Plasmodium falciparum Polymorphisms Associated with Ex Vivo Drug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin
In: ISSN: 0066-4804, 2014
academicJournal
Zugriff:
International audience ; Artemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association of Plasmodium falciparum polymorphisms and ex vivo drug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine ( n = 96), fixed-dose artesunate-amodiaquine ( n = 96), and sulfadoxine-pyrimethamine ( n = 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed. pfcrt , pfmdr1 , pfmrp1 , pfdhfr , and pfdhps polymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates by Plasmodium lactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC 50 ) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC 50 s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for the pfmdr1 N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance of pfmdr1 N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC 50 s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection of pfmdr1 loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical, ex vivo , ...
Titel: |
Plasmodium falciparum Polymorphisms Associated with Ex Vivo Drug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin
|
---|---|
Autor/in / Beteiligte Person: | Dahlström, Sabina ; Aubouy, Agnès ; Maïga-Ascofaré, Oumou ; Faucher, Jean-François ; Wakpo, Abel ; Ezinmègnon, Sèm ; Massougbodji, Achille ; Houzé, Pascal ; Kendjo, Eric ; Deloron, Philippe ; Le Bras, Jacques ; Houzé, Sandrine ; Institut de médecine et d'épidémiologie appliquée AP-HP Hôpital Bichat-Claude Bernard (IMEA) ; AP-HP - Hôpital Bichat - Claude Bernard Paris ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) ; Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261) ; Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité) ; Pharmacochimie et Biologie pour le Développement (PHARMA-DEV) ; Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT) ; Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT) ; Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon) ; Centre d’Etude et de Recherche sur le Paludisme Associé à la Grossesse et l’Enfance Cotonou, Bénin (CERPAGE) ; Université d’Abomey-Calavi = University of Abomey Calavi (UAC) ; Service de Biochimie AP-HP Hôpital Saint-Louis, Paris ; Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal Paris ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) ; Institute for Tropical Medicine = Institut für Tropenmedizin, Reisemedizin, Humanparasitolgie Tübingen, Allemagne (ITM) ; Eberhard Karls Universität Tübingen = University of Tübingen |
Link: | |
Zeitschrift: | ISSN: 0066-4804, 2014 |
Veröffentlichung: | HAL CCSD ; American Society for Microbiology, 2014 |
Medientyp: | academicJournal |
DOI: | 10.1128/AAC.01790-12 |
Schlagwort: |
|
Sonstiges: |
|