Comparative Efficacy and Safety of Pneumocystis Jirovecii Pneumonia Prophylaxis Regimens for People Living with HIV: a Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BackgroundPneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PLWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone.ObjectiveTo compare the efficacy and safety of PCP prophylaxis regimens in PLWH by network meta-analysis.Data SourcesEmbase, MedLine, and CENTRAL from inception to June 21, 2023.Study Eligibility CriteriaComparative randomized controlled trials (RCTs).ParticipantsPLWH.InterventionsRegimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo.Assessment of Risk of BiasCochrane risk-of-bias tool for RCTs 2.Methods of Data SynthesisTitle/abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked via a network meta-analysis. Subgroup analyses of primary vs. secondary prophylaxis, by year, and by dosage were conducted.ResultsA total of 26 RCTs, comprising 55 treatment arms involving 7516 PLWH were included. For the prevention of PCP, TMP-SMX was ranked the most favorable agent and was superior to DBRs (Risk Ratio [RR]=0.54, 95%Confidence Interval [95%CI]=0.36-0.83) and AP (RR=0.53, 95%CI=0.36-0.77). TMP-SMX was also the only agent with a mortality benefit compared to no treatment/placebo (RR=0.79, 95%CI=0.64-0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR=1.25, 95%CI=1.01-1.54) and AP (7.20, 95%CI=5.37-9.66). No significant differences in PCP prevention or mortality were detected amongst the other regimens. Findings remained consistent within subgroups.ConclusionTMP-SMX is the most effective agent for PCP prophylaxis in PLWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity.