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Title: The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: A meta-analysis of individual patient data
Authors: Martin A. Adjuik
Richard Allan
Anupkumar R. Anvikar
Elizabeth A. Ashley
Mamadou S. Ba
Hubert Barennes
Karen I. Barnes
Quique Bassat
Elisabeth Baudin
Anders Björkman
François Bompart
Maryline Bonnet
Steffen Borrmann
Philippe Brasseur
Hasifa Bukirwa
Francesco Checchi
Michel Cot
Prabin Dahal
Umberto D'Alessandro
Philippe Deloron
Meghna Desai
Graciela Diap
Abdoulaye A. Djimde
Grant Dorsey
Ogobara K. Doumbo
Emmanuelle Espié
Jean Francois Etard
Caterina I. Fanello
Jean François Faucher
Babacar Faye
Jennifer A. Flegg
Oumar Gaye
Peter W. Gething
Raquel González
Francesco Grandesso
Philippe J. Guerin
Jean Paul Guthmann
Sally Hamour
Armedy Ronny Hasugian
Simon I. Hay
Georgina S. Humphreys
Vincent Jullien
Elizabeth Juma
Moses R. Kamya
Corine Karema
Jean R. Kiechel
Peter G. Kremsner
Sanjeev Krishna
Valérie Lameyre
Laminou M. Ibrahim
Sue J. Lee
Bertrand Lell
Andreas Martensson
Achille Massougbodji
Hervé Menan
Didier Ménard
Clara Menéndez
Martin Meremikwu
Clarissa Moreira
Carolyn Nabasumba
Michael Nambozi
Jean Louis Ndiaye
Frederic Nikiema
Christian Nsanzabana
Francine Ntoumi
Bernhards R. Ogutu
Piero Olliaro
Lyda Osorio
Jean Bosco Ouédraogo
Louis K. Penali
Mbaye Pene
MENTOR Initiative
National Institute of Malaria Research India
Universite Cheikh Anta Diop
Centre MURAZ
French Foreign Affairs
WorldWide Antimalarial Resistance Network
University of Cape Town
Centro de Investigação em Saúde de Manhiça
Instituto de Salud Global de Barcelona
Karolinska Institutet
Sanofi S.A.
Universitat Tubingen
German Centre for Infection Research
Institut de Recherche pour le Developpement Dakar
Uganda Malaria Surveillance Project
IRD Institut de Recherche pour le Developpement
Universite Paris Descartes
WorldWide Antimalarial Resistance Network (WWARN)
Nuffield Department of Clinical Medicine
Prins Leopold Instituut voor Tropische Geneeskunde
Medical Research Council Unit
Centers for Disease Control and Prevention
Drugs for Neglected Diseases Initiative
University of Bamako Faculty of Medicine, Pharmacy and Odonto-Stomatology
University of California, San Francisco
Institut Pasteur de Dakar
IRD Centre de Montpellier
Mahidol University
Besançon University Medical Center
Monash University
University of Oxford
Badan Penelitian Dan Pengembangan Kesehatan, Kementerian Kesehatan Republik Indonesia
Kenya Medical Research Institute
Makerere University
Ministry of Health
Centre de Recherches Médicales de Lambaréné
University of London
Centre de Recherche Médicale et Sanitaire
Uppsala Universitet
University of Abomey-Calavi
University of Cocody
Institut Pasteur du Cambodge
University of Calabar
Mbarara University of Science and Technology
Tropical Diseases Research Centre
Institut de Recherche en Sciences de la Santé
Universite Marien Ngouabi
United States Army
Organisation Mondiale de la Sante
Centro Internacional de Entrenamiento e Investigaciones Medicas
WorldWide Antimalarial Resistance Network (WWARN)-West Africa Regional Centre
Institut Pasteur de Madagascar
Menzies School of Health Research
London School of Hygiene & Tropical Medicine
Centre Hospitalier et Universitaire de Yaounde
Drugs for Neglected Diseases initiative
University of Washington, Seattle
Universite de la Mediterranee Aix-Marseille II
Centre National de Recherche et de Formation sur le Paludisme (CNRFP)
World Wide Antimalarial Resistance Network (WWARN)-Asia Regional Centre
University of Maryland School of Medicine
Médecins sans Frontières/Holland
Medical Action Myanmar
Infectious Diseases Research Collaboration
Médecins Sans Frontières
East Africa Regional Office
Hopitaux universitaires de Geneve
Swiss Tropical and Public Health Institute (Swiss TPH)
Universitat Basel
Keywords: Medicine
Issue Date: 31-Mar-2015
Citation: BMC Medicine. Vol.13, No.1 (2015)
Abstract: © The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group; licensee BioMed Central. Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
ISSN: 17417015
Appears in Collections:Scopus 2011-2015

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