Post doctoral fellow University of California, San Francisco San Francisco, California, United States
Background: Malaria is a leading cause of death in African children under 5 years old. While artemisinin-based combination therapies (ACTs) such as artemether-lumefantrine (AL) are highly effective, ACTs are dosed based on weight bands leaving children, particularly those underweight, vulnerable to underdosing. This analysis investigated the prevalence of underdosing AL and risk of malaria reinfection in children, using real world data from countries with the highest malaria burdens across sub-Saharan Africa (SSA). Methods: Measures of growth and nutrition for 372,363 children 0-5 years living in SSA were acquired for 25 countries from the Demographic and Health Surveys Program. Each child was assigned an AL dose based on actual and expected weight (calculated using WHO growth charts). Four AL dosing regimens (standard [twice daily for 3 days], extended][twice daily for 5 days], intensified [thrice daily for 3 days], and increased [standard + one extra-tablet]) were investigated. The probability of reaching the efficacy targets (day 7 lumefantrine (LF) concentration >200 ng/mL and reinfection free for 42 days) was evaluated using a population PK/PD model (Chotsiri et al. 2019). Simulations were performed using NONMEM. Results: Simulations revealed 75% of children reached the 200 ng/mL LF threshold and 77% were malaria free for 42 days when the standard regimen was dosed using actual weight. The extended regimen using expected weight was the most efficacious with 97% of children reaching 200 ng/mL LF and 88% remaining malaria free for 42 days. The prevalence of underdosing was highest in children 3-5 years old (23%). Conclusion: This study highlights the inadequacies of current weight-based AL dosing regimens particularly in children 3-5 years old. Clinical trials testing expected weight and extended dosing are urgently needed.
