Adverse Events of First-Line Therapy for Pediatric Tuberculosis: A Systematic Review and Meta-Analysis.

BACKGROUND: In 2010, the World Health Organization (WHO) increased the recommended doses of first-line tuberculosis (TB) drugs for children. In this systematic review, we aimed to determine the proportion of children who developed adverse events (AEs) on first-line TB treatment and determine whether a change in toxicity was observed with WHO 2010 dosing.

METHODS: We searched MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials, WHO Global Index Medicus, and ClinicalTrials.gov for studies that reported AEs for children and adolescents aged ≤19 years with TB disease receiving first-line medications. A meta-analysis of proportions was performed to generate pooled proportions of AEs. The protocol was registered with the International Prospective Register of Systematic Reviews.

RESULTS: Of forty studies comprising 5021 participants, 682 (13.6%) participants experienced 712 AEs; 60 (1.2%) participants experienced a change in therapy due to AEs. The proportion of children with any AE was significantly higher with WHO 2010 dosing (26%; 95% confidence interval [CI], 18%-34%) compared with pre-WHO 2010 dosing (8%, 95% CI, 4%-15%), as was the proportion of children who developed severe AEs. There was no significant difference in hepatotoxicity before and after 2010 dosing recommendations; however, significant increases in hepatotoxicity were seen in several subgroups with 2010 dosing. There was substantial heterogeneity between studies; none were at high risk of bias.

CONCLUSIONS: Higher-dose regimens in children were associated with increased AEs, raising caution for further dose increases and necessitating additional study of treatment tolerability. These findings are limited by publication bias in observational trials.