Study Spells End of the Road for One Anti-HIV Gel

By Michael Smith, North American Correspondent, MedPage Today
Published: September 19, 2010
Reviewed by Barry S. Zingman, MD; Professor of Clinical Medicine, Albert Einstein College of Medicine, Bronx, NY
and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

A microbicide gel -- PRO2000 -- aimed at preventing HIV infection in women was ineffective, despite promising early clinical trials, researchers reported.

In a large randomized phase III trial, the PRO2000 microbicide was safe, but did nothing to prevent women from acquiring HIV, according to Sheena McCormack, MD, of the MRC Clinical Trials Unit in London, and colleagues.

The report, online in The Lancet, comes only a few weeks after researchers studying another microbicide gel combined with an antiretroviral drug reported partial success -- a significant 39% reduction in the risk of HIV infection. Further studies of microbicides that include antiretroviral drugs are underway.

The PRO2000 compound is a synthetic naphthalene sulphonate polymer that -- in animals and the lab -- had shown anti-HIV activity, McCormack and colleagues noted. A phase II/IIb trial, reported in 2009, also found a nonsignificant but promising trend toward protection in humans.

But only a few days after that report, the data monitoring committee of this study called a halt to one of the arms -- testing a 2% solution of PRO2000 -- on the grounds that there was little likelihood of benefit. The other arm, testing a 0.5% solution, was allowed to continue to completion, McCormack and colleagues reported.

The study, conducted in 13 clinics in South Africa, Tanzania, Uganda, and Zambia, randomly assigned sexually active, HIV-negative women to get one of three gels -- a hydroxyethylcellulose placebo, 0.5% PRO2000, or 2% PRO2000.

The researchers reported two efficacy analyses -- all three arms compared at the time of the 2% PRO2000 discontinuation and the placebo and 0.5% PRO2000 arms compared at the planned end of the study.

Overall, McCormack and colleagues found, adherence was high, with an average reported gel use at the last sex act of 89%.

Despite that, the incidence of HIV was much the same in both analyses:

• At the discontinuation of the 2% PRO2000 arm, the incidence per 100 woman-years was 4.7 for 2% PRO2000, 3.9 for 0.5% PRO2000, and 3.9 for placebo. Neither treatment was significantly better than placebo.

• At study's end, the incidence per 100 woman-years was 4.5 for 0.5% PRO2000 and 4.3 for placebo. The 1.05 hazard ratio had a 95% confidence interval from 0.82 to 1.34 and was nonsignificant at P=0.71.

The primary safety endpoint was an adverse event of grade 3 or worse, and again there was little difference -- 4.6 per 100 woman-years in the 0.5% PRO2000 group and 3.9 in the placebo group at study's end. It was 4.5 in the 2% PRO2000 group at discontinuation, the researchers reported.

The findings are "disappointing," especially in view of the earlier trial that showed a nearly significant result, according to Sandra McCoy, PhD, of the University of California Berkeley, and colleagues.

Writing in an accompanying commentary, McCoy and colleagues said the report "will certainly indicate the end of the road for PRO2000 as a potential HIV-prevention tool for women."

But, they noted, the positive results of the latest microbicide study, combined with other interventions that are showing promise in reducing HIV incidence among women, "have the potential to greatly expand prevention options for women in sub-Saharan Africa."

The study was supported by the Microbicides Development Programme, the U.K. Department for International Development, the European and Developing Countries Clinical Trials Partnership, and the U.K. Medical Research Council. Study gels were provided by Endo Pharmaceutical Solutions. McCormack reported no conflicts.

Commentary author Charlotte Watts, of the London School of Hygiene and Tropical Medicine, is supported by the Sigrid Rausing Trust and the Microbicides Development Programme.

All authors said they had no conflicts.

Primary source: The Lancet
Source reference:
McCormack S, et al "PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial" Lancet 2010; DOI: 10.1016/S0140-6736(10)61086-0.

Additional source: The Lancet
Source reference:
McCoy SI, et al "Preventing HIV infection: Turning the tide for young women" Lancet 2010; DOI: 10.1016/S0140-6736(10)61309-8.

Source