Mapping Partner Drug Resistance to Guide Antimalarial Combination Therapy Policies in Sub-Saharan Africa

Abstract

BACKGROUND: Resistance to artemisinin-based combination therapies (ACTs) threatens the global control of Plasmodium falciparum malaria. ACTs combine artemisinin-derived compounds with partner drugs to enable multiple mechanisms of clearance. Although ACTs remain widely effective in sub-Saharan Africa, long-standing circulation of parasite alleles associated with reduced partner drug susceptibility may contribute to the development of clinical resistance. METHODS: We fit a hierarchical Bayesian spatial model to data from over 500 molecular surveys to predict the prevalence and frequency of 4 key transport markers (pfcrt76T, pfmdr1 86Y, 184F, and 1246Y) in first-level administrative divisions in sub-Saharan Africa, from the uptake of ACTs (2004–2009) to their widespread usage (2010–2018). FINDINGS: Our models estimated that the pfcrt 76T mutation decreased in prevalence in 90% of regions, the pfmdr1 N86 and D1246 wild-type genotypes increased in prevalence in 96% and 82% of regions, respectively, and there was no significant directional selection at the pfmdr1 Y184F loci. Rainfall seasonality was the strongest predictor of the prevalence of wild-type genotypes, with other covariates including first-line drug policy and transmission intensity more weakly associated. We finally identified regions of high priority for additional surveillance that could signify decreased susceptibility to the local first-line ACT. INTERPRETATION: This approach can be used to infer the degree of molecular resistance and magnitude of wild-type reversion in regions without survey data to inform therapeutic policy decisions. FUNDING: The authors were supported by the following grants from the National Institutes of Health: F31-AI150168 (HYE), K01-TW010496 (AKB), R01-AI137093 (DMW, JLW), R21-AI135477 (SP). DECLARATION OF INTERESTS: The authors have no conflicts of interest to disclose. ETHICS APPROVAL STATEMENT: Data was publicly available and did not require IRB review.