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. PrEP indicates preexposure prophylaxis; STI, sexually transmitted infection.
aAlso 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
KQ indicates key question.
aSome 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
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 the calculate the heterogeneity [I2] test statistic. PrEP indicates preexposure prophylaxis; PWID, people who inject drugs.
aTenofovir disoproxil fumarate group.
bStudy conducted in the United States, Canada, or Europe.
cTenofovir disoproxil fumarate/emtricitabine group.
Figure 4. Meta-analysis: HIV Infection Stratified by Adherence
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 the calculate the heterogeneity [I2] test statistic. NA indicates not available; PrEP, preexposure prophylaxis.
aStudy conducted in the United States, Canada, or Europe.
bAssessed using medication event monitoring system.
cNot estimable.
dAssessed by self-report, confirmed by plasma sample.
eAssessed by self-report.
Table 1. Study Characteristics of RCTs of PrEP
Table 2. Risk of HIV Infection in Randomized Clinical Trials of PrEP vs Placebo or No PrEP
Table 3. Adverse Events and Sexually Transmitted Infections in Randomized Clinical Trials of PrEP vs Placebo/No PrEP
Table 4. Summary of Evidence
US Preventive Services Task Force
Evidence Report
June 11, 2019
Preexposure Prophylaxis for the Prevention of HIV Infection: Evidence Report and Systematic Review for the US Preventive Services Task Force
JAMA. 2019;321[22]:2214-2230. doi:10.1001/jama.2019.2591
- US Preventive Services Task Force USPSTF Guideline: Preexposure Prophylaxis for the Prevention of HIV Infection US Preventive Services Task Force; Douglas K. Owens, MD, MS; Karina W. Davidson, PhD, MASc; Alex H. Krist, MD, MPH; Michael J. Barry, MD; Michael Cabana, MD, MA, MPH; Aaron B. Caughey, MD, PhD; Susan J. Curry, PhD; Chyke A. Doubeni, MD, MPH; John W. Epling Jr, MD, MSEd; Martha Kubik, PhD, RN; C. Seth Landefeld, MD; Carol M. Mangione, MD, MSPH; Lori Pbert, PhD; Michael Silverstein, MD, MPH; Melissa A. Simon, MD, MPH; Chien-Wen Tseng, MD, MPH, MSEE; John B. Wong, MD JAMA
- JAMA Patient Page Can HIV Infection Be Prevented With Medication? Jill Jin, MD, MPH JAMA
- News From the Centers for Disease Control and Prevention PrEP Awareness Is Low Among Heterosexual People Bridget M. Kuehn, MSJ JAMA
- Viewpoint Enhancing HIV Prevention With New Modalities and Routine Sexual History Discussions Kenneth H. Mayer, MD; Lao-Tzu Allan-Blitz, MD JAMA
Conversations with Dr Bauchner [25:40]
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.
Preexposure prophylaxis [PrEP] involves use of antiretroviral therapy regularly [eg, daily] or before and after possible HIV exposure events such as sex [“on-demand” or “event-driven”] to decrease risk of acquiring HIV infection. The purpose of this report was to synthesize the evidence on effects of PrEP on HIV acquisition risk, mortality, harms, and other clinical outcomes; effects of adherence on PrEP-associated outcomes; and accuracy of methods for identifying potential candidates for PrEP. It was used by the United States Preventive Services Task Force [USPSTF] to develop a new recommendation on PrEP for the prevention of HIV infection.
Detailed methods are available in the full evidence report at //www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/prevention-of-human-immunodeficiency-virus-hiv-infection-pre-exposure-prophylaxis. 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 [eMethods 1 in the ]. 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.
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. 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.,
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 [eMethods 2 in the ]. Quality ratings for individual studies are provided in eTables 1-3 in the .
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. The applicability of the findings to US primary care populations and settings was also assessed.
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. When I2 was greater than 30%, the analysis was also performed with the profile likelihood method using Stata/IC Version 13.1 [StataCorp]. 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 PrEP 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 40 to