Systematic review of clinical trials and cohort studies evaluating HIV post‐exposure prophylaxis (PEP) regimens to inform updated Canadian guidelines

Abstract Background We conducted a systematic review of clinical trials and cohort studies on HIV post‐exposure prophylaxis (PEP) regimens to inform updated 2025 Canadian guidelines. Methods We searched Medline and Embase (July 2017–June 2024) for studies reporting on: HIV acquisition, PEP completion, adverse events (AEs) leading to discontinuation and/or moderate to severe adverse events. Two reviewers independently screened abstracts and publications and extracted data from eligible articles. Results Of 5226 abstracts screened, we retrieved 112 full‐text articles and included 22. Median study size was 160 (range = 52–26 988) participants. Regimens included DTG + TDF/XTC ( n = 4, 18%), EVG/c/TDF/FTC ( n = 4, 18%), BIC/TAF/FTC ( n = 4, 18%), RAL + TDF/FTC ( n = 4, 18%), EVG/c/TAF/FTC ( n = 3, 14%), RPV/TDF/FTC ( n = 2, 9%), DOR/TDF/FTC ( n = 2, 9%), MVC + TDF/FTC ( n = 1, 5%), a wide variety of protease inhibitor‐based regimens ( n = 7, 32%) and novel combinations with the injectable fusion inhibitor albuvirtide ( n = 1, 5%); a third of studies included three or more regimens ( n = 8, 36%). Among studies examining PEP completion rates ( n = 12, 55%), cumulative completion rate was 86.6% (7779/8983 PEP episodes) and appeared highest for RAL + TDF/FTC, BIC/FTC/TAF and DOR/TDF/3TC at 96.4%, 96.3% and 95.0%, respectively. PEP tolerability was good, with few discontinuations due to adverse events; where data were available, this was lowest for INSTI‐based regimens at 0.5% (pooled across two studies) for RAL + TDF/FTC, 1.0% (1/99) for DTG + TDF/XTC, 1.8% (2/109) for BIC/TAF/FTC and zero with albuvirtide (0/198). HIV seroconversions were rare ( n = 5/8134, 0.06%) and often related to premature PEP discontinuation or repeated exposures. Conclusions Multiple PEP regimens have been associated with high completion, good tolerability and rare seroconversion, supporting their inclusion in clinical guidelines.