Effectiveness of Pre-exposure Prophylaxis (PrEP) in the Prevention of Human Immunodeficiency Virus (HIV): A Systematic Review of Randomized Controlled Trials With Narrative Synthesis

Human immunodeficiency virus (HIV) prevention has advanced substantially, yet ending new transmissions by 2030 remains uncertain. Pre-exposure prophylaxis (PrEP) has high biological efficacy, but real-world effectiveness varies due to adherence, access, and delivery barriers. This review aims to synthesize evidence on the efficacy of PrEP in reducing HIV incidence and to discuss its implications for achieving the Joint United Nations Programme on HIV/AIDS (UNAIDS) 2030 targets. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidance, MEDLINE, Embase, Scopus, and Cochrane Library were searched for English-language studies published between January 2010 and January 2025 assessing PrEP efficacy in high-risk populations. Nine randomized controlled trials (RCTs) comprising more than 20,000 participants across multiple continents were included. Across oral tenofovir-based PrEP trials, risk reduction ranged from 49% to 86% in intention-to-treat (ITT) analyses, with markedly higher efficacy in adherence-defined subgroups (e.g., up to 92-99% in trials with pharmacokinetic confirmation). Long-acting injectable cabotegravir (CAB-LA) was superior to daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) in two large RCTs, with relative risk reduction up to 89% and high observed adherence consistent with clinic-based dosing. Adverse events were generally mild to moderate (gastrointestinal symptoms, headache), with expected renal marker changes in some oral PrEP trials and injection-site reactions for CAB-LA; no consistent evidence of risk compensation was observed. PrEP is highly effective when taken as prescribed, but achieving population-level impact aligned with UNAIDS targets requires scale-up, improved access, and interventions that support persistence and adherence, including expanded delivery models and longer-acting options.