Selection of N86F184D1246 haplotype of Pfmrd1 gene by artemether–lumefantrine drug pressure on Plasmodium falciparum populations in Senegal

Mbaye, Aminata; Dièye, Baba; Ndiaye, Yaye Dié; Bei, Amy K.; Affara, Muna; Déme, Awa B.; Yade, Mamadou Samb; Diongue, Khadim; Gaye, Amy; Ndiaye, Ibrahima; Ndiaye, Tolla; Sy, Mouhamad; Diallo, Mama Sy; Badiane, Aïda Sadikh; Ndiaye, Mouhamadou; Seck, Mame Cheikh; Sy, Ngayo; Koïta, Ousmane; Krogstad, Donald J.; Nwakanma, Davis; Ndiaye, Daouda

doi:10.1186/s12936-016-1490-4

Cited by 36 publications

(39 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AL also selects for other pfmdr1 haplotypes, like the NYD, which showed a steady increase in frequencies between temporal populations ( 39 ). This is consistent with studies in West Africa that found selection of these haplotypes by AL ( 40 – 42 ). Considering the risk to AL efficacy, an extended study of the temporal trends and association of these alleles with drug efficacy as parasite prevalence reduces could guide policy on ACTs in The Gambia.…”

Section: Discussionsupporting

confidence: 92%

Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia

Amambua-Ngwa

Okebe

Mbye

et al. 2017

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Antimalarial interventions have yielded a significant decline in malaria prevalence in The Gambia, where artemether-lumefantrine (AL) has been used as a first-line antimalarial for a decade. Clinical Plasmodium falciparum isolates collected from 2012 to 2015 were analyzed ex vivo for antimalarial susceptibility and genotyped for drug resistance markers (pfcrt K76T, pfmdr1 codons 86, 184, and 1246, and pfk13) and microsatellite variation. Additionally, allele frequencies of single nucleotide polymorphisms (SNPs) from other drug resistance-associated genes were compared from genomic sequence data sets from 2008 (n = 79) and 2014 (n = 168). No artemisinin resistance-associated pfk13 mutation was found, and only 4% of the isolates tested in 2015 showed significant growth after exposure to dihydroartemisinin. Conversely, the 50% inhibitory concentrations (IC50s) of amodiaquine and lumefantrine increased within this period. pfcrt 76T and pfmdr1 184F mutants remained at a prevalence above 80%. pfcrt 76T was positively associated with higher IC50s to chloroquine. pfmdr1 NYD increased in frequency between 2012 and 2015 due to lumefantrine selection. The TNYD (pfcrt 76T and pfmdr1 NYD wild-type haplotype) also increased in frequency following AL implementation in 2008. These results suggest selection for pfcrt and pfmdr1 genotypes that enable tolerance to lumefantrine. Increased tolerance to lumefantrine calls for sustained chemotherapeutic monitoring in The Gambia to minimize complete artemisinin combination therapy (ACT) failure in the future.

show abstract

Section: Discussionsupporting

confidence: 92%

Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia

Amambua-Ngwa

Okebe

Mbye

et al. 2017

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…In multivariate analysis, none of the Pfmdr1 alleles had no significant association with treatment failure or risk of new-infections after treatment with ASAQ. In AL treatment arm, patients harbouring Pfmdr1 -184F had significantly higher risk of new-infection, in line with a study that reported an association between lumefantrine and Pfmdr1 F184 in ex-vivo assay [ 32 ]. Interestingly, patients with anemia were increasingly at high risk of recrudescence in AL treatment arm, this may be supported the fact that the risk of acquiring anaemia is high in patients with high parasite density (<200,000/μL)) which was shown to be an independent risk factor for clinical treatment failure by up to 60% for the different antimalarial treatment[ 33 ].…”

Section: Discussionsupporting

confidence: 84%

Impact of treatment and re-treatment with artemether-lumefantrine and artesunate-amodiaquine on selection of Plasmodium falciparum multidrug resistance gene-1 polymorphisms in the Democratic Republic of Congo and Uganda

Baraka¹,

Mavoko²,

Nabasumba³

et al. 2018

PLoS ONE

View full text Add to dashboard Cite

BackgroundThe emergence of resistance against artemisinin combination treatment is a major concern for malaria control. ACTs are recommended as the rescue treatment, however, there is limited evidence as to whether treatment and re-treatment with ACTs select for drug-resistant P. falciparum parasites. Thus, the purpose of the present study is to investigate the impact of (re-)treatment using artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) on the selection of P. falciparum multidrug resistance-1 (Pfmdr1) alleles in clinical settings.MethodsP. falciparum positive samples were collected from children aged 12–59 months in a clinical trial in DR Congo and Uganda. Pfmdr1 single nucleotide polymorphisms (SNPs) analysis at codons N86Y, Y184F, and D1246Y were performed at baseline and post-treatment with either AL or ASAQ as a rescue treatment using nested PCR followed by restriction fragment length polymorphism (RFLP) assays.ResultsThe pre-treatment prevalence of Pfmdr1 N86 and D1246Y varied significantly between the sites, (p>0.001) and (p = 0.013), respectively. There was borderline significant directional selection for Pfmdr1 184F in recurrent malaria infections after treatment with AL in Uganda site (p = 0.05). Pfmdr1 NFD haplotype did not significantly change in post-treatment infections after re-treatment with either AL or ASAQ. Comparison between pre-treatment and post-treatment recurrences did not indicate directional selection of Pfmdr1 N86, D1246 alleles in the pre-RCT, RCT and post-RCT phases in both AL and ASAQ treatment arms. Pfmdr1 86Y was significantly associated with reduced risk of AL treatment failure (RR = 0.34, 95% CI:0.11–1.05, p = 0.04) while no evidence for D1246 allele (RR = 1.02; 95% CI: 0.42–2.47, p = 1.0). Survival estimates showed that the Pfmdr1 alleles had comparable mean-time to PCR-corrected recrudescence and new infections in both AL and ASAQ treatment arms.ConclusionWe found limited impact of (re-)treatment with AL or ASAQ on selection for Pfmdr1 variants and haplotypes associated with resistance to partner drugs. These findings further supplement the evidence use of same or alternative ACTs as a rescue therapy for recurrent P.falciparum infections. Continued monitoring of genetic signatures of resistance is warranted to timely inform malaria (re-)treatment policies and guidelines.

show abstract

“…An association was found between the presence of the 76T allele and the decrease in sensitivity to chloroquine (p = 0.0195) but not to amodiaquine (0.0539) and piperaquine (0.9370). A decrease in ex vivo sensitivity and an increase in the prevalence of the N86Y mutation relationship was not significantly found with amodiaquine (p = 0.5290) and the geometric mean for piperaquine was very low compared to that found in other countries [30–34]. These compounds are currently used in combination with dihydroartemisinin for piperaquine, SP and artesunate for amodiaquine.…”

Section: Discussionmentioning

confidence: 92%

Ex vivo susceptibility and genotyping of Plasmodium falciparum isolates from Pikine, Senegal

Mbaye

Gaye

Dièye

et al. 2017

Malar J

Self Cite

View full text Add to dashboard Cite

BackgroundThe monitoring of Plasmodium falciparum sensitivity to anti-malarial drugs is a necessity for effective case management of malaria. This species is characterized by a strong resistance to anti-malarial drugs. In Senegal, the first cases of chloroquine resistance were reported in the Dakar region in 1988 with nearly 7% population prevalence, reaching 47% by 1990. It is in this context that sulfadoxine–pyrimethamine temporarily replaced chloroquine as first line treatment in 2003, pending the introduction of artemisinin-based combination therapy in 2006. The purpose of this study is to assess the ex vivo sensitivity to different anti-malarial drugs of the P. falciparum population from Pikine.MethodsFifty-four samples were collected from patients with non-complicated malaria and aged between 2 and 20 years in the Deggo health centre in Pikine in 2014. An assay in which parasites are stained with 4′, 6-di-amidino-2-phenylindole (DAPI), was used to study the ex vivo sensitivity of isolates to chloroquine, amodiaquine, piperaquine, pyrimethamine, and dihydroartemisinin. High resolution melting was used for genotyping of pfdhps, pfdhfr, pfmdr1, and pfcrt genes.ResultsThe mean IC50s of chloroquine, amodiaquine, piperaquine, dihydroartemisinin, and pyrimethamine were, respectively, 39.44, 54.02, 15.28, 2.23, and 64.70 nM. Resistance mutations in pfdhfr gene, in codon 437 of pfdhps gene, and an absence of mutation at position 540 of pfdhps were observed. Mutations in codons K76T of pfcrt and N86Y of pfmdr1 were observed at 51 and 11% population prevalence, respectively. A relationship was found between the K76T and N86Y mutations and ex vivo resistance to chloroquine.ConclusionAn increase in sensitivity of isolates to chloroquine was observed. A high sensitivity to dihydroartemisinin was observed; whereas, a decrease in sensitivity to pyrimethamine was observed in the parasite population from Pikine.

show abstract

Selection of N86F184D1246 haplotype of Pfmrd1 gene by artemether–lumefantrine drug pressure on Plasmodium falciparum populations in Senegal

Cited by 36 publications

References 34 publications

Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia

Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia

Impact of treatment and re-treatment with artemether-lumefantrine and artesunate-amodiaquine on selection of Plasmodium falciparum multidrug resistance gene-1 polymorphisms in the Democratic Republic of Congo and Uganda

Ex vivo susceptibility and genotyping of Plasmodium falciparum isolates from Pikine, Senegal

Contact Info

Product

Resources

About