Prevent and Conquer

Research updates that headlined this year's Conference on Retroviruses and Opportunistic Infections

By Kristen Jill Kresge

The success of antiretrovirals (ARVs) for the treatment of HIV/AIDS is a remarkable victory in the now 29-year-old battle against the pandemic. In his plenary talk at the 17th Conference on Retroviruses and Opportunistic Infections (CROI), which was held February 16-19 in San Francisco, Anthony Fauci, directorof the National Institute of Allergy and Infectious Diseases (NIAID), called ARV therapy “one of the best success stories in biomedical research as it gets translated to the patient.”

At the end of 2008, approximately four million HIV-infected people in low- and middle-income countries were receiving ARVs. “As the years go by we’re doing better in getting drugs to people who need them,” said Fauci. “That’s the good news.”

“The sobering news,” Fauci continued, “is that it’s not sustainable.” Despite this progress, there is still a huge gap between the number of people who need treatment and those who receive it—a gap recently widened by the World Health Organization’s (WHO) decision to revise treatment guidelines in response to mounting evidence for the benefits of earlier initiation of treatment. Based on the updated guidelines, only 30% of the HIV-infected people in the world who qualify for therapy are receiving it.

Closing this gap is a huge priority in battling HIV/AIDS, and critical to that is reducing the number of new infections. Fauci outlined a triumvirate of HIV prevention strategies that top the research agenda at NIAID, including the development of a preventive HIV vaccine; test and treat, which calls for universal HIV testing and immediate treatment for those infected; and pre-exposure prophylaxis, which involves delivering ARVs orally or in a microbicide gel to uninfected individuals. Several research updates on these three areas dominated the discussions at this year’s CROI.

Building on RV144

One of the main planks in the HIV vaccine research agenda is building on the results of RV144, the first AIDS vaccine trial to show any evidence of vaccine-induced protection against HIV. The results of this large efficacy trial in Thailand showed that a combination of two vaccine candidates provided about 31% protection against HIV infection.

In his remarks at CROI, Fauci made it clear that, in his opinion, a much higher efficacy should be the goal. “I think we’ve got to do better than 60%-70%,” he said. “We’re setting the bar very high, but the history of AIDS tells us we’ll clear that bar with the best minds, resources, and political will.”

The RV144 results may also affect the design of future trials. “We really have to focus future trials on the prevention of acquisition,” said Fauci. “Understanding the T-cell response [through trials of candidates that are solely designed to impact viral load] is very important, but when we do a large clinical trial in humans, it is my opinion that we’ve really got to look at acquisition.”

One obvious way to improve upon the RV144 results is to try to determine the immune correlates of protection—the specific types of immune responses induced by the vaccine that had a protective effect. Nelson Michael, director of the US Military HIV Research Program (MHRP), said work on trying to determine the correlates of protection is just getting underway. In the meantime, researchers are continuing to analyze the RV144 data. At CROI, Michael provided results from an RV144 analysis that showed that the level of vaccine-induced protection against HIV was significantly lower in individuals who reported behavior that put them at risk of HIV infection at any time during the three-year trial. But Michael warned against over-interpretation of these results since the analysis was not part of the initial trial design. Michael also suggested that the association between risk behaviors and lack of protection may have more to do with the seemingly transient impact of vaccination—the protective effect of the vaccine candidates appears to have been concentrated almost entirely during the first year—than with risk, as the reporting of risk behaviors continued throughout the trial.

The test and treat approach

When researchers at the WHO published results from a mathematical model showing that universal annual testing and immediate ARV treatment for all HIV-infected individuals could make a major dent in the number of new HIV infections, the model ignited much discussion and debate. Despite the attention test and treat has received, there is limited data to support the premise. “All of the mathematical models assume much lower HIV transmission rates when on ARV therapy but there is very little empiric evidence,” said Deborah Donnell, deputy director of the HIV Prevention Trials Network (HPTN) statistical center.

This is beginning to change. At CROI, Donnell presented data that helps bolster the connection between ARV treatment and prevention. In an observational sub-study of the Partners in Prevention Study, Donnell and colleagues analyzed HIV transmission rates among 3,381 serodiscordant couples, in which one person is HIV infected.

At the start of the study, the HIV-infected partners were not already taking ARVs. During the study, 10% (349) of the HIV-infected partners initiated ARV treatment. At the end of the two-year study, researchers analyzed 103 new HIV infections among the initially uninfected partners and determined that only one occurred when the HIV-infected partner was on ARV treatment. This correlates to a statistically significant 92% reduction in HIV transmission if the infected partner was taking ARVs. “There was a substantial prevention benefit for ARV therapy,” said Donnell. Researchers are hopeful that a randomized, five-year, Phase III clinical trial known as HPTN 052 will provide a conclusive answer about the protective effects of ARV therapy.

Another method researchers are employing to gauge the ability of ARV treatment to reduce HIV transmission rates is estimating the community viral load—the mean viral load of all HIV-infected individuals in a given community. And in some cases, declines in community viral load are correlated with declines in the number of individuals newly diagnosed with HIV.

Moupali Das-Douglas, director of the research unit at the San Francisco Department of Public Health, presented data indicating that a significant 40% decrease in the community viral load among men who have sex with men in San Francisco that occurred between 2004 and 2008 correlated with a 45% reduction in the number of new HIV infections during this same four-year period. The declines in community viral load and the number of new HIV diagnoses were credited to an increase in HIV testing rates in San Francisco, as well as an increase in the number of infected individuals who are receiving ARVs.

Julio Montaner, director of the British Columbia Centre for HIV/AIDS, reported similar results from a prospective study in British Columbia, Canada, which evaluated the community viral load of all HIV-infected people in the province who are on ARV treatment. Montaner said the rapid uptake of HAART in this population is “driving down viral load steadily,” and that this has resulted in a decrease in the number of new HIV diagnoses, particularly among injection-drug users (IDUs).

However, a third study conducted in Washington, D.C., which has the highest HIV prevalence in the US with about 3% of the population living with HIV/AIDS, showed a different trend than what was observed in San Francisco and British Columbia. Researchers from George Washington University School of Public Health and Health Services reported a 17% increase in the number of new HIV diagnoses in Washington D.C. from 2004 to 2007 following a dramatic expansion of routine HIV testing services and efforts to provide those infected with treatment.

Intermittent PrEP

While randomized trials and feasibility studies of test and treat have only recently started, several clinical trials of PrEP will soon be yielding results. Kenneth Mayer, an investigator involved in a PrEP trial in the US, said 2010 will be a “major year in our understanding of PrEP.” The results of four PrEP trials should be reported this year. The preliminary results of a pilot feasibility study of intermittent PrEP use, rather than daily administration, are also expected this year.

Meanwhile, two new intermittent PrEP studies (HPTN 066 and 067) are slated to begin this year. These studies will collect extensive pharmacokinetic data, which will hopefully shed light on the optimal dosing regimens for intermittent PrEP. “We have many things to learn about optimal [PrEP] dosing,” said Mayer.

In addition to oral dosing, researchers are also studying the use of gel formulation of ARVs that can be used as microbicides. Several efficacy trials of non-ARV-based microbicides have provided disappointing results. “Microbicides without ARVs aren’t a dead issue, but they’re definitely on a resuscitator,” said Fauci. “The time has come to look at an ARV-based microbicide.”

There are two clinical trials underway to evaluate the use of ARVs formulated as topical microbicides, with the first results expected later this year. Meanwhile, researchers are also experimenting with other ARVs that may be effective topical PrEP agents. One of these is maraviroc, the first licensed ARV that blocks HIV entry into cells. At CROI, John Moore, a professor of microbiology and immunology at Weill Cornell Medical College, reported that maraviroc was able to protect nonhuman primates against simian immunodeficiency virus (SIV), the monkey version of HIV, in a dose-dependent manner.

Richard Jeffreys, Basic Science Project Director at Treatment Action Group, contributed to this article.