Abstract
.Antimalarial drug resistance has threatened global malaria control since chloroquine (CQ)-resistant Plasmodium falciparum emerged in Asia in the 1950s. Understanding the impacts of changing antimalarial drug policy on resistance is critical for resistance management. Plasmodium falciparum isolates were collected from 2003 to 2015 in western Kenya and analyzed for genetic markers associated with resistance to CQ (Pfcrt), sulfadoxine–pyrimethamine (SP) (Pfdhfr/Pfdhps), and artemether–lumefantrine (AL) (PfKelch13/Pfmdr1) antimalarials. In addition, household antimalarial drug use surveys were administered. Pfcrt 76T prevalence decreased from 76% to 6% from 2003 to 2015. Pfdhfr/Pfdhps quintuple mutants decreased from 70% in 2003 to 14% in 2008, but increased to near fixation by 2015. SP “super resistant” alleles Pfdhps 581G and 613S/T were not detected in the 2015 samples that were assessed. The Pfmdr1 N86-184F-D1246 haplotype associated with decreased lumefantrine susceptibility increased significantly from 4% in 2005 to 51% in 2015. No PfKelch13 mutations that have been previously associated with artemisinin resistance were detected in the study populations. The increase in Pfdhfr/Pfdhps quintuple mutants that associates with SP resistance may have resulted from the increased usage of SP for intermittent preventative therapy in pregnancy (IPTp) and for malaria treatment in the community. Prevalent Pfdhfr/Pfdhps mutations call for careful monitoring of SP resistance and effectiveness of the current IPTp program in Kenya. In addition, the commonly occurring Pfmdr1 N86-184F-D1246 haplotype associated with increased lumefantrine tolerance calls for surveillance of AL efficacy in Kenya, as well as consideration for a rotating artemisinin-combination therapy regimen.
Highlights
Antimalarial drug resistance has significantly hindered malaria control efforts and played a key role in shaping global drug policies since the first reports of chloroquine (CQ) resistance arose from Southeast Asia in 1957.1 Since because of widespread drug resistance, global recommendations for the first-line treatment of malaria have changed from CQ to sulfadoxine–pyrimethamine (SP), and again, most recently, from SP to artemisinin-combination therapy (ACT).[1]
As both CQ and SP drug resistance arose in Southeast Asia before spreading to Africa,[2] the emergence of ACT resistance in several Southeast Asian countries and recent report on the emergence of indigenous artemisinin-resistant Plasmodium falciparum in Africa[3] triggers major concern on the efficacy of malaria control programs in Africa where most of the global malaria burden falls.[4]
Significant changes in frequencies of drug resistance molecular markers were observed with changes in antimalarial drug policy and reported use over the 13-year study period in western Kenya
Summary
Antimalarial drug resistance has significantly hindered malaria control efforts and played a key role in shaping global drug policies since the first reports of chloroquine (CQ) resistance arose from Southeast Asia in 1957.1 Since because of widespread drug resistance, global recommendations for the first-line treatment of malaria have changed from CQ to sulfadoxine–pyrimethamine (SP), and again, most recently, from SP to artemisinin-combination therapy (ACT).[1] As both CQ and SP drug resistance arose in Southeast Asia before spreading to Africa,[2] the emergence of ACT resistance in several Southeast Asian countries and recent report on the emergence of indigenous artemisinin-resistant Plasmodium falciparum in Africa[3] triggers major concern on the efficacy of malaria control programs in Africa where most of the global malaria burden falls.[4]. We examined whether the observed amino acid changes have been undergoing selection through a longitudinal comparison of mutation frequencies in these drug resistance genes.
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