Every day, approximately 7,000 new people are infected with human immunodeficiency virus (HIV). This occurs despite huge public health efforts to slow transmission through better education and use of condoms. Every day more people are infected. HIV/AIDS is no longer a death sentence since anti-retroviral therapy has been valuable in extending the life expectancy of those who have been infected. But preventing HIV infection in the first place remains the highest priority.
In a recent article published in NEJM, Grant et al report the findings of a study that investigated the effectiveness of using prophylactic antiretroviral medication in preventing HIV infection. This randomized, placebo-controlled, double-blind trial, called the Preexposure Prophylaxis Initiative (iPrEx) study, was conducted at 11 sites in the Americas, South Africa, and Thailand. Nearly 2500 men and transgender women who have sex with men, all of whom tested as HIV seronegative at the beginning of the trial, were enrolled. About half of all enrollees were assigned to receive a combination of the anti-retroviral medications emtricitabine and tenofovir (FTC-TDF) on a daily basis. The other half received a placebo. Enrollees in both groups received traditional prevention services such as condoms, HIV testing, and risk-reduction counseling; furthermore, all enrollees were instructed to use conventional methods of prophylaxis to protect themselves from HIV infection. The median study follow-up time was 1.2 years.
The authors report that 64 HIV infections developed in the placebo group during the trial, as compared with 36 HIV infections in the FTC-TDF group. This translates to an estimated efficacy of 44%. In other words, FTC-TDF prophylaxis could possibly prevent 44 out of every 100 HIV infections that would occur if only conventional prevention methods were used in this high-risk population.
Encouragingly, within the group receiving the FTC-TDF treatment, the study drug was pharmacologically detectable in 51% of participants who remained infection-free, as compared with only 9% of those who became infected with HIV. This supports the interpretation that the observed protective benefits of FTC-TDF were associated with actual use of the drug.
But not all of the study findings were positive. The results also suggested that certain risks might be associated with the use of FTC-TDF prophylaxis. Most concerning is the risk of viral resistance to FTC. Two of the participants in the study arm receiving FTC-TDF were later found to have had acute HIV infections at the time of enrollment; in both of these individuals, the HIV virus became FTC-resistant. This finding may carry implications for the potential utility of FTC-TDF as therapy in these patients, as well as for prophylaxis at a societal level — especially among populations that are not only at greater risk for HIV infection, but also more likely to go undiagnosed.
An increased risk of renal dysfunction was also observed in the FTC-TDF group as compared with the placebo group. The interpretation of this finding (with p = 0.08) remains uncertain, and the total number of enrollees who developed renal insufficiency was small. Nevertheless, the finding suggests there may be reason for concern, especially if the side effect profile of FTC-TDF was diluted by poor compliance in the trial.
In an accompanying editorial, Dr. Nelson L. Michael, Director of the Division of Retrovirology at the Walter Reed Army Institute of Research and Director of the U.S. Military HIV Research Program, writes, “The results of the iPrEx study represent a significant advance in HIV-prevention research in providing the proof of concept that a combination antiretroviral drug in widespread clinical use in the treatment of chronic HIV infection reduces the risk of HIV acquisition in men who have sex with men.”
Dr. Lindsey Baden, NEJM deputy editor and infectious disease specialist, commented, “Over the last 25 years, tremendous advances in the treatment of HIV infection have occurred with the development of more than a dozen antiretroviral medications. However, HIV prevention remains the most important factor in stemming the tide of this pandemic. These data demonstrate another potential tool for HIV prevention, pre-exposure prophylaxis for individuals at very high risk of HIV acquisition. The coming public health debate as to how this tool can be combined with other HIV prevention approaches, given the unique complexities of this approach, will be quite illuminating.”
More answers are needed, and still more questions remain. But this study opens up a new world of possibility for HIV prevention. It offers the promise that some day, instead of racing against the clock of infection, it will be possible to stop HIV from ever running its course.
How do you think the results of this study will affect HIV prevention efforts and attainment? In what ways, if any, will it influence how you manage patients who may be at increased risk for infection?