Abstract
Antimalarial resistance is an inevitable feature of control efforts and a key threat to achieving malaria elimination. Plasmodium falciparum, the deadliest of several species causing human malaria, has developed resistance to essentially all antimalarials. This study sought to investigate the prevalence of molecular markers associated with resistance to sulfadoxine-pyrimethamine (SP) and artemether-lumefantrine (AL) in Southern and Western provinces in Zambia. SP is used primarily for intermittent preventive treatment during pregnancy, while AL is the first-line antimalarial for uncomplicated malaria in Zambia. Blood samples were collected from household members of all ages in a cross-sectional survey conducted during peak malaria transmission, April to May of 2017, and amplified by polymerase chain reaction (PCR). Amplicons were then analysed by high-resolution melt following PCR to identify mutations associated with SP resistance in the P. falciparum dihydrofolate reductase (Pfdhfr) and P. falciparum dihydropteroate synthase (Pfdhps) genes and lumefantrine resistance in the P. falciparum multi-drug resistance 1 (Pfmdr1) gene. Finally, artemether resistance was assessed in the P. falciparum Kelch 13 (PfK13) gene using nested PCR followed by amplicon sequencing. The results showed a high frequency of genotypic-resistant Pfdhps A437G (93.2%) and Pfdhfr C59R (86.7%), N51I (80.9%), and S108N (80.8%) of which a high proportion (82.4%) were quadruple mutants (Pfdhfr N51I, C59R, S108N +Pfdhps A437G). Pfmrd1 N86Y, Y186F, and D1246Y - NFD mutant haplotypes were observed in 41.9% of isolates. The high prevalence of quadruple dhps/dhfr mutants indicates strong antifolate drug pressure from SP or other drugs (e.g., co-trimoxazole). Three samples contained PfK13 mutations, two synonymous (T478 and V666) and one non-synonymous (A578S), none of which have been associated with delayed clearance. This suggests that artemisinin remains efficacious in Zambia, however, the moderately high prevalence of approximately 40% Pfmdr1 NFD mutations calls for close monitoring of AL.
Highlights
Antimalarial drug resistance is a key threat to eliminating malaria
For Zambia, mass drug administration (MDA) with an artemisinin-based combination therapy, given to populations of all ages with the exception of children under three months of age, has been added as an accelerator in Southern Province, an area selected for sub-national elimination (MOH, 2017)
Resistance to SP is mediated by mutations in two enzymes, namely Plasmodium falciparum dihydrofolate reductase (Pfdhfr), which confers resistance to pyrimethamine, and P. falciparum dihydropteroate synthetase (Pfdhps), which confers resistance to sulfadoxine (Cowman et al, 1988; Marks et al, 2005; Peterson et al, 1988)
Summary
Antimalarial drug resistance is a key threat to eliminating malaria. Strategies to eliminate the disease include early case diagnosis and prompt treatment using an effective and efficacious antimalarial (MOH, 2017). For Zambia, mass drug administration (MDA) with an artemisinin-based combination therapy (i.e., dihydroartemisinin-piperaquine [DHAP]), given to populations of all ages with the exception of children under three months of age, has been added as an accelerator in Southern Province, an area selected for sub-national elimination (MOH, 2017). Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by the World Health Organization in areas of Africa with moderate to high malaria transmission. While artemisinin-based therapies (ACTs) are used for treatment of malaria cases, namely artemether-lumefantrine (AL) for uncomplicated malaria with DHAP as an alternative, and injectable artesunate for severe malaria (MOH, 2014; WHO, 2015). To reduce the likelihood of selection for resistance, it is recommended to use drug combinations (Majori, 2004) and regularly monitor drug efficacy
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