Clinical trials have firmly established the efficacy of tenofovir/emtricitabine (TDF/FTC, Truvada) as pre-exposure prophylaxis (PrEP) to prevent HIV infection in both men and women. The fixed-dose combination was approved by the U.S. Food and Drug Administration (FDA) in 2012 for this indication. However, in these studies there were large differences in the rates of protection afforded by PrEP overall and among those who had detectable levels of drug (~50% versus >90%). This raises the concern that the actual effectiveness of daily TDF/FTC could be less impressive if real world adherence tended toward the lower end of the spectrum.
Two important pragmatic trials of PrEP among men who have sex with men (MSM) and transgender women refute such concerns. In the PROUD trial, 544 patients attending sexually transmitted infection (STI) clinics in London were assigned to start daily PrEP or defer for a year. Over 12 months, there were three new HIV infections in the PrEP arm compared to 20 in those who were assigned deferral -- an 86% reduction that rivals responses reported in previous clinical trials.
The French IPERGAY trial looked at event-driven PrEP with two tablets of TDF/FTC taken between two to 24 hours before sex and then one tablet taken each day on the following two days. In this placebo-controlled trial, 400 patients were randomized and again an 86% reduction in incidence of HIV infection was observed (two cases versus 14).
In both trials unprotected sex was rampant with high rates of sexually transmitted infections (STIs), including some acute hepatitis C, reported. Risk behaviors changed little pre- and post-study entry. Adherence to PrEP was OK but not spectacular.
On this side of the pond, a report from the Kaiser Permanente group in San Francisco found that among 657 patients starting PrEP there were no new cases of acquired HIV over 388 person-years of follow-up. At 12 months 50% had an STI, including a third with a rectal STI, demonstrating risk was certainly present.
The Bottom Line
These are impressive real world experiences with PrEP that show: a) PrEP works, perhaps even better than was predicted in the earlier clinical trials, b) concerns for risk compensation, that is increased risky behaviors with PrEP, are not borne out by the data and c) PrEP is an important tool in the HIV prevention toolbox for those who cannot or will not use condoms reliably.
Unfortunately, despite a wealth of supportive data, PrEP utilization is poor. This is a consequence of a lack of both knowledge and access among those who could benefit from this intervention, as only a fraction of primary care providers offer and prescribe it. This has got to change.
General health must include sexual health, and sexual health must incorporate PrEP for those at risk of acquiring HIV. Much more needs to be done to educate front-line providers in primary care and in STI clinics about PrEP. Health departments should take on PrEP as they have vaccinations and STI treatment. Medical school and primary care residency training program curricula are obligated to include instruction on PrEP. In addition, one should not discount the value of marketing in guiding prescriber behavior. Advertising TDF/FTC to providers and directly to consumers has the potential to be most effective in raising the profile of this life-saving strategy.
The studies described above show that treating just a dozen or so people at risk will prevent one HIV infection. How many infections are we going to allow by not making PrEP more available?
What are some other top clinical developments of 2015? Read more of Dr. Wohl's picks.
David Alain Wohl, M.D., is an associate professor of medicine in the Division of Infectious Diseases at the University of North Carolina and site leader of the University of North Carolina AIDS Clinical Trials Unit at Chapel Hill.