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      Lack of artemisinin resistance in Plasmodium falciparum in northwest Benin after 10 years of use of artemisinin-based combination therapy Translated title: Absence de résistance à l’artémisinine chez Plasmodium falciparum dans le Nord-ouest du Bénin après dix ans d’utilisation de combinaisons thérapeutiques à base de dérivés d’artémisinine

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          Abstract

          Aim: In Benin, artemisinin-based combination therapy (ACT) has been recommended as the first-line treatment for uncomplicated Plasmodium falciparum malaria since 2004. The emergence in Southeast Asia of parasites that are resistant to artemisinins poses a serious threat to global control of this disease. The presence of artemisinin resistance genotypes in parasite populations in Benin is currently unknown. The present study investigated the prevalence of relevant K13-propeller gene polymorphisms in parasite isolates from the north-western region of Benin.

          Method: Plasmodium falciparum isolates were collected from children with a confirmed diagnosis of malaria aged 6 months to 5 years in two towns, Cobly and Djougou, in the north-western part of Benin. The study was conducted during the rainy season from July to November 2014 in local health facilities. The K13-propeller gene was amplified in parasite isolates using nested PCR and subsequently sequenced.

          Results: A total of 108 children were recruited into the study. The efficiency of amplification reactions was 72% (78/108). The propeller domain of the K13 gene was successfully sequenced in 78 P. falciparum isolates; all of them were wild type with no polymorphisms detectable.

          Conclusion: The absence of mutations in the K13 gene indicates that P. falciparum parasite populations in the study area are still fully susceptible to artemisinins.

          Translated abstract

          Contexte : Au Bénin, depuis 2004, les combinaisons thérapeutiques à base d’artémisinine ont été recommandées comme traitement de première intention du paludisme à Plasmodium falciparum non compliqué. L’émergence en Asie du Sud-Est de parasites qui sont résistants à l’artémisinine pose une menace sérieuse pour la lutte mondiale contre cette maladie. La présence de génotypes de résistance à l’artémisinine dans les populations de parasites au Bénin est actuellement inconnue. Cette étude a étudié la prévalence des polymorphismes du gène K13-propeller chez des parasites isolés de la région nord-ouest du Bénin.

          Méthodes : Les isolats de Plasmodium falciparum ont été recueillis auprès d’enfants ayant un diagnostic confirmé de paludisme, âgés de 6 mois à 5 ans, dans deux villes, Cobly et Djougou, dans la partie nord-ouest du Bénin. L’étude a été menée pendant la saison des pluies de juillet à novembre 2014 dans les établissements de santé locaux. Le gène K13-propeller a été amplifié dans les isolats de parasites par PCR imbriquée, et ensuite séquencé.

          Résultats : Un total de 108 enfants a été recruté dans l’étude. L’efficacité des réactions d’amplification a été de 72 % (78/108). Le gène K13-propeller a été séquencé avec succès dans 78 isolats de P. falciparum ; tous étaient de type sauvage sans polymorphisme détectable.

          Conclusion : l’absence de mutations dans le gène K13 indique que les populations du parasite P. falciparum dans la zone d’étude sont encore pleinement sensibles aux artémisinines.

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          Most cited references 27

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          Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

          Summary Background Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand–Myanmar (Burma) border. Methods In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. Findings 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5–2·7) in 2001, to 3·7 h (3·6–3·8) in 2010, compared with a mean of 5·5 h (5·2–5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. Interpretation Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2–6 years. Funding The Wellcome Trust and National Institutes of Health.
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            Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.

            Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America, but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map, here we show that the level of genetic diversity varies substantially among different regions of the parasite genome, revealing extensive linkage disequilibrium surrounding the key CQR gene pfcrt and at least four CQR founder events. This disequilibrium and its decay rate in the pfcrt-flanking region are consistent with strong directional selective sweeps occurring over only approximately 20-80 sexual generations, especially a single resistant pfcrt haplotype spreading to very high frequencies throughout most of Asia and Africa. The presence of linkage disequilibrium provides a basis for mapping genes under drug selection in P. falciparum.
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              Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

              We describe an analysis of genome variation in 825 Plasmodium falciparum samples from Asia and Africa that reveals an unusual pattern of parasite population structure at the epicentre of artemisinin resistance in western Cambodia. Within this relatively small geographical area we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and remarkably high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalogue of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in various transporter proteins and DNA mismatch repair proteins. These data provide a population genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist its elimination.
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                Author and article information

                Journal
                Parasite
                Parasite
                parasite
                Parasite
                EDP Sciences
                1252-607X
                1776-1042
                2016
                21 July 2016
                : 23
                : ( publisher-idID: parasite/2016/01 )
                Affiliations
                [1 ] Unité d’Enseignement et de Recherche en Parasitologie – Mycologie/Faculté des Sciences de la Santé; 01 BP 188 Cotonou Bénin
                [2 ] Laboratoire du centre de lutte intégrée contre le paludisme; 01 BP 188 Cotonou Bénin
                [3 ] Institut de Recherche pour le Développement. UMR 224-MIVEGEC; 08 BP 841 Cotonou Bénin
                [4 ] Laboratory of Parasitology Mycology, Aristide le Dantec Hospital BP 16477 Dakar Senegal
                [5 ] UMR 216 MERIT-IRD Parasitology Department Noguchi Memorial Institute for Medical Research College of Health Sciences, University of Ghana P.O. Box LG581 Legon Accra Ghana
                [6 ] Centre de santé de la Commune de Djougou 02 BP 681 Porto Novo Benin
                [7 ] Centre de santé de la Commune de Cobly BP 40 Tanguiéta Bénin
                Author notes
                [* ]Corresponding author: aurorefel@ 123456yahoo.fr
                Article
                parasite160022 10.1051/parasite/2016028
                10.1051/parasite/2016028
                4956913
                27443837
                © A. Ogouyèmi-Hounto et al., published by EDP Sciences, 2016

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 35, Pages: 6
                Categories
                Research Article

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