effects.

"This result is disheartening," particularly in light of the smaller NIH trial, said MDP 301 Chief Investigator Sheena McCormack. "Nevertheless we know this is an important result and it shows clearly the need to undertake trials which are large enough to provide definitive evidence for whether or not a product works."

"We all knew that the trend observed in HPTN 035 could have been due to chance," said Yasmin Halima, Director of the Global Campaign for Microbicides in a press release issued Monday. "While we are deeply disappointed to learn definitively that PRO 2000 is not effective, it is our responsibility as advocates to turn our full attention now to the candidates currently in clinical trials."

"These candidates, being tested as oral pills as well as microbicides, contain antiretroviral drugs or ARVs, the same life-saving medications used as treatment by people living with HIV," she continued. "In laboratory and animal studies, they appear to be many times more potent than any of the non-ARV-based candidates."

Among the ARVs, tenofovir (Viread) and emtricitabine (Emtriva) -- the 2 drugs in the Truvada coformulation -- have undergone the most testing as a method of pre-exposure prevention (PrEP), administered as microbicides, injections, or pills.

"We know that women and their partners liked the gels and used them [in the MDP 301 trial]," said McCormack. "Women reported that using it increased sexual pleasure and fostered intimacy by helping women talk about sex with their partners. So we know that we have the method right. Now we just need a product with the potency to stop HIV."

MDP 301 trial participants are currently being informed of the trial findings. Complete results will be submitted for presentation at international conferences in 2010, as well as for publication in a peer-reviewed journal.

12/15/09

Source

U.K. Medical Research Council. HIV 'prevention' gel PRO 2000 proven ineffective. Press release. December 14, 2009.

Global Campaign for Microbicides. Microbicide trial results signal end of one chapter, focus turns to promising ARV-based candidates. Press release. December 14, 2009.