Low prevalence of highly sulfadoxine‐resistant dihydropteroate synthase alleles in Plasmodium falciparum isolates in Benin

Abstract

Background In 2004, in response to high levels of treatment failure associated with sulfadoxine-pyrimethamine (SP) resistance, Benin changed its first-line malaria treatment from SP to artemisinin-based combination therapy for treatment of uncomplicated Plasmodium falciparum malaria. Resistance to SP is conferred by accumulation of single nucleotide polymorphisms (SNPs) in P. falciparum genes involved in folate metabolism, dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps), targeted by pyrimethamine and sulfadoxine, respectively. Because SP is still used for intermittent preventive treatment in pregnant women (IPTp) and seasonal malaria chemoprevention (SMCP) in Benin, the prevalence of Pfdhfr and Pfdhps SNPs in P. falciparum isolates collected in 2017 were investigated. Methods This study was carried out in two sites where the transmission of P. falciparum malaria is hyper-endemic: Klouékanmey and Djougou. Blood samples were collected from 178 febrile children 6–59 months old with confirmed uncomplicated P. falciparum malaria and were genotyped for SNPs associated with SP resistance. Results The Pfdhfr triple mutant IRN (N51I, C59R, and S108N) was the most prevalent (84.6%) haplotype and was commonly found with the Pfdhps single mutant A437G (50.5%) or with the Pfdhps double mutant S436A and A437G (33.7%). The quintuple mutant, PfdhfrIRN/PfdhpsGE (A437G and K540E), was rarely observed (0.8%). The A581G and A613S mutant alleles were found in 2.6 and 3.9% of isolates, respectively. Six isolates (3.9%) were shown to harbour a mutation at codon I431V, recently identified in West African parasites. Conclusions This study showed that Pfdhfr triple IRN mutants are near fixation in this population and that the highly sulfadoxine-resistant Pfdhps alleles are not widespread in Benin. These data support the continued use of SP for chemoprevention in these study sites, which should be complemented by periodic nationwide molecular surveillance to detect emergence of resistant genotypes.

Prevalence of Mutations in the Pfdhfr, Pfdhps, and Pfmdr1 Genes of Malarial Parasites Isolated from Symptomatic Patients in Dogondoutchi, Niger

“…These results could be explained by high drug pressure, as sulfadoxine pyrimethamine has been used in Niger in the chemoprevention of malaria in pregnant women and children for several years [11]. Our results match those found in other countries in Africa [24][25][26][27][28][29]. In countries with high drug pressure, these mutations are the main cause of decreased sulfadoxine pyrimethamine efficacy [30,31].…”

Molecular Determinants of Sulfadoxine-Pyrimethamine Resistance in Plasmodium falciparum Isolates from Central Africa between 2016 and 2021: Wide Geographic Spread of Highly Mutated Pfdhfr and Pfdhps Alleles

“…Notably, according to our study, the novel mutation I431V, which has been widespread in Nigeria in recent years ( 32 ), has emerged in more African countries ( 23 , 33 , 34 ). We detected it in isolates from seven of the eight countries from which malaria was exported, especially in Chad (20.00%), Equatorial Guinea (10.81%), Congo DR (9.09%), Cameroon (8.47%), and Congo (8.33%).…”

Antimalarial drug resistance in the Central and Adamawa regions of Cameroon: Prevalence of mutations in P. falciparum crt, Pfmdr1, Pfdhfr and Pfdhps genes

“…The octal mutant genotype which combines the Pfdhfr N51I, C59R, S108N and Pfdhps I431V, S436A, A437G, A581G, A613S (IRN/VAGKGS) could be strongly associated with SP failure in Central Africa for which the efficacy of IPTp-SP may be limited [ 9 ]. However, its role in parasite resistance to SP has yet to be described [ 51 ].…”