A vaginal gel containing the microbicide PRO2000 failed to prevent HIV transmission, according to results from a randomized, controlled trial that enrolled more than 9,000 African women who inserted either PRO2000 or a placebo gel before having sex. The results were published Sept. 20 by the Lancet.

But the phase III trial’s lead investigator said that some of the lessons learned during the trial bode well for anti-HIV gels at a time when more effective ones are being tested, and that the failure of one agent shouldn’t be confused with the failure of gels as a prevention strategy – not least because women like using them. (Lancet 2010 Sept. 20 [doi:10.1016/S0140-6736(10)61086-0]).

For their research, Sheena McCormack of the U.K. Medical Research Council’s Clinical Trials Unit, in London, and colleagues, randomized 9,385 women aged 18-45 years (16 years and older in two countries) from 13 clinics in Tanzania, Zambia, Uganda, and South Africa to receive prefilled vaginal applicators with gel containing PRO2000 2%, PRO2000 0.5%, or placebo (ratio, 1:1:1). Professional sex workers (or women who are likely to have sex more than 14 times a week) and pregnant women were not enrolled. All women were HIV negative at enrollment; all were instructed to insert the gel before sexual intercourse.

The results showed that although compliance with the gel regimen was nearly 90% (measured in part by the return of used applicators), neither concentration of PRO2000 was more effective than was placebo in preventing new HIV infections after a year of use.

PRO2000, a synthetic naphthalene sulphonate polymer, had been shown to prevent HIV transmission in primate trials, and data from a smaller and unrelated study (presented in Montreal at the 2009 conference on retroviruses and opportunistic infections) had shown a 30% reduction in infections with the 0.5% concentration of PRO2000, compared with placebo, a statistically insignificant but promising result.

Dr. McCormack and colleagues’ interim trial results had shown that 2% PRO2000, the higher of the two concentrations tested, was ineffective as early as 2008, when the 2% arm of the trial was discontinued. However, the investigators had hypothesized that the higher-concentration gel might prove to be the less effective because of its potential to irritate the vagina, undermining some of its potential protective effect.

At the study’s end, the less-concentrated gel also disappointed, with the incidence of new HIV infections per 100 woman-years at 4.5 for 0.5% PRO2000 and 4.3 for placebo. Although it had biological potency in the lab, “it seemed that the most likely explanation is that the ejaculate disturbs the equilibrium in some way,” precluding PRO2000’s effectiveness, Dr. McCormack said in an interview.

But even though the final results were a surprise and a letdown, Dr. McCormack said, much was learned during the trial that could prove to be good omens for a gel containing the antiretroviral drug tenofovir. In interim results from an ongoing South African trial (n = 889) released in July (Science 2010 July 19 [doi:10.1126/science.1193748]), tenofovir 1% vaginal gel, used before sex, was shown to reduce a woman’s risk of HIV infection by 39%. Women who used the gel 80% of the time saw a 54% reduction in HIV infections.

Dr. McCormack’s group saw more than 80% compliance in the PRO2000 study, and found that – despite reports of some mild adverse effects, such as itching, in both the treatment and placebo arms – women generally reported that they enjoyed using the gel, “and a portion raved about it,” Dr. McCormack said. “Adherence around the sex act has been very good,” comparing favorably with condom use, which was found to be very low among enrollees in some of the trial countries.

The popularity of the gels would seem auspicious for an effective one, but Dr. McCormack, who is struggling to raise funds for a new study involving tenofovir gel, said she feared a waning of donor interest in vaginal gels – many of which have been disappointments – at the time when a truly effective antitransmission agent seems to have finally been discovered. This month, the New York Times reported that the U.K. government, which funded much of Dr. McCormack’s study and contributed to other gel trials, had become noncommittal on its plans to fund further research into gels.

“I am anxious not to confuse the results of our trial with [the tenofovir trial]. PRO2000 is much less potent than tenofovir,” Dr. McCormack said. “You’ve got to think about this in a bigger picture: At the moment, there’s a real possibility in tenofovir gel.”

Dr. McCormack’s study was funded by the U.K. government, the European and Developing Countries Clinical Trials Partnership, the International Partnership for Microbicides, and Endo Pharmaceuticals, the manufacturer of PRO2000, which donated the gels for the study. One coauthor of the study was an employee of Endo Pharmaceuticals with an equity interest in the company.

Researchers See Silver Lining in Anti-HIV Gel's Failure