Declining Efficacy of Artemisinin Combination Therapy Against P. Falciparum Malaria on the Thai-Myanmar Border (2003-2013): The Role of Parasite Genetic Factors.
Deployment of mefloquine-artesunate (MAS3) on the Thailand-Myanmar border has led to a sustained reduction in falciparum malaria, although antimalarial efficacy has declined substantially in recent years. The role of Plasmodium falciparum K13 mutations (a marker of artemisinin resistance) in reducing treatment efficacy remains controversial.



Between 2003 and 2013, we studied the efficacy of MAS3 in 1005 patients with uncomplicated P. falciparum malaria in relation to molecular markers of resistance.



Polymerase chain reaction (PCR)-adjusted cure rates declined from 100% in 2003 to 81.1% in 2013 as the proportions of isolates with multiple Pfmdr1 copies doubled from 32.4% to 64.7% and those with K13 mutations increased from 6.7% to 83.4%. K13 mutations conferring moderate artemisinin resistance (notably E252Q) predominated initially but were later overtaken by propeller mutations associated with slower parasite clearance (notably C580Y). Those infected with both multiple Pfmdr1 copy number and a K13 propeller mutation were 14 times more likely to fail treatment. The PCR-adjusted cure rate was 57.8% (95% confidence interval [CI], 45.4, 68.3) compared with 97.8% (95% CI, 93.3, 99.3) in patients with K13 wild type and Pfmdr1 single copy. K13 propeller mutation alone was a strong risk factor for recrudescence (P = .009). The combined population attributable fraction of recrudescence associated with K13 mutation and Pfmdr1 amplification was 82%.



The increasing prevalence of K13 mutations was the decisive factor for the recent and rapid decline in efficacy of artemisinin-based combination (MAS3) on the Thailand-Myanmar border.
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.
Aung Pyae
AP
Phyo
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Elizabeth A
EA
Ashley
Department of Genetics, Texas Biomedical Research Institute, San Antonio; and.
Tim J C
TJC
Anderson
Division of Molecular Genetics & Cell Biology, School of Biological Sciences, Nanyang Technological University, Singapore.
Zbynek
Z
Bozdech
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Verena I
VI
Carrara
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
Kanlaya
K
Sriprawat
Department of Genetics, Texas Biomedical Research Institute, San Antonio; and.
Shalini
S
Nair
Department of Genetics, Texas Biomedical Research Institute, San Antonio; and.
Marina McDew
MM
White
Division of Molecular Genetics & Cell Biology, School of Biological Sciences, Nanyang Technological University, Singapore.
Jerzy
J
Dziekan
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Clare
C
Ling
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
Stephane
S
Proux
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
Kamonchanok
K
Konghahong
Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Atthanee
A
Jeeyapant
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Charles J
CJ
Woodrow
Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Mallika
M
Imwong
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.
Rose
R
McGready
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Khin Maung
KM
Lwin
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Nicholas P J
NPJ
Day
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.|Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Nicholas J
NJ
White
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.
Francois
F
Nosten
D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology / Q000469:parasitology; D008297:Male; D015767:Mefloquine / Q000494:pharmacology / Q000627:therapeutic use; D002052:Myanmar / Q000453:epidemiology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000472:pathogenicity; D011446:Prospective Studies; D013785:Thailand / Q000453:epidemiology
D000962:Antimalarials; D037621:Artemisinins; D015767:Mefloquine
K13 mutation; Pfmdr1; Plasmodium falciparum malaria; artemisinin resistance; mefloquine–artesunate