Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study

Area of Science:

• Pediatric infectious diseases
• Pharmacokinetics and pharmacodynamics
• Global health and epidemiology

Background:

• Young children, especially those malnourished, face higher risks of severe tuberculosis and poor treatment response.
• Current World Health Organization (WHO) weight-based dosing guidelines for pediatric tuberculosis may lead to underdosing.
• This study addresses the impact of WHO guidelines in high-burden countries.

Purpose of the Study:

• To assess and quantify the population effect of WHO dosing guidelines for drug-susceptible tuberculosis in children.
• To evaluate alternative dosing strategies considering age and nutritional status.

Main Methods:

• Integrated modeling linking country-specific demographic data with pharmacokinetic, outcome, and epidemiological models.
• Estimation of treatment outcomes under WHO guidelines versus two alternative strategies (age/weight-based algorithm and individualized algorithm).
• Focus on children under 5 years in the 20 countries with the highest tuberculosis burden.

Main Results:

• An estimated 43% of children under 5 treated for tuberculosis in 2017 were underdosed by WHO guidelines, with only 47% reaching the rifampicin exposure target.
• Underdosing and subtherapeutic exposures were more prevalent in malnourished children.
• A proposed age/nutritional status-based approach improved rifampicin target exposure to 62% and could resolve an estimated third of unfavorable outcomes, potentially saving over 2400 lives annually.

Conclusions:

• A simple adjustment to tuberculosis drug dosing in children, incorporating age and nutritional status, can improve treatment outcomes.
• This approach is particularly beneficial for malnourished children at high risk of mortality.
• No new measurements or drug formulations are required, making it a feasible intervention.