Abstract
BackgroundThere are concerns that resistance to artemisinin-based combination therapy might emerge in Kenya and sub-Saharan Africa (SSA) in the same pattern as was with chloroquine and sulfadoxine–pyrimethamine. Single nucleotide polymorphisms (SNPs) in critical alleles of pfmdr1 gene have been associated with resistance to artemisinin and its partner drugs. Microsatellite analysis of loci flanking genes associated with anti-malarial drug resistance has been used in defining the geographic origins, dissemination of resistant parasites and identifying regions in the genome that have been under selection.MethodsThis study set out to investigate evidence of selective sweep and genetic lineages in pfmdr1 genotypes associated with the use of artemether–lumefantrine (AL), as the first-line treatment in Kenya. Parasites (n = 252) from different regions in Kenya were assayed for SNPs at codons 86, 184 and 1246 and typed for 7 neutral microsatellites and 13 microsatellites loci flanking (± 99 kb) pfmdr1 in Plasmodium falciparum infections.ResultsThe data showed differential site and region specific prevalence of SNPs associated with drug resistance in the pfmdr1 gene. The prevalence of pfmdr1 N86, 184F, and D1246 in western Kenya (Kisumu, Kericho and Kisii) compared to the coast of Kenya (Malindi) was 92.9% vs. 66.7%, 53.5% vs. to 24.2% and 96% vs. to 87.9%, respectively. The NFD haplotype which is consistent with AL selection was at 51% in western Kenya compared to 25% in coastal Kenya.ConclusionSelection pressures were observed to be different in different regions of Kenya, especially the western region compared to the coastal region. The data showed independent genetic lineages for all the pfmdr1 alleles. The evidence of soft sweeps in pfmdr1 observed varied in direction from one region to another. This is challenging for malaria control programs in SSA which clearly indicate effective malaria control policies should be based on the region and not at a country wide level.
Highlights
There are concerns that resistance to artemisinin-based combination therapy might emerge in Kenya and sub-Saharan Africa (SSA) in the same pattern as was with chloroquine and sulfadoxine–pyrimethamine
Regardless of the emergence and spread of resistance to artemisinin-based combination therapy (ACT) in Southeast Asia (SEA) [1,2,3,4,5], ACT is still widely used as the first-line treatment for uncomplicated malaria worldwide [5] and has maintained high efficacy in sub-Saharan Africa (SSA) with fast clearance rates [5, 6]
There is heightened concern that resistance to ACT in SEA might follow the same pattern in expansion globally as previously did for chloroquine and SP [9]
Summary
There are concerns that resistance to artemisinin-based combination therapy might emerge in Kenya and sub-Saharan Africa (SSA) in the same pattern as was with chloroquine and sulfadoxine–pyrimethamine. There is heightened concern that resistance to ACT in SEA might follow the same pattern in expansion globally as previously did for chloroquine and SP [9] With this in mind, routine monitoring of the therapeutic efficacy of ACT is critical in detecting early changes in Plasmodium falciparum sensitivity to anti-malarial drugs, and deemed necessary for timely enactment of changes to treatment policy [10]. Longitudinal studies have shown the prevalence of pfcrt 76T and pfmdr1 86Y reached over 90% in western and coastal regions of Kenya before the introduction of ACT, and reversed to the sensitive genotypes with the withdrawal of chloroquine and the introduction of AL [31,32,33,34]. Recent studies have suggested changes in the prevalence of these alleles can be a sensitive indicator of selection of parasite populations by AL which can be used to signal early reduced susceptibility [30, 35]
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