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Adverse Events of First-Line Therapy for Pediatric Tuberculosis: A Systematic Review and Meta-Analysis
Michael Prodanuk1,2, Sarah L Silverberg1,2, Pierre-Philippe Piché-Renaud1,2
1Department of Paediatrics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Insights
Higher tuberculosis (TB) drug doses for children, recommended since 2010 by the World Health Organization (WHO), are linked to more adverse events (AEs). Further research is needed to understand treatment tolerability with these increased pediatric TB drug dosages.
Area of Science:
- Pediatric infectious diseases
- Pharmacovigilance
- Tuberculosis treatment
Background:
- In 2010, the World Health Organization (WHO) updated guidelines, increasing first-line tuberculosis (TB) drug dosages for pediatric patients.
- Concerns exist regarding the safety and tolerability of these higher pediatric TB treatment doses.
Purpose of the Study:
- To determine the incidence of adverse events (AEs) in children receiving first-line TB treatment.
- To evaluate if the 2010 WHO dosing recommendations have altered the toxicity profile of pediatric TB therapy.
Main Methods:
- A systematic review and meta-analysis of proportions were conducted.
- Searches included major databases (MEDLINE, Embase, Scopus, Cochrane) and clinical trial registries.
- Studies reporting AEs in children and adolescents (≤19 years) with TB receiving first-line drugs were included.
Main Results:
- Forty studies involving 5,021 participants were analyzed.
- The overall incidence of any AE was significantly higher with 2010 WHO dosing (26%) compared to pre-2010 dosing (8%).
- While overall hepatotoxicity showed no significant change, some subgroups experienced increased hepatotoxicity with 2010 dosing. AEs led to therapy changes in 1.2% of participants.
Conclusions:
- Increased first-line TB drug dosages in children are associated with a higher occurrence of adverse events.
- Caution is advised regarding further dose escalations in pediatric TB treatment, emphasizing the need for more research on treatment tolerability.
- Publication bias in observational studies may limit the generalizability of findings.
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.
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