Persistence of Sulfadoxine-Pyrimethamine Resistance Despite Reduction of Drug Pressure in Malawi

Artimovich, Elena; Schneider, Kristan A.; Taylor, Terrie E.; Kublin, James G.; Dzinjalamala, Fraction K.; Escalante, Ananías A.; Plowe, Christopher V.; Laufer, Miriam K.; Takala-Harrison, Shannon

doi:10.1093/infdis/jiv078

Cited by 28 publications

(30 citation statements)

References 33 publications

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“…A similarly high prevalence of this dhps triple mutation has been recently reported in several African countries and is associated with SP treatment failure . It has been suggested that the dhps 581G mutation normally occurs after the dhfr triple (51I/59R/108N) mutation . This was not true for the findings of the current study, where none of the dhps 581G mutations occurred with the dhfr triple mutation, but rather with the dhfr double (51I/108N).…”

Section: Discussionsupporting

confidence: 61%

Efficacy of artesunate + sulphadoxine/pyrimethamine and artemether + lumefantrine and dhfr and dhps mutations in Somalia: evidence for updating the malaria treatment policy

Warsame

Hassan

Hassan³

et al. 2017

Tropical Med Int Health

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The findings demonstrate a failing first-line treatment (AS + SP), with a failure rate above the threshold (10%) for policy change, and a high prevalence of quintuple mutations. In contrast, AL was highly efficacious. Based on these findings and the results from a previous AS + SP study, AL was selected to replace AS + SP as the first-line treatment for uncomplicated malaria in Somalia in 2016. Dihydroartemisinin + piperaquine (DHA + PPQ) has been recommended as the second-line treatment. Routine monitoring of recommended ACTs should continue to inform treatment policy.

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Section: Discussionsupporting

confidence: 61%

Efficacy of artesunate + sulphadoxine/pyrimethamine and artemether + lumefantrine and dhfr and dhps mutations in Somalia: evidence for updating the malaria treatment policy

Warsame

Hassan

Hassan³

et al. 2017

Tropical Med Int Health

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“…The A613S mutation, which is rarely found in Africa, was present in only one isolate. No A613T mutations described in Asia and East Africa were found in our study 24,60,61…”

Section: Discussionmentioning

confidence: 43%

Prevalence of <em>Plasmodium falciparum</em> antimalarial drug resistance genes in Southeastern Gabon from 2011 to 2014

Voumbo-Matoumona¹,

Kouna²,

Madamet³

et al. 2018

IDR

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PurposeThe introduction of artemisinin-based combination therapies (ACTs) in treating uncomplicated malaria and sulfadoxine–pyrimethamine (SP) as intermittent preventive treatment during pregnancy drastically decreased the burden of malarial disease around the world. However, ACTs are known to select for drug resistance markers. In Gabon, artemether–lumefantrine induced an increase in the prevalence of N86-Pfmdr1, which is associated with treatment failure. However, little data are available regarding resistance markers in Southeastern Gabon. This study aimed to evaluate the evolution of resistance haplotypes in the Pfcrt, Pfdhps, Pfdhfr, and PfK13 genes from 2011 to 2014 in Southeastern Gabon.MethodsA total of 233 Plasmodium falciparum DNA samples were collected from febrile pediatric patients in South Gabon: Franceville, an urban area; Koulamoutou, a semi-urban area; and Lastourville, a rural area. Pfcrt, Pfdhps, Pfdhfr, and the propeller domain of PfK13 were sequenced for all isolates.ResultsThe overall prevalence (3.7%–11.5%) of the wild-type haplotype Pfcrt 72-76 CVMNK was not significantly different between 2011 and 2014 in Southeast Gabon. For Pfdhfr (codons 51, 59, 108, 164), the IRNI triple-mutant haplotype was the most prevalent (>89.0%). The ICNI and NCNI mutant haplotypes and the NCSI wild-type haplotype showed a minor prevalence. There were no differences in the distributions of these haplotypes across the 4 years and the three study sites. For Pfdhps, the AAKAA and SGKAA mutant haplotypes and the SAKAA wild-type haplotype were similarly present in the three areas during the study period. The AGKAA double mutant was first observed in 2013 in Franceville and in 2014 in Koulamoutou and Lastourville. Interestingly, only the A578S mutation (0.4%) and two new A494V (0.4%) and V504A (0.9%) mutations were found in PfK13.ConclusionDespite the withdrawal of chloroquine, the frequency of the resistant allele 76T remained high in the south of Gabon. Moreover, a high level of resistant haplotypes against IPTp-SP was found.

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“…As one of the first African countries to switch from chloroquine to sulfadoxine/pyrimethamine (SP) in 1993, and the last to switch from SP to ACT in 2007, Malawi stands out from the rest of Africa in having a significantly prolonged exposure to SP [4]. Whilst this meant the reduced frequency of chloroquine resistance alleles in the Plasmodium population [5], the same cannot currently be said for SP resistance [6]. Resistance to SP is thought to be a cumulative process whereby mutations are successively acquired in both the dhfr (S108N, N51I, C59R, then I164L) and dhps (A437G then K540E) genes.…”

Section: Introductionmentioning

confidence: 99%

“…These dhps and dhfr polymorphisms persist at high frequency in the Malawian Plasmodium population despite exposure to SP being reduced. Retention of these variants may be due in part to the use of SP in intermittent preventive treatment for pregnant women (IPTp) or a lower than expected fitness cost associated with these variants [6]. The scaling up of the distribution of ACT and IPTp contributed to a 36% drop in the mortality rate between 2004 and 2014 for children under 5 years of age, to an estimated 85 deaths per 1000 live births [2].…”

Section: Introductionmentioning

confidence: 99%

Characterizing the impact of sustained sulfadoxine/pyrimethamine use upon the Plasmodium falciparum population in Malawi

Ravenhall

Benavente

Mipando

et al. 2016

Malar J

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BackgroundMalawi experienced prolonged use of sulfadoxine/pyrimethamine (SP) as the front-line anti-malarial drug, with early replacement of chloroquine and delayed introduction of artemisinin-based combination therapy. Extended use of SP, and its continued application in pregnancy is impacting the genomic variation of the Plasmodium falciparum population.MethodsWhole genome sequence data of P. falciparum isolates covering 2 years of transmission within Malawi, alongside global datasets, were used. More than 745,000 SNPs were identified, and differences in allele frequencies between countries assessed, as well as genetic regions under positive selection determined.ResultsPositive selection signals were identified within dhps, dhfr and gch1, all components of the parasite folate pathway associated with SP resistance. Sitting predominantly on a dhfr triple mutation background, a novel copy number increase of ~twofold was identified in the gch1 promoter. This copy number was almost fixed (96.8% frequency) in Malawi samples, but found at less than 45% frequency in other African populations, and distinct from a whole gene duplication previously reported in Southeast Asian parasites.ConclusionsSP resistance selection pressures have been retained in the Malawian population, with known resistance dhfr mutations at fixation, complemented by a novel gch1 promoter duplication. The effects of the duplication on the fitness costs of SP variants and resistance need to be elucidated.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1634-6) contains supplementary material, which is available to authorized users.

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Persistence of Sulfadoxine-Pyrimethamine Resistance Despite Reduction of Drug Pressure in Malawi

Abstract: In contrast to the rapid and complete return of chloroquine-susceptible falciparum malaria after chloroquine was withdrawn from Malawi, a reemergence of SP efficacy is unlikely in the near future.

Cited by 28 publications

References 33 publications

Efficacy of artesunate + sulphadoxine/pyrimethamine and artemether + lumefantrine and dhfr and dhps mutations in Somalia: evidence for updating the malaria treatment policy

Efficacy of artesunate + sulphadoxine/pyrimethamine and artemether + lumefantrine and dhfr and dhps mutations in Somalia: evidence for updating the malaria treatment policy

Prevalence of <em>Plasmodium falciparum</em> antimalarial drug resistance genes in Southeastern Gabon from 2011 to 2014

Characterizing the impact of sustained sulfadoxine/pyrimethamine use upon the Plasmodium falciparum population in Malawi

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