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Reference - PROUD trial (Lancet 2015 Sep 9 early online) (level 2 [mid-level] evidence)
- Preexposure prophylaxis (PrEP) has consistently reduced the risk of HIV transmission in high risk groups compared to placebo, but there are concerns that patients knowingly receiving preexposure prophylaxis may increase risky behavior.
- The present unblinded randomized trial found immediate initiation of PrEP significantly reduced HIV transmission compared to delayed initiation 1 year after randomization in men who have sex with men reporting anal intercourse without a condom in the 90 days prior to randomization.
- While sexual behaviors and PrEP adherence could not be evaluated directly, the rate of bacterial sexually transmitted infections was similar between the immediate and delayed PrEP groups, suggesting PrEP may not substantially impact sexual behaviors.
Preexposure prophylaxis (PrEP) is a strategy used to prevent HIV transmission. This approach involves treating HIV-uninfected individuals at high risk of acquiring HIV with daily antiretroviral agents. While HIV testing and consistent condom use are the cornerstones of HIV prevention, PrEP has been shown to consistently reduce HIV transmission compared to placebo in high risk groups in randomized trials (N Engl J Med 2010 Dec 30;363(27):2587, N Engl J Med 2012 Aug 2;367(5):399, Lancet 2013 Jun 15;381(9883):2083). Based on these findings, both the Centers for Disease Control and Prevention and the World Health Organization currently recommend PrEP regimens as an option for all persons at substantial risk for HIV infection (CDC PrEP for HIV 2014 May 14 PDF, WHO 2015 Sep PDF). There are concerns, however, that patients knowingly receiving PrEP may engage in riskier behaviors, thereby decreasing its value as a public health intervention. To further assess the efficacy of PrEP in a real world setting, a recent unblinded randomized trial compared immediate initiation of PrEP (tenofovir plus emtricitabine daily) vs. delayed initiation 1-year after randomization in 544 men who have sex with men (mean age 35 years) reporting anal intercourse without a condom within 90 days prior to randomization. In the previous 12 months, 61% of men were diagnosed with a sexually transmitted infection and 34% used post-exposure prophylaxis.
The overall follow-up time was 243 person-years in the immediate PrEP group and 222 person-years in the delayed PrEP group. Incidence of HIV infection per 100 person-years was 1.2 with immediate PrEP vs. 9 with delayed PrEP (p = 0.0001), corresponding to an 86% reduction in infection. Of the 3 men in the immediate therapy group with newly diagnosed HIV infections, 1 tested positive at the 4-week visit and is likely to have been infected before the trial began and 2 had lapsed PrEP prescriptions several weeks before testing positive. These results suggest that there were no breakthrough HIV infections in patients actively taking PrEP. Comparing immediate vs. delayed PrEP, bacterial sexually transmitted infections were diagnosed in 57% vs. 50% (not significant). However men in the immediate PrEP group were screened more frequently for sexually transmitted infections due to increased clinic visits to receive PrEP prescriptions. Eight percent of patients in the immediate PrEP group reported interrupted or missed PrEP due to adverse events and the most common adverse events were nausea, headache, and arthralgia. In the delayed PrEP group, 32% used at least one course of post-exposure prophylaxis.
This trial was designed to recruit 5,000 men, but was terminated early after the pilot phase due to a higher than expected rate of HIV infection in the delayed PrEP group. It also intended to evaluate PrEP adherence and sexual behaviors through monthly questionnaires and daily diaries, but few patients completed these evaluations. While these factors limit the ability of this trial to fully evaluate PrEP as a public health intervention, the benefit of PrEP for preventing HIV transmission is clear. The similar rates of bacterial sexually transmitted diseases with immediate and delayed PrEP also suggests that the overall impact of PrEP on sexual behavior may be minimal. Two recent cohort studies also evaluated the incidence of HIV infection and changes in sexual behaviors in patients receiving PrEP. In one study, while the number of sexual partners remained fairly stable after PrEP initiation, 41% of patients reported decreased condom use (Clin Infect Dis 2015 Nov 15;61(10):1601). The second cohort study found that the number of sexual partners declined during the 48 week follow-up, but the number of patients reporting anal intercourse without a condom remained stable (JAMA Intern Med 2015 Nov 16 early online). Overall, these results suggest that PrEP is an effective method of HIV prevention in small trials, but further study will be needed to help define the optimal delivery setting, cost, behavioral risk compensation, and long-term safety profile in order to scale this strategy as a public health intervention.
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