Comparative efficacy and safety of treatment regimens for Pneumocystis jirovecii pneumonia in people living with HIV: a systematic review and network meta-analysis of randomized controlled trials.

Background: Pneumocystis jirovecii pneumonia (PCP) is a serious opportunistic infection in people living with HIV (PWH) who have low CD4 counts. Despite its side effects, trimethoprim-sulfamethoxazole (TMP-SMX) is currently considered the primary treatment for PCP.

Objectives: The objectives of this study are to compare the efficacy (treatment failure and mortality) and tolerability (treatment change) of PCP treatment regimens with a frequentist network meta-analysis.

Data Sources: Data sources include Embase, Medline, and CENTRAL from inception to 3 February 2024.

Study Eligibility Criteria: Study eligibility criteria include comparative randomized controlled trials (RCTs) of at least two PCP treatment regimens.

Participants: Participants include PWH.

Interventions: Interventions include treatment regimens for PCP compared head-to-head.

Assessment Of Risk Of Bias: Assessment of risk of bias includes Cochrane Risk-of-bias tool for RCTs (Cochrane Risk-of-Bias 2).

Methods Of Data Synthesis: Title, abstract, and full-text screening, along with data extraction, were conducted by two independent reviewers. Data on PCP treatment failure, all-cause mortality, and discontinuation because of toxicity were pooled and ranked.

Results: Fourteen RCTs conducted between 1983 and 1996 included 1788 participants across 27 treatment arms. No regimen showed statistically significant superiority over TMP-SMX in direct comparison. In the network meta-analysis, clindamycin/primaquine was ranked the best (surface under the cumulative ranking curve, 0.8), followed by intravenous pentamidine (0.8) and TMP-SMX (0.8) regarding treatment failure. Regarding all-cause mortality, TMP-SMX was superior to atovaquone in direct comparison, but no treatment was superior in the full network analysis. Dapsone-TMP (0.7) and intravenous pentamidine (0.8) were ranked the highest for mortality reduction. For safety and tolerability, comparator drugs consistently outperformed TMP-SMX, with significant reductions in toxicity observed for dapsone-TMP, inhaled pentamidine, and atovaquone. Inhaled pentamidine (0.9) was the best tolerated, followed by trimetrexate (0.8) and atovaquone (0.8).

Conclusions: We conclude that TMP-SMX should be reassessed as the standalone first-line therapy for PCP in PWH, given the better tolerability and comparable efficacy of other treatments. In places with access to alternative drugs for PCP treatment, our analysis suggests that alternative regimens may offer comparable effectiveness, providing flexibility to use alternative treatments when comorbidities necessitate it.