Pre-Exposure Prophylaxis for the Prevention of HIV Infection: A Systematic Review for the U.S. Preventive Services Task Force [Internet]

Excerpt

Background: Effective prevention strategies for HIV infection are an important public health priority. Pre-exposure prophylaxis (PrEP) involves use of antiretroviral therapy (ART) regularly (e.g., daily) or before and after HIV exposure events to decrease the risk of acquiring HIV infection.

Purpose: To synthesize evidence for the U.S. Preventive Services Task Force (USPSTF) on effects of PrEP on risk of HIV acquisition, mortality, harms, and other clinical outcomes; effects of adherence on PrEP-associated outcomes; and accuracy of methods for identifying potential candidates for PrEP.

Data Sources: We searched the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, MEDLINE, and Embase from inception to June 2018 and manually reviewed reference lists; additional surveillance for new literature was conducted through January 25, 2019.

Study Selection: Randomized, controlled trials on the benefits and harms of PrEP versus placebo or no PrEP in adults without HIV infection at high risk of becoming infected; studies on the diagnostic accuracy of instruments for predicting incident HIV infection; studies on effects of adherence to PrEP on risk of HIV infection; and studies on rates of adherence to PrEP in U.S. populations.

Data Extraction: One investigator abstracted data and a second investigator checked data abstraction for accuracy. Two investigators independently assessed study quality using methods developed by the USPSTF.

Data Synthesis (Results): In populations at higher risk of acquiring HIV infection, PrEP was associated with decreased risk of HIV infection versus placebo or no PrEP (11 trials; relative risk [RR], 0.46 [95% confidence interval (CI), 0.33 to 0.66; I²=67%; absolute risk reduction, −2.0% [95% CI, −2.8% to −1.2%] after 4 months to 4 years). Effects were consistent across HIV risk categories and for PrEP with tenofovir disoproxil fumarate plus emtricitabine or tenofovir alone. There was a strong association between higher adherence and greater efficacy (adherence ≥70%: 6 trials; RR, 0.27 [95% CI, 0.19 to 0.39]; I²=0%; adherence >40% to <70%: 3 trials; RR, 0.51 [95% CI, 0.38 to 0.70]; I²=0%; and adherence ≤40%: 2 trials; RR, 0.93 [95% CI, 0.72 to 1.20]; I²=0%; p<0.00001 for interaction). No trial reported effects of nondaily dosing except for one trial of event-driven PrEP (RR, 0.14 [95% CI, 0.03 to 0.63]). There was no difference between PrEP and placebo or no PrEP in risk of serious adverse events (12 trials; RR, 0.93 [95% CI, 0.77 to 1.12]; I²=56%). PrEP was associated with increased risk of renal adverse events (12 trials; RR, 1.43 [95% CI, 1.18 to 1.75]; I²=0%; absolute risk difference, 0.56% [95% CI, 0.09% to 1.04%]) and gastrointestinal adverse events (12 trials; RR, 1.63 [95% CI, 1.26 to 2.11]; I²=43%; absolute risk difference, 1.95% [95% CI, 0.48% to 3.43%]); most adverse events were mild and resolved with discontinuation of PrEP or with longer therapy. The association between PrEP and fracture was not statistically significant (7 trials; RR, 1.23 [95% CI, 0.97 to 1.56]; I²=0%). There were no differences between PrEP and placebo in risk of sexually transmitted infections, but most trials were blinded. Among women who became pregnant in trials of PrEP, PrEP was not associated with increased risk of spontaneous abortion (3 trials; RR, 1.09 [95% CI, 0.79 to 1.50]; I²=0%) or other adverse pregnancy outcomes. Instruments for predicting risk of incident HIV infection had moderate discrimination and require further validation. Adherence to PrEP in U.S. populations of men who have sex with men varied from high to low.

Limitations: Restricted to English language, statistical heterogeneity in some pooled analyses, most randomized trials were conducted in low-income settings, limited evidence on adherence in U.S. populations, and evidence lacking in adolescents and pregnant women.

Conclusions: In adults at increased risk of HIV infection, oral PrEP with tenofovir or tenofovir disoproxil fumarate plus emtricitabine is associated with decreased risk of HIV infection compared with placebo or no PrEP, although effectiveness decreases with inadequate adherence. PrEP is associated with increased risk of renal and gastrointestinal adverse events. Evidence on the accuracy of instruments for identifying persons at high risk of HIV infection is limited, with further validation needed.