Background:

Effective prevention strategies for HIV infection are an important public health priority. A 2019 review for the US Preventive Services Task Force (USPSTF) found oral pre-exposure prophylaxis (PrEP) associated with decreased risk of HIV infection compared with placebo or no PrEP in adults at increased risk of HIV infection, although effectiveness decreases with inadequate adherence. Newer PrEP regimens, including an extended release injectable formulation, are available.

Purpose:

To synthesize evidence for the USPSTF on effects of PrEP on risk of HIV acquisition, mortality, harms, and other clinical 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 January 2019 to May 16, 2022, carried forward relevant included studies from the prior report, and manually reviewed reference lists; surveillance for new literature was conducted through March 24, 2023.

Study Selection:

Randomized, controlled trials on the benefits and harms of PrEP versus placebo/no PrEP in adults and adolescents without HIV infection at high risk of becoming infected; trials on the benefits and harms of newer versus older PrEP regimens; and studies on the diagnostic accuracy of instruments for predicting incident HIV infection.

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, 11 trials (all in the prior USPSTF review) found oral PrEP was associated with decreased risk of HIV infection versus placebo or no PrEP (N=18,172; relative risk [RR], 0.46 [95% confidence interval (CI), 0.33 to 0.66; I²=67%; absolute risk difference [ARD], −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 (TDF) plus emtricitabine (FTC) or TDF 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). All trials of oral PrEP versus placebo evaluated daily PrEP, except for one trial of event-driven PrEP (n=400; RR, 0.14 [95% CI, 0.03 to 0.63]). There was no difference between PrEP versus placebo/no PrEP in risk of serious adverse events (12 trials, N=18,292; RR, 0.93 [95% CI, 0.77 to 1.12]; I²=56%), sexually transmitted diseases, or adverse pregnancy-related outcomes; PrEP was associated with a non-statistically significant increased risk of fracture (7 trials, N=15,241; RR, 1.23 [95% CI, 0.97 to 1.56]; I²=0%). PrEP was associated with increased risk of renal adverse events (12 trials, N=18,170; RR, 1.43 [95% CI, 1.18 to 1.75]; I²=0%; ARD, 0.56% [95% CI, 0.09% to 1.04%]) and gastrointestinal adverse events (12 trials, N=18,300; RR, 1.63 [95% CI, 1.26 to 2.11]; I²=43%; ARD, 1.95% [95% CI, 0.48% to 3.43%]); most adverse events were mild and reversible. Two trials not included in the 2019 USPSTF review found the dapivirine vaginal ring associated with decreased risk of HIV infection versus placebo ring in African women at higher risk of HIV infection (2 trials, N=4,564; RR, 0.71 [95% CI, 0.57 to 0.89]; I²=0%; ARD, −2.23%, 95% CI, −3.75% to −0.74% at 1.4 to 1.6 years). One new trial found daily oral tenofovir alafenamide (TAF)-FTC to be non-inferior to TDF-FTC in men who have sex with men (MSM; n=5,387; RR, 0.53 [95% CI, 0.23 to 1.26]); TAF-FTC was associated with positive short-term effects on bone mineral density versus TDF-FTC and negative effects on lipid parameters and weight gain (mean difference 1.2 kg), without differences in clinical adverse events. Long-acting injectable cabotegravir was associated with decreased risk of HIV infection versus oral TDF-FTC in one new trial of cisgender MSM and transgender women (n=4,490, RR, 0.33 [95% CI, 0.18 to 0.62]) and one new trial of women at higher risk of HIV infection (n=3,178, RR, 0.11 [95% CI, 0.04 to 0.31]). Cabotegravir was associated with increased risk of injection site reactions and weight gain (mean differences <1 kg).

Instruments for predicting incident HIV infection had moderate discrimination in MSM (5 studies, N=25,488; area under the receiver operating characteristic [AUROC] curve ranged from 0.60 to 0.73) and moderate to high discrimination general populations of HIV-uninfected persons (2 studies, N=5,477,291; AUROC, 0.77 [95% CI, 0.74 to 0.79] and 0.84 [95% CI, 0.80 to 0.89]). Evidence on the accuracy of instruments for predicting incident HIV infection in specific populations other than MSM was very limited.

Limitations:

Restricted to English language; some pooled analyses with statistical heterogeneity or imprecise estimates; most trials evaluating risk of sexually transmitted infections were blinded to receipt of PrEP; most randomized trials were conducted in low-income settings, potentially limiting applicability to U.S. primary care; and evidence lacking in adolescents and pregnant women.

Conclusions:

In adults at increased risk of HIV infection, oral PrEP with TDF or TDF-FTC is associated with decreased risk of HIV infection compared with placebo or no PrEP, although effectiveness decreases with inadequate adherence. TAF-FTC was non-inferior to TDF-FTC in MSM and long-acting injectable cabotegravir was associated with decreased risk of HIV infection versus TDF-FTC in MSM or transgender women and women at higher risk for HIV infection. Instruments for predicting risk of incident HIV infection have moderate discrimination in MSM and moderate to high discrimination in general populations of persons without HIV infection.