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
Meera Venkatesan,Nahla B Gadalla,Kasia Stepniewska,Prabin Dahal,Christian Nsanzabana,Clarissa Moriera,Ric N. Price,Andreas Mårtensson,Philip J. Rosenthal,Grant Dorsey,Colin J. Sutherland,Philippe J Guerin,Timothy M. E. Davis,Didier Menard,Ishag Adam,George O. Ademowo,Cesar Arze,Frederick N. Baliraine,Nicole Berens-Riha,Anders Björkman,Steffen Borrmann,Francesco Checchi,Meghna Desai,Mehul Dhorda,Abdoulaye Djimde,Badria B. El-Sayed,Teferi Eshetu,Frederick Eyase,Catherine O. Falade,Jean-François Faucher,Gabrielle Fröberg,Anastasia Grivoyannis,Sally Hamour,Sandrine Houzé,Jacob D. Johnson,Erasmus Kamugisha,Simon Kariuki,Jean-René Kiechel,Fred Kironde,Fred Kironde,Poul-Erik Kofoed,Jacques Lebras,Maja Malmberg,Maja Malmberg,Leah Mwai,Leah Mwai,Billy Ngasala,François Nosten,Samuel L. Nsobya,Alexis Nzila,Alexis Nzila,Mary C. Oguike,Sabina Dahlström Otienoburu,Bernhards Ogutu,Jean-Bosco Ouédraogo,Patrice Piola,Patrice Piola,Lars Rombo,Birgit Schramm,A. Fabrice Some,Julie Thwing,Johan Ursing,Rina P. M. Wong,Ahmed Zeynudin,Issaka Zongo,Christopher V. Plowe,Carol Hopkins Sibley,Carol Hopkins Sibley +67 more
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TLDR
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.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 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.read more
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Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data
Elizabeth A. Ashley,Francesca T. Aweeka,Karen I. Barnes,Quique Bassat,Steffen Borrmann,Steffen Borrmann,Prabin Dahal,Prabin Dahal,Tme Davis,Philippe Deloron,Mey Bouth Denis,Abdoulaye Djimde,Jean-François Faucher,Blaise Genton,Blaise Genton,Philippe J Guerin,Kamal Hamed,Eva Maria Hodel,Eva Maria Hodel,Liusheng Huang,Jullien,Harin Karunajeewa,Harin Karunajeewa,Kiechel,Poul-Erik Kofoed,Gilbert Lefèvre,Niklas Lindegardh,Kevin Marsh,Kevin Marsh,Andreas Mårtensson,Mayfong Mayxay,Mayfong Mayxay,Rose McGready,C Moreira,Paul N. Newton,Billy Ngasala,François Nosten,Christian Nsanzabana,Christian Nsanzabana,Sunil Parikh,Ric N. Price,Pascal Ringwald,Lars Rombo,Lars Rombo,Birgit Schramm,Carol Hopkins Sibley,Kasia Stepniewska,Johan Ursing,Michèle van Vugt,Michèle van Vugt,Nicholas J. White,Lesley Workman +51 more
TL;DR: Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia, as well as patients in very low transmission intensity areas with emerging parasite resistance.
Journal ArticleDOI
Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic.
TL;DR: Recent advances in understanding how antimalarials act and how resistance develops are reviewed, and new strategies for effectively combatting resistance, optimizing treatment and advancing the global campaign to eliminate malaria are discussed.
Journal ArticleDOI
Drug resistance in Plasmodium
TL;DR: The identification of mutations in the propeller domains of Kelch 13 as the primary marker for artemisinin resistance in P. falciparum is described and two major mechanisms of resistance that have been independently proposed are explored: the activation of the unfolded protein response and proteostatic dysregulation of parasite phosphatidylinositol 3- kinase.
Journal ArticleDOI
Artemisinin Action and Resistance in Plasmodium falciparum.
TL;DR: This work describes recent progress made in defining the molecular basis of artemisinin resistance, which has identified a primary role for the P. falciparum K13 protein and suggests potential ways to overcome resistance.
Journal ArticleDOI
Artemisinin-Resistant Plasmodium falciparum Malaria
TL;DR: Clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials to forestall the spread of artemisinin and partner drug resistance.
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