Importance: Effective prevention strategies for HIV infection are an important public health priority. Preexposure prophylaxis (PrEP) involves use of antiretroviral therapy (ART) daily or before and after sex to decrease risk of acquiring HIV infection.

Objective: To synthesize the evidence on the benefits and harms of PrEP, instruments for predicting incident HIV infection, and PrEP adherence to inform the US Preventive Services Task Force.

Data Sources: Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and EMBASE through June 2018, with surveillance through January 2019.

Study Selection: English-language placebo-controlled randomized clinical trials of oral PrEP with tenofovir disoproxil fumarate/emtricitabine or tenofovir disoproxil fumarate monotherapy; studies on the diagnostic accuracy of instruments for predicting incident HIV infection; and studies on PrEP adherence.

Data Extraction and Synthesis: Dual review of titles and abstracts, full-text articles, study quality, and data abstraction. Data were pooled using the Dersimonian and Laird random-effects model for effects of PrEP on HIV infection, mortality, and harms.

Main Outcomes and Measures: HIV acquisition, mortality, and harms; adherence to PrEP; and diagnostic test accuracy and discrimination.

Results: Fourteen RCTs (N = 18,837), 8 observational studies (N = 3884), and 7 studies of diagnostic accuracy (N = 32,279) were included. PrEP was associated with decreased risk of HIV infection vs placebo or no PrEP after 4 months to 4 years (11 trials; relative risk [RR], 0.46 [95% CI, 0.33-0.66]; I² = 67%; absolute risk reduction [ARD], −2.0% [95% CI, −2.8% to −1.2%]). Greater adherence was associated with greater efficacy (RR with adherence ≥70%, 0.27 [95% CI, 0.19-0.39]; I² = 0%) in 6 trials. PrEP was associated with an increased risk of renal adverse events (12 trials; RR, 1.43 [95% CI, 1.18-1.75]; I² = 0%; ARD, 0.56% [95% CI, 0.09%-1.04%]) and gastrointestinal adverse events (12 trials; RR, 1.63 [95% CI, 1.26-2.11]; I² = 43%; ARD, 1.95% [95% CI, 0.48%-3.43%]); most adverse events were mild and reversible. Instruments for predicting incident HIV infection had moderate discrimination (area under the receiver operating characteristic curve, 0.49-0.72) and require further validation. Adherence to PrEP in the United States in men who have sex with men varied widely (22%-90%).

Conclusions and Relevance: In adults at increased risk of HIV infection, PrEP with oral tenofovir disoproxil fumarate monotherapy or tenofovir disoproxil fumarate/emtricitabine was associated with decreased risk of acquiring HIV infection compared with placebo or no PrEP, although effectiveness decreased with suboptimal adherence.

In adults at increased risk of HIV infection, PrEP with oral tenofovir disoproxil fumarate monotherapy or tenofovir disoproxil fumarate/emtricitabine was associated with decreased risk of acquiring HIV infection compared with placebo or no PrEP, although effectiveness decreased with suboptimal adherence.

Scope of the Review

Detailed methods are available in the full evidence report at https://www.uspreventiveservicestaskforce.org/uspstf/document/final-evidence-review/prevention-of-human-immunodeficiency-virus-hiv-infection-pre-exposure-prophylaxis. Figure 1 shows the analytic framework and key questions (KQs) that guided the review. The full report also includes contextual questions (not systematically reviewed) that addressed factors associated with PrEP adherence and rates of antiretroviral drug–resistant HIV in PrEP-treated individuals.

Data Sources and Searches

Ovid MEDLINE, the Cochrane Library, and EMBASE were searched for English-language articles published from inception through June 2018. Searches were supplemented by review of reference lists of included studies. Since June 2018,ongoing surveillance was conducted through article alerts and targeted searches of journals to identify major studies published in the interim that may affect the conclusions or understanding of the evidence and the related USPSTF recommendation. The last surveillance was conducted on January 25, 2019, and identified no eligible randomized trials.

Study Selection

Two investigators independently reviewed titles, abstracts, and full-text articles using predefined eligibility criteria. Randomized clinical trials (RCTs) of PrEP vs placebo or no PrEP in HIV-uninfected adults and adolescents (13-18 years) at higher risk for acquiring HIV were eligible for KQ1 and KQ5. Trials had to evaluate oral combination tenofovir disoproxil fumarate/emtricitabine or tenofovir disoproxil fumarate monotherapy and report HIV infection, mortality, quality of life, or harms. Tenofovir disoproxil fumarate/emtricitabine is the only medication approved by the US Food and Drug Administration (FDA) and recommended for PrEP; tenofovir disoproxil fumarate monotherapy is an alternate regimen for people who inject drugs (PWID) and in persons at risk because of heterosexual behavior.² Studies of the diagnostic accuracy of instruments to predict HIV acquisition in the United States or US-applicable settings were eligible for KQ2. United States–based RCTs and observational studies of PrEP implementation that reported adherence were eligible for KQ3 and KQ4.^3,4

Data Abstraction and Quality Rating

For each included study, 1 investigator abstracted information on populations, interventions or screening instruments, comparators, adherence, outcomes, study designs, and settings. A second investigator reviewed abstracted information for accuracy. Two independent investigators assessed the quality of each study as good, fair, or poor using predefined criteria developed by the USPSTF. 

For all KQs, the overall strength of the body of evidence was assessed as high, moderate, low, or insufficient using methods developed for the USPSTF, based on the overall quality of studies, consistency of results between studies, precision of findings, and risk of reporting bias.¹ The applicability of the findings to US primary care populations and settings was also assessed.

Data Synthesis

Meta-analysis was conducted to calculate pooled relative risks (RRs) for effects of PrEP vs placebo or no PrEP on HIV infection, mortality, and harms, using the DerSimonian and Laird random effects model in Review Manager Version 5.3 (Cochrane Collaboration Nordic Cochrane Centre). Statistical heterogeneity was assessed using the I² statistic.⁵ When I² was greater than 30%, the analysis was also performed with the profile likelihood method using Stata/IC Version 13.1 (StataCorp).⁶ Results using the profile likelihood method were similar to those from the DerSimonian and Laird model and are not reported in this article. Sensitivity analyses and stratified analyses were conducted on study quality, PrEP regimen, HIV risk category, dosing schedule, study duration, and country. Stratified analyses were assessed for interactions using a test for heterogeneity across subgroups.

Sensitivity analyses were also conducted using data from the FDA medical review of PrEP⁷ on HIV incidence and fracture rates in place of data reported in journal articles when there were discrepancies. Results were very similar, and this article presents findings based on journal article data. Study-level adherence was assessed as a categorical variable in a stratified analysis (≥70%, >40% to <70%, or ≤40%)⁸ and as a continuous variable through meta-regression, and a plot of adherence against effectiveness (log RR) was constructed. For trials that used multiple adherence measurement methods, adherence data were selected using a prioritized list.⁹ For analyses with at least 10 trials, funnel plots were constructed and the Egger test conducted for small sample effects.¹⁰

All significance testing was 2-tailed; P values of 0.05 or less were considered statistically significant.

Across all KQs, 14 RCTs (in 37 articles^11-47) (N = 18,837), 8 observational studies^48-55 (N = 3884), and 7 studies of diagnostic accuracy of HIV risk prediction instruments^56-62 (N = 32,279) were included (Figure 2). The main results for each key question are summarized below.

Benefits of PrEP

Key Question 1. What are the benefits of PrEP in individuals without preexisting HIV infection vs placebo or no PrEP on the prevention of HIV infection and quality of life?

Key Question 1a. How do the benefits of PrEP differ by population subgroups?

Key Question 1b. How do the benefits of PrEP differ by dosing strategy or regimen?

Twelve RCTs (reported in 33 publications^11-44) evaluated PrEP vs placebo (11 trials^{12,14,17,18,21,27,33,39,40,42,43}) or immediate vs delayed PrEP (1 trial³¹) (Table 1). The trials enrolled between 72 and 4726 participants (total n = 18,244). The mean age in all trials was younger than 40 years. No trial enrolled pregnant women or people younger than 18 years. Duration of follow-up ranged from 4 months to 4 years. All trials enrolled persons at increased risk for HIV infection. Six trials^{12,21,27,40,42,43} enrolled persons at increased risk because of heterosexual contact, 4 trials^17,18,31,33 men who have sex with men or transgender women, 1 trial³⁹ high-risk women and men who have sex with men, and 1 trial¹⁴ PWID. All trials of persons at increased risk because of heterosexual contact were conducted in Africa and the trial of PWID was conducted in Thailand; all trials conducted in the United States, Canada, and Europe focused on men who have sex with men.

Five trials^{12,14,18,27,40} evaluated tenofovir disoproxil fumarate monotherapy (300 mg), 8 trials^{12,17,21,27,33,39,42,43} tenofovir disoproxil fumarate (300 mg)/emtricitabine (200 mg), and 1 trial³¹ tenofovir disoproxil fumarate (245 mg)/emtricitabine (200 mg). Eleven trials evaluated daily PrEP.^{12,14,17,18,21,27,31,39,40,42,43} Dosing was intermittent or event-driven in 3 trials,^21,33,39 but only 1 reported results for event-driven (before and after sex) PrEP.³³ In the other 2 trials, there were no HIV infections or results were combined with daily PrEP.^21,39 In all trials, all patients received HIV risk reduction and adherence counseling. All trials provided free condoms, except for 1 trial³¹ that did not require it.

The adherence level, method for measuring adherence, and funding source of each trial are reported in Table 1. All trials were rated good quality except for 1 trial³¹ rated fair quality because of unclear allocation concealment methods and open-label design.

PrEP was associated with reduced risk of HIV infection vs placebo or no PrEP (11 trials [n = 18,172]; RR, 0.46 [95% CI, 0.33- 0.66]), but statistical heterogeneity was present (I² = 67%) (Figure 3).^{12,14,17,18,27,31,33,39,40,42,43} The absolute risk difference (ARD) was −2.0% (95% CI, −2.8% to −1.2%). Estimates were very similar (P = .79 for interaction) for PrEP with tenofovir disoproxil fumarate monotherapy (5 trials [n = 7546]; RR, 0.49 [95% CI, 0.28- 0.84]; I² = 58%)^{12,14,18,27,40} or tenofovir disoproxil fumarate/ emtricitabine (8 trials [n = 10,626]; RR, 0.44 [95% CI, 0.27-0.72]; I² = 74%).^{12,17,27,31,33,39,42,43} Funnel plot asymmetry was present (P = .03 by Egger test) (eFigure 1 in the Supplement).

A stratified analysis found a significant interaction (P < .001) between level of adherence (≤40%, >40% to <70%, or ≥70%) and effectiveness of PrEP; stratification by adherence eliminated statistical heterogeneity (Table 2, Figure 4). In 6 trials (n = 7328) with adherence 70% or greater, the RR was 0.27 (95% CI, 0.19-0.39; I² = 0%).^{12,18,31,33,39,42} There was also a strong association between effectiveness and adherence analyzed as a continuous variable (P < .001) (eFigure 2 in the Supplement), which accounted for all of the between-study heterogeneity. Findings were similar when analyses were restricted to trials that evaluated adherence based on plasma levels.

PrEP was effective across HIV risk categories (persons at risk because of heterosexual contact, men who have sex with men, or PWID; P = 0.43 for interaction) (Table 2). Four trials^12,14,17,43 found similar PrEP effectiveness in subgroups defined by age, and 3 trials^12,14,42 found similar effectiveness in male and female participants. Few trials examined the interaction between presence of risk behaviors and effectiveness of PrEP, the risk behaviors examined in these trials varied (receptive anal intercourse, condomless sex, drug injection or needle sharing), and effectiveness of PrEP did not consistently vary according to presence of risk behaviors.^12,14,17

Estimates were similar when trials were stratified according to duration of follow-up, when the analysis was restricted to good-quality trials, or when trials were stratified according to whether they reported some industry support (usually donated study drugs) (Table 2). The estimate from 1 trial (n = 400) of event-driven PrEP (RR, 0.14 [95% CI, 0.03-0.63]) was similar to the pooled estimate from daily-dosing trials that reported high adherence (5 trials [n = 6928]; RR, 0.28 [95% CI, 0.20-0.41]).^{12,18,31,39,42} In this trial, men who have sex with men randomized to PrEP took a median of about 4 doses of PrEP per week (15 doses per month) based on pill counts. PrEP was more effective in trials conducted in the United States, Europe, or Canada (3 trials [n = 1323]; RR, 0.13 [95% CI, 0.05- 0.32]; I² = 0%)^18,31,33 than in trials conducted in Africa, Asia, or internationally (8 trials [n = 16,849]; RR, 0.54 [95% CI, 0.37- 0.79]; I² = 72%; P = 0.004 for interaction).^{12,14,17,21,27,39,40,42,43} All trials conducted in the United States, Europe, or Canada reported high adherence and enrolled men who have sex with men.

Associations of PrEP vs placebo or no PrEP with mortality did not meet the threshold for statistical significance (9 trials [n = 17,744]; RR, 0.81 [95% CI, 0.59-1.11]; I² = 0%).^{12,14,17,18,27,31,40,42,43} Individual trials reported few mortality events and risk estimates were imprecise. No trial reported effects of PrEP on quality of life.

Diagnostic Accuracy of Risk Assessment Tools

Key Question 2. What is the diagnostic accuracy of provider or patient risk assessment tools in identifying individuals at increased risk of HIV acquisition who are candidates for PrEP?

Seven studies evaluated instruments developed and validated in US cohorts for predicting incident HIV infection^56-62. Six studies evaluated men who have sex with men^56-59,61,62 and 1 study evaluated PWID.⁶⁰ Sample sizes (including development and validation cohorts) ranged from 300 to 9481 patients (total n = 32,311). Methodological shortcomings included application of risk instruments to previously collected data, evaluation of older (before 2000) cohorts,^58-60 failure to validate accuracy in a separate (nondevelopment) cohort,^56,60 and failure to predefine positive test thresholds.^56-60

For men who have sex with men, studies evaluated the predictive utility of 4 different instruments (number of criteria ranged from 4 to 10). For 3 instruments (n = 20,064), discrimination was similar, with area under the receiver operating characteristic (AUROC) curves in the original validation cohorts ranging from 0.66 to 0.72.^57-59 A fourth study (n = 9481)⁵⁶ found a 10-item instrument associated with better goodness of fit than 2 of these instruments^58,59 but did not report AUROC values and did not validate findings in a separate (nondevelopment) sample. The initial development and validation cohorts used to develop these instruments primarily consisted of white men who have sex with men. Two subsequent studies (n = 862) reported poorer discrimination in black men who have sex with men, with AUROC values ranging from 0.49 to 0.63.^61,62

A 7-item instrument for predicting risk in PWID reported an AUROC value of 0.72 (CI not reported) in a cohort of 1904 primarily (93%) black participants.⁶⁰ This instrument was not evaluated in a separate validation cohort.

No study evaluated a US-applicable instrument for predicting risk of HIV infection in persons at risk of HIV infection due to heterosexual contact. Instruments for predicting risk in women were developed using African cohorts.^63-65

PrEP Adherence

Key Question 3. What are rates of adherence to PrEP in US primary care–applicable settings?

Ten studies evaluated rates of adherence to PrEP in US primary care and primary care–applicable settings.^{18,46-50,52-55} The studies enrolled between 20 and 1086 study participants (total n = 3177), and duration of PrEP use ranged from 6 months to 2 years. One study was rated good quality¹⁸ and the others were rated fair quality.

Three observational studies of US men who have sex with men (mean age, 34-36 years; n = 908) found adherence to PrEP of 66% to 90%, based on a tenofovir diphosphate level of 700 fmol/punch or greater on dried blood sampling (consistent with ≥4 doses/wk).^52-54 Using the same measure, 2 observational studies of younger US men who have sex with men (mean age, 16-20 years; n = 272) found adherence to PrEP of approximately 50% at 12 weeks and 22% to 34% at 48 weeks.^49,50 An RCT (n = 179) of primarily (97%) US men who have sex with men found adherence was higher with daily (48%) than with intermittent (31%) or event-driven (17%) PrEP during weeks in which sex was reported.⁴⁶ No study evaluated PrEP adherence rates in US PWID or persons at increased risk of HIV infection due to heterosexual contact.

Key Question 4. What is the association between adherence to PrEP and effectiveness for preventing HIV acquisition?

Three RCTs (n = 5591) found PrEP associated with greater effectiveness compared with placebo for reducing risk of HIV infection among participants having higher adherence to daily PrEP based on daily pill counts or daily diaries, compared with participants having lower adherence.^{12,14,16,17,29} Four of 5 RCTs (n = 6013) found that among participants randomized to PrEP, presence of tenofovir in plasma samples was associated with decreased likelihood of HIV infection compared with no detectable tenofovir.^{12,14,16,27,29,42,43} Five studies (n = 1138)^{33,49,50,52,54} found that all participants with seroconversion receiving PrEP had undetectable plasma levels of tenofovir or levels consistent with low adherence. The number of participants with seroconversion in each study was small (1 to 4 patients per study).

Harms of PrEP

Key Question 5. What are the harms of PrEP vs placebo or no PrEP when used for the prevention of HIV infection?

There was no significant difference between PrEP vs placebo in risk of serious adverse events (12 trials [n = 18,282]; RR, 0.93 [95% CI, 0.77-1.12]; I² = 56%) (Table 3)^{12,14,17,18,21,27,31,33,39,40,42,43} or withdrawal because of adverse events (4 trials [n = 9704]; RR, 1.25 [95% CI, 0.99-1.59]; I² = 0%).^12,17,33,40

PrEP was associated with increased risk vs placebo of renal adverse events (12 trials [n = 18,170]; RR, 1.43 [95% CI, 1.18-1.75]; I² = 0%; ARD, 0.56% [95% CI, 0.09%-1.04%])^{12,14,17,18,21,27,31,33,39,40,42,43} and gastrointestinal (primarily nausea) adverse events (12 trials [n = 18,300]; RR, 1.63 [95% CI, 1.26-2.11]; I² = 43%; ARD, 1.95% [95% CI, 0.48%-3.43%]).^{12,14,17,18,21,27,31,33,39,40,42,43} Renal abnormalities were primarily 1 or more grade-1 elevation of serum creatinine level and generally resolved following PrEP cessation^12,25,28,41 or with ongoing PrEP.^21,39 Three trials reported that the risk of gastrointestinal events diminished over time.^14,17,42 Serious renal and gastrointestinal events were rare. There was no significant difference between PrEP vs placebo in risk of fracture (7 trials [n = 15,241]; RR, 1.23 [95% CI, 0.97-1.56]; I² = 0%).^{12,14,17,18,27,33,42}

There were no significant differences between PrEP vs placebo or no PrEP in risk of gonorrhea, chlamydia, or syphilis (Table 3).^{12,17,31,42,43} All of the trials except 1 were blinded, which could attenuate sexual risk behaviors associated with use of PrEP. One open-label trial (n = 544), which enrolled men who have sex with men, found no statistically significant associations between PrEP vs no PrEP and risk of bacterial sexually transmitted infections (STIs), although estimates for syphilis (RR, 1.28 [95% CI, 0.76-2.16]) and chlamydia (RR, 1.32 [95% CI, 0.98-1.79]) may have been underpowered.³¹ There was no significant difference between PrEP vs placebo in risk of herpes simplex virus infection (3 trials [n = 4088]; RR, 0.85 [95% CI, 0.67-1.07]; I² = 19%)^26,42,66 or hepatitis C virus infection (2 trials [n = 896]; RR, 0.73 [95% CI, 0.25-2.10]; I² = 0%).^31,33

No trial of PrEP enrolled pregnant women. In women withdrawn from PrEP trials because of pregnancy, PrEP was not associated with increased risk of spontaneous abortion (RR, 1.09 [95% CI, 0.79-1.50]; I² = 0%).^21,34,43 The Partners PrEP trial (n = 4706) found no significant differences between PrEP vs placebo in pregnancy rate, risk of preterm birth, birth anomalies, or postpartum infant mortality, and the FEM-PrEP trial (n = 2120) found no significant difference in risk of any adverse pregnancy outcome.³⁴

For all adverse events, there was no statistically significant interaction between PrEP regimen and any adverse event except for gonorrhea and chlamydia infection (Table 3). However, for both of these adverse events there was only 1 trial of tenofovir disoproxil fumarate. There was no statistically significant interaction between HIV risk category and risk of STIs.

The findings in this evidence report are summarized in Table 4. In populations at increased HIV infection risk, PrEP was associated with decreased risk of acquiring HIV infection that varies according to the level of adherence. In trials for which adherence was 70% or greater, the reduction in risk was approximately 75%, with a number needed to treat of approximately 33.^{12,18,31,33,39,42} In studies of US men who have sex with men, adherence varied widely and was generally lower in younger (16-20 years) men who have sex with men.^49,50,52-54 Trials were not designed to assess effects of PrEP on mortality, and no trial reported effects on quality of life.

Event-driven or intermittent (nondaily) dosing strategies might improve adherence while maintaining effectiveness.⁶⁷ One trial found event-driven PrEP in men who have sex with men associated with substantially reduced risk of HIV infection vs no PrEP.³³ No study evaluated the effectiveness of intermittent or event-driven dosing in women or PWID, which may depend on the antiretroviral drugs used, how quickly and at what concentrations they accumulate at exposure sites (eg, genital vs rectal mucosa), and the correlation between tissue concentration and effectiveness.^68,69

Findings were robust in subgroup and stratified analyses based on the PrEP drugs used (tenofovir disoproxil fumarate/emtricitabine [the only FDA-approved PrEP regimen] or tenofovir disoproxil fumarate monotherapy), HIV risk category, study duration, study quality, age, and sex. Evidence in PWID was limited to 1 Thai trial,¹⁴ and all trials of persons at risk due to heterosexual contact were conducted in Africa. No randomized trial enrolled adolescents. In 2018, the FDA approved tenofovir disoproxil fumarate/emtricitabine for PrEP in adolescents who weigh 35 kg or more, based on safety data.⁴⁹

Although PrEP was associated with increased risk of gastrointestinal and renal adverse events, most events appeared mild and reversible. There was no statistically significant association between PrEP and increased risk of fracture,^{12,14,17,18,27,33,42} based on trials with relatively brief follow-up. Although there was no association between PrEP and increased risk of bacterial STIs,^{12,17,31,42,43} most trials blinded patients to PrEP allocation, and sexual risk behaviors might differ in persons who know they are taking PrEP. A systematic review of an open-label RCT and nonrandomized studies found PrEP associated with an increased risk of rectal chlamydia (4 studies; odds ratio, 1.59 [95% CI, 1.19-2.13]) but found no association between PrEP and risk of chlamydia at any site, STIs overall, syphilis, or gonorrhea.⁷⁰ Individuals who engage in riskier behaviors may be more adherent to PrEP,^14,50,54 which could offset any adverse behavioral effects.

The findings of this review are generally consistent with those from other recent meta-analyses that found PrEP to be effective at reducing risk effectiveness in trials reporting higher adherence.^8,71,72 The findings are strengthened by the inclusion of recent large new trials, including the only trial of event-driven PrEP³³ and an open-label pragmatic trial.³¹

Data on effects on PrEP in pregnancy were very limited. Trials excluded pregnant women and discontinued PrEP at the time pregnancy was confirmed. FDA labeling information and perinatal antiretroviral treatment guidelines permit use of tenofovir disoproxil fumarate/emtricitabine during pregnancy, although guidelines note that data on safety of PrEP during pregnancy and lactation are limited.⁷³

For predicting incident HIV infection, several instruments inmen who have sex with men^56-59 and 1 instrument in PWID⁶⁰ were associated with moderate discrimination, but studies had methodological shortcomings. Discrimination was poorer in some studies of black men who have sex with men,^61,62 and all instruments require further validation. Instruments for predicting risk of HIV infection in women were developed using African cohorts.

Research is needed to directly compare effects of daily vs alternative PrEP dosing strategies in studies adequately powered to assess effects on HIV infection;^45,46 to verify the effectiveness of PrEP in high-income settings in persons at higher risk because of heterosexual contact and PWID; to determine the safety and effectiveness of PrEP during pregnancy or lactation and in transgender women and men; to understand effectiveness and long-term safety in adolescents; to understand effects of PrEP on quality of life; to understand effects of PrEP on behavioral risk compensation using open-label studies; to develop accurate instruments for identifying persons at higher risk for acquiring HIV infection; and to determine methods for increasing uptake and adherence to PrEP, to optimize effectiveness. Research on a number of alternative PrEP drugs and regimens is ongoing.^74-79

Limitations

This review had some limitations. First, the DerSimonian and Laird random-effects model was used to pool studies, which may result in CIs that are too narrow, particularly when heterogeneity is present.⁶ However, analyses were repeated using the profile likelihood method, which resulted in similar findings. Second, these findings are based on analyses of study-level data, limiting the ability to evaluate subgroup effects. Third, non–English-language articles were excluded, but large non–English-language trials of PrEP were not identified. Fourth, in the pooled analysis of HIV infection, graphical and statistical tests indicated small sample effects, a potential marker for publication bias. However, no unpublished PrEP trials were identified in searches on a clinical trials registry (ClinicalTrials.gov) or reviews of reference lists. Fifth, trials of PrEP in persons at risk because of heterosexual contact were conducted in Africa and 1 trial of PrEP in PWID was conducted in Asia, which could limit applicability to the United States and other high-income settings.

In adults at increased risk of HIV infection, PrEP with oral tenofovir disoproxil fumarate monotherapy or tenofovir disoproxil fumarate/emtricitabine was associated with decreased risk of HIV infection compared with placebo or no PrEP, although effectiveness decreased with suboptimal adherence.

Source: This article was first published in the Journal of the American Medical Association on June 11, 2019 (JAMA. 2016;315(9):915-933).

Conflict of Interest Disclosures: Dr Korthuis reported receiving grants from the National Institutes of Health (NIH)/National Institute on Drug Abuse and serving as principal investigator of NIH-funded clinical trials that receive donated study drug from Alkermes (extended-release naltrexone) and Inidivior (sublingual buprenorphine/naloxone). No other disclosures were reported.

Funding/Support: This research was funded under contract HHSA-290-2015-00009-I, Task Order No. 10, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the USPSTF.

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Information: A draft version of this evidence report underwent external peer review from 3 content experts (Sybil Hosek, PhD, John H. Stroger, Jr. Hospital of Cook County; Douglas Krakower, MD, Beth Israel Deaconess Medical Center, Harvard Medical School; and Albert Liu, MD, MPH, HIV Prevention Interventions, San Francisco Department of Public Health and UCSF School of Medicine) and 5 federal partner reviewers from the US Food and Drug Administration, the Centers for Disease Control and Prevention, and the Department of Veterans Affairs. Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

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34. Mugo NR, Hong T, Celum C, et al; Partners PrEP Study Team. Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a randomized clinical trial. JAMA. 2014;312(4):362-371. 
35. Mugwanya KK, Wyatt C, Celum C, et al; Partners PrEP Study Team. Changes in glomerular kidney function among HIV-1–uninfected men and women receiving emtricitabine-tenofovir disoproxil fumarate preexposure prophylaxis: a randomized clinical trial. JAMA Intern Med. 2015;175(2):246-254. 
36. Mulligan K, Glidden DV, Anderson PL, et al; Preexposure Prophylaxis Initiative Study Team. Effects of emtricitabine/tenofovir on bone mineral density in HIV-negative persons in a randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2015;61(4):572-580. 
37. Murnane PM, Celum C, Mugo N, et al; Partners PrEP Study Team. Efficacy of preexposure prophylaxis for HIV-1 prevention among high-risk heterosexuals: subgroup analyses from a randomized trial. AIDS. 2013;27(13):2155-2160. 
38. Murnane PM, Brown ER, Donnell D, et al; Partners PrEP Study Team. Estimating efficacy in a randomized trial with product nonadherence: application of multiple methods to a trial of preexposure prophylaxis for HIV prevention. Am J Epidemiol. 2015;182(10):848-856. 
39. Mutua G, Sanders E, Mugo P, et al. Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sexworkers. PLoS One. 2012;7(4):e33103. 
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41. Solomon MM, Lama JR, Glidden DV, et al; iPrEx Study Team. Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS. 2014;28(6):851-859. 
42. Thigpen MC, Kebaabetswe PM, Paxton LA, et al; TDF2 Study Group. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367(5):423-434. 
43. Van Damme L, Corneli A, Ahmed K, et al; FEM-PrEP Study Group. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411-422. 
44. Were EO, Heffron R, Mugo NR, et al; Partners PrEP Study Team. Pre-exposure prophylaxis does not affect the fertility of HIV-1-uninfected men. AIDS. 2014;28(13):1977-1982. 
45. Bekker LG, Roux S, Sebastien E, et al; HPTN 067 (ADAPT) Study Team. Daily and non-daily pre-exposure prophylaxis in African women (HPTN 067/ADAPT Cape Town Trial): a randomised, open-label, phase 2 trial. Lancet HIV. 2018;5(2):e68-e78. 
46. Grant RM, Mannheimer S, Hughes JP, et al. Daily and nondaily oral preexposure prophylaxis in men and transgender women who have sex with men: the Human Immunodeficiency Virus Prevention Trials Network 067/ADAPT study. Clin Infect Dis. 2018;66(11):1712-1721. 
47. Hosek SG, Siberry G, Bell M, et al; Adolescent Trials Network for HIV/AIDS Interventions (ATN). The acceptability and feasibility of an HIV preexposure prophylaxis (PrEP) trial with young men who have sex with men. J Acquir Immune Defic Syndr. 2013;62(4):447-456. 
48. Chan PA, Mena L, Patel R, et al. Retention in care outcomes for HIV pre-exposure prophylaxis implementation programmes among men who have sex with men in three US cities. J Int AIDS Soc. 2016;19(1):20903. 
49. Hosek SG, Landovitz RJ, Kapogiannis B, et al. Safety and feasibility of antiretroviral preexposure prophylaxis for adolescent men who have sex with men aged 15 to 17 years in the United States. JAMA Pediatr. 2017;171(11):1063-1071. 
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51. Grant RM, Anderson PL, McMahan V, et al; iPrEx Study Team. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis. 2014;14(9):820-829. 
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55. van Epps P, Maier M, Lund B, et al. Medication adherence in a nationwide cohort of veterans initiating pre-exposure prophylaxis (PrEP) to prevent HIV infection. J Acquir Immune Defic Syndr. 2018;77(3):272-278. 
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Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes. A dashed line indicates a health outcome that immediately follows an intermediate outcome. Refer to the USPSTF Procedure Manual for further details.¹ PrEP indicates preexposure prophylaxis; STI, sexually transmitted infection.
^a Also includes renal insufficiency, fractures, pregnancy-related outcomes, infection with antiretroviral drug–resistant HIV, gastrointestinal harms, headaches, and discontinuation due to adverse events.

KQ indicates key question.
^a Some articles are included in multiple KQs. Twenty-two articles addressed the contextual questions in the larger Agency for Healthcare Research and Quality report, of which 19 overlap with the articles that addressed KQs.

The area of each square represents theweight given to the study in the meta-analysis. The area of each diamond represents the sample size for each pooled estimate (subgroup or overall analysis), and the width of each diamond represents the confidence interval for the pooled estimate. The Mantel-Haenszel method was used the calculate the heterogeneity (I²) test statistic. PrEP indicates preexposure prophylaxis; PWID, people who inject drugs.
^a Tenofovir disoproxil fumarate group.
^b Study conducted in the United States, Canada, or Europe.
^c Tenofovir disoproxil fumarate/emtricitabine group.

Adherence was based on plasma testing, unless otherwise noted. The area of each square represents the weight given to the study in the meta-analysis. The area of each diamond represents the sample size for each pooled estimate (subgroup or overall analysis), and the width of each diamond represents the confidence interval for the pooled estimate. The Mantel-Haenszel method was used to calculate the heterogeneity (I²) test statistic. NA indicates not available; PrEP, preexposure prophylaxis.
^a Study conducted in the United States, Canada, or Europe.
^b Assessed using medication event monitoring system.
^c Not estimable.
^d Assessed by self-report, confirmed by plasma sample.
^e Assessed by self-report.

Abbreviations: ART, antiretroviral therapy; CDC, Centers for Disease Control and Prevention; FEM-PrEP, PRe-Exposure Prophylaxis trial for HIV Prevention Among AfricanWomen; IAVI, International AIDS Vaccine Initiative; IPERGAY, Intervention Préventive de l’Exposition aux Risques avec et pour les GAYs; iPrEx, Pre-Exposure Prophylaxis Initiative; MEMS, medication event monitoring system; MSM, men who have sex with men; NIH, National Institutes of Health; NR, not reported; PrEP, preexposure prophylaxis; PROUD, PRe-exposure Option for Reducing HIV in the UK: immediate or Deferred; PWID, people who inject drugs; STI, sexually transmitted infection; TDF2, Tenofovir Disoproxil Fumarate 2 study; USAID, United States Agency for International Development; VOICE, Vaginal and Oral Interventions to Control the Epidemic.
^a Primary publication; details on all included publications appear in full evidence report at https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/prevention-of-humanimmunodeficiency-virus-hiv-infection-pre-exposure-prophylaxis.
^b Daily, oral dose unless specified.
^c Sample of patient who reported that they were taking PrEP.

Abbreviations: NA, not applicable; PrEP, preexposure prophylaxis; RR, relative risk.

Abbreviations: MSM, men who have sex with men; PrEP, preexposure prophylaxis; RR, relative risk.
^a Two trials included both tenofovir disoproxil fumarate and tenofovir disoproxil fumarate/emtricitabine groups.
^b Both trials evaluated tenofovir disoproxil fumarate/emtricitabine in MSM.

Abbreviations: ARD, adjusted risk difference; ARR, adjusted relative risk; AUROC, area under the receiver operating characteristics curve; EPC, Evidence-based Practice Center; KQ, key question, MSM, men who have sex with men; NA, not applicable; NR, not reported; OR, odds ratio; PrEP, preexposure prophylaxis; PWID, people who inject drugs; RCT, randomized clinical trial; RR, relative risk; STI, sexually transmitted infection.
^a For KQ1 and KQ5, number of participants included in analysis.
^b In women who became pregnant while receiving PrEP.