What if there was a medication that one could take every day to prevent the acquisition of HIV? This approach to combat HIV is called pre-exposure prophylaxis, or PrEP. The idea behind PrEP is that the same antiretroviral medications that are used to treat HIV infected individuals could also help protect non-infected individuals from acquiring the virus in the first place.
The ideal medication for PrEP would have few side effects, and it should preferably be long-acting to allow for once-daily dosing. It would achieve high levels in both the blood and body mucosal surfaces though which HIV usually gains entry. And finally, it would have a high barrier to resistance, so that the virus could not elude the medication by means of mutation.
Tenofovir (TDF) and the combination pill tenofovir-emtricitabine (TDF-FTC) seem to fit most of these requirements. Over the past few years, a number of large trials have studied the efficacy of these medications in preventing HIV transmission. The iPrEx study, published in NEJM in December, 2010, showed that TDF-FTC is effective in preventing HIV infection in high risk men who have sex with men. The CAPRISA 004 trial found tenofovir as a vaginal gel to be effective in reducing HIV transmission to women.
This week, NEJM published three large studies of oral TDF and TDF-FTC for HIV prophylaxis. Two of the trials showed these medications to be effective in preventing HIV transmission, while the third trial did not show a benefit. What were the differences between these three trials, and why did they disagree on the benefits of anti-retroviral medication for HIV prevention?
Let’s begin with the studies showing benefit. The Partners PrEP Trial enrolled nearly 5000 heterosexual couples in Kenya and Uganda in which one partner was infected with HIV-1 and the other partner was not infected. The non-infected partners were randomized to one of three arms: TDF, combination TDF-FTC, or placebo. The relative reduction in HIV-1 incidence was 67% for TDF and 75% for TDF-FTC as compared with placebo (both were significantly different from placebo but there was not a significant difference between the efficacy of TDF versus TDF-FTC). There was also no difference in the protective effects of these drugs between men and women. The TDF2 Study followed 1200 HIV seronegative individuals in Botswana who were randomized to receive TDF-FTC or placebo. TDF-FTC treatment reduced incidence of HIV by 62% as compared with placebo; this difference was significant. Finally, the FEM-PrEP Study randomized over 2000 HIV-negative women in South Africa, Kenya, and Tanzania to receive either TDF-FTC or placebo once daily. In contrast to the TDF2 and Partners-PrEP trials, FEM-PrEP did not show TDF-FTC to be effective in preventing transmission of HIV to women. In none of the three trials was there evidence that the use of PrEP led to riskier sexual behavior.
One of the big differences between the two positive trials and the negative FEM-PrEP trial was the rate of medication adherence amongst participants. In the Partners PrEP study, study medication was detected in 82% of the samples of randomly selected study participants. In comparison, fewer than 40% of women in the FEM-PrEP trial had adequate blood levels of the study drug. Within the TDF2 Study, serum analysis of drug levels showed that those assigned to the treatment arm who acquired HIV were more likely to have a lower level of TDF-FTC in their blood – thus, those who skipped doses and did not take their medication regularly seemed to have a greater chance of acquiring HIV infection.
These findings, in concordance with the earlier iPrEx trial, helped sway the FDA last month to approve TDF-FTC for the indication of HIV prophylaxis. This is the first time that a medication has been approved by the FDA specifically for the indication of preventing HIV.
However, the approval of TDF-FTC for HIV prevention opens a new set of questions for practicing clinicians. How do we define the population that would most benefit from daily HIV prophylactic medication? How do we monitor healthy individuals who are taking TDF-FTC? How long should they continue to take the medication? What are the potential adverse effects of this preventive strategy? Think about these questions as you read the two Clinical Decisions cases on NEJM.org. Read the vignettes and vote online to let us know who you think should receive PrEP.
NEJM Deputy Editor Lindsey Baden sees pre-exposure prophylaxis as one more tool in the toolkit for HIV prevention. According to Baden, “HIV transmission continues at a staggering rate, and every effort to prevent it should be embraced.” However, he also reminds us that all medical interventions carry potential risks as well as benefits. “We need to ensure that we implement this new tool in a manner that mitigates any potential harm to otherwise healthy individuals.” (Read his editorial on NEJM.org.)
Pre-exposure HIV prophylaxis was the hot topic at the International AIDs Conference in Washington DC held July 22-27, 2012. Over the coming months, look for HIV and public health societies to issue guidelines to help clinicians best implement this new tool.