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Disappointing Data from Anti-HIV Microbicide Trials

The 2007 IAS Conference provided new details about the two cellulose-sulfate trials that were halted earlier this year.

Despite some progress, anti-HIV microbicides have generally yielded disappointing results, and the studies presented at this year’s IAS Conference on HIV Pathogenesis, Treatment and Prevention were no exception.

Trials Halted
As previously reported, two phase III, randomized, placebo-controlled trials of cellulose sulfate were stopped earlier this year, after one of the trials showed an increased incidence of HIV infection among women using the investigational compound (ACC Feb 12 2007). Now, researchers have provided more details about those trials.

The CONRAD study took place in Africa and India and involved 1428 HIV-uninfected women (mean age, 30) who had multiple sex partners [Abstract WESS301]. At baseline, study participants reported having vaginal intercourse an average of 11 times during the past 7 days, and about 90% reported previous pregnancies. Self-reported condom use was about 60% at screening and increased to about 80% at enrollment. Participants were randomly assigned to use either cellulose-sulfate or placebo gel and were instructed to apply the gel vaginally no more than 1 hour before sexual intercourse. About 88% of women completed the 1-year follow-up visit, 10% were lost to follow-up, and 2% discontinued the study prematurely. At the time of the interim analysis, 35 women were newly infected with HIV — 24 in the cellulose-sulfate arm, compared with 11 in the placebo arm (relative risk, 2.23; 95% confidence interval, 1.05–5.03). The two arms had similar incidence rates of gonorrhea and chlamydia infections. The reason for the high rate of new HIV infections in the cellulose-sulfate arm is unclear, but possibilities include inflammatory reactions, localized immune dysfunction, and disruption of the normal vaginal flora with frequent use of cellulose sulfate.

Based on the CONRAD results, investigators with Family Health International halted a similar trial in Nigeria, involving 1644 women, 1153 of whom had completed 1-year follow-up [Abstract WESS302]. No significant difference was seen in the incidence of HIV infection between the cellulose-sulfate and placebo arms (9 vs. 12 new infections; RR, 0.8; 95% CI, 0.3–2.0).

Two additional phase III microbicide trials were stopped early in Nigeria and Ghana because the overall incidence of HIV infection was lower than expected, and investigators did not anticipate being able to detect any treatment effect [Abstract TUPEC008]. Several other microbicide trials, using various approaches, are ongoing or planned.

Alarming Findings from a Macaque Study
The most alarming microbicide news at the IAS conference came from a small animal study, in which macaques were challenged with HIV following the vaginal application of a single dose of the HIV-specific CCR5-blocker PSC-RANTES [Abstract WESS303]. Resistant virus was found in 1 of 10 macaques studied, and that virus did not demonstrate any reduction in viral fitness. This finding is of concern because the viral inoculum was not diverse, unlike what would be expected in natural human exposures. This first identification and characterization of a resistant virus selected with a locally applied anti-HIV microbicide alone is worrisome because it indicates that topical therapies might affect and potentially jeopardize systemic treatment options.

— Helmut Albrecht, MD

Published in AIDS Clinical Care September 10, 2007