HIV vaccine research

Microbicide results aren’t gelling
In February, the Population Council announced the results of a Phase III trial of Carraguard, a microbicide gel containing the compound carrageenan, which is a seaweed derivative used as a stabilizer and thickening agent in food and cosmetics. This randomized, double-blind, placebo-controlled trial was conducted at three sites in South Africa and involved 6,202 women between the ages of 16 and 72. This was the first Phase III efficacy trial of any microbicide candidate to reach completion. Last year a Phase III trial with another candidate, known as cellulose sulfate, was terminated early by the trial’s data safety monitoring board (DSMB) because a higher number of HIV infections occurred among microbicide recipients than in those receiving a placebo gel (see VAX June 2007 Primer on Understanding Data Safety Monitoring Boards). Data collected in the Carraguard trial showed that 134 individuals who received the microbicide candidate became HIV infected, compared to 151 individuals who received an inactive placebo gel. The difference was not deemed statistically significant and researchers concluded that Carraguard was not effective at protecting women from HIV (see VAX February 2008 Primer on Understanding Biostatistics and the STEP Trial).

Measuring usage
Similarly to the HSV suppression study, a critical aspect of the Carraguard trial was women’s adherence to the product being tested. Women were counseled to apply the microbicide before every sex act, and although the self-reported adherence rates were 96%, researchers estimate that the actual adherence was much lower. To measure adherence to the gel, researchers collected behavioral information directly from participants and also conducted an applicator test. All applicators used to apply the gel were treated with a compound that, when subjected later to a stain, would change colors if it had been exposed to vaginal mucous. The results of these tests showed that only 44% of women actually used the gel. And only 10% of women were estimated to have used it during every sex act.

An applicator test is one method researchers are using to better estimate adherence, but even this approach is complicated. Barbara Friedland of the Population Council says it was difficult to determine the effectiveness of the applicator test. “All we can tell is whether the applicator was inserted in the vagina or not,” she says. “We don’t know when in relation to the sex act the applicator was inserted into the vagina.”

“It’s possible that low levels of adherence in the trial were responsible for why the product didn’t show an effect,” Friedland notes. “It’s also possible that there was a biological reason—it worked in the lab but it didn’t have the same effect in humans.” Researchers conducted tests of the microbicide in human cell cultures but did not conduct preclinical studies in nonhuman primates with the monkey equivalent of HIV, known as simian immunodeficiency virus (SIV), to gauge the efficacy of the product. Prior to initiating the Phase III trial, the Population Council conducted two Phase II safety studies of Carraguard in South Africa and Thailand, involving a total of 565 HIV-uninfected women.

Additional research was also presented at both CROI and Microbicides 2008 on the previously-halted cellulose sulfate microbicide trial conducted by CONRAD, a US-based reproductive health organization. After the trial was stopped by the DSMB, researchers tried to find out if the microbicide gel was in any way enhancing the risk of HIV infection. Researchers from Albert Einstein College of Medicine in New York conducted laboratory studies with the candidate microbicide in vaginal tissues. They found that cellulose sulfate disrupts the proteins that help form tight junctions between the cells that comprise the vaginal tissue layers, which are the first line of defense against HIV. This disruption makes it easier for HIV to cross the mucosal barrier (see VAX January 2008 Primer on Understanding HIV Transmission). These findings provide a possible explanation for how cellulose sulfate may have increased women’s vulnerability to HIV, and the researchers argue that this type of laboratory study should be conducted for all future microbicide candidates.

Together these results offer some sobering news for the HIV prevention field, but at the same time researchers also reported great progress in understanding basic scientific questions that open potential avenues of exploration for both HIV prevention and treatment.

GLOBAL NEWS:

Addressing the challenges of HIV prevention trials
The prestigious US Institute of Medicine (IOM), an independent advisory group on public health policy, convened a series of meetings last year on the methodological challenges of conducting non-vaccine HIV prevention trials. The final report based on these proceedings, as well as site visits by IOM committee members to clinical trial sites in Uganda and South Africa, was just issued in February (www.nap.edu/catalog/12056.html).

These meetings and the final report were commissioned by the Bill & Melinda Gates Foundation. The foundation requested that the IOM committee focus in particular on research involving microbicides and pre-exposure prophylaxis (PrEP; see VAX May 2006 Spotlight article, Treatment as prevention), and provide recommendations on how future trials could be conducted in a way that could increase the likelihood of success and enable donors to optimally invest their limited financial resources.

At the public meetings, committee members and leading researchers in the field discussed several of the most-pressing issues surrounding the design and conduct of large-scale HIV prevention trials (see Advisory Panel considers complexities of HIV prevention trials, IAVI Report, January-February 2007 and Optimizing HIV prevention research, IAVI Report, March-April 2007).

The final report outlines the recent spate of late-stage clinical trials in the HIV prevention field that have failed to provide any benefit in reducing the risk of HIV infection (see Spotlight, this issue), leading the authors to conclude that, “A near-perfect biomedical intervention for preventing HIV infection is unlikely to be available in the near future.”

The importance of accurately estimating HIV incidence is among the main issues highlighted in the report. This became a concern when multiple prevention trials were stopped early because the HIV incidence observed during the trial was lower than initial estimates on which the trial was based (see VAX July 2007 Primer on Understanding HIV Incidence). The IOM committee recommends that all late-stage trials be designed based on incidence estimates collected through traditional cohort follow-up studies of HIV-uninfected individuals in the communities where the trial will occur. The authors also suggest that this estimate should be corroborated by at least one other source.

High pregnancy rates during HIV prevention trials, and the impact on retention of female volunteers, was another critical issue that was discussed at the committee meetings and is addressed in the report (see Primer, this issue). Female volunteers are typically not allowed to receive the experimental intervention during pregnancy because of potential safety risks to the fetus. But their exclusion from the trial can confound the results. On this issue, the authors suggest that researchers should try to determine the safety of the intervention in pregnant women to determine circumstances where women could potentially continue to participate in HIV prevention trials while pregnant.

The report also outlines several other ways that trials can be designed to more efficiently determine the influence of behavior and adherence on the final results.