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 - Worldwide Antimalarial Resistance Network (WWARN) DP 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 - Mårtensson, 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-François
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
N1 - FTX; (CC BY 4.0)
PY - 2014
Y1 - 2014
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 resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (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 resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (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.
KW - Amino Acid Substitution
KW - Amodiaquine/therapeutic use
KW - Antimalarials/pharmacology
KW - Artemether
KW - Artemisinins/therapeutic use
KW - Child
KW - Child, Preschool
KW - Chloroquine/pharmacology
KW - Datasets as Topic
KW - Drug Combinations
KW - Drug Resistance/genetics
KW - Drug Therapy, Combination
KW - Ethanolamines/therapeutic use
KW - Fluorenes/therapeutic use
KW - Genetic Markers/genetics
KW - Genotype
KW - Humans
KW - Infant
KW - Kaplan-Meier Estimate
KW - Lumefantrine
KW - Malaria, Falciparum/drug therapy
KW - Membrane Transport Proteins/genetics
KW - Multidrug Resistance-Associated Proteins/genetics
KW - Plasmodium falciparum/drug effects
KW - Polymorphism, Genetic
KW - Protozoan Proteins/genetics
KW - Risk Factors
U2 - 10.4269/ajtmh.14-0031
DO - 10.4269/ajtmh.14-0031
M3 - A1: Web of Science-article
C2 - 25048375
SN - 0002-9637
VL - 91
SP - 833
EP - 843
JO - American Journal of Tropical Medicine and Hygiene
JF - American Journal of Tropical Medicine and Hygiene
IS - 4
ER -