Ex vivo susceptibility and molecular signature assessment of antimalarial-based combination therapies (ACT) partner drugs resistance in Senegal

Abstract Background Over the last decades, Plasmodium falciparum – the main causative agent of malaria – has constantly developed resistance to antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine or artemisinin derivatives. Therefore, active surveillance in the ex vivo susceptibility to the antimalarial drugs used as partner drugs in artemisinin-based combination therapies (the current frontline antimalarial) such as amodiaquine, lumefantrine or piperaquine, is essential. Methods Here, we evaluated the ex vivo susceptibility, expressed with the ex vivo SYBR™ Green, to six antimalarial drugs (amodiaquine, chloroquine, lumefantrine, mefloquine, piperaquine and quinine) from 34 P. falciparum isolates collected in 2018 in Thiès (Senegal). Whole-genome sequencing (WGS) was used to search for mutations in P. falciparum genes known to be associated with drug resistance. Results P. falciparum isolates showed reduced ex vivo susceptibility only to chloroquine (16% of the isolates). Mutations in pfcrt K76T (21%) and pfmdr1 Y184F (53%) were the most prevalent. A significant correlation was observed between the mutants pfcrt 76T and pfmdr1 184F and IC 50 values for chloroquine. A significant decrease in ex vivo susceptibility to chloroquine and quinine associated with the pfcrt R371I was also detected ( P < 0.001) . Conclusion Our results suggest that the ex vivo susceptibility of P. falciparum isolates to amodiaquine, lumefantrine, mefloquine, piperaquine and quinine remains high in Thiès. Directly measuring ex vivo parasite drug response and sequencing resistance mutations overtime are both useful tools for monitoring parasite drug response in field samples.