Efforts to develop vaginal microbicides that will help protect women against HIV infection have sustained another blow with the news that Carraguard, a candidate microbicide under development by US-based non-profit group the Population Council, proved safe but not effective in a Phase III clinical trial.

Carraguard was the first microbicide to complete the final stage of clinical testing. The Phase III trial ran from March 2004 to March 2007, enrolling 6,202 women at high risk of HIV infection at three sites in South Africa. The results showed 134 new infections in the Carreguard group (an incidence of 3.3 per 100 woman-years) and 151 new infections in the placebo arm (3.7 per 100 woman-years), a difference that was not statistically significant.

However, there were marked adherence problems with the trial that could have confounded the outcome. The women participating in the study reported using the vaginal gel (Carreguard or placebo) only 44% of the times they had sex, while only 10% of the participants said they used the gel consistently.

The Population Council also emphasised the importance of the trial’s finding that there were no safety-related differences between women using Carraguard and those on placebo, while gel-related side-effects were minor and infrequent.

Carraguard is a “key component” of next-generation microbicides under development by the Council, many of which combine Carraguard with one or more ingredients shown to be effective in preventing HIV virus transmission in laboratory settings, it noted. One such project will involve PC-815, a combination of Carraguard and the non-nucleoside reverse transcriptase inhibitor MIV-150.

Long path

“We have always known that the path to developing a successful microbicide would be a long one,” commented Jeff Spieler, senior science advisor in population and reproductive health at the US Agency for International Development (USAID), which funded the trial along with the Bill & Melinda Gates Foundation.

“The Population Council has done groundbreaking work in completing this trial, even though we are terribly disappointed that the product was not shown to be effective,” Spieler added. “Now we all have to redouble our efforts to develop a microbicide that women can use to protect themselves.”

Carreguard is made from carrageenan, a seaweed derivative that is on the US Food and Drug Administration’s ‘Generally Recognized As Safe’ list. Laboratory research had demonstrated that Carreguard was effective at blocking HIV infection of cells and protecting mice from some other sexually transmitted infections.

In the Phase III trial, half the women enrolled were given Carreguard gel and condoms, the other half a placebo gel and condoms. Participants also received HIV education, gynaecological examinations, and risk-reduction and safer-sex counselling, as well as testing and treatment for curable sexually transmitted infections.

The bad news about Carreguard came just after the Microbicides Development Programme announced that one arm of a trial involving its vaginal gel PRO 2000/5 was being halted, as the higher concentration of the gel was unlikely to benefit participants. That trial will continue with the lower-strength vaginal microbicide, 0.5% PRO 2000/5.

Earlier this month, clinical trials of Canadian company Polydex Pharmaceuticals’ cellulose sulphate vaginal gel for protecting against HIV infection were stopped prematurely after it emerged that women using the gel were more likely to become infected than those on placebo.