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Vaginal microbicide gel had no protective effect against HIV transmission
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Two formulations of the vaginal microbicide gel PRO2000 failed to demonstrate efficacy against transmission of HIV, according to study findings.
Sheena McCormack, MD, of the Imperial College in London, said that “both the 0.5% and 2% gels failed to live up to expectations.” The findings were presented at the 17th Conference on Retroviruses and Opportunistic Infections in San Francisco.
The trial involved 9,385 healthy women at six sites in East and Southern Africa who were randomly assigned to 0.5% gel, 2% gel or placebo for 12 months or up to 24 months. The 2% gel was discontinued on Feb. 14, 2008, according to McCormack.
A modified intention-to-treat analysis at week 52 was the primary efficacy outcome and was censored for pregnancy. A secondary intention-to-treat analysis was also conducted using all available data.
The primary study outcome was HIV infection or grade-3 adverse events, McCormack said. Secondary outcomes included incidence of one of a variety of STDs or solicited genital and systemic adverse events.
There were 2,734 women randomly assigned to the 2% formulation, 3,326 to the 0.5% formulation and 3,325 who were administered placebo. Efficacy analysis was conducted for 95% of the women, which resulted in 84% of the maximum possible person-years for the modified intention-to-treat analysis and 88% of the intention-to-treat analysis.
“We were pleased to have more than 2,800 woman-years of data collected for the 0.5% gel and placebo,” McCormack said. “This was largely because retention in the program was high.”
The overall incidence of HIV was 4.6 per 100 person-years. There were 418 seroconversions. The modified intention-to-treat analysis involved 253 of those seroconversions among participants assigned to 0.5% gel or placebo.
Consistent gel users were determined to be women who reported using the gel at the last sex act at more than 92% of their visits and who had attended a minimum of seven of 13 visits. The mean rate of gel use at the last sex act was 89.3%.
The HR for acquiring HIV among consistent 0.5% gel users compared with participants assigned to placebo was 0.97 (95% CI, 0.87-1.35). For inconsistent users, the HR was 1.17 (95% CI, 0.42-1.72).
In the modified intention-to-treat analysis, the HR for the 0.5% gel vs. placebo was 1.05 (95% CI, 0.82-1.34). In the intention-to-treat analysis, the HR was 1.00 (95% CI, 0.79-1.26).
Results for the 2% gel also were calculated despite the fact that the treatment was discontinued. The incidence of HIV was 4.7 per 100 person-years compared with 3.9 per 100 person-years for placebo. The HR for acquiring HIV was 1.21 (95% CI, 0.88-1.68).
No differences in primary safety, local or systemic toxicity were observed among the three arms. “There was a high proportion of nonmenstrual bleeding, but those rates were not different among the three groups,” McCormack said.
She indicated that there was a great deal of diversity among the centers regarding condom use. “In the settings where HIV prevalence was high, condom use was not always high.”
McCormack offered possible explanations for the poor performance of the microbicidal gels. “It may have been a lack of in vivo potency,” she said. “It may also have been poor bioavailability or sticking to the epithelial cells. Another explanation is that the gel may have been diluted in semen, or leakage with ejaculate may have occurred. — by Rob Volansky
These definitive negative findings for PRO 2000 almost certainly signal the death knell for nonspecific microbicides. These results are particularly disheartening because an earlier, smaller study had suggested that PRO 2000 might provide some protection. Most experts now believe that an effective microbicide must incorporate agents with specific anti-HIV activity such as reverse transcriptase inhibitors or CCR5 antagonists. An effective microbicide continues to be of the highest priority as many women at risk for HIV desire to bear children, and will not use barrier methods. One of the most surprising findings from the study was the widespread acceptance of PRO 2000, as 89% of women reported its use at the time of their last sexual act. This information is encouraging as it suggests that an effective microbicide might be accepted by many women and their partners.
– Elizabeth Connick, MD
Director, University of Colorado Center for AIDS
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