TY - JOUR
T1 - Evolution of multidrug resistance in plasmodium falciparum
T2 - A longitudinal study of genetic resistance markers in the greater mekong subregion
AU - Imwong, Mallika
AU - Suwannasin, Kanokon
AU - Srisutham, Suttipat
AU - Vongpromek, Ranitha
AU - Promnarate, Cholrawee
AU - Saejeng, Aungkana
AU - Pyae Phyo, Aung
AU - Proux, Stephane
AU - Pongvongsa, Tiengkham
AU - Chea, Nguon
AU - Miotto, Olivo
AU - Tripura, Rupam
AU - Hoang, Chau Nguyen
AU - Dysoley, Lek
AU - Trung, Nghia Ho Dang
AU - Peto, Thomas J.
AU - Callery, James J.
AU - van der Pluijm, Rob W.
AU - Amaratunga, Chanaki
AU - Mukaka, Mavuto
AU - von Seidlein, Lorenz
AU - Mayxay, Mayfong
AU - Thuy-Nhien, Nguyen Thanh
AU - Newton, Paul N.
AU - Day, Nicholas P. J.
AU - Ashley, Elizabeth A.
AU - Nosten, Francois H.
AU - Smithuis, Frank M.
AU - Dhorda, Mehul
AU - White, Nicholas J.
AU - Dondorp, Arjen M.
N1 - Funding Information: This study was supported by Mahidol University, Thailand Science Research and Innovation (TSRI) (award RTA6280006), and Initiative 5%, Expertise France. Some patient samples were from TRAC studies supported by the United Kingdom Foreign Commonwealth Development Office (FCDO) (program code 201900); other samples from healthy individuals were from studies of targeted malaria elimination funded by the Wellcome Trust (grant 101148/Z/13/Z) and the Bill and Melinda Gates Foundation (grant OPP1081420). These studies were part of the Mahidol University–Oxford Tropical Medicine Research Program, funded by the Wellcome Trust of the United Kingdom (core grant 106698/B/14/Z). For the purpose of open access, the authors have applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. Publisher Copyright: © 2021 American Society for Microbiology. All rights reserved.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Increasing 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.
AB - Increasing 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.
KW - Genetic resistance markers
KW - Greater Mekong subregion
KW - Plasmodium falciparum
UR - http://www.scopus.com/inward/record.url?scp=85119422974&partnerID=8YFLogxK
U2 - https://doi.org/10.1128/AAC.01121-21
DO - https://doi.org/10.1128/AAC.01121-21
M3 - Article
C2 - 34516247
SN - 0066-4804
VL - 65
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 12
M1 - e01121-21
ER -