Environmental, pharmacological and genetic influences on the spread of drug-resistant malaria

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Abstract
Plasmodium falciparum malaria is subject to artificial selection from antimalarial drugs that select for drug-resistant parasites. We describe and apply a flexible new approach to investigate how epistasis, inbreeding, selection heterogeneity and multiple simultaneous drug deployments interact to influence the spread of drug-resistant malaria. This framework recognizes that different human 'environments' within which treatment may occur (such as semi- and non-immune humans taking full or partial drug courses) influence the genetic interactions between parasite loci involved in resistance. Our model provides an explanation for how the rate of spread varies according to different malaria transmission intensities, why resistance might stabilize at intermediate frequencies and also identifies several factors that influence the decline of resistance after a drug is removed. Results suggest that studies based on clinical outcomes might overestimate the spread of resistant parasites, especially in high-transmission areas. We show that when transmission decreases, prevalence might decrease without a corresponding change in frequency of resistance and that this relationship is heavily influenced by the extent of linkage disequilibrium between loci. This has important consequences on the interpretation of data from areas where control is being successful and suggests that reducing transmission might have less impact on the spread of resistance than previously expected.