Oral pre-exposure prophylaxis (PrEP) to prevent HIV: a systematic review and meta-analysis of clinical effectiveness, safety, adherence and risk compensation in all populations

Abstract

Objective: To conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) of the effectiveness and safety of oral pre-exposure prophylaxis (PrEP) to prevent HIV.

Methods: Databases (PubMed, Embase and the Cochrane Register of Controlled Trials) were searched up to 5 July 2020. Search terms for 'HIV' were combined with terms for 'PrEP' or 'tenofovir/emtricitabine'. RCTs were included that compared oral tenofovir-containing PrEP to placebo, no treatment or alternative medication/dosing schedule. The primary outcome was the rate ratio (RR) of HIV infection using a modified intention-to-treat analysis. Secondary outcomes included safety, adherence and risk compensation. All analyses were stratified a priori by population: men who have sex with men (MSM), serodiscordant couples, heterosexuals and people who inject drugs (PWIDs). The quality of individual studies was assessed using the Cochrane risk-of-bias tool, and the certainty of evidence was assessed using GRADE.

Results: Of 2803 unique records, 15 RCTs met our inclusion criteria. Over 25 000 participants were included, encompassing 38 289 person-years of follow-up data. PrEP was found to be effective in MSM (RR 0.25, 95% CI 0.1 to 0.61; absolute rate difference (RD) -0.03, 95% CI -0.01 to -0.05), serodiscordant couples (RR 0.25, 95% CI 0.14 to 0.46; RD -0.01, 95% CI -0.01 to -0.02) and PWID (RR 0.51, 95% CI 0.29 to 0.92; RD -0.00, 95% CI -0.00 to -0.01), but not in heterosexuals (RR 0.77, 95% CI 0.46 to 1.29). Efficacy was strongly associated with adherence (p<0.01). PrEP was found to be safe, but unrecognised HIV at enrolment increased the risk of viral drug resistance mutations. Evidence for behaviour change or an increase in sexually transmitted infections was not found.

Conclusions: PrEP is safe and effective in MSM, serodiscordant couples and PWIDs. Additional research is needed prior to recommending PrEP in heterosexuals. No RCTs reported effectiveness or safety data for other high-risk groups, such as transgender women and sex workers.

Prospero registration number: CRD42017065937.

Keywords: HIV & AIDS; epidemiology; infectious diseases; public health.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram of the study selection. Diagram provides details on the selection process of studies for inclusion. Note that the exclusion of 2703 citations at the ‘screening’ stage did not meet our study inclusion/exclusion criteria based on screening of title/abstract. CDC, Centers for Disease Control and Prevention; DISCOVER, study by Mayer et al.; FEM-PrEP, study by Van Damme et al.; HPTN 067/ADAPT, study by Bekker et al; IPERGAY, study by Molina et al.; iPrEX, study by Grant et al; OLE, open label extension; PrEP, pre-exposure prophylaxis; PROUD, study by McCormack et al.; RCT, randomised controlled trial.

Figure 2

Funnel plot for publication bias. The funnel plot of all studies (n=13) is presented. There is no evidence of significant small study bias. RR, rate ratio.

Figure 3

Meta-analysis: HIV acquisition in MSM, all studies. Forest plot of the meta-analysis of HIV incidence in all MSM trials, PrEP versus placebo or no drug. Subgroups include high (≥80%) adherence and low (<80%) adherence. ‘Events’ refers to new HIV infections and ‘total’ refers to total person-years at risk during the study period. MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; RR, rate ratio.

Figure 4

Fitted metaregression line of the relationship between trial-level PrEP adherence and efficacy. Only trials that reported plasma drug concentration from a representative sample contributed to the analysis, represented as circles (Baeten 2012 (Partners PrEP), Choopanya 2013 (Bangkok Tenofovir Study), Grant 2010 (iPrEx), Mazzarro 2015 (VOICE), McCormack 2015 (PROUD), Molina 2015 (IPERGAY) and Van Damme 2012 (FEM-PrEP)). The solid line represents the fitted regression line and the shaded area represents the 95% CI. The X-axis represents the trial-level adherence as a proportion, and the Y-axis represents the efficacy as rate ratios. PrEP, pre-exposure prophylaxis.