Canvassing CROI

HIV prevention strategies stoke excitement at recent scientific meeting

By Kristen Jill Kresge and Regina McEnery

At the opening session of the 16th Conference on Retroviruses and Opportunistic Infections (CROI)—which was held this year from February 8-11 in Montreal, Canada—the two opening lectures focused, at least in part, on the success of antiretrovirals (ARVs) in treating HIV/AIDS. Indeed it seems much hope in combating HIV these days is pinned to ARVs, whether it is in expanding access among HIV-infected individuals worldwide, developing microbicide gels based on existing ARVs, or using them prior to exposure as a means of pre-exposure prophylaxis (PrEP) to block HIV infection.

Without doubt, there is still much to be done to accomplish any one of these goals, but this year’s CROI showcased some promising results from both clinical trials and animal studies evaluating microbicides—both ARV-based and the non-specific PRO 2000 candidate—and PrEP, providing a burst of enthusiasm around new HIV prevention strategies. Data was also presented on studies relating to control of HIV infection that may help inform future vaccine design.

First hint of microbicide efficacy

Some of the more encouraging data at CROI came from clinical and nonhuman primate studies with new HIV prevention strategies. The first study, known as HPTN 035, evaluated the safety and efficacy of the microbicide candidate PRO 2000, a topical gel composed of a synthetic compound non-specifically designed to block attachment of HIV to host cells and thereby prevent infection.

This Phase IIb study, which was funded by the US National Institutes of Health and conducted by the HIV Prevention Trials Network and the Microbicide Trials Network, enrolled 3,099 women at seven clinical trial centers in Africa and the US and evaluated the efficacy of PRO 2000, as well as a second topical microbicide called BufferGel, which is designed to boost the natural acidity of the vagina in the presence of seminal fluid. The study also had two control groups—one received a placebo gel and the other, which was unblinded, received only condoms and no gel. A no-gel arm was included in the trial over concerns that the placebo gel might have antimicrobial properties that could have a protective effect against HIV.

The study showed that women who randomly received both PRO 2000 gel and condoms had 30% fewer HIV infections than those using a placebo gel and condoms. At the conclusion of this three-year trial, there were 36 HIV infections among women in the PRO 2000 group, compared to 54 in the BufferGel group, 51 in the placebo gel group, and 53 in the no gel group.

However, Salim Abdool Karim, a clinical infectious disease specialist who led this study, cautioned that the PRO 2000 results were not statistically significant compared to either the placebo gel or no gel groups. “This could be a chance finding,” he said. Therefore additional evidence would be necessary to “conclusively determine whether PRO 2000 is an effective microbicide,” said Karim.

Researchers also analyzed the data based on how often women in the PRO 2000 trial reported using the gel. Among those who said they applied the microbicide candidate at their last sexual act at least 85% of the time, there was an overall 44% reduction in HIV infection compared to the placebo gel. And in women who reported using the gel that often, without regularly using condoms, there was a 78% reduction in HIV infection compared to placebo gel users.

At the conclusion of Karim's presentation, there was a palpable level of excitement among attendees, with many rushing to the microphones to congratulate the researchers on the conduct and results of the trial. Karim said this excitement was understandable given recent results from trials of two other microbicide candidates. Carraguard, made from a seaweed derivative, was found to have no effect on HIV acquisition in a three-year Phase III study of 3,200 women from South Africa. And a Phase III trial of cellulose sulfate that enrolled 1,333 women was discontinued in December 2007 after early data suggested that the candidate might be contributing to an increased risk of HIV infection.

“We are at the end of a series of disappointments,” Karim said. “We need something that gives us hope. The HPTN 035 trial results represent that hope.” A Phase III trial of PRO 2000 involving 9,000 women is nearing completion in South Africa, Tanzania, Uganda, and Zambia, and results from this trial are expected later this year.

New animal data on PrEP

Other excitement came from two separate studies in rhesus macaques—both conducted by the US Centers for Disease Control and Prevention (CDC)—which provided additional evidence for the effectiveness of PrEP. One study evaluated intermittent use of oral PrEP—a strategy referred to as iPrEP.

Researchers administered the human equivalent doses of oral Truvada—a combination pill of two ARVs, tenofovir and emtricitabine (FTC)—at various times both before and after rectal exposure to a simian immunodeficiency virus (SIV)/HIV hybrid virus known as SHIV. All animals were exposed to SHIV weekly over a 14-week period. It took on average two exposures to infect a group of 32 untreated control animals. However, three of six animals that received Truvada just two hours before and 22 hours after SHIV exposure remained uninfected, and three of the six macaques that received the drugs seven days before and two hours after exposure to SHIV, were protected against infection.

The best results were seen in the group that received Truvada either 22 hours before and two hours after, or three days before and two hours after SHIV exposure. In these two groups, five of the six animals were completely protected against infection over the entire study period.

All of the ongoing clinical PrEP trials are testing the efficacy of a daily dose of either Truvada or tenofovir but there is also interest in iPrEP because of concern that adherence could prove to be a major barrier to the effectiveness of this intervention. Intermittent use would also slash the cost of providing PrEP.

Results were also presented from another study, which compared the effectiveness of two different topical PrEP gels. Two groups of six female pigtailed macaques received either a tenofovir gel or a tenofovir/FTC combination gel. These groups, as well as two animals that received no gel and nine that received a placebo gel, were then exposed to a low-dose vaginal SHIV challenge twice a week. Both animals that received no gel became infected, and eight of the nine animals that received the placebo gel were infected after an average of four exposures to SHIV. However, both groups of six animals that received either the tenofovir or tenofovir/FTC combination gel were completely protected against SHIV infection throughout the duration of the 10-week study.

There are currently six clinical trials of PrEP involving nearly 21,000 volunteers. One of these trials known as the VOICE study, which involves 4,200 women in Africa, is comparing the safety and acceptability of oral PrEP to a topical microbicide formulation. The first data on the effectiveness of PrEP from clinical trials will be available in 2010. “It’s an exciting time in the prevention field,” said Sharon Hillier, vice chairman of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh.

Clues from controllers

At a symposium titled “Learning from Negative Trials,” Emory University researcher Eric Hunter said the STEP trial—the recently conducted Phase IIb trial of Merck’s adenovirus serotype-5 based vaccine candidate that showed the candidate offered no protection against HIV—has provided an opportunity to explore the basis for this lack of protection, which could help inform the design of future vaccine candidates.

Researchers are also carefully analyzing long-term nonprogressors (LTNPs) and more specifically elite controllers—individuals who can control HIV infection so that it is undetectable by standard tests for an extended period of time without ARV therapy—to mine for clues that may indicate the types of immune responses a vaccine candidate should induce. David Heckerman, a researcher at Microsoft Research, in collaboration with Bruce Walker, director of the newly formed Ragon Institute and Harvard AIDS researcher Florencia Pereyra, analyzed a group of LTNPs and mapped the specific regions on HIV that were targeted by their cellular immune responses.

They then analyzed a sub-group of vaccinated volunteers from the STEP trial who became HIV infected, despite vaccination, from natural exposure to the virus, to see if individuals with immune responses that targeted these same regions of the virus were better able to control HIV infection. Heckerman reported that this was indeed what they found. When the immune responses in STEP trial volunteers targeted one of what Heckerman identified as the six critical regions on the virus, it correlated with their having lower levels of HIV in their blood.

This suggests that these bulls-eye regions on the virus may be important for generating an immune response that could control HIV infection, and could be used in the design of future AIDS vaccine candidates.

Several other studies were also presented on the unique characteristics that lead to control of HIV infection. Mark Connors, chief of the HIV-Specific Immunity Section at the US National Institutes of Allergy and Infectious Diseases said, in his estimation, it is likely that there will be evidence from clinical trials in the near future showing that candidate vaccines can induce similar T-cell responses to those seen in elite controllers.