Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes

Parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine

WWARN AL and ASAQ Molecular Marker Study Group

Research output: Contribution to journalArticle

Abstract

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemetherlumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29-9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

Original languageEnglish (US)
Pages (from-to)833-843
Number of pages11
JournalAmerican Journal of Tropical Medicine and Hygiene
Volume91
Issue number4
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

MDR Genes
Falciparum Malaria
Plasmodium falciparum
Parasites
Amodiaquine
Confidence Intervals
Antimalarials
Drug Resistance
Genes
Single Nucleotide Polymorphism
Plasmodium falciparum PfCRT protein
artesunate drug combination amodiaquine
lumefantrine
artemether
Therapeutics
Clinical Trials
Recurrence
Pharmaceutical Preparations
artemisinine

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases
  • Virology

Cite this

@article{701e41236e454dcabe23c91c4704bfe5,
title = "Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: Parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine",
abstract = "Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemetherlumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95{\%} confidence interval = 2.29-9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95{\%} confidence interval = 2.36-17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.",
author = "{WWARN AL and ASAQ Molecular Marker Study Group} and Meera Venkatesan and Gadalla, {Nahla B.} and Kasia Stepniewska and Prabin Dahal and Christian Nsanzabana and Clarissa Moriera and Price, {Ric N.} and Andreas Ma˚rtensson and Rosenthal, {Philip J.} and Grant Dorsey and Sutherland, {Colin J.} and Philippe Gu{\'e}rin and Davis, {Timothy M.E.} and Didier M{\'e}nard and Ishag Adam and George Ademowo and Cesar Arze and Baliraine, {Frederick N.} and Nicole Berens-Riha and Anders Bj{\"o}rkman and Steffen Borrmann and Francesco Checchi and Meghna Desai and Mehul Dhorda and Djimd{\'e}, {Abdoulaye A.} and El-Sayed, {Badria B.} and Teferi Eshetu and Frederick Eyase and Catherine Falade and Faucher, {Jean Franc¸ois} and Gabrielle Fr{\"o}berg and Anastasia Grivoyannis and Sally Hamour and Sandrine Houz{\'e} and Jacob Johnson and Erasmus Kamugisha and Simon Kariuki and Kiechel, {Jean Ren{\'e}} and Fred Kironde and Kofoed, {Poul Erik} and Jacques LeBras and Maja Malmberg and Leah Mwai and Billy Ngasala and Francois Nosten and Nsobya, {Samuel L.} and Alexis Nzila and Mary Oguike and Otienoburu, {Sabina Dahlstr{\"o}m} and Bernhards Ogutu",
year = "2014",
month = "1",
day = "1",
doi = "10.4269/ajtmh.14-0031",
language = "English (US)",
volume = "91",
pages = "833--843",
journal = "American Journal of Tropical Medicine and Hygiene",
issn = "0002-9637",
publisher = "American Society of Tropical Medicine and Hygiene",
number = "4",

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TY - JOUR

T1 - Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes

T2 - Parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine

AU - WWARN AL and ASAQ Molecular Marker Study Group

AU - Venkatesan, Meera

AU - Gadalla, Nahla B.

AU - Stepniewska, Kasia

AU - Dahal, Prabin

AU - Nsanzabana, Christian

AU - Moriera, Clarissa

AU - Price, Ric N.

AU - Ma˚rtensson, Andreas

AU - Rosenthal, Philip J.

AU - Dorsey, Grant

AU - Sutherland, Colin J.

AU - Guérin, Philippe

AU - Davis, Timothy M.E.

AU - Ménard, Didier

AU - Adam, Ishag

AU - Ademowo, George

AU - Arze, Cesar

AU - Baliraine, Frederick N.

AU - Berens-Riha, Nicole

AU - Björkman, Anders

AU - Borrmann, Steffen

AU - Checchi, Francesco

AU - Desai, Meghna

AU - Dhorda, Mehul

AU - Djimdé, Abdoulaye A.

AU - El-Sayed, Badria B.

AU - Eshetu, Teferi

AU - Eyase, Frederick

AU - Falade, Catherine

AU - Faucher, Jean Franc¸ois

AU - Fröberg, Gabrielle

AU - Grivoyannis, Anastasia

AU - Hamour, Sally

AU - Houzé, Sandrine

AU - Johnson, Jacob

AU - Kamugisha, Erasmus

AU - Kariuki, Simon

AU - Kiechel, Jean René

AU - Kironde, Fred

AU - Kofoed, Poul Erik

AU - LeBras, Jacques

AU - Malmberg, Maja

AU - Mwai, Leah

AU - Ngasala, Billy

AU - Nosten, Francois

AU - Nsobya, Samuel L.

AU - Nzila, Alexis

AU - Oguike, Mary

AU - Otienoburu, Sabina Dahlström

AU - Ogutu, Bernhards

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemetherlumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29-9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

AB - Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemetherlumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29-9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

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DO - 10.4269/ajtmh.14-0031

M3 - Article

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EP - 843

JO - American Journal of Tropical Medicine and Hygiene

JF - American Journal of Tropical Medicine and Hygiene

SN - 0002-9637

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