Prevention gains momentum

Discussion of HIV prevention technologies tops the bill at international meeting

Over the past several years the number of people in developing countries 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). But the number of new HIV infections continues to be high—four million individuals were newly infected last year—and this has shifted attention back to halting transmission of the virus. The need to focus on improving prevention services was fully emphasized at the International AIDS Society's (IAS) XVI International AIDS Conference in Toronto from August 13-18, where a record 26,000 attendees from around the world gathered. Bill Gates, who addressed the conference during the opening session, said "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."

Expanding HIV prevention programs and research into new approaches for preventing transmission, including discussion of the ongoing microbicide, male circumcision, and pre-exposure prophylaxis (PrEP; see VAX May 2006Spotlight article, Treatment as prevention) trials, held prominence in the following days. The efficacy of some of these approaches is still being tested, but there is a shared optimism among researchers that a combination of these strategies, along with continuing education efforts, will help curtail the epidemic's spread. Few speakers, including former US President Bill Clinton who made several appearances during the first days of the conference, failed to note the overwhelming need for new prevention technologies and ultimately a preventive vaccine. "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 women, who are often not able to negotiate condom use, even within marriage. Now that newer prevention technologies are in development, researchers are introducing a new series of prevention acronyms. The latest, referred to as CBS—circumcision, barrier methods (such as the female diaphragm), and syringe exchange—are the next crop of options that researchers hope will enter the prevention arsenal 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 (see VAX August 2005Spotlight article,A comprehensive response). Three other circumcision trials are ongoing in Kenya and Uganda and interim data from two of these trials sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID)-one in Uganda and one in Kenya-were recently analyzed by a data safety monitoring board. The efficacy data at this point are not sufficient to warrant stopping either trial but another analysis was recommended before the trials conclude in September 2007. Many public health officials, including those at the Joint United Nations Programme on HIV/AIDS (UNAIDS), took advantage of the opportunity provided by the conference to say 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 mentioned 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, who reported that enrollment of volunteers is now complete at sites in Harare, Zimbabwe, as well as in Durban and Johannesburg, South Africa.

The implementation of syringe-exchange programs was covered in a plenary talk by Alex Wodak of St. Vincent's Hospital in Sydney, Australia. Wodak reported that 10% of all new HIV infections globally last year occurred among injection-drug users (IDUs). This route of HIV transmission is responsible for 68% of new infections in the Ukraine and is also reported now in at least 10 countries of Africa, where the epidemic has so far been fueled almost exclusively by sexual transmission. Although harm reduction programs that promote syringe exchange or provide safe-injection facilities to IDUs are among what Wodak calls the "most effective interventions in the HIV/AIDS repertoire" they remain under-utilized.

Next generation

The next generation of prevention options, called MTV—microbicides, treatment or PrEP (providing ARVs to uninfected individuals to try to prevent infection), and vaccines—are also under evaluation in several ongoing clinical trials. Currently 5 microbicide candidates are in large-scale efficacy trials, with results expected as early as next year, and another 14 are now in earlier safety studies. "We're not a long way from finding out if a microbicide will work or not," said Ramjee.

Five trials are also ongoing to test the efficacy of PrEP to prevent HIV transmission (see VAX May 2006 Spotlightarticle, Treatment as prevention). Leigh Peterson, a principal investigator from the US-based organization Family Health International (FHI), presented the first preliminary safety data from a PrEP trial involving women at high risk of HIV infection in Ghana. In a late-breaker presentation Peterson reported that so far no serious adverse events were associated with taking tenofovir, the ARV being tested in this trial. Peterson also reported that among the 936 women enrolled in this study only 2 HIV infections occurred in the group of women receiving tenofovir, compared to 6 in women receiving placebo. But since the overall number of new infections was so small it is not possible for researchers to conclude yet whether this approach will be effective.

Another late-breaker presentation on PrEP involved 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 sexually-transmitted disease clinics in San Francisco. Only one of the 851 men who completed the questionnaire between February and June reported already using PrEP in an effort to prevent HIV infection and only 2% of responders said they knew of someone else who was using PrEP. The majority of men surveyed (68%) said they would be willing to take ARVs to try to prevent HIV infection if this method were proven safe.

Researchers also stressed the advancements researchers are making in developing and testing AIDS vaccine candidates. In a plenary session on the dynamics of HIV/AIDS vaccine research, Françoise Barré-Sinoussi of the Institut Pasteur in Paris highlighted the 85 Phase I and II trials that have taken place since 1987 with more than 30 different vaccine candidates, and summarized the key challenges that remain.

Less than the best

Many of the vaccine candidates currently in clinical trials are only capable of inducing HIV-specific cellular immune responses, and not the neutralizing antibodies that most researchers consider will be a necessary component of the immune response if a vaccine is to completely protect a person from HIV infection. This raises questions about what to expect from a vaccine that primarily induces cellular immunity. "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. This type of vaccine is often referred to as partially effective since it wouldn't provide sterilizing immunity that is capable of completely preventing HIV infection.

Disease course in HIV-infected humans is partly predicted over the long term by the amount of virus that is circulating in the blood, a measurement known as viral load. A vaccine that could lower viral load in someone who was subsequently HIV infected could therefore extend the amount of time it takes for that person to progress to AIDS (seePrimer). Lowering viral load would also lower the likelihood that an HIV-infected individual could then transmit the virus to others and could help limit the epidemic's spread.

Two presentations by Lisa Jacobson and Thomas Quinn from Johns Hopkins University focused on how a partially-effective AIDS vaccine, which didn't protect against HIV infection but reduced viral load, would influence the number of new HIV infections. HIV viral load is the major predictor of HIV transmission from mother-to-child and is also a key determinant in sexual transmission, although Quinn acknowledges that this route of transmission is far more complicated.

Studies from Rakai, Uganda with discordant couples—where one partner is HIV-infected and the other is not—showed that transmission between partners did not occur when the HIV-infected individual had an undetectable viral load, meaning it was lower than could be measured by conventional tests. "It's the dominating factor in transmission," said Quinn. "If you can modify transmission, you can control the epidemic."

This gives scientists hope that a partially-effective vaccine could still reverse the course of the epidemic. According to Quinn, even a vaccine that is only 50% effective at lowering viral load (by 0.5-1.0 log) would dramatically reduce the HIV prevalence in 20 years, as long as efforts were made simultaneously to bolster existing HIV prevention strategies to counteract any increased level of risk behaviors (behavioral disinhibition) among those who received the vaccine.

Several researchers, including Sally Blower of the University of California in Los Angeles and her colleagues, also 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 receive it, the duration of protection, and the vaccine-induced reduction in viral load (which corresponds to a reduction in transmissibility and increased survival time), would influence HIV prevalence.

"What we'll need with partially-effective vaccines is very high coverage," says Blower. Based on models of the incidence rates in communities of men who have sex with men 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."