Preventing Antimalarial Drug Resistance with Triple Artemisinin-Based Combination Therapies

Background: Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs) which combine artemisinin derivatives with two partner drugs are efficacious and well tolerated in clinical trials, including in areas of multidrug-resistant malaria. Whether early TACT adoption could delay the emergence and spread of antimalarial drug resistance is a question of vital importance.Methods: Using two independent individual-based models of Plasmodium falciparum epidemiology and evolution, we evaluated whether introduction of either artesunate-mefloquine-piperaquine or artemether-lumefantrine-amodiaquine resulted in lower long-term artemisinin-resistance levels and treatment failure rates compared with continued ACT use.Findings: In countries with 1% P. falciparum prevalence, immediate adoption of TACTs would result in substantially lower frequency of artemisinin-resistant alleles 10 years later. Median estimates were 70%, 33%, and 18% lower allele frequency for countries currently deploying dihydroartemisinin-piperaquine, artesunate-amodiaquine, or artemether-lumefantrine, respectively. Corresponding median treatment failure rate decreases are 74%, 34%, and 17%. Delaying TACT introduction increases future resistance frequencies and treatment failure rates. The most significant threat to the success of TACTs is the emergence of a triple-resistant genotype. which if above 0.01 frequency may undermine elimination efforts in low-prevalence regions.Interpretation: Introduction of TACTs could delay the emergence and spread of artemisinin resistance and treatment failure, extending the useful therapeutic life of current antimalarial drugs and improving the chances of malaria elimination. Immediate introduction of TACTs should be considered by policy makers in areas of emerging artemisinin resistance.Funding: This research falls under the auspices of the Development of Triple Artemisinin-based Combination Therapies (DeTACT) project funded by UK Aid and the UK Government’s Foreign, Commonwealth and Development Office. Funding from Wellcome Trust (220211) is also acknowledged. MFB, TDN, TN-AT acknowledge funding from the National Institutes of Health grant NIAID R01AI153355 and The Bill and Melinda Gates Foundation INV-005517 grant awarded to Pennsylvania State University. RA acknowledges funding from the Bill and Melinda Gates Foundation (OPP1193472).Declaration of Interest: None to declare.