Introduction: Selection of resistant malaria strains occurs when parasites are exposed to inadequate antimalarial drug concentrations. The proportion of uncomplicated falciparum malaria patients at risk of being sub-optimally dosed with the current World Health Organization (WHO) recommended artemisinin-based combination therapies (ACTs) is unknown. This study aims to estimate this proportion and the excess number of treatment failures (recrudescences) associated with sub-optimal dosing in Sub-Saharan Africa. Methods: Sub-populations at risk of sub-optimal dosing include wasted children <5 years of age; patients with hyperparasitaemia; pregnant women; people living with HIV; and overweight adults. Country-level data on population structure were extracted from openly accessible data sources. Pooled adjusted Hazard Ratios for PCR-confirmed recrudescence were estimated for each risk group from published meta-analyses using fixed-effect meta-analysis. Results: In 2020, of 153.1 million uncomplicated P. falciparum malaria patients in Africa, the largest risk groups were the hyperparasitaemic patients (13.2 million, 8.6% of uncomplicated malaria cases) and overweight adults (10.3 million, 6.7% of uncomplicated cases). The excess total number of treatment failures ranged from 323,247 for a 98% baseline ACT efficacy to 1,292,987 for a 92% baseline ACT efficacy. Conclusion: An estimated 1 in nearly 4 people with uncomplicated confirmed P. falciparum malaria in Africa are at risk of receiving a sub-optimal antimalarial drug dosing. This increases the risk of antimalarial drug resistance and poses a serious threat to malaria control and elimination efforts. Changes in antimalarial dosing or treatment duration of current antimalarials may be needed and new antimalarials development should ensure sufficient drug concentration levels in these sub-populations that carry a high malaria burden.

The authors have declared no competing interest.

Bill & Melinda Gates Foundation (grant INV-004713) and the University of Oxford. The funders of the study had no role in the study design, evidence synthesis, writing of the manuscript or the decision to submit it for publication.

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