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The Effect of Dosing Strategies on the Therapeutic Efficacy of Artesunate Amodiaquine for Uncomplicated Malaria: A Meta-Analysis of Individual Patient Data
7 8 9 The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group
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WorldWide Antimalarial Resistance Network (WWARN)
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Running title: WWARN AS-AQ Dose Impact Study Group
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Keywords: malaria, Plasmodium falciparum, drug resistance, artesunate, amodiaquine, dosing,
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efficacy
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The members of the WorldWide Antimalarial Resistance Network (WWARN) AS-AQ
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Study Group are the authors of this paper:
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Martin A Adjuik, INDEPTH NETWORK Secretariat, Accra, Ghana; Richard Allan, The
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MENTOR Initiative, Crawley, UK; Anupkumar R Anvikar, National Institute of Malaria
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Research, New Delhi, India; Elizabeth A Ashley, Epicentre, Paris, France; Mamadou S Ba,
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Department of Parasitology, Faculty of Medicine, University Cheikh Anta Diop, Dakar,
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Senegal; Hubert Barennes, Unité d'Epidémiologie d'Intervention Centre Muraz, Bobo
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Dioulasso, Burkina Faso; French Foreign Affairs, Biarritz, France; Karen I Barnes, World
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Wide Antimalarial Resistance Network (WWARN), Pharmacology module, Cape Town,
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South Africa and Division of Clinical Pharmacology, Department of Medicine, University of
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Cape Town, Cape Town, South Africa; Quique Bassat, Centro de Investigacao em Saude de
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Manhiça, Manhiça, Mozambique and ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB),
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Hospital Clínic - Universitat de Barcelona, Barcelona, Spain; Elisabeth Baudin, Epicentre,
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Paris, France; Anders Björkman, Dept Microbiology, Tumor and Cell Biology, Karolinska
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Institutet, Stockholm, Sweden; François Bompart, Direction Accès au Médicament / Access
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to Medicines, Sanofi Aventis, Gentilly, France; Maryline Bonnet, Epicentre, Geneva,
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Switzerland; Steffen Borrmann,
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Tübingen,Tübingen, Germany and German Centre for Infection Research, Tübingen,
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Germany; Philippe Brasseur, Institut de Recherche pour le Développement (IRD), Dakar,
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Sénégal; Hasifa Bukirwa, Uganda Malaria Surveillance Project, Kampala, Uganda;
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Francesco Checchi, Epicentre, Paris, France; Michel Cot, Institut de Recherche pour le
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Développement (IRD), Mother and Child Health in the Tropics Research Unit, Paris, France
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and PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France; Prabin Dahal,
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World Wide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for
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Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford,
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UK; Umberto D'Alessandro, Institute of Tropical Medicine, Antwerp, Belgium and
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Medical Research Council Unit, Fajara, The Gambia; Philippe Deloron, Institut de
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Recherche pour le Développement (IRD), Mother and Child Health in the Tropics Research
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Unit, Paris, France
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Meghna Desai, Division of Parasitic Diseases and Malaria, Centers for Disease Control and
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Prevention, Atlanta, Georgia; Graciela Diap, Drugs for Neglected Diseases initiative,
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Geneva, Switzerland; Abdoulaye A Djimde, Malaria Research and Training Center,
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Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and
Institute for Tropical Medicine, University of
PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France;
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Odonto-Stomatology, University of Bamako, Bamako, Mali; Grant Dorsey, Department of
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Medicine, University of California San Francisco, San Francisco, USA; Ogobara K
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Doumbo, Malaria Research and Training Center, Department of Epidemiology of Parasitic
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Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology, University of Bamako,
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Bamako, Mali; Emmanuelle Espié, Institut Pasteur de Dakar, Dakar, Sénégal; Jean-
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Francois Etard, Epicentre, Paris, France and Institut de Recherche pour le Développement
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(IRD), Montpellier, France; Caterina I Fanello, Faculty of Tropical Medicine, Mahidol
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University, Bangkok, Thailand
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of Clinical Medicine, University of Oxford, Oxford, UK; Jean‐‐François Faucher, Institut de
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Recherche pour le Développement (IRD), Mother and Child Health in the Tropics Research
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Unit, Department of Infectious Diseases, Besançon University Medical Center, Besançon;
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Babacar Faye, Department of Medical Parasitology, Medical Faculty, Université Cheikh
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Anta Diop, Dakar, Senegal; Jennifer A Flegg, World Wide Antimalarial Resistance Network
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(WWARN), Oxford, UK
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Medicine, University of Oxford, Oxford, UK; Oumar Gaye, Department of Medical
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Parasitology, Medical Faculty, Université Cheikh Anta Diop, Dakar, Senegal; Peter W
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Gething, Spatial Ecology and Epidemiology Group, Department of Zoology, University of
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Oxford, Oxford, UK ; Raquel González, Centro de Investigacao em Saude de Manhiça,
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Manhiça, Mozambique
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Hospital Clínic - Universitat de Barcelona, Barcelona, Spain; Francesco Grandesso,
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Epicentre, Paris, France; Philippe J Guerin, World Wide Antimalarial Resistance Network
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(WWARN), Oxford, UK and Centre for Tropical Medicine, Nuffield Department of Clinical
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Medicine, University of Oxford, Oxford, UK; Jean-Paul Guthmann
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France; Sally Hamour, UCL Centre for Nephrology, Royal Free hospital, London, UK;
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Armedy Ronny Hasugian, National Institute of Health Research and Development, Ministry
and Centre for Tropical Medicine, Nuffield Department
Centre for Tropical Medicine, Nuffield Department of Clinical
and ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB),
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Epicentre,
Paris,
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of Health, Jakarta, Indonesia; Simon I Hay, Spatial Ecology and Epidemiology Group,
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Department of Zoology, University of Oxford, Oxford, UK ;
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World Wide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for
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Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford,
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UK; Vincent Jullien, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris,
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Paris, France; Elizabeth Juma, Kenya Medical Research Institute - Centre for Clinical
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Research, Nairobi, Kenya; Moses R Kamya, College of Health Sciences, Makerere
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University, Kampala, Uganda; Corine Karema, Malaria & Other Parasitic Diseases
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Division-RBC, Ministry of Health, Kigali, Rwanda; Jean R Kiechel, Drugs for Neglected
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Diseases initiative, Geneva, Switzerland; Peter G Kremsner, Centre de Recherches
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Médicales de Lambaréné, Lambaréné, Gabon and Institut für Tropenmedizin, Universität
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Tübingen, Tübingen, Germany; Sanjeev Krishna, Institute for Infection and Immunity, St.
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George’s, University of London,
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Médicament / Access to Medicines, Sanofi Aventis, Gentilly, France; Ibrahim Maman
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Laminou, Centre de Recherche Médicale et Sanitaire, Niamey, Niger; Sue J Lee, Mahidol
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Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol
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University, Bangkok, Thailand and Centre for Tropical Medicine, Nuffield Department of
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Clinical Medicine, University of Oxford, Oxford, UK; Bertrand Lell, Institute for Tropical
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Medicine, University of Tubingen, Tubingen, Germany and Centre de Recherches Médicales
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de Lambaréné, Lambaréné, Gabon; Andreas Mårtensson, Department of Microbiology,
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Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden, Department of Public
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Health Sciences, Karolinska Institutet, Stockholm, Sweden and Centre for Clinical Research
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Sörmland, Uppsala University, Sweden; Achille Massougbodji, Centre d’Etudes et de
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Recherche sur le Paludisme Associé à la Grossesse et à l’Enfant (CERPAGE), Faculté des
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Sciences de la Santé (FSS), Université d’Abomey-Calavi, Cotonou, Bénin; Hervé Menan,
Georgina
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Humphreys,
London, UK; Valérie Lameyre , Direction Accès au
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Department of Parasitology, Faculty of Pharmacy, University of Cocody, Abidjan, Côte
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d'Ivoire; Didier Ménard, Unité d'Epidémiologie Moléculaire du Paludisme, Institut Pasteur
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du Cambodge, Phnom Penh, Cambodia; Clara Menéndez, Centro de Investigacao em Saude
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de Manhiça, Manhiça, Mozambique and ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB),
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Hospital Clínic - Universitat de Barcelona, Barcelona, Spain; Martin Meremikwu,
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Department of Paediatrics, University of Calabar, Calabar, Nigeria; Institute of Tropical
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Diseases Research & Prevention, Calabar, Nigeria; Clarissa Moreira, World Wide
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Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine,
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Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Carolyn
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Nabasumba, Epicentre, Paris, France and Faculty of Medicine, Mbarara University of
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Science and Technology, Mbarara, Uganda; Michael Nambozi, Tropical Diseases Research
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Centre, Ndola, Zambia; Jean-Louis Ndiaye, Department of Medical Parasitology, Medical
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Faculty, Université Cheikh Anta Diop, Dakar, Senegal; Frederic Nikiema, Institut de
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Recherche en Science de la Sante, Bobo Dioulasso, Burkina Faso; Christian Nsanzabana,
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World Wide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for
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Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford,
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UK; Francine Ntoumi, Fondation Congolaise pour la Recherche Médicale (FCRM), Faculté
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des Sciences de la Santé, Université Marien Ngouabi, Brazzaville, République du Congo and
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Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany; Bernhards R
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Ogutu, Kenya Medical Research Institute/United States Army Medical Research Unit,
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Kisumu, Kenya; Piero Olliaro, UNICEF/UNDP/World Bank/WHO Special Programme for
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Research and Training in Tropical Diseases (TDR) World Health Organization, Geneva,
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Switzerland; Lyda Osorio, Internacional Centre for Medical Research and Training
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(CIDEIM), Cali, Colombia; Jean-Bosco Ouédraogo, Institut de Recherche en Sciences de la
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Santé, Direction Régionale de l'Ouest, Bobo-Dioulasso, Burkina Faso; Centre Muraz, Bobo-
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Dioulasso, Burkina Faso; Louis K Penali, World Wide Antimalarial Resistance Network
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(WWARN)-West Africa Regional Centre, Dakar, Senegal; Mbaye Pene, Department of
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Medical Parasitology, Medical Faculty, Université Cheikh Anta Diop, Dakar, Senegal;
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Loretxu Pinoges, Epicentre, Paris, France; Patrice Piola, Institut Pasteur de Madagascar,
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Antananarivo, Madagascar; Ric N Price, Menzies School of Health Research and Charles
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Darwin University, Darwin, Australia and Centre for Tropical Medicine, Nuffield
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Department of Clinical Medicine, University of Oxford, Oxford, UK; Cally Roper,
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Department of Pathogen Molecular Biology, Faculty of Infectious and Tropical Diseases,
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London School of Hygiene & Tropical Medicine, London, UK; Philip J Rosenthal,
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Department of Medicine, University of California San Francisco, San Francisco, USA;
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Claude Emile Rwagacondo, RBM Focal Point, UNICEF WCARO, Dakar, Senegal; Albert
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Same-Ekobo, Centre Hospitalier Universitaire de Yaoundé,Yaoundé, Cameroun; Birgit
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Schramm, Epicentre, Paris, France; Amadou Seck, World Wide Antimalarial Resistance
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Network (WWARN)-West Africa Regional Centre, Dakar, Senegal; Bhawna Sharma, Drugs
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for Neglected Diseases initiative, New Delhi, India; Carol Hopkins Sibley, World Wide
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Antimalarial Resistance Network (WWARN), Oxford, UK and Department of Genome
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Sciences, University of Washington, Seattle, USA; Véronique Sinou, UMR-MD3, Faculty
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of Pharmacy, Aix-Marseille University, Marseille, France; Sodiomon B Sirima, Centre
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National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina
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Faso; Jeffery J Smith, World Wide Antimalarial Resistance Network (WWARN)-Asia
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Regional Centre, Bangkok, Thailand and Center for Vaccine Development, University of
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Maryland School of Medicine, Baltimore, USA; Frank Smithuis, Médecins sans
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Frontières/Holland, Yangon, Myanmar and Medical Action Myanmar, Yangon, Myanmar;
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Fabrice A Somé, Institut de Recherche en Sciences de la Santé, Direction Régionale de
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l'Ouest, Bobo-Dioulasso, Burkina Faso; Doudou Sow, Department of Parasitology, Faculty
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of Medicine, University Cheikh Anta Diop, Dakar, Senegal; Sarah G Staedke, Department
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of Clinical Research, Faculty of Infectious & Tropical Diseases, London School of Hygiene
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& Tropical Medicine, London, UK and Infectious Disease Research Collaboration, Kampala,
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Uganda; Kasia Stepniewska, World Wide Antimalarial Resistance Network (WWARN),
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Oxford, UK; Todd D Swarthout, Médecins Sans Frontières, London, UK; Khadime Sylla,
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Service de Parasitologie-Mycologie Médicale, Université Cheikh Anta Diop, Dakar, Senegal;
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Ambrose O Talisuna, World Wide Antimalarial Resistance Network (WWARN)-East
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Africa Regional Centre, Nairobi, Kenya and University of Oxford/KEMRI/Wellcome Trust
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Research Programme, Nairobi, Kenya; Joel Tarning, Mahidol-Oxford Tropical Medicine
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Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and
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Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of
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Oxford, Oxford, UK; Walter RJ Taylor, UNICEF/UNDP/WB/WHO Special Programme for
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Research & Training in Tropical Diseases (TDR), Geneva, Switzerland and Service de
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Médecine Internationale et Humanitaire, Hopitaux Universitaries de Genève, Geneva,
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Switzerland; Emmanuel A Temu, The MENTOR Initiative, Crawley, UK; Julie I Thwing,
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Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention,
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Atlanta, Georgia; Emiliana Tjitra, National Institute of Health Research and Development,
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Ministry of Health, Jakarta, Indonesia; Roger CK Tine, Department of Medical Parasitology,
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Medical Faculty, Université Cheikh Anta Diop, Dakar, Senegal; Halidou Tinto, Institut de
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Recherce en Sciences de la Sante, Bobo Dioulasso, Burkina Faso
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Dioulasso, Burkina Faso; Michel T Vaillant, Methodology and Statistical Unit, Center for
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Health Studies, CRP Santé, Luxembourg, Luxembourg and Unité 3677, Bases thérapeutiques
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des inflammations et infections, Université Victor Segalen Bordeaux 2, Bordeaux, France;
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Neena Valecha, National Institute of Malaria Research, New Delhi, India; Ingrid Van den
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Broek, Médecins sans Frontières, London, UK and Centre for Infectious Disease Control,
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and Centre Muraz, Bobo
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National Institute for Public Health and the Environment, Bilthoven, The Netherlands;
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Nicholas J White, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
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and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of
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Oxford, Oxford, UK; Adoke Yeka, Uganda Malaria Surveillance Project, Kampala, Uganda
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and School of Public Health, Makerere University, Kampala, Uganda; Issaka Zongo, Institut
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de Recherche en Sciences de la Santé, Bobo-Dioulasso, Burkina Faso
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Corresponding authors:
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Prof Philippe J Guerin, Worldwide Antimalarial Resistance Network, Centre for Tropical Medicine,
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Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Email:
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[email protected]; Tel: +44 (1865) 857552; Fax: +44 (1865) 857407
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Dr Christian Nsanzabana, Worldwide Antimalarial Resistance Network, Centre for Tropical
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Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK, UK. Email:
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[email protected]; Tel: +44 (1865) 857552; Fax: +44 (1865) 857407
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Abstract: 354
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Words Count: 4556 8
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ABSTRACT
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Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-
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based combination therapies (ACTs) to treat uncomplicated P. falciparum malaria in Africa.
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We investigated the impact of different dosing strategies on the efficacy of this combination
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for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ
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clinical trials were pooled using WWARN standardised methodology. Risk factors for
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treatment failure were identified using a Cox regression model with shared frailty across
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study sites. Results: Forty three studies representing 9,106 treatments from 1999-2012 were
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included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with a
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AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with
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AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose
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combination with AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257
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(13.8%) with a co-blistered non-fixed dose combination with a AQ target dose of 30 mg/kg
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(co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-
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38.2], the highest dose being administered to patients treated with co-blistered NFDC
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(median=35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25
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(median=25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of
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32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial
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efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95%
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Confidence Interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; p=0.799),
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but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose
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NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (p
