Recent uptake of intermittent preventive treatment during pregnancy with sulfadoxine–pyrimethamine is associated with increased prevalence of Pfdhfr mutations in Bobo-Dioulasso, Burkina Faso

Abstract

BackgroundThe impact of sulfadoxine–pyrimethamine (SP) used as intermittent preventive treatment during pregnancy (IPTp-SP) on mutant parasite selection has been poorly documented in Burkina Faso. This study sought first to explore the relationship between IPTp-SP and the presence of mutant parasites. Second, to assess the relationship between the mutant parasites and adverse pregnancy outcomes.Methods From September to December 2010, dried blood spots (DBS) were collected during antenatal care visits and at delivery from 109 pregnant women with microscopically confirmed falciparum malaria infection. DBS were analysed by PCR–restriction fragment length polymorphism (PCR–RFLP) for the polymorphisms at codons 51, 59, 108, and 164 of the Pfdhfr gene and codons 437 and 540 in the Pfdhps gene.ResultsBoth the Pfdhfr and Pfdhps genes were successfully genotyped in 92.7% (101/109) of the samples. The prevalence of Pfdhfr mutations N51I, C59R and S108N was 71.3, 42.6 and 64.4%, respectively. Overall, 80.2% (81/101) of samples carried the Pfdhps A437G mutation. None of the samples had the Pfdhfr I164L and the Pfdhps K540E mutations. The prevalence of the triple mutation N51I + C59R + S108N was 25.7% (26/101). The use of IPTp-SP was associated with a threefold increased odds of Pfdhfr C59R mutation [crude OR 3.29; 95% CI (1.44–7.50)]. Pregnant women with recent uptake of IPTp-SP were at higher odds of both the Pfdhfr C59R mutation [adjusted OR 4.26; 95% CI (1.64–11.07)] and the Pfdhfr intermediate-to-high resistance, i.e., ≥ 2 Pfdhfr mutations [adjusted OR 3.45; 95% CI (1.18–10.07)]. There was no statistically significant association between the presence of the Pfdhfr intermediate-to-high resistance and parasite densities or both maternal haemoglobin level and anaemia.ConclusionThe data indicate that despite the possibility that IPTp-SP contributes to the selection of resistant parasites, it did not potentiate pregnancy-associated malaria morbidity, suggesting the continuation of SP use as IPTp in Burkina Faso.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1695-1) contains supplementary material, which is available to authorized users.

Nationwide Monitoring for Plasmodium falciparum Drug-Resistance Alleles to Chloroquine, Sulfadoxine, and Pyrimethamine, Haiti, 2016–2017

“…This observation is consistent with the hypothesis that the S108N mutation does not affect fitness of the parasites carrying this allele (41). S108N mutation confers only low-level resistance to pyrimethamine, and the presence of >3 mutations (leading to the N51I/C59R/S108N triple mutant) is required for high-level resistance (42)(43)(44)(45). Outside of pyrimethamine, the atovaquone/proguanil chemoprophylactic regimen often used by travelers to Haiti might also have the potential to induce drug pressure on the Pfdhfr gene and might lose efficacy if multiple codon mutations would arise in the gene (46).…”

Mutation Profile of pfdhfr and pfdhps in Plasmodium falciparum among Returned Chinese Migrant Workers from Africa

“…SP is no longer used for current clinical treatment of malaria in Africa due to drug resistance, but it still serves as prophylaxis and is implemented routinely as an intermittent preventive treatment (IPT) for malaria, particularly during pregnancy (IPTp) and in infants (IPTi) (3,4). The emergence of SP resistance is caused by substitutions in two enzymes, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), in the folate synthesis pathway (5,6). It has been associated with A16V, N51I, C59R, S108N, and I164L mutations in the pfdhfr gene, which confer pyrimethamine resistance, as well as I431V, S436A/F, A437G, K540E, A581G, and A613S/T mutations in the pfdhps gene, which confer sulfadoxine resistance (7).…”

Resistance of <i>Plasmodium falciparum</i> to Sulfadoxine-Pyrimethamine (<i>Dhfr</i> and <i>Dhps</i>) and Artemisinin and Its Derivatives (K13): A Major Challenge for Malaria Elimination in West Africa

“…The distribution of mutations at codons 59, 540 and triple/quadruple/quintuple mutations of the pfdhfr and pfdhps genes would be highly predictive of treatment failures in SP [42]. Most of these SP resistance markers present at the majority of sites in West Africa could seriously compromise the effectiveness of intermittent preventive treatment for years to come [10] [43]. This situation would call for new approaches and new strategies with regard to the efficient use of SP in West Africa and in general in sub-Saharan Africa.…”

“…In the case of Sub-Saharan Africa, the data in the literature are controversial on the probable relationship between the presence of k13 mutants and resistance to artemisinin [4] [7]. On the other hand, cases of resistance to SP have already been demonstrated by several authors, while SP continues to be offered as an intermittent and preventive treatment against malaria [5] [8] [9] [10] [11]. In the current context of West Africa, the insufficiency of information and the divergence of the conclusions of most of the studies on the Plasmodium resistance genes to SP and to artemisinin contribute to disseminate uncertainties on the choice of certain molecules such as SP for intermittent preventive treatment (IPT) and the probable presence of mutations in the k13 gene associated with resistance to artemisinin [12].…”