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Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether–lumefantrine and artesunate–amodiaquine in Africa

Artemether–lumefantrine (AL) and artesunate–amodiaquine (AS-AQ) are the most commonly used artemisinin-based combination therapies (ACT) for treatment of Plasmodium falciparum in Africa. Both treatments remain efficacious, but single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multi...

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Autores principales: Okell, Lucy C, Reiter, Lisa Malene, Ebbe, Lene Sandø, Baraka, Vito, Bisanzio, Donal, Watson, Oliver J, Bennett, Adam, Verity, Robert, Gething, Peter, Roper, Cally, Alifrangis, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202998/
https://www.ncbi.nlm.nih.gov/pubmed/30397515
http://dx.doi.org/10.1136/bmjgh-2018-000999
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author Okell, Lucy C
Reiter, Lisa Malene
Ebbe, Lene Sandø
Baraka, Vito
Bisanzio, Donal
Watson, Oliver J
Bennett, Adam
Verity, Robert
Gething, Peter
Roper, Cally
Alifrangis, Michael
author_facet Okell, Lucy C
Reiter, Lisa Malene
Ebbe, Lene Sandø
Baraka, Vito
Bisanzio, Donal
Watson, Oliver J
Bennett, Adam
Verity, Robert
Gething, Peter
Roper, Cally
Alifrangis, Michael
author_sort Okell, Lucy C
collection PubMed
description Artemether–lumefantrine (AL) and artesunate–amodiaquine (AS-AQ) are the most commonly used artemisinin-based combination therapies (ACT) for treatment of Plasmodium falciparum in Africa. Both treatments remain efficacious, but single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multidrug resistance 1 (Pfmdr1) gene may compromise sensitivity. AL and AS-AQ exert opposing selective pressures: parasites with genotype 86Y, Y184 and 1246Y are partially resistant to AS-AQ treatment, while N86, 184 F and D1246 are favoured by AL treatment. Through a systematic review, we identified 397 surveys measuring the prevalence of Pfmdr1 polymorphisms at positions 86 184 or 1246 in 30 countries in Africa. Temporal trends in SNP frequencies after introduction of AL or AS-AQ as first-line treatment were analysed in 32 locations, and selection coefficients estimated. We examined associations between antimalarial policies, consumption, transmission intensity and rate of SNP selection. 1246Y frequency decreased on average more rapidly in locations where national policy recommended AL (median selection coefficient(s) of −0.083), compared with policies of AS-AQ or both AL and AS-AQ (median s=−0.035 and 0.021, p<0.001 respectively). 86Y frequency declined markedly after ACT policy introduction, with a borderline significant trend for a more rapid decline in countries with AL policies (p=0.055). However, these trends could also be explained by a difference in initial SNP frequencies at the time of ACT introduction. There were non-significant trends for faster selection of N86 and D1246 in areas with higher AL consumption and no trend with transmission intensity. Recorded consumption of AS-AQ was low in the locations and times Pfmdr1 data were collected. SNP trends in countries with AL policies suggest a broad increase in sensitivity of parasites to AS-AQ, by 7–10 years after AL introduction. Observed rates of selection have implications for planning strategies to cycle drugs or use multiple first-line therapies to maintain drug efficacy.
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spelling pubmed-62029982018-11-05 Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether–lumefantrine and artesunate–amodiaquine in Africa Okell, Lucy C Reiter, Lisa Malene Ebbe, Lene Sandø Baraka, Vito Bisanzio, Donal Watson, Oliver J Bennett, Adam Verity, Robert Gething, Peter Roper, Cally Alifrangis, Michael BMJ Glob Health Research Artemether–lumefantrine (AL) and artesunate–amodiaquine (AS-AQ) are the most commonly used artemisinin-based combination therapies (ACT) for treatment of Plasmodium falciparum in Africa. Both treatments remain efficacious, but single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multidrug resistance 1 (Pfmdr1) gene may compromise sensitivity. AL and AS-AQ exert opposing selective pressures: parasites with genotype 86Y, Y184 and 1246Y are partially resistant to AS-AQ treatment, while N86, 184 F and D1246 are favoured by AL treatment. Through a systematic review, we identified 397 surveys measuring the prevalence of Pfmdr1 polymorphisms at positions 86 184 or 1246 in 30 countries in Africa. Temporal trends in SNP frequencies after introduction of AL or AS-AQ as first-line treatment were analysed in 32 locations, and selection coefficients estimated. We examined associations between antimalarial policies, consumption, transmission intensity and rate of SNP selection. 1246Y frequency decreased on average more rapidly in locations where national policy recommended AL (median selection coefficient(s) of −0.083), compared with policies of AS-AQ or both AL and AS-AQ (median s=−0.035 and 0.021, p<0.001 respectively). 86Y frequency declined markedly after ACT policy introduction, with a borderline significant trend for a more rapid decline in countries with AL policies (p=0.055). However, these trends could also be explained by a difference in initial SNP frequencies at the time of ACT introduction. There were non-significant trends for faster selection of N86 and D1246 in areas with higher AL consumption and no trend with transmission intensity. Recorded consumption of AS-AQ was low in the locations and times Pfmdr1 data were collected. SNP trends in countries with AL policies suggest a broad increase in sensitivity of parasites to AS-AQ, by 7–10 years after AL introduction. Observed rates of selection have implications for planning strategies to cycle drugs or use multiple first-line therapies to maintain drug efficacy. BMJ Publishing Group 2018-10-19 /pmc/articles/PMC6202998/ /pubmed/30397515 http://dx.doi.org/10.1136/bmjgh-2018-000999 Text en © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: http://creativecommons.org/licenses/by/4.0
spellingShingle Research
Okell, Lucy C
Reiter, Lisa Malene
Ebbe, Lene Sandø
Baraka, Vito
Bisanzio, Donal
Watson, Oliver J
Bennett, Adam
Verity, Robert
Gething, Peter
Roper, Cally
Alifrangis, Michael
Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether–lumefantrine and artesunate–amodiaquine in Africa
title Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether–lumefantrine and artesunate–amodiaquine in Africa
title_full Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether–lumefantrine and artesunate–amodiaquine in Africa
title_fullStr Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether–lumefantrine and artesunate–amodiaquine in Africa
title_full_unstemmed Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether–lumefantrine and artesunate–amodiaquine in Africa
title_short Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether–lumefantrine and artesunate–amodiaquine in Africa
title_sort emerging implications of policies on malaria treatment: genetic changes in the pfmdr-1 gene affecting susceptibility to artemether–lumefantrine and artesunate–amodiaquine in africa
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202998/
https://www.ncbi.nlm.nih.gov/pubmed/30397515
http://dx.doi.org/10.1136/bmjgh-2018-000999
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