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Title: 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
Authors: Elizabeth A. Ashley
Francesca Aweeka
Karen I. Barnes
Quique Bassat
Steffen Borrmann
Prabin Dahal
Timothy M.E. Davis
Mey Bouth Denis
Abdoulaye A. Djimde
Jean François Faucher
Blaise Genton
Philippe J. Guérin
Kamal Hamed
Eva Maria Hodel
Liusheng Huang
Vincent Jullien
Harin A. Karunajeewa
Jean René Kiechel
Poul Erik Kofoed
Gilbert Lefèvre
Niklas Lindegardh Lindegardh
Andreas Mårtensson
Mayfong Mayxay
Rose Mcgready
Clarissa Moreira
Paul N. Newton
Billy E. Ngasala
Francois Nosten
Christian Nsanzabana
Sunil Parikh
Patrice Piola
Ric N. Price
Pascal Ringwald
Lars Rombo
Birgit Schramm
Carol Hopkins Sibley
Kasia Stepniewska
Joel Tarning
Johan Ursing
Michele Van Vugt
Nicholas J. White
Lesley J. Workman
Philippe Deloron
Kevin Marsh
Shoklo Malaria Research Unit
Mahidol University
University of California, San Francisco
WorldWide Antimalarial Resistance Network (WWARN)
University of Cape Town
Instituto de Salud Global de Barcelona
Centro de Investigação em Saúde de Manhiça (CISM)
Wellcome Trust Research Laboratories Nairobi
Universitat Tubingen
Nuffield Department of Clinical Medicine
University of Western Australia
IRD Institut de Recherche pour le Developpement
Universite Paris Descartes
National Center for Parasitology
Organisation Mondiale de la Sante
University of Bamako Faculty of Medicine, Pharmacy and Odonto-Stomatology
Hopital Jean Minjoz
Swiss Tropical and Public Health Institute (Swiss TPH)
Centre Hospitalier Universitaire Vaudois
Novartis Pharmaceuticals Corporation
Liverpool School of Tropical Medicine
Drugs for Neglected Diseases Initiative
Syddansk Universitet
Kolding Sygehus
Novartis International AG
Kenya Medical Research Institute
Karolinska Institutet
Wellcome Trust
Muhimbili University of Health and Allied Sciences
Yale Schools of Public Health and Medicine
Department of Clinical Pharmacology
Institut Pasteur de Madagascar
Menzies School of Health Research
Uppsala Universitet
University of Washington, Seattle
University of Amsterdam
Keywords: Medicine
Issue Date: 18-Sep-2015
Citation: BMC Medicine. Vol.13, No.1 (2015)
Abstract: © 2015 WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group. Background: Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the 'therapeutic' day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations. Methods: The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data. Results: Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (<3 years), among whom underweight-for-age children had 23 % (95 % CI -1 to 41 %) lower concentrations than adequately nourished children of the same age and 53 % (95 % CI 37 to 65 %) lower concentrations than adults. Day 7 lumefantrine concentrations were 44 % (95 % CI 38 to 49 %) lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated with >98 % cure rates (if parasitemia <135,000/μL). Conclusions: Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.
ISSN: 17417015
Appears in Collections:Scopus 2011-2015

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