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. 2021 Nov 17;65(12):e0112121.
doi: 10.1128/AAC.01121-21. Epub 2021 Sep 13.

Evolution of Multidrug Resistance in Plasmodium falciparum: a Longitudinal Study of Genetic Resistance Markers in the Greater Mekong Subregion

Mallika Imwong  1   2 , Kanokon Suwannasin  2 , Suttipat Srisutham  3 , Ranitha Vongpromek  4 , Cholrawee Promnarate  4 , Aungkana Saejeng  5 , Aung Pyae Phyo  6 , Stephane Proux  7 , Tiengkham Pongvongsa  8 , Nguon Chea  9 , Olivo Miotto  2   10   11 , Rupam Tripura  2   11 , Chau Nguyen Hoang  12 , Lek Dysoley  9 , Nghia Ho Dang Trung  12 , Thomas J Peto  2   11 , James J Callery  2 , Rob W van der Pluijm  2 , Chanaki Amaratunga  2   11 , Mavuto Mukaka  2   11 , Lorenz von Seidlein  2   11 , Mayfong Mayxay  11   13   14 , Nguyen Thanh Thuy-Nhien  12 , Paul N Newton  11 , Nicholas P J Day  2   11 , Elizabeth A Ashley  11   14 , Francois H Nosten  7   11 , Frank M Smithuis  6   11 , Mehul Dhorda  2   3   11 , Nicholas J White  2   11 , Arjen M Dondorp  2   11
Affiliations

Evolution of Multidrug Resistance in Plasmodium falciparum: a Longitudinal Study of Genetic Resistance Markers in the Greater Mekong Subregion

Mallika Imwong et al. Antimicrob Agents Chemother. .

Abstract

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.

Keywords: Greater Mekong subregion; Plasmodium falciparum; genetic resistance markers.

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Figures

FIG 1
FIG 1
Changes in the frequencies of amplification of the PfPlasmepsin2/3 and PfMDR1 genes and in the frequency of novel piperaquine resistance-related PfCRT mutations during 2007–2019 in Cambodia. Error bars indicate 95% confidence intervals.
FIG 2
FIG 2
Distribution of PfPlasmepsin2/3 and PfMDR1 copy number estimates in 6,722 P. falciparum samples obtained from Greater Mekong subregion countries between 2007 and 2019, color-coded according to country. The shaded areas represent PfPlasmepsin2/3 and PfMDR1 estimates with indeterminate results, defined as a <90% chance of representing a single copy number versus multiple copy numbers of the gene.
FIG 3
FIG 3
Relation between PfMDR1 amplification, PfPlasmepsin2/3 amplification, and novel piperaquine resistance-associated PfCRT mutations.
See this image and copyright information in PMC

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