Revisiting the Evidence Base for Modern-Day Practice of the Treatment of Toxoplasmic Encephalitis: A Systematic Review and Meta-Analysis

• Published in: Clinical infectious diseases 2023-02, Vol.76 (3), p.e1302-e1319
• Main Authors: Prosty, Connor, Hanula, Ryan, Levin, Yossef, Bogoch, Isaac I, McDonald, Emily G, Lee, Todd C
• Format: Article
• Language: English
• Subjects: Encephalitis - drug therapy; HIV Infections - complications; HIV Infections - drug therapy; Humans; Pyrimethamine - therapeutic use; Toxoplasmosis, Cerebral - drug therapy; Trimethoprim, Sulfamethoxazole Drug Combination - therapeutic use
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/ciac645

Abstract Background Toxoplasmic encephalitis (TE) is an opportunistic infection of people with human immunodeficiency virus (HIV) or other causes of immunosuppression. Guideline-recommended treatments for TE are pyrimethamine and sulfadiazine (P-S) or pyrimethamine and clindamycin (P-C); however, a substantial price increase has limited access to pyrimethamine. Consequently, some centers have transitioned to trimethoprim-sulfamethoxazole (TMP-SMX), an inexpensive alternative treatment. We aimed to review the evidence on the efficacy and safety of pyrimethamine-containing therapies vs TMP-SMX. Methods We searched for and included randomized controlled trials (RCTs) and observational studies of TE treatments, regardless of HIV status. Data for each therapy were pooled by meta-analysis to assess the proportions of patients who experienced clinical and radiologic responses to treatment, all-cause mortality, and discontinuation due to toxicity. Sensitivity analyses limited to RCTs directly compared therapies. Results We identified 6 RCTs/dose-escalation studies and 26 single-arm/observational studies. Identified studies included only persons with HIV, and most predated modern antiretroviral treatment. Pooled proportions of clinical and radiologic response and mortality were not significantly different between TMP-SMX and pyrimethamine-containing regimens (P > .05). Treatment discontinuation due to toxicity was significantly lower in TMP-SMX (7.3%; 95% confidence interval [CI], 4.7–11.4; I2 = 0.0%) vs P-S (30.5%; 95% CI, 27.1–34.2; I2 = 0.0%; P < .01) or P-C (13.7%; 95% CI, 9.8–18.8; I2 = 32.0%; P = .031). These results were consistent in analyses restricted to RCT data. Conclusions TMP-SMX appears to be as effective and safer than pyrimethamine-containing regimens for TE. These findings support modern RCTs comparing TMP-SMX to pyrimethamine-based therapies and a revisiting of the guidelines. In treatment of toxoplasmic encephalitis, trimethoprim-sulfamethoxazole has similar efficacy and improved safety compared with pyrimethamine-containing therapies. Data are lacking in patients without human immunodeficiency virus. Our results support reconsideration of current guidelines and support the need for further clinical trials. Graphical Abstract Graphical Abstract Created with BioRender.com