Mallika ImwongKanokon SuwannasinSuttipat SrisuthamRanitha VongpromekCholrawee PromnarateAungkana SaejengAung Pyae PhyoStephane ProuxTiengkham PongvongsaNguon CheaOlivo MiottoRupam TripuraChau Nguyen HoangLek DysoleyNghia Ho Dang TrungThomas J. PetoJames J. CalleryRob W. Van der PluijmChanaki AmaratungaMavuto MukakaLorenz Von SeidleinMayfong MayxayNguyen Thanh Thuy-NhienPaul N. NewtonNicholas P.J. DayElizabeth A. AshleyFrancois H. NostenFrank M. SmithuisMehul DhordaNicholas J. WhiteArjen M. DondorpFaculty of Tropical Medicine, Mahidol UniversityMinistry of Health LaosChulalongkorn UniversityUniversity College London Hospitals NHS Foundation TrustThailand Ministry of Public HealthMahosot Hospital, LaoNuffield Department of MedicineWellcome Sanger InstituteMyanmar Oxford Clinical Research UnitEntomologySavannakhet Provincial Health Department2022-08-042022-08-042021-12-01Antimicrobial Agents and Chemotherapy. Vol.65, No.12 (2021)10986596006648042-s2.0-85119422974https://repository.li.mahidol.ac.th/handle/123456789/77477Increasing resistance in Plasmodium falciparum to artemisinins and their artemisinin combination therapy (ACT) partner drugs jeopardizes effective antimalarial treatment. Resistance is worst in the Greater Mekong subregion. Monitoring genetic markers of resistance can help to guide antimalarial therapy. Markers of resistance to artemisinins (PfKelch mutations), mefloquine (amplification of P. falciparum multidrug resistance-1 [PfMDR1]), and piperaquine (PfPlasmepsin2/3 amplification and specific P. falciparum chloroquine resistance transporter [PfCRT] mutations) were assessed in 6,722 P. falciparum samples from Vietnam, Lao People's Democratic Republic (PDR), Cambodia, Thailand, and Myanmar between 2007 and 2019. Against a high background prevalence of PfKelch mutations, PfMDR1 and PfPlasmepsin2/3 amplification closely followed regional drug pressures over time. PfPlasmepsin2/3 amplification preceded piperaquine resistance- associated PfCRT mutations in Cambodia and reached a peak prevalence of 23/28 (82%) in 2015. This declined to 57/156 (38%) after first-line treatment was changed from dihydroartemisinin-piperaquine to artesunate-mefloquine (ASMQ) between 2014 and 2017. The frequency of PfMDR1 amplification increased from 0/293 (0%) between 2012 and 2017 to 12/156 (8%) in 2019. Amplification of PfMDR1 and PfPlasmepsin2/3 in the same parasites was extremely rare (4/6,722 [0.06%]) and was dispersed over time. The mechanisms conferring mefloquine and piperaquine resistance may be counterbalancing. This supports the development of ASMQ plus piperaquine as a triple artemisinin combination therapy.Mahidol UniversityMedicinePharmacology, Toxicology and PharmaceuticsArticleSCOPUS10.1128/AAC.01121-21