Evaluation of Dosing Guidelines for Childhood Tuberculosis: A Mathematical Modeling Study

Background: Malnourished and young children are particularly vulnerable to severe forms of tuberculosis and poor treatment response. Current World Health Organization (WHO) dosing guidelines are only based on weight, which may lead to systematic underdosing and worse outcomes in these vulnerable children. We evaluate and quantify the population impact of current WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with highest disease burden. Methods: Using an integrated model which links country-specific individual-level demographic data to pharmacokinetic, outcome, and epidemiological models, we assessed tuberculosis treatment outcomes in children under five years of age following the current WHO guidelines and two alternative dosing strategies: a simple algorithm that utilizes age, weight, and available formulations, and an individualized algorithm without dose limitations. Findings: We estimated that 11-55% of all children and >70% of underweight children were underdosed with WHO dosing. Rifampicin exposure target attainment was only 48% following WHO dosing. Subtherapeutic exposures were more common in malnourished children. The proposed simple dosing approach improved exposure attainment to 62% and equalized outcomes by nutritional status. At least one-third of unfavorable treatment outcomes might be resolved with this simple dosing strategy, saving a minimum of 2436 children in these countries annually. With individualized dosing approaches, almost all children could be cured. Interpretation: A simple change in dosing procedure to include age and nutritional status would require no additional measurements or new drug formulations and could improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality. Funding Statement: Research reported in this publication was supported by The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health under award number R01HD083047 (AGP, RMS). This work was also supported by a fellowship from the UK Medical Research Council (MRC) (MR/P022081/1; PJD). Declaration of Interests: The authors declare no competing interests.