HIV Prevention Picks Up Momentum

Discussion of microbicides, vaccines, and other new prevention technologies tops the bill at international AIDS conference

By Kristen Jill Kresge

Over the past several years the number of people receiving antiretroviral (ARV) therapy has steadily increased due to efforts mounted by the Global Fund to Fight AIDS, Tuberculosis, and Malaria and other international programs, including the US President's Emergency Plan for AIDS Relief (PEPFAR), which are bringing treatment to developing countries. But the number of new HIV infections continues to be high, with four million individuals becoming newly infected last year, and this has shifted attention back to halting transmission of the virus. The need for a concomitant improvement and scale-up of treatment and prevention services was never more emphasized than when a record 26,000 delegates from around the world gathered in Toronto from August 13-18 for the International AIDS Society's (IAS) XVI International AIDS Conference.

The conference kicked off with speeches from Bill and Melinda Gates and former US president Bill Clinton. The trio recently visited Africa to gather a first-hand picture of the toll that HIV/AIDS is taking there, and between them they made several appearances in the first days of the meeting. At the opening ceremony Bill Gates emphasized the need for focusing on HIV prevention, saying, "the goal of universal treatment—or even the more modest goal of significantly increasing the percentage of people who get treatment—cannot happen unless we dramatically reduce the rate of new infections." Measures to expand HIV prevention programs and research into new approaches to prevent transmission of the virus, including new technologies like vaccines and microbicides, held prominence in the days to follow. Helene Gayle, who left her post as president of IAS following the conference, said this meeting will undoubtedly be remembered as the one that placed HIV prevention back on the agenda.

Late-stage clinical trials with several microbicide candidates were highlighted by scientists and activists, and other HIV prevention strategies like pre-exposure prophylaxis (PrEP; see Treatment as prevention, IAVI Report 10, 3, 2006) and male circumcision (see Cutting HIV transmission, IAVI Report 9, 3, 2005) were touted by Gates, Clinton, and many others. There is a shared optimism among researchers that a combination of these strategies could help curtail the epidemic's spread, although conclusive research on their efficacy is still unavailable. And despite the scientific obstacles to developing an AIDS vaccine the number of candidates is expanding and the Vaccine Research Center at the US National Institutes of Health (NIH) is now moving towards advancing its lead candidate into a preliminary efficacy trial. "It's going to be a rocky road until we have a vaccine," said Clinton.

Alphabet soup

The promotion of ABC—abstinence, being faithful, and using condoms—has long been a point of controversy in the HIV prevention field since it offers few options to disempowered women, particularly those who are victims of abuse. Now that newer prevention technologies are winding through development, researchers are ushering in a new era of prevention acronyms. The next generation, referred to as CBS—for circumcision, barrier methods (such as the female diaphragm), and syringe exchange—are the next crop of options that researchers hope will enter the prevention armamentarium and be implemented more broadly.

The results of the first prospective study from South Africa showing that adult male circumcision could reduce the risk of HIV transmission to men were reported a year ago at the IAS meeting in Rio de Janeiro (PLoS Med. 7, e262, 2006). Three other circumcision trials are ongoing in Kenya and Uganda and interim data from two of these trials-one in Uganda, one in Kenya-sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID) were recently analyzed by a data safety monitoring board. The efficacy data at this point were not sufficient to warrant stopping either trial, but another interim analysis was recommended within the next year. Both trials are scheduled for completion by September 2007 and many public health officials, including some from the Joint United Nations Programme on HIV/AIDS (UNAIDS), took the opportunity provided by the conference to reinforce messages that governments and communities should delay recommending this surgical procedure to men in regions with high HIV prevalence rates until further evidence is accumulated. Still, the topic was covered often by speakers and was the focus of lively discussion among attendees.

Researchers also eagerly await the results from an ongoing Phase III trial to evaluate the efficacy of the female diaphragm in preventing HIV transmission. An update on this study was provided in a plenary session by Gita Ramjee of the HIV Prevention Research Unit in Durban, South Africa. Enrollment of volunteers is now complete in Harare, Zimbabwe, as well as in Johannesburg and Durban, South Africa. Researchers at the University of California in San Francisco expect the trial will be completed by June of next year (see Capping infection).

Harm reduction programs that promote syringe exchange or provide safe-injection facilities to IDUs (see Injection of hope) are among what Wodak calls the "most effective interventions in the HIV/AIDS repertoire," but they remain severely under-utilized. In most countries IDUs also lack access to ARVs. Beyrer noted that 34,000 IDUs in developing countries are currently receiving treatment, but only 4000 of these are outside of Brazil.

Beyond CBS

The next generation of prevention options, called MTV—for microbicides, treatment or PrEP (providing ARVs to try to prevent infection), and vaccines—were also widely discussed. Currently five microbicides are in large-scale efficacy trials with results expected as early as next year. "We're not a long way from finding out if a microbicide will work or not," said Ramjee, who emphasized in a plenary talk on HIV prevention technologies that this progress has occurred without any investment from the private sector. Funding for these advanced trials has been provided by the Bill & Melinda Gates Foundation, the NIH, the United States Agency for International Development (USAID), and the Department for International Development (DFID) in the UK. Another 14 microbicides are in early safety trials and several of these second-generation candidates are gel formulations of ARVs that have a more specific mechanism of action and may be longer lasting.

Even as five trials are ongoing to test the efficacy of PrEP to prevent HIV transmission (see Treatment as prevention, IAVI Report 10, 3, 2006), researchers presented the preliminary safety data from one trial involving women at high risk of infection in Ghana, which is sponsored by the US-based organization Family Health International (FHI). In a late-breaker presentation Leigh Peterson of FHI, principal investigator of the trial, reported that so far no serious adverse events were related to receipt of tenofovir, the nucleoside reverse transcriptase inhibitor being tested in this trial. Peterson also reported that among the 936 women enrolled in this study only two HIV infections occurred in the group of women receiving tenofovir, compared to six in women receiving placebo. But since the infection rate was so low it is still unclear whether this approach will be prove effective.

Another late-breaker presentation on PrEP detailed a survey conducted by researchers at the San Francisco Department of Health to gauge the use of PrEP amongst men who participated in gay pride events or visited a sexually-transmitted disease clinic in San Francisco. Only one of the 851 men who completed the questionnaire between February and June of 2006 reported already using PrEP in an effort to prevent HIV infection, and only 2% of responders said they knew someone who is HIV uninfected and is already taking ARVs to try to prevent HIV infection. The survey showed that the majority of men surveyed (68%) would be willing to take ARVs to try to prevent HIV infection if this method were proven safe.

As microbicide and PrEP trials continue, researchers also stressed the advances researchers are making in developing and testing AIDS vaccine candidates. In a plenary session on the dynamics of HIV/AIDS vaccine research, Francoise Barre-Sinoussi of the Institut Pasteur in Paris highlighted progress, including the 85 Phase I and II trials that have taken place since 1987 with more than 30 different vaccine candidates. She also summarized the key challenges that remain. In another vaccine session at the conference Jose Esparza of the Gates Foundation applauded the announcement of a Russian vaccine center that will coordinate regional AIDS vaccine research for Eastern Europe and central Asia. The first vaccine candidate developed by Russian researchers, known as Vichrepol, at the Institute of Immunology in Moscow is now in Phase I clinical trials (seeVaccine Briefs).

Less than the best

The majority of the vaccine candidates currently in clinical trials primarily induce cellular immune responses rather than neutralizing antibodies, and researchers are now questioning what they can expect from this type of vaccine. "The best thing we can hope for at this point is vaccines that impact viral load," said Ronald Veazey of the Tulane National Primate Research Center in the US. In a satellite symposium preceding the official opening of the conference several researchers discussed and debated the use of clinical trials to evaluate a partially-effective vaccine, one that may not prevent HIV infection but rather delay disease progression or viral set point, and how it might affect the course of the pandemic. This session, sponsored by the Postgraduate Institute for Medicine, was hosted by Larry Corey of the HIV Vaccine Trials Network (HVTN) and focused on viral load as a surrogate marker for vaccine efficacy.

Norm Letvin of Beth Israel Deaconess Medical Center in Boston opened this provocative session by seeing how administration of a cellular-immunity based vaccine would affect progression of simian-immunodeficiency virus (SIV) in rhesus macaques (Science 312, 1530, 2006). Macaques were vaccinated with a two-part DNA prime and adenovirus serotype 5 (Ad5) vaccine boost, containing gag, pol, and env genes from SIVmac239. All vaccinated animals had robust T-cell responses to all three viral proteins encoded, but no neutralizing antibodies were elicited.

Disease course in HIV-infected humans is best predicted over the long term by plasma viral load, so in these studies Letvin and colleagues were interested in comparing the SIV viral loads between vaccinated and control animals. Throughout 112 days following immunization the vaccinated macaques maintained significantly lower viral loads as compared to controls, but soon after the difference was lost and viral loads of animals in both groups were comparable.

Letvin continued monitoring these animals through 850 days and saw that even though vaccinated macaques lost the ability to suppress viral replication they still had improved survival rates over the unvaccinated control animals. When researchers looked more closely at the sub-populations of CD4+ T cells in both groups of macaques they found that the central memory CD4+ T cells were more highly preserved and the Gag-specific CD4+ and CD8+ T-cell responses were stronger in vaccinated animals. These differences conferred a survival advantage, even though there was only a transient reduction in viral load, indicating that using viral load as a surrogate marker for vaccine efficacy may not in itself be sufficient.

Partially-effective vaccines

Two other presentations by Lisa Jacobson and Thomas Quinn from Johns Hopkins University focused on how an AIDS vaccine that reduces viral load could reduce transmission rates. HIV viral load is the major predictor of HIV transmission from mother-to-child. Quinn acknowledged that sexual transmission is far more complicated but there is evidence from a study of discordant couples in Rakai, Uganda that transmission from HIV-infected to uninfected partner did not occur when their viral load was undetectable. "It's not always viral load, but it's the dominating factor in transmission," said Quinn. "If you can modify transmission, you can control the epidemic."

If a 50% efficacious vaccine could reduce viral load by 0.5-1.0 log in individuals who eventually become infected, the prevalence of HIV would drop dramatically in 20 years, according to Quinn, as long as efforts are made simultaneously to bolster existing HIV prevention strategies to counteract any behavioral disinhibition among those that receive the vaccine.

But according to Sally Blower of the University of California in Los Angeles, even if vaccinated individuals don't increase their risk behavior a partially-effective vaccine could still make the epidemic worse because as infected individuals live longer there is a greater potential for them to transmit the virus to others, as long as their viral load remains at detectable levels (>50 viral copies/ml blood). Blower and her colleagues work on modeling the effects of partially-effective AIDS vaccines on the spread of the epidemic. These models help researchers predict how variables like the degree of protection offered by the vaccine, the number of people who take it, the duration of protection, and the vaccine-induced reduction in viral load (which is associated with a reduction in transmissibility and increased survival time) would influence HIV prevalence.

"What we'll need with partially-effective vaccines is very high coverage," said Blower. Based on models of the incidence rates in communities of men who have sex with men (MSM) in San Francisco, she calculates that 100% of people in highly affected communities would need to be vaccinated for a 50% effective AIDS vaccine to blunt the epidemic in these highly-affected groups.

But with the continuing expansion of the epidemic, the need for a preventive vaccine remains stronger than ever and this was echoed by Stephen Lewis, United Nations special envoy for HIV/AIDS in Africa, who said "a vaccine is the only way, conclusively and categorically, to end the pandemic."