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Title: The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data
Authors: Jane Achan
Ishag Adam
Emmanuel Arinaitwe
Elizabeth A. Ashley
Ghulam Rahim Awab
Mamadou S. Ba
Karen I. Barnes
Quique Bassat
Steffen Borrmann
Teun Bousema
Prabin Dahal
Umberto D'Alessandro
Timothy M.E. Davis
Arjen M. Dondorp
Grant Dorsey
Chris J. Drakeley
Caterina I. Fanello
Babacar Faye
Jennifer A. Flegg
Oumar Gaye
Peter W. Gething
Raquel González
Philippe J. Guerin
Simon I. Hay
Tran T. Hien
Bart Janssens
Moses R. Kamya
Corine Karema
Harin A. Karunajeewa
Moussa Koné
Bertrand Lell
Kevin Marsh
Mayfong Mayxay
Clara Menéndez
Petra F. Mens
Martin Meremikwu
Clarissa Moreira
Ivo Mueller
Carolyn Nabasumba
Michael Nambozi
Jean Louis Ndiaye
Paul N. Newton
Thuy Nhien Nguyen
Francois Nosten
Christian Nsanzabana
Sabah A. Omar
Jean Bosco Ouédraogo
Louis K. Penali
Mbaye Pene
Aung Pyae Phyo
Patrice Piola
Ric N. Price
P. Sasithon
Philip J. Rosenthal
Albert Same-Ekobo
Patrick Sawa
Henk D.F.H. Schallig
Seif A. Shekalaghe
Carol Hopkins Sibley
Jeff Smith
Frank Smithuis
Anyirékun Fabrice Somé
Kasia Stepniewska
Ambrose O. Talisuna
Joel Tarning
Emiliana Tjitra
Roger C.K. Tine
Uganda Malaria Surveillance Project
Khartoum University
Infectious Diseases Research Collaboration
Shoklo Malaria Research Unit
Mahidol University
Ministry of Public Health
Universite Cheikh Anta Diop
University of Cape Town
Centro de Investigação em Saúde de Manhiça
Centre de Recerca en Salut Internacional de Barcelona (CRESIB)
Kenya Medical Research Institute
Universitat Heidelberg
London School of Hygiene & Tropical Medicine
Radboud University Nijmegen Medical Centre
WorldWide Antimalarial Resistance Network (WWARN)
Nuffield Department of Clinical Medicine
Prins Leopold Instituut voor Tropische Geneeskunde
Medical Research Council Unit
University of Western Australia
Churchill Hospital
University of California, San Francisco
University of Oxford
Oxford University Clinical Research Unit
Médecins Sans Frontières
Makerere University
Ministry of Health
Department of Parasitology and Mycology
Universitat Tubingen
Centre de Recherches Médicales de Lambaréné
Mahosot Hospital
National University of Laos
Centro de Investigação em Saúde de Manhiça (CISM)
Royal Tropical Institute - KIT
Academic Medical Centre, University of Amsterdam
University of Calabar
Institute of Tropical Diseases Research and Prevention
Kenya Medical Research Institute
Papua New Guinea Institute of Medical Research
Walter and Eliza Hall Institute of Medical Research
Tropical Diseases Research Centre
Wellcome Trust-Mahosot Hospital-Oxford University Tropical Medicine Research Collaboration
International Centre for Insect Physiology and Ecology (Icipe)
Institut de Recherche en Sciences de la Santé
Centre MURAZ
WorldWide Antimalarial Resistance Network (WWARN)-West Africa Regional Centre
Institut Pasteur de Madagascar
Menzies School of Health Research
Centre Hospitalier et Universitaire de Yaounde
Kilimanjaro Christian Medical Centre
Ifakara Health Institute
University of Washington, Seattle
World Wide Antimalarial Resistance Network (WWARN)-Asia Regional Centre
World Wide Antimalarial Resistance Network (WWARN)-East Africa Regional Centre
Wellcome Trust Research Laboratories Nairobi
Badan Penelitian Dan Pengembangan Kesehatan, Kementerian Kesehatan Republik Indonesia
Institut de Recherche en Sciences de la Santé
National Institute of Malaria Research India
Medecins Sans Frontieres, Brussels
Mahidol-Oxford University Tropical Medicine Research Unit (MORU)
National Institute of Public Health
Keywords: Medicine
Issue Date: 1-Jan-2013
Citation: PLoS Medicine. Vol.10, No.12 (2013), 1-17
Abstract: Background:Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy.Methods and Findings:A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan-Meier survival estimates were 97.7% (95% CI 97.3%-98.1%) at day 42 and 97.2% (95% CI 96.7%-97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3-2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%-96.2%], p<0.001). After adjusting for confounding factors, the mg/kg dose of piperaquine was found to be a significant predictor for recrudescence, the risk increasing by 13% (95% CI 5.0%-21%) for every 5 mg/kg decrease in dose; p = 0.002. In a multivariable model increasing the target minimum total dose of piperaquine in children aged 1 to 5 years old from 48 mg/kg to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of patients; such an increment was not associated with gastrointestinal toxicity in the ten studies in which this could be assessed.Conclusions:DP demonstrates excellent efficacy in a wide range of transmission settings; however, treatment failure is associated with a lower dose of piperaquine, particularly in young children, suggesting potential for further dose optimisation.Please see later in the article for the Editors' Summary. © 2013 Price et al.
ISSN: 15491676
Appears in Collections:Scopus 2011-2015

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