Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa

Holmgren, Gabrielle; Hamrin, Johan; Svärd, Jenny; Mårtensson, Andreas; Gil, José Pedro; Björkman, Anders

doi:10.1016/j.meegid.2007.03.005

Cited by 109 publications

(132 citation statements)

References 34 publications

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“…The recent detection of ART resistance in Southeast Asia (10), in regions where the partner drug (mefloquine) is failing (6), supports the importance of maintaining the integrity of the efficacy of the long-standing partner drug. With its very long half-life, PPQ is potentially at risk in settings of high transmission, due to the possibility of a large posttreatment drug resistance selection window, akin to what has been seen with other ACTs (15,31). This, associated with the knowledge that PPQ resistance has already emerged in the past (13), commands urgency regarding the research of its molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…However, P. falciparum resistance to several partner drugs, namely, artesunate-mefloquine (25), artemether-lumefantrine (26,31), and artesunate-amodiaquine (15), has been documented. These early signs have been associated with decreased parasite responses to the slowly eliminated partner drugs, a phenomenon believed to be accelerated in circumstances of high transmission due to the exposure of reinfecting parasites to subtherapeutic concentrations (14).…”

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confidence: 99%

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pfmdr1 Amplification Is Related to Increased Plasmodium falciparum In Vitro Sensitivity to the Bisquinoline Piperaquine

Veiga

Ferreira

Malmberg

et al. 2012

Antimicrob Agents Chemother

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The 4-aminoquinoline bisquinoline piperaquine is an important partner drug in one of the presently recommended artemisinin combination therapies. Recent clinical trials have confirmed its high efficacy in combination with dihydroartemisinin. Resistance to piperaquine alone has, however, been documented. Amplification in copy number of the Plasmodium falciparum multidrug resistance locus on chromosome 5, containing the pfmdr1 gene, has been shown to confer resistance to structurally unrelated antimalarials. Through the determination of the 50% inhibitory concentrations (IC 50 s) and IC 90 s for piperaquine and chloroquine in a set of 46 adapted P. falciparum cultures originating from the Thai-Burmese border, we have characterized the regions around the pfmdr1 gene and identified a significant association between the presence of pfmdr1 duplications and enhanced sensitivity to piperaquine (P ‫؍‬ 0.005 for IC 50 and P ‫؍‬ 0.002 for IC 90 ) and chloroquine, reaching statistical significance at IC 90 s (P ‫؍‬ 0.026). These results substantiate the potential importance of pfmdr1 copy number amplifications in the efficacy of the combination therapy piperaquine-dihydroartemisinin. It supports the rational use of 4-aminoquinolines and artemisininbased compounds, as they independently select for mutually incompatible combinations of mutations.A rtemisinin combination therapy (ACT) is instrumental in the global decrease of Plasmodium falciparum malaria in recent years. However, P. falciparum resistance to several partner drugs, namely, artesunate-mefloquine (25), artemether-lumefantrine (26, 31), and artesunate-amodiaquine (15), has been documented. These early signs have been associated with decreased parasite responses to the slowly eliminated partner drugs, a phenomenon believed to be accelerated in circumstances of high transmission due to the exposure of reinfecting parasites to subtherapeutic concentrations (14).A more recent ACT, dihydroartemisinin-piperaquine (DHA-PPQ), has been widely used in Southeast Asia and is now ready to be launched in sub-Saharan Africa. PPQ is a bisquinoline, structurally a 4-aminoquinoline-based antimalarial like chloroquine (CQ). Piperaquine is not a recent newcomer, having been extensively used in monotherapy regimens in the southern regions of China in the 1970s and 1980s, as a response to the rise of CQ resistance. Later, it was adopted by the national Vietnamese malaria control program in several formulations (9). The most recent development of PPQ-based ACT is commercially known as Artekin (Hollekyn Pharmaceuticals, China) or Eurartesim (SigmaTau, Italy), each tablet containing 40 mg dihydroartemisinin plus 320 mg piperaquine phosphate.DHA-PPQ has shown excellent efficacy in recent clinical trials in Africa (1,4,17), making it a promising fixed-dose formulation for malaria treatment on the continent. Nevertheless, the PPQ long elimination half-life of Ͼ4 weeks after the standard 3-day course (2.25 mg/kg [of body weight] DHA and 18 mg/kg of piperaquine phosphate per day) raises concer...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

pfmdr1 Amplification Is Related to Increased Plasmodium falciparum In Vitro Sensitivity to the Bisquinoline Piperaquine

Veiga

Ferreira

Malmberg

et al. 2012

Antimicrob Agents Chemother

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“…3,15,24 SNPs at codons 86, 184, and 1246 of the Pfmdr-1 gene has been suggested to be markers of changes in parasite susceptibility to various drugs, including ACTs. [7][8][9][10] Initially, SNPs in Pfmdr-1 were associated with CQ and AQ resistance. 25 However, recent studies have suggested a relationship between SNPs in Pfmdr-1 and ACT drugs.…”

Section: Discussionmentioning

confidence: 99%

“…7,22 Similarly, this study also showed that the frequency of the N86-184F haplotype showed tendencies to increase, and N86-D1246 haplotypes increased in the years after AL introduction, largely supporting previous studies from Tanzania. 7,10,22 However, one study found recrudescent infections after artemisinin-AQ (ACT) treatment selected for 86Y, Y184, and 1246Y combinations, 8 indicating differences in selection by various ACT combination therapies.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the Pfmdr-1 86Y mutation has been associated with high CQ resistance if present along with the P. falciparum chloroquine resistance transporter ( Pfcrt ) K76T genotype, 5,6 whereas two studies have shown that the combination of Pfmdr-1 86Y, Y184, and 1246Y was selected by AQ monotherapy and increased the risk of treatment failure. 7,8 Conversely, when artesunate-AQ or artemether-lumefantrine (AL) was administered 7,8 the N86, 184F, and D1246 were selected. Similarly, in vivo selection of SNPs N86, 7, 9, 10 184F, 7,10 and D1246 7 of Pfmdr-1 after AL treatment has been reported.…”

Section: Introductionmentioning

confidence: 99%

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Prevalence of Single Nucleotide Polymorphisms in the Plasmodium falciparum Multidrug Resistance Gene (Pfmdr-1) in Korogwe District in Tanzania Before and After Introduction of Artemisinin-Based Combination Therapy

Thomsen

Ishengoma²,

Mmbando³

et al. 2011

The American Society of Tropical Medicine and Hygiene

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Abstract. Tanzania implemented artemether-lumefantrine (AL) as the first-line treatment for uncomplicated malaria in November of 2006 because of resistance to sulfadoxine-pyrimethamine. AL remains highly efficacious, but widespread use may soon facilitate emergence of artemisinin tolerance/resistance, which initially may be detected at the molecular level as temporal changes in the frequency of single nucleotide polymorphisms (SNPs) in the Pfmdr-1 gene associated with AL resistance. In Tanzania The observed changes may be because of introduction of AL, and if so, this finding gives cause for concern and argues for continued surveillance of these molecular markers.

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Artesunate plus amodiaquine combination therapy: reviewing the evidence

Adjei

Kudzi

Dodoo

et al. 2009

Drug Development Research

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The combination of artesunate plus amodiaquine (AS/AQ) is, next to the fixed-dose combination of artemether-lumefantrine, the most widely adopted artemisinin combination therapy (ACT) regimen being used as first-line therapy for uncomplicated malaria by National Malaria Control Programs in sub-Saharan Africa. In contrast to other ACT regimens in current use, on which reviews of the available evidence on safety and efficacy have been periodically published, no, or few summaries of the extensive data available on the safety and efficacy of this widely used ACT are available in the published literature. The available evidence on AS/AQ indicates high efficacy of this combination in children, variable tolerability in adults, and an interaction between artesunate and amodiaquine that could have implications for medium term efficacy or safety of the combination. In this article, a review of the available evidence on the efficacy and safety on AS/AQ, with a particular focus on parameters that could have operational significance for malaria control in endemic areas, is presented and discussed. Drug Dev Res 71:33-43, 2010.

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Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa

Cited by 109 publications

References 34 publications

pfmdr1 Amplification Is Related to Increased Plasmodium falciparum In Vitro Sensitivity to the Bisquinoline Piperaquine

pfmdr1 Amplification Is Related to Increased Plasmodium falciparum In Vitro Sensitivity to the Bisquinoline Piperaquine

Prevalence of Single Nucleotide Polymorphisms in the Plasmodium falciparum Multidrug Resistance Gene (Pfmdr-1) in Korogwe District in Tanzania Before and After Introduction of Artemisinin-Based Combination Therapy

Artesunate plus amodiaquine combination therapy: reviewing the evidence

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