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

BACKGROUND: Pneumocystis 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.

OBJECTIVE: To compare the efficacy and safety of PCP prophylaxis regimens in PLWH by network meta-analysis.

DATA SOURCES: Embase, MedLine, and CENTRAL from inception to June 21, 2023.

STUDY ELIGIBILITY CRITERIA: Comparative randomized controlled trials (RCTs).

PARTICIPANTS: PLWH.

INTERVENTIONS: Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo.

ASSESSMENT OF RISK OF BIAS: Cochrane risk-of-bias tool for RCTs 2.

METHODS OF DATA SYNTHESIS: Title/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.

RESULTS: A 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.

CONCLUSION: TMP-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.