Evolution of multidrug resistance in Plasmodium falciparum : a longitudinal study of genetic resistance markers in the Greater Mekong Subregion
Imwong M., Suwannasin K., Srisutham S., Vongpromek R., Promnarate C., Saejeng A., Phyo AP., Proux S., Pongvongsa T., Nguon C., Miotto O., Tripura R., Chau NH., Lek D., Dang Trung Nghia H., Peto TJ., Callery JJ., van der Pluijm RW., Amaratunga C., Mukaka M., von Seidlein L., Mayxay M., Thuy-Nhien NT., Newton PN., Day NPJ., Ashley EA., Nosten FH., Smithuis FM., Dhorda M., White NJ., Dondorp AM.
Increasing drug resistance in Plasmodium falciparum to artemisinins and their ACT partner drugs jeopardises 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 PDR, Cambodia, Thailand, 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 changing first-line treatment away from dihydroartemisinin-piperaquine to artesunate-mefloquine (ASMQ) between 2014 and 2017. 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 dispersed over time. Mechanisms conferring mefloquine and piperaquine resistance may be counterbalancing. This supports the development of ASMQ plus piperaquine as a triple artemisinin combination therapy.