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Evidence Summary

Other Supporting Document for Prevention of Human Immunodeficiency Virus (HIV) Infection: Preexposure Prophylaxis

By Roger Chou, MD; Christopher Evans, MD, MPH; Adam Hoverman, DO; Christina Sun, PhD; Tracy Dana, MLS; Christina Bougatsos, MPH; Sara Grusing, BA; P. Todd Korthuis, MD

The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was published in JAMA on 11 June, 2019 (JAMA 2019;321(22):2214-2230).

Abstract

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.

Introduction

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.

Methods

Scope of the Review

Detailed methods are available in the full evidence report at https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/prevention-of-human-immunodeficiencyvirus-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.

Results

Across all KQs, 14 RCTs (in 37 articles11-47) (N = 18,837), 8 observational studies48-55 (N = 3884), and 7 studies of diagnostic accuracy of HIV risk prediction instruments56-62 (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 publications11-44) evaluated PrEP vs placebo (11 trials12, 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 trials12, 21, 27, 40, 42, 43 enrolled persons at increased risk because of heterosexual contact, 4 trials17, 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 trials12, 14, 18, 27, 40 evaluated tenofovir disoproxil fumarate monotherapy (300 mg), 8 trials12, 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 trials12, 14, 17, 43 found similar PrEP effectiveness in subgroups defined by age, and 3 trials12, 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 infection56-62. Six studies evaluated men who have sex with men56-59, 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 instruments58, 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 cessation12, 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.

Discussion

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 men56-59 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.

Conclusions

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.

Article Information

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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11. Agot K, Taylor D, Corneli AL, et al. Accuracy of self-report and pill-count measures of adherence in the FEM-PrEP clinical trial: implications for future HIV-prevention trials. AIDS Behav. 2015;19(5):743-751. 
12. Baeten JM, Donnell D, Ndase P, et al; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410. 
13. Chirwa LI, Johnson JA, Niska RW, et al. CD4(+) cell count, viral load, and drug resistance patterns among heterosexual breakthrough HIV infections in a study of oral preexposure prophylaxis. AIDS. 2014;28(2):223-226. 
14. Choopanya K, Martin M, Suntharasamai P, et al; Bangkok Tenofovir Study Group. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381(9883):2083-2090. 
15. Deutsch MB, Glidden DV, Sevelius J, et al; iPrEx Investigators. HIV pre-exposure prophylaxis in transgender women: a subgroup analysis of the iPrEx trial. Lancet HIV. 2015;2(12):e512-e519. 
16. Donnell D, Baeten JM, Bumpus NN, et al. HIV protective efficacy and correlates of tenofovir blood concentrations in a clinical trial of PrEP for HIV prevention. J Acquir Immune Defic Syndr. 2014;66(3):340-348. 
17. Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599. 
18. Grohskopf LA, Chillag KL, Gvetadze R, et al. Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States. J Acquir Immune Defic Syndr. 2013;64(1):79-86. 
19. Haberer JE, Baeten JM, Campbell J, et al. Adherence to antiretroviral prophylaxis for HIV prevention: a substudy cohort within a clinical trial of serodiscordant couples in East Africa. PLoS Med. 2013;10(9):e1001511. 
20. Heffron R, Mugo N, Were E, et al; Partners PrEP Study Team. Preexposure prophylaxis is efficacious for HIV-1 prevention among women using depot medroxyprogesterone acetate for contraception. AIDS. 2014;28(18):2771-2776. 
21. Kibengo FM, Ruzagira E, Katende D, et al. Safety, adherence and acceptability of intermittent tenofovir/emtricitabine as HIV pre-exposure prophylaxis (PrEP) among HIV-uninfected Ugandan volunteers living in HIV-serodiscordant relationships: a randomized, clinical trial. PLoS One. 2013;8(9):e74314. 
22. Lehman DA, Baeten JM, McCoy CO, et al; Partners PrEP Study Team. Risk of drug resistance among persons acquiring HIV within a randomized clinical trial of single- or dual-agent preexposure prophylaxis. J Infect Dis. 2015;211(8):1211-1218.
23. Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One. 2011;6(8):e23688. 
24. Liu A, Glidden DV, Anderson PL, et al; iPrEx Study Team. Patterns and correlates of PrEP drug detection among MSM and transgender women in the global iPrEx study. J Acquir Immune Defic Syndr. 2014;67(5):528-537. 
25. Mandala J, Nanda K, Wang M, et al. Liver and renal safety of tenofovir disoproxil fumarate in combination with emtricitabine among African women in a pre-exposure prophylaxis trial. BMC Pharmacol Toxicol. 2014;15:77. 
26. Marcus JL, Glidden DV, McMahan V, et al. Daily oral emtricitabine/tenofovir preexposure prophylaxis and herpes simplex virus type 2 among men who have sex with men. PLoS One. 2014;9(3):e91513. 
27. Marrazzo JM, Ramjee G, Richardson BA, et al; VOICE Study Team. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372(6):509-518. 
28. Martin M, Vanichseni S, Suntharasamai P, et al; Bangkok Tenofovir Study Group. Renal function of participants in the Bangkok Tenofovir Study—Thailand, 2005-2012. Clin Infect Dis. 2014;59(5):716-724. 
29. Martin M, Vanichseni S, Suntharasamai P, et al; Bangkok Tenofovir Study Group. The impact of adherence to preexposure prophylaxis on the risk of HIV infection among people who inject drugs. AIDS. 2015;29(7):819-824. 
30. Matthews LT, Heffron R, Mugo NR, et al; Partners PrEP Study Team. High medication adherence during periconception periods among HIV-1-uninfected women participating in a clinical trial of antiretroviral pre-exposure prophylaxis. J Acquir Immune Defic Syndr. 2014;67(1):91-97. 
31. McCormack S, Dunn DT, Desai M, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet. 2016;387(10013):53-60. 
32. Mirembe BG, Kelly CW, Mgodi N, et al; MTN-003B Protocol Team. Bone mineral density changes among young, healthy African women receiving oral tenofovir for HIV preexposure prophylaxis. J Acquir Immune Defic Syndr. 2016;71(3):287-294. 
33. Molina JM, Capitant C, Spire B, et al; ANRS IPERGAY Study Group. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015;373(23):2237-2246. 
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. 
40. Peterson L, Taylor D, Roddy R, et al. Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clin Trials. 2007;2(5):e27. 
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. 
50. Hosek SG, Rudy B, Landovitz R, et al; Adolescent Trials Network (ATN) for HIV/AIDS Interventions. An HIV preexposure prophylaxis demonstration project and safety study for young MSM. J Acquir Immune Defic Syndr. 2017;74(1):21-29. 
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. 
52. Landovitz RJ, Beymer M, Kofron R, et al. Plasma tenofovir levels to support adherence to TDF/FTC preexposure prophylaxis for HIV prevention in MSM in Los Angeles, California. J Acquir Immune Defic Syndr. 2017;76(5):501-511. 
53. Montgomery MC, Oldenburg CE, Nunn AS, et al. Adherence to pre-exposure prophylaxis for HIV prevention in a clinical setting. PLoS One. 2016;11(6):e0157742. 
54. Liu AY, Cohen SE, Vittinghoff E, et al. Preexposure prophylaxis for HIV infection integrated with municipal- and community-based sexual health services. JAMA Intern Med. 2016;176(1):75-84. 
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. 
56. Beymer MR,Weiss RE, Sugar CA, et al. Are Centers for Disease Control and Prevention guidelines for preexposure prophylaxis specific enough? formulation of a personalized HIV risk score for pre-exposure prophylaxis initiation. Sex Transm Dis. 2017;44(1):48-56. 
57. Hoenigl M, Weibel N, Mehta SR, et al. Development and validation of the San Diego Early Test Score to predict acute and early HIV infection risk in men who have sex with men. Clin Infect Dis. 2015;61(3):468-475. 
58. Menza TW, Hughes JP, Celum CL, Golden MR. Prediction of HIV acquisition among men who have sex with men. Sex Transm Dis. 2009;36(9):547-555. 
59. Smith DK, Pals SL, Herbst JH, Shinde S, Carey JW. Development of a clinical screening index predictive of incident HIV infection among men who have sex with men in the United States. J Acquir Immune Defic Syndr. 2012;60(4):421-427. 
60. Smith DK, Pan Y, Rose CE, et al. A brief screening tool to assess the risk of contracting HIV infection among active injection drug users. J Addict Med. 2015;9(3):226-232. 
61. Lancki N, Almirol E, Alon L, McNulty M, Schneider JA. Preexposure prophylaxis guidelines have low sensitivity for identifying seroconverters in a sample of young black MSM in Chicago. AIDS. 2018;32(3):383-392.
62. Jones J, Hoenigl M, Siegler AJ, Sullivan PS, Little S, Rosenberg E. Assessing the performance of 3 human immunodeficiency virus incidence risk scores in a cohort of black and white men who have sex with men in the South. Sex Transm Dis. 2017;44(5):297-302. 
63. Balkus JE, Brown E, Palanee T, et al. An empiric HIV risk scoring tool to predict HIV-1 acquisition in African women. J Acquir Immune Defic Syndr. 2016;72(3):333-343. 
64. Kahle EM, Hughes JP, Lingappa JR, et al; Partners in Prevention HSVHIV Transmission Study and the Partners PrEP Study Teams. An empiric risk scoring tool for identifying high-risk heterosexual HIV-1-serodiscordant couples for targeted HIV-1 prevention. J Acquir Immune Defic Syndr. 2013;62(3):339-347. 
65. Pintye J, Drake AL, Kinuthia J, et al. A risk assessment tool for identifying pregnant and postpartum women who may benefit from preexposure prophylaxis. Clin Infect Dis. 2017;64(6):751-758.
66. Celum C, Morrow RA, Donnell D, et al; Partners PrEP Study Team. Daily oral tenofovir and emtricitabine-tenofovir preexposure prophylaxis reduces herpes simplex virus type 2 acquisition among heterosexual HIV-1-uninfected men and women: a subgroup analysis of a randomized trial. Ann Intern Med. 2014;161(1):11-19. 
67. Anderson PL, Glidden DV, Liu A, et al; iPrEx Study Team. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med. 2012;4(151):151ra125. 
68. Cottrell ML, Yang KH, Prince HM, et al. A translational pharmacology approach to predicting outcomes of preexposure prophylaxis against HIV in men and women using tenofovir disoproxil fumarate with or without emtricitabine. J Infect Dis. 2016;214(1):55-64. 
69. Massud I, Mitchell J, Babusis D, et al. Chemoprophylaxis with oral emtricitabine and tenofovir alafenamide combination protects macaques from rectal simian/human immunodeficiency virus infection. J Infect Dis. 2016;214(7):1058-1062. 
70. Traeger MW, Schroeder SE, Wright EJ, et al. Effects of pre-exposure prophylaxis for the prevention of human immunodeficiency virus infection on sexual risk behavior in men who have sex with men: a systematic review and meta-analysis. Clin Infect Dis. 2018;67(5):676-686. 
71. Okwundu CI, Uthman OA, Okoromah CA. Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals. Cochrane Database Syst Rev. 2012;7(7):CD007189.
72. Jiang J, Yang X, Ye L, et al. Pre-exposure prophylaxis for the prevention of HIV infection in high-risk populations: a meta-analysis of randomized controlled trials. PLoS One. 2014;9(2):e87674. 
73. Centers for Disease Control and Prevention. Updated Guidelines for Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV—United States, 2016.Washington, DC: US Dept of Health and Human Services; 2016.
74. Gilead Sciences. Safety and efficacy of emtricitabine and tenofovir alafenamide (F/TAF) fixed-dose combination once daily for pre-exposure prophylaxis in men and transgender women who have sex with men and are at risk of HIV-1 infection (DISCOVER) [NCT02842086]. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02842086?term=NCT02842086&rank=1. 2016. Accessed December 8, 2017.
75. Gulick RM, Wilkin TJ, Chen YQ, et al. Safety and tolerability of maraviroc-containing regimens to prevent HIV infection in women: a phase 2 randomized trial. Ann Intern Med. 2017;167(6):384-393. 
76. Gulick RM, Wilkin TJ, Chen YQ, et al. Phase 2 study of the safety and tolerability of maraviroc-containing regimens to prevent HIV infection in men who have sex with men (HPTN 069/ACTG A5305). J Infect Dis. 2017;215(2):238-246.
77. National Institute of Allergy and Infectious Diseases. Safety and efficacy study of injectable cabotegravir compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), for pre-exposure prophylaxis in HIV-uninfected cisgender men and transgender women who have sex with men [NCT02720094]. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02720094. 2016. Accessed December 11, 2017.
78. National Institute of Allergy and Infectious Diseases. Evaluating the safety and efficacy of long-acting injectable cabotegravir compared to daily oral TDF/FTC for pre-exposure prophylaxis in HIV-uninfected women [NCT03164564]. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03164564. 2017. Accessed February 2, 2018.
79. PATH. Phase II safety and acceptability of an investigational injectable product, TMC278LA, for pre-exposure prophylaxis (TMC278LA) [NCT02165202]. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02165202. 2017. Accessed December 8, 2017.

Figure 1. Analytic Framework: HIV Preexposure Prophylaxis

The analytic framework depicts the relationship between the population, intervention, outcomes, and harms of pre-exposure prophylaxis (PrEP) for the prevention of HIV infection. The far left of the framework describes the target population as persons without pre-existing HIV infection. To the right of the population is an arrow which represents assessment of patients for use of PrEP (key question 2) which leads to boxes representing candidate for PrEP or not a candidate for PrEP. From the candidate for PrEP population box, an arrow representing the use of PrEP to reduce risk for HIV infection leads to the effects of PrEP on the clinical outcomes of HIV infection, quality of life, and mortality (key question 1; and also key questions 1a and 1b for whether population subgroups and dosing strategy or regimen affect effectiveness), and the assessment of any potential harms of PrEP (key question 5), which include other STIs, renal insufficiency, fractures, pregnancy-related outcomes, infection with antiretroviral drug–resistant HIV, gastrointestinal harms, headaches, and discontinuation due to adverse events. Adherence is represented in the center of the figure, as key questions 3 and 4 address the rates of adherence in U.S.-relevant populations and the association between adherence and effectiveness, respectively.

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.

Figure 2. Literature Search Flow Diagram: HIV Preexposure Prophylaxis

Figure 2 is a literature flow diagram depicting the search and selection of articles for the review. The diagram shows that 3,865 citations were identified through literature database searches and 89 citations were identified through other sources. Three thousand one hundred and sixteen citations were screened after duplicates were removed, and 308 articles were reviewed at the full-text level after excluding 2,808 citations based on review of title and abstract. Two hundred and fifty two total full-text articles were excluded for the following reasons: wrong population (11), wrong intervention (19), wrong outcome (67), wrong comparator (6), wrong study design for key question (52), not a study (75), inadequate duration (3), systematic review or meta-analysis used as a source document only to identify individual studies (14), or wrong country (5). Twenty-nine studies (in 56 articles) were included that provide evidence for the key questions, as follows: 12 trials (in 33 articles) for Key Question 1, 7 studies for Key Question 2, 3 trials and 7 observational studies for Key Question 3, 7 trials (in 10 articles) and 5 observational studies for Key Question 4, and 12 trials (in 21 articles) for Key Question 5. A footnote indicates that 22 articles were used to address a Contextual Question, of which 19 overlap with the articles that addressed Key Questions.

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.

Figure 3. Meta-Analysis: HIV Infection Stratified by Study Drug

Figure 3. Meta-analysis: HIV Infection Stratified by Study Drug

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.

Figure 4. Meta-Analysis: HIV Infection Stratified by Adherence

Figure 4 is a forest plot of HIV infection stratified by adherence with three subgroups. The risk ratio for 7 studies in the adherence greater than or equal to 70% subgroup is 0.27 (95% confidence interval 0.19 to 0.39) with an I-squared value of 0%. The risk ratio for 3 studies in the adherence greater than 40% and less than 70% subgroup is 0.51 (95% confidence interval 0.38 to 0.70) with an I-squared value of 0%. The risk ratio for 2 studies in the adherence less than 40% subgroup is 0.93 (95% confidence interval 0.72 to 1.20) with an I-squared value of 0%. The overall risk ratio for all studies is 0.44 (95% confidence interval 0.29 to 0.65) with an I-squared value of 72%.

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.

Table 1. Study Characteristics of RCTs of PrEP

Sourcea Country Duration of
Follow-up
Interventionsb HIV Risk Group;
Risk-Based Inclusion Criteria
Patient Characteristics Adherence, %
(Method Used to Assess Adherence)
Quality Rating
Bangkok Tenofovir Study Choopanya et al,14 2013 Thailand 4 y (mean) A. Tenofovir disoproxil fumarate (300 mg) (n = 1204)
B. Placebo (n = 1209)
PWID: Injection drug use in the previous 12 mo A vs B:
Age 20-29 y: 43% vs 43%
Age 30-39 y: 38% vs 37%
Age 40-49 y: 15% vs 15%
Age 50-60 y: 5% vs 5%
Men: 80% vs 80%
Race: NR
67 (plasma) Good CDC; Bangkok Metropolitan Administration
CDC Safety Study Grohskopf et al,18 2013 United States 2 y A. Tenofovir disoproxil fumarate (300 mg) (n = 201)
B. Placebo (n = 199)
MSM: Biological male engaging in anal sex with another man in the previous 12 mo A vs B:
Mean age: 38 vs 37 y
White: 79.6% vs 66.8%
African American: 23% vs 37%
Asian/Pacific Islander: 10% vs 4%
Other race: 8% vs 25%
92 (pill count) Good US Department of Health and Human Services; CDC
FEM PrEP
Van Damme et al,43 2012
Kenya, South Africa, Tanzania 1 y A. Tenofovir disoproxil fumarate/emtricitabine (300/200 mg) (n = 1062)
B. Placebo (n = 1058)
High-risk women: >1 vaginal sex act in previous 2 wk or >1 sex partner in previous mo A vs B:
Mean age: 24 vs 24 y
Race: NR
37 (plasma) Good USAID; Bill and Melinda Gates Foundation; Gilead Sciences (provided study drug)
IAVI Uganda Study
Kibengo et al,21 2013
Uganda 4 mo A. Tenofovir disoproxil fumarate/emtricitabine (300/200 mg) (n = 24)
B. Intermittent tenofovir disoproxil fumarate/emtricitabine (n = 24)
C. Daily placebo (n = 12)
D. Intermittent placebo (n = 12)
High-risk heterosexual men and women: Unprotected vaginal sex with ART-naive HIV-infected partner in the previous 3 mo A vs B vs C vs D:
Mean age: 33 vs 33 vs 33 vs 33 y
Women: 50% vs 46% vs 67% vs 42%
Race: NR
98 (MEMS) Good IAVI; Gilead Sciences (provided study drug)
IAVI Kenya Study
Mutua et al,39 2012
Kenya 4 mo A. Tenofovir disoproxil
fumarate/emtricitabine (300/200 mg) (n = 24)
B. Intermittent tenofovir disoproxil fumarate/emtricitabine (n = 24)
C. Daily placebo (n = 12)
D. Intermittent placebo (n = 12)
MSM and high-risk women: Current or previous STI, multiple episodes of unprotected vaginal or anal sex, or engaging in transactional sex in the previous 3 mo A vs B vs C vs D:
Mean age: 26 vs 26 vs 27 vs 28 y
Women: 12% vs 0% vs 8% vs 8%
Race: NR
82 (MEMS) Good IAVI; Gilead Sciences (provided study drug)
IPERGAY
Molina et al,33 2015
France, Canada 9 mo (median) A. On-demand tenofovir disoproxil fumarate/emtricitabine (300/200 mg) (n = 199)
B. Placebo (n = 201)
MSM: Unprotected anal sex with ≥2 partners in previous 6 mo A vs B:
Median age: 35 vs 34 y (IQR, 29-43)
White: 94% vs 89%
Other races: NR
86 (plasma) Good ANRS; Canadian HIV Trials Network; Fonds de Dotation Pierre Berge pour la Prevention; Bill and Melinda Gates Foundation
iPrEx
Grant et al,17 2010
Brazil, Ecuador, Peru, Thailand, South Africa, United States 1.2 y (median) A. Tenofovir disoproxil fumarate/emtricitabine (300/200 mg) (n = 1251)
B. Placebo (n = 1248)
MSM: Anal sex with ≥4 male partners, a diagnosis of STI, history of transactional sex activity, condomless anal sex with an HIV-infected partner or of unknown infection status in previous 6 mo A vs B:
Age 18-24 y: 47% vs 53%
Age 25-29 y: 22% vs 19%
Age 30-39 y: 20% vs 18%
Age ≥40 y: 11% vs 10%
Born male: 100% vs 100%
Black: 9% vs 8%
White: 18% vs 17%
Mixed race or other: 68% vs 70%
Asian: 5% vs 5%
Hispanic: 72% vs 73%
51 (plasma) Good NIH; Bill and Melinda Gates Foundation
Partners PrEP
Baeten et al,12 2012
Kenya, Uganda 2 y (median) A. Tenofovir disoproxil fumarate (300 mg) + placebo tenofovir disoproxil fumarate/emtricitabine (n = 1571)
B. Tenofovir disoproxil fumarate/emtricitabine (300/200 mg) + placebo tenofovir disoproxil fumarate (n = 1565)
C. Placebo tenofovir disoproxil fumarate + placebo tenofovir disoproxil fumarate/emtricitabine (n = 1570)
High-risk heterosexual men and women: ART-naive HIV-infected partner A vs B vs C:
Age 18-24 y: 12% vs 11% vs 11%
Age 25-34 y: 46% vs 44% vs 43%
Age 35-44 y: 30% vs 32% vs 32%
Age ≥45 y: 13% vs 14% vs 13%
Men: 62% vs 64% vs 61%
Race: NR
82 (plasma) Good Bill and Melinda Gates Foundation
PROUD
McCormack et al,31 2016
England 1 y A. Immediate tenofovir disoproxil fumarate/emtricitabine (245/200 mg) (n = 275)
B. Tenofovir disoproxil fumarate/emtricitabine deferred for 1 y (n = 269)
MSM: Anal intercourse without a condom in the previous 90 d and likely to have anal intercourse without a condom in the next 90 d A vs B
Mean age: 35 vs 35 y
White: 81% vs 83%
Asian: 5% vs 6%
Black: 4% vs 4%
Other race: 10% vs 8%
100 (plasma)c Fair Medical Research Counsel Clinical Trials Unit; Public Health England; Gilead Sciences
Study of TDF
Peterson et al,40 2007
Cameroon, Ghana, Nigeria 6 mo (mean) A. Tenofovir disoproxil fumarate (300 mg) (n = 469)
B. Placebo (n = 467)
High-risk women: Mean of ≥3 coital acts per wk and ≥4 sexual partners per mo A vs B:
Mean age: 24 vs 24 y
Race: NR
69 (pill count) Good Bill and Melinda Gates Foundation
TDF2
Thigpen et al,42 2012
Botswana 1 y (median) A. Tenofovir disoproxil fumarate/emtricitabine (300/200 mg) (n = 611)
B. Placebo (n = 608)
High-risk heterosexual men and women: Sexually active in high-prevalence area A vs B:
Age 18-20 y: 2% vs 3%
Age 21-29 y: 90% vs 87%
Age 30-39 y: 8% vs 10%
Women: 46% vs 46%
Race: NR
80 (plasma) Good Division of HIV/AIDS Prevention, CDC, and Division of AIDS, NIH; 1 investigator reported royalties from Roche and 1 reported funding from Gilead
VOICE
Marrazzo et al,27 2015
South Africa, Uganda, Zimbabwe 3 y (maximum) A. Tenofovir disoproxil fumarate (300 mg) + placebo (n = 1007)
B. Tenofovir disoproxil fumarate/emtricitabine (300/200 mg) + placebo (n = 1003)
C. Placebo only (n = 1009)
High-risk women: Sexually active in a high-prevalence area A vs B vs C:
Mean age: 26 vs 25 vs 25 y
Race: NR
30 (plasma) Good NIH

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.

Table 2. Risk of HIV Infection in Randomized Clinical Trials of PrEP vs Placebo or No PrEP

  No. of Trials RR (95% CI) I2, %
All trials 1112, 14, 17, 18, 27, 31, 33, 39, 40, 42, 43 0.46 (0.33-0.66) 67
Restricted to good-quality trials 1012, 14, 17, 18, 27, 33, 39, 40, 42, 43 0.48 (0.33-0.71) 71
PrEP drug regimen
(P = 0.79 for interaction)
  Tenofovir disoproxil fumarate 512, 14, 18, 27, 40 0.49 (0.28-0.84) 58
  Tenofovir disoproxil fumarate/emtricitabine 812, 17, 27, 31, 33, 39, 40, 43 0.44 (0.27-0.72) 67
Adherence, %
(P < 0.001 for interaction)
  ≥70 612, 18, 31, 33, 39, 42 0.27 (0.19-0.39) 0
  >40 to <70 314, 17, 40 0.51 (0.38-0.70) 0
  ≤40 227, 43 0.93 (0.72-1.20) 0
HIV risk category
(P = 0.43 for interaction)
  Heterosexual men and women 512, 27, 40, 42, 43 0.54 (0.31-0.97) 82
  Men who have sex with men 417, 18, 31, 33 0.23 (0.08-0.62) 64
  People who inject drugs 114 0.52 (0.29-0.92) NA
Dosing schedule
(P = 0.13 for interaction)
  Daily 912, 14, 17, 18, 27, 31, 39, 40, 42, 43 0.47 (0.32-0.71) 75
  On-demand 133 0.14 (0.03-0.63) NA
Duration of follow-up, y
(P = 0.35 for interaction)
  <1 333, 39, 40 0.21 (0.07-0.58) 0
  ≥1-2 417, 31, 42, 43 0.48 (0.28-0.84) 70
  ≥2 412, 14, 18, 27 0.47 (0.22-1.00) 86
Study-reported support
(P = 0.38 for interaction)
  Industry 339, 42, 43 0.58 (0.27-1.22) 5
  Government or not-for-profit funding only 812, 14, 17, 18, 27, 31, 33, 40 0.39 (0.23-0.64) 77
Country setting
(P = 0.004 for interaction)
  United States or other high-income countries 318, 31, 33 0.13 (0.05-0.32) 0
  Africa, Asia, or international trial 812, 14, 17, 27, 39, 40, 42, 43 0.54 (0.37-0.79) 72

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

Table 3. Adverse Events and Sexually Transmitted Infections in Randomized Clinical Trials of PrEP vs Placebo/No PrEP

Outcome No. of Trialsa RR (95% CI) I2, %
Serious adverse events 1212, 14, 17, 18, 21, 27, 31, 33, 39, 40, 42, 43 0.93 (0.77-1.12) 56
   PrEP drug regimen (P = 0.23 for interaction)
     Tenofovir disoproxil fumarate 512, 14, 18, 27, 40 0.79 (0.56-1.12) 72
     Tenofovir disoproxil fumarate/emtricitabine 912, 17, 21, 27, 31, 33, 39, 42, 43 1.02 (0.81-1.30) 46
Withdrawal due to adverse events 412, 17, 33, 43 1.25 (0.99-1.59) 0
   PrEP drug regimen (P = 0.67 for interaction)
     Tenofovir disoproxil fumarate 112 1.00 (0.34-2.92) NA
     Tenofovir disoproxil fumarate/emtricitabine 412, 17, 33, 43 1.27 (1.00-1.59) 0
Fracture 812, 14, 17, 18, 27, 31, 33, 42 1.23 (0.97-1.56) 0
   PrEP drug regimen (P = 0.50 for interaction)
     Tenofovir disoproxil fumarate 412, 14, 18, 27 1.29 (0.98-1.70) 0
     Tenofovir disoproxil fumarate/emtricitabine 612, 17, 27, 31, 33, 42 1.06 (0.66-1.72) 0
Renal adverse events 1212, 14, 17, 18, 21, 27, 31, 33, 39, 40, 42, 43 1.43 (1.18-1.75) 0
   PrEP drug regimen (P = 0.31 for interaction)
     Tenofovir disoproxil fumarate 512, 14, 18, 27, 40 1.24 (0.87-1.76) 0
     Tenofovir disoproxil fumarate/emtricitabine 912, 17, 21, 27, 31, 33, 39, 42, 43 1.54 (1.21-1.96) 0
Gastrointestinal adverse events 1212, 14, 17, 18, 21, 27, 31, 33, 39, 40, 42, 43 1.63 (1.26-2.11) 43
   PrEP drug regimen (P = 0.30 for interaction)
     Tenofovir disoproxil fumarate 512, 14, 18, 27, 40 1.45 (1.13-1.85) 0
     Tenofovir disoproxil fumarate/emtricitabine 912, 17, 21, 27, 31, 33, 39, 42, 43 1.84 (1.26-2.70) 49
Any bacterial sexually transmitted infection 212, 31 1.14 (0.97-1.34) 16
   PrEP drug regimen (P = 0.60 for interaction)
     Tenofovir disoproxil fumarate 112 1.21 (0.86-1.72) NA
     Tenofovir disoproxil fumarate/emtricitabine 212, 31 1.07 (0.80-1.44) 58
   HIV risk category (P = 0.38 for interaction)
     Heterosexual men and women 112 1.05 (0.82-1.35) NA
     MSM 131 1.20 (1.01-1.42) NA
Syphilis 412, 17, 27, 31 1.08 (0.98-1.18) 0
   PrEP drug regimen (P = 0.86 for interaction)
     Tenofovir disoproxil fumarate 212, 27 1.13 (0.66-1.93) 0
     Tenofovir disoproxil fumarate/emtricitabine 412, 17, 27, 31 1.07 (0.98-1.18) 0
   HIV risk category (P = 0.90 for interaction)
     Heterosexual men and women 212, 27 1.05 (0.71-1.54) 0
     MSM 217, 31 1.08 (0.98-1.18) 0
Gonorrhea 517, 27, 31, 42, 43 1.07 (0.82-1.39) 49
   PrEP drug regimen (P = 0.02)
     Tenofovir disoproxil fumarate 127 0.57 (0.33-0.98) NA
     Tenofovir disoproxil fumarate/emtricitabine 517, 27, 31, 42, 43 1.15 (0.97-1.37) 2
   HIV risk category (P = 0.59 for interaction)
     Heterosexual men and women 327, 42, 43 1.20 (0.76-1.92) 69
     MSM 217, 31 1.05 (0.85-1.30) 0
Chlamydia 517, 27, 31, 42, 43 0.97 (0.80-1.18) 59
   PrEP drug regimen (P =0.004 for interaction)
     Tenofovir disoproxil fumarate 127 0.68 (0.52-0.90) NA
     Tenofovir disoproxil fumarate/emtricitabine 517, 27, 31, 42, 43 1.07 (0.94-1.22) 0
   HIV risk category (P = 0.46 for interaction)
     Heterosexual men and women 327, 42, 43 0.81 (0.47-1.41) 93
     MSM 217, 31 1.09 (0.62-1.92) 50
Herpes simplex virus infection 326, 42, 66 0.85 (0.67-1.07) 19
   PrEP drug regimen (P = 0.67 for interaction)
     Tenofovir disoproxil fumarate 166 0.76 (0.48-1.21) NA
     Tenofovir disoproxil fumarate/emtricitabine 326, 42, 66 0.86 (0.62-1.18) 40
   HIV risk category (P = 0.06 for interaction)
     Heterosexual men and women 242, 66 0.73 (0.56-0.96) 0
     MSM 126 1.12 (0.80-1.56) NA
Hepatitis C virus infectionb 231, 33 0.73 (0.25-2.10) 0

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.

Table 4. Summary of Evidence

No. of Studies; No. of Participants; Study Designa Summary of Findings by Outcome Consistency/Precision; Reporting Bias Overall Quality Body of Evidence Limitations EPC Assessment
of Strength of Evidence for KQ
Applicability
KQ1: Benefits of PrEP vs Placebo or No PrEP
HIV infection
12 RCTs (n = 18,244)
11 Trials: RR, 0.46 (95% CI, 0.33-0.66); I2 = 67%; ARR, −2.0% (95% CI, −2.8% to −1.2%) after 4 mo to 4 y
Stratified by adherence (P < 0.001 for interaction)
≥70% adherence: 6 trials; RR, 0.27 (95% CI, 0.19-0.39); I2 = 0%
>40% to <70% adherence: 3 trials; RR, 0.51 (95% CI, 0.38-0.70); I2 = 0%
≤40% adherence: 2 trials; RR, 0.93 (95% CI, 0.72-1.20); I2 = 0%
Some inconsistency explained by level of adherence; precise Funnel plot asymmetry and Egger test statistically significant (P = 0.03), but no unpublished studies identified Good Variability in duration of follow-up, but results consistent when trials stratified according to follow-up duration
Three trials reported some industry support, but no significant difference between studies that only reported industry support and those that only reported governmental or not-for-profit funding
High Studies of women and men at increased risk of heterosexual contact conducted in Africa; the only study of PWID was conducted in Asia; several studies of MSM were conducted in the United States, Europe, and Canada
PrEP was more effective in trials conducted in the United States, Europe, and Canada (all of these trials reported high adherence and enrolled MSM)
Mortality
9 RCTs (n = 17,756)
RR, 0.81 (95% CI, 0.59-1.11); I2 = 0% Consistent; imprecise
No reporting bias detected
Good See Body of Evidence Limitations column for KQ1, HIV infection Moderate See Applicability column for KQ1, HIV infection
Quality of life
0
NA NA NA NA NA NA
KQ1b: Benefits of PrEP by Dosing Strategy or Regimen
HIV infection
12 RCTs of PrEP vs placebo or no PrEP (n = 18,172); 1 RCT of daily vs intermittent or on-demand PrEP (n = 535)
PrEP vs placebo or no PrEP:
Stratified by tenofovir disoproxil fumarate or tenofovir disoproxil fumarate/emtricitabine (P = 0.65 for interaction)
Tenofovir disoproxil fumarate: 5 trials; RR, 0.49 (95% CI, 0.28-0.84); I2 = 58%
Tenofovir disoproxil fumarate/emtricitabine: 8 trials; RR, 0.44 (95% CI, 0.27-0.72); I2 = 74%
Stratified by daily or on-demand dosing (P = 0.13 for interaction)
Daily dosing: 9 trials; RR, 0.47 (95% CI, 0.32-0.71); I2 = 75%
On-demand dosing: 1 trial; RR, 0.14 (95% CI, 0.03-0.63)
One head-to-head trial found no significant difference between daily vs intermittent or on-demand PrEP but not powered to assess effects on HIV infection
Some inconsistency in stratified analyses (may be explained by level of adherence); precise
No reporting bias detected
Good See Body of Evidence Limitations column for KQ1, HIV infection High for tenofovir disoproxil fumarate vs tenofovir disoproxil fumarate/emtricitabine, moderate for daily dosing vs on-demand dosing Five trials evaluated tenofovir disoproxil fumarate monotherapy, which is not approved for PrEP in the United States
One trial evaluated on-demand dosing of PrEP vs placebo in MSM; no studies on intermittent or on-demand dosing in women or PWID
KQ2: Diagnostic Accuracy of Instruments for Identifying Individuals at Risk of Incident HIV Infection
7 studies of risk prediction or diagnostic accuracy
(n = 32,311)
MSM: AUROC 0.66-0.72 for different instruments in 3 studies; a fourth study reported better goodness of fit than with instruments evaluated in other studies (AUROC NR)
AUROC 0.49-0.63 for different instruments in 2 studies of black MSM PWID: AUROC 0.72 in 1 study
Consistent; precise
No reporting bias detected
Fair Retrospective design; each instrument validated in 1 study or not validated in a cohort independent from the one used to develop the instrument; cutoffs not predefined in any study Low All studies conducted in the United States;
3 studies used cohorts that included individuals who underwent HIV testing before the year 2000; no study evaluated a US-applicable instrument for risk prediction in women
KQ3: Adherence to PrEP in US Primary Care–Applicable Settings
3 RCTs and 7 observational studies (n = 3177) In 5 studies of US MSM, adherence to PrEP (based on dried blood spot sampling levels consistent with ≥4 doses/wk) ranged from 22% to 90%; adherence rates were lower in studies of younger (mean age, 16-20 y) MSM
One RCT of US MSM found higher adherence with daily than with intermittent or event-driven PrEP
Inconsistent; precise
No reporting bias detected
Fair Observational data from implementation studies; variability in duration of PrEP use; high attrition; variability in methods for measuring adherence Moderate Most studies evaluated US MSM; no direct evidence on adherence in US PWID or women and men at increased risk of HIV infection because of heterosexual contact; adherence rates were higher in some studies that evaluated a lower threshold for adherence
KQ4: Association Between Adherence to PrEP and Effectiveness for Preventing HIV Acquisition
7 RCTs and 5 observational studies (n = 11,479) Three RCTs found higher adherence to PrEP associated with greater effectiveness for reducing risk of HIV infection than lower adherence
Four of 5 RCTs found presence of tenofovir in plasma samples associated with decreased likelihood of HIV infection, compared with no detectable tenofovir (ORs ranged from 0.10-0.54)
Consistent; precise
No reporting bias detected; however, not all RCTs of PrEP reported on the association between adherence and PrEP effectiveness
Good Findings based on within-study subgroup analyses from RCTs and case-control analyses of patients randomized to PrEP; some studies reported small numbers of seroconverters with PrEP High Studies performed in diverse geographic settings; only 1 study evaluated PWID
KQ5: Harms of PrEP
Serious adverse events
12 RCTs (n = 18,282)
RR, 0.93 (95% CI, 0.77-1.12); I2 = 56% Some inconsistency; some imprecision
No reporting bias detected
Good Small number of serious adverse events in most trials
Composite outcome, some trials had limited details on serious adverse events
Moderate See Applicability column for KQ1, HIV infection
Withdrawals resulting from adverse events
4 RCTs (n = 10,563)
RR, 1.25 (95% CI, 0.99-1.59); I2 = 0% Consistent; some imprecision
No reporting bias detected, but most trials did not report withdrawals resulting from adverse events
Good Most trials did not report withdrawals resulting from adverse events Composite outcome, with variability in cause of withdrawal (clinical or laboratory adverse event) and whether adverse event temporary or permanent Moderate See Applicability column for KQ1, HIV infection
Renal adverse events
12 RCTs (n = 18,170)
RR, 1.43 (95% CI, 1.18-1.75); I2 = 0%; ARD, 0.56% (95% CI, 0.09%-1.04%) Consistent; precise
No reporting bias detected
Good Variability in definition of adverse renal events (most trials defined as ≥1 grade 1 elevation of serum creatinine level) High See Applicability column for KQ1, HIV infection
Gastrointestinal adverse events
12 RCTs (n = 18,300)
RR, 1.63 (95% CI, 1.26-2.11); I2 = 43%; ARD, 1.95% (95% CI, 0.48%-3.43%) Some inconsistency; precise
No reporting bias detected
Good Composite outcome, with no significant difference for specific gastrointestinal adverse events High See Applicability column for KQ1, HIV infection
Fracture
7 RCTs (n = 15,241)
RR, 1.23 (95% CI, 0.97-1.56); I2 = 0% Consistent; precise
No reporting bias detected
Moderate Limited details on fracture site; most fractures traumatic in studies that reported this information
Results heavily weighted by 1 trial
Low See Applicability column for KQ1, HIV infection
Syphilis
4 RCTs (n = 10,775)
RR, 1.08 (95% CI, 0.98-1.18); I2 = 0% Consistent; precise
No reporting bias detected, but NR in most trials
Good Most trials were blinded, which might affect behaviors differently than when patients know they are receiving PrEP Moderate See Applicability column for KQ1, HIV infection
Gonorrhea
5 RCTs (n = 9296)
RR, 1.07 (95% CI, 0.82-1.39); I2 = 49% Some inconsistency; some imprecision
No reporting bias detected, but NR in most trials
Good Most trials were blinded, which might affect behaviors differently than when patients know they are receiving PrEP Moderate See Applicability column for KQ1, HIV infection
Chlamydia
5 RCTs (n = 9296)
RR, 0.97 (95% CI, 0.80-1.18); I2 = 59% Consistent; precise
No reporting bias detected, but NR in most trials
Good Most trials were blinded, which might affect behaviors differently than when patients know they are receiving PrEP Moderate See Applicability column for KQ1, HIV infection
Combined bacterial STIs
2 RCTs (n = 5291)
RR, 1.14 (95% CI, 0.97-1.34); I2 = 0% Consistent; some imprecision
No reporting bias detected, but NR in most trials
Good Most trials were blinded, which might affect behaviors differently than when patients know they are receiving PrEP Moderate See Applicability column for KQ1, HIV infection
Herpes simplex virus infection
3 RCTs (n = 4103)
RR, 0.85 (95% CI, 0.67-1.07); I2 = 19% Some inconsistency; some imprecision
No reporting bias detected, but NR in most trials
Good Trials were blinded, which might affect behaviors differently than when patients know they are receiving PrEP Moderate See Applicability column for KQ1, HIV infection
Hepatitis C virus infection
2 RCTs (n = 896)
RR, 0.73 (95% CI, 0.25-2.10); I2 = 0% Some inconsistency; imprecise
No reporting bias detected, but NR in most trials
Good One trial was blinded, which might affect behaviors differently than when patients know they are receiving PrEP Low See Applicability column for KQ1, HIV infection
Spontaneous abortion
3 RCTs (n = 485)b
RR, 1.09 (95% CI, 0.79-1.50); I2 = 0% Consistent; some imprecision
No reporting bias detected
Good Analysis restricted to women who became pregnant in trials of PrEP and were taken off PrEP Moderate Analyses of women at high risk of HIV infection due to heterosexual contact who were taken off PrEP at time of pregnancy

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.

Current as of: June 2019

Internet Citation: Evidence Summary: Prevention of Human Immunodeficiency Virus (HIV) Infection: Preexposure Prophylaxis. U.S. Preventive Services Task Force. June 2019.
https://www.uspreventiveservicestaskforce.org/Page/Document/evidence-summary/prevention-of-human-immunodeficiency-virus-hiv-infection-pre-exposure-prophylaxis

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