摘要：SummaryBackground Artemisinin combination therapies (ACTs) are used worldwide as first-line treatment against confirmed or suspected Plasmodium falciparum malaria. Despite the success of {ACTs} at reducing the global burden of malaria, emerging resistance to artemisinin threatens these gains. Countering onset of resistance might need deliberate tactics aimed at slowing the reduction in {ACT} effectiveness. We assessed optimum use of {ACTs} at the population level, specifically focusing on a strategy of multiple first-line therapies (MFT), and comparing it with strategies of cycling or sequential use of single first-line ACTs. Methods With an individual-based microsimulation of regional malaria transmission, we looked at how to apply a therapy as widely as possible without accelerating reduction of efficacy by drug resistance. We compared simultaneous distribution of artemether–lumefantrine, artesunate–amodiaquine, and dihydroartemisinin–piperaquine (ie, MFT) against strategies in which these {ACTs} would be cycled or used sequentially, either on a fixed schedule or when population-level efficacy reaches the {WHO} threshold of 10% treatment failure. The main assessment criterion was total number of treatment failures per 100 people per year. Additionally, we analysed the benefits of including a single non-ACT therapy in an {MFT} strategy, and did sensitivity analyses in which we varied transmission setting, treatment coverage, partner-drug half-life, fitness cost of drug resistance, and the relation between drug concentration and resistance evolution. Findings Use of {MFT} was predicted to reduce the long-term number of treatment failures compared with strategies in which a single first-line {ACT} is recommended. This result was robust to various epidemiological, pharmacological, and evolutionary features of malaria transmission. Inclusion of a single non-ACT therapy in an {MFT} strategy would have substantial benefits in reduction of pressure on artemisinin resistance evolution, delaying its emergence and slowing its spread. Interpretation Adjusting national antimalarial treatment guidelines to encourage simultaneous use of {MFT} is likely to extend the useful therapeutic life of available antimalarial drugs, resulting in long-term beneficial outcomes for patients. Funding Wellcome Trust, {UK} Medical Research Council, Li Ka Shing Foundation.
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