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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
The effect of dose on the antimalarial efficacy of artemether-lumefantrine: A systematic review and pooled analysis of individual patient data
The Lancet Infectious Diseases, Volume 15, No. 6, Year 2015
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Description
Background: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. Methods: We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. Findings: We included 61 studies done between January, 1998, and December, 2012, and included 14 327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). Interpretation: The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. Funding: Bill & Melinda Gates Foundation. © 2015 Elsevier Ltd.
Authors & Co-Authors
Anstey, Nicholas M.
Australia, Darwin
Charles Darwin University
Price, Ric N.
Australia, Darwin
Charles Darwin University
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
United Kingdom, Oxford
University of Oxford
Davis, Timothy M.E.
Australia, Perth
The University of Western Australia
Karunajeewa, Harin A.
Australia, Melbourne
Walter and Eliza Hall Institute of Medical Research
Australia
Western Health
Mueller, Ivo
Australia, Melbourne
Walter and Eliza Hall Institute of Medical Research
Spain, Barcelona
Centre de Recerca en Salut Internacional de Barcelona
D'Alessandro, Umberto
Belgium, Antwerpen
Prins Leopold Instituut Voor Tropische Geneeskunde
Gambia, Banjul
Medical Research Council Laboratories Gambia
Massougbodji, Achille
Benin, Cotonou
University of Abomey-calavi
Nikiema, Frederic
Burkina Faso, Ouagadougou
Institut de Recherche en Sciences de la Santé
Ouedraogo, Jean Bosco
Burkina Faso, Ouagadougou
Institut de Recherche en Sciences de la Santé
Burkina Faso, Ouagadougou
Centre Muraz
Tinto, Halidou
Burkina Faso, Ouagadougou
Institut de Recherche en Sciences de la Santé
Burkina Faso, Ouagadougou
Centre Muraz
Zongo, Issaka D.
Burkina Faso, Ouagadougou
Institut de Recherche en Sciences de la Santé
Samè-Ekobo, Albert
Cameroon, Yaounde
Université de Yaoundé I
Koné, Moussa S.
Cote D'ivoire, Abidjan
Université de Cocody-abidjan
Ménan, Hervé Eby
Cote D'ivoire, Abidjan
Université de Cocody-abidjan
Yavo, William
Cote D'ivoire, Abidjan
Université de Cocody-abidjan
Cote D'ivoire, Abidjan
National Institute of Public Health
Toure, Offianan Andre
Cote D'ivoire, Abidjan
Institut Pasteur de Cote-d'ivoire
Kofoed, Poul Erik Lund
Denmark, Kolding
Sygehus Lillebælt - Kolding
Guinea-bissau
Projecto de Saúde de Bandim
Alemayehu, Bereket Hailegiorgis
Ethiopia, Addis Ababa
International Center for Aids Care and Treatment Programs
Jima, Daddi
Ethiopia, Addis Ababa
Federal Ministry of Health - Ethiopia
Baudin, Elisabeth
France, Paris
Epicentre
Espié, Emmanuelle
France, Paris
Epicentre
Nabasumba, Carolyn
France, Paris
Epicentre
Uganda, Mbarara
Mbarara University of Science and Technology
Pinoges, Loretxu L.P.
France, Paris
Epicentre
Schramm, Birgit
France, Paris
Epicentre
Cot, Michel
France, Marseille
Ird Institut de Recherche Pour le Developpement
France, Paris
Université Paris Cité
Deloron, Philippe
France, Marseille
Ird Institut de Recherche Pour le Developpement
France, Paris
Université Paris Cité
Faucher, Jean François
France, Marseille
Ird Institut de Recherche Pour le Developpement
France, Paris
Université Paris Cité
France, Besancon
Université de Franche-comté
Guthmann, Jean Paul
France, Saint-maurice
Institut de Veille Sanitaire
Lell, Bertrand
Gabon, Gabon
Centre de Recherches Médicales de Lambaréné
Germany, Tubingen
Eberhard Karls Universität Tübingen
Borrmann, Steffen
Germany, Tubingen
Eberhard Karls Universität Tübingen
Kenya, Nairobi
Kenya Medical Research Institute
Adjei, George Obeng
Ghana, Accra
University of Ghana
Ursing, Johan
Guinea-bissau
Projecto de Saúde de Bandim
Sweden, Stockholm
Karolinska Institutet
Tjitra, Emiliana
Indonesia, Jakarta
Kementerian Kesehatan Republik Indonesia
Marsh, Kevin
Kenya, Nairobi
Kenya Medical Research Institute
United Kingdom, Oxford
University of Oxford
Peshu, Judy
Kenya, Nairobi
Kenya Medical Research Institute
Juma, Elizabeth A.
Kenya, Nairobi
Kenya Medical Research Institute
Ogutu, Bernhards R.
Kenya, Nairobi
Kenya Medical Research Institute
Omar, Sabah Ahmed
Kenya, Nairobi
International Centre of Insect Physiology and Ecology Nairobi
Sawa, Patrick
Kenya, Nairobi
International Centre of Insect Physiology and Ecology Nairobi
Talisuna, Ambrose Otau
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
Kenya, Nairobi
Kenya Medical Research Institute
Khanthavong, Maniphone
Unknown Affiliation
Mayxay, Mayfong
Thailand
Mahosot Hospital, Lao
Laos, Vientiane
National University of Laos
Newton, Paul N.
Thailand
Mahosot Hospital, Lao
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
United Kingdom, Oxford
University of Oxford
Piola, Patrice
Madagascar, Antananarivo
Institut Pasteur de Madagascar
Djimde, Abdoulaye A.
Mali, Bamako
University of Bamako
Doumbo, Ogobara K.
Mali, Bamako
University of Bamako
Fofana, Bakary
Mali, Bamako
University of Bamako
Sagara, Issaka
Mali, Bamako
University of Bamako
Bassat, Quique
Mozambique, Manhica
Centro de Investigação em Saúde de Manhiça Cism
Spain, Barcelona
Centre de Recerca en Salut Internacional de Barcelona
González, Raquel
Mozambique, Manhica
Centro de Investigação em Saúde de Manhiça Cism
Spain, Barcelona
Centre de Recerca en Salut Internacional de Barcelona
Menéndez, Clara
Mozambique, Manhica
Centro de Investigação em Saúde de Manhiça Cism
Spain, Barcelona
Centre de Recerca en Salut Internacional de Barcelona
Smithuis, Frank M.
Myanmar, Yangon
Myanmar Oxford Clinical Research Unit
Myanmar, Yangon
Medical Action Myanmar
Bousema, Teun
Netherlands, Nijmegen
Radboud University Medical Center
United Kingdom, London
London School of Hygiene & Tropical Medicine
Kager, Petrus A.
Netherlands, Amsterdam
Amsterdam Umc - University of Amsterdam
Mens, Pètra Francisca
Netherlands, Amsterdam
Amsterdam Umc - University of Amsterdam
Netherlands, Amsterdam
Royal Tropical Institute - Kit
Schallig, H. D. F. H.
Netherlands, Amsterdam
Royal Tropical Institute - Kit
van den Broek, I. V.
Netherlands, Bilthoven
Rijksinstituut Voor Volksgezondheid en Milieu
Switzerland, Geneva
Medecins Sans Frontieres
van Vugt, Michèle V.
Netherlands, Amsterdam
Amsterdam Umc - University of Amsterdam
Ibrahim, Maman Laminou
Niger
Centre de Recherche Médicale et Sanitaire
Falade, Catherine Olufunke
Nigeria, Ibadan
University of Ibadan
Meremikwu, Martin Madu
Nigeria, Calabar
University of Calabar
Nigeria, Calabar
Institute of Tropical Diseases Research and Prevention
Gil, Jose Pedro
Portugal, Lisbon
Universidade de Lisboa
Sweden, Stockholm
Karolinska Institutet
United States, Binghamton
Binghamton University State University of new York
Karema, Corine Kakizi
Rwanda, Kigali
Ministry of Health
Bâ, Mamadou Sarifou
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Faye, Babacar Félix
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Faye, Oumar K.
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Gaye, Oumar H.
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Ndiaye, Jean Louis Abdourahim
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Pene, Mbaye
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Sow, Doudou Diagne
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Sylla, Khadime
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Tine, Roger C.K.
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Pénali, Louis Koné
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
Barnes, Karen Irma
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
South Africa, Cape Town
University of Cape Town
Workman, Lesley J.
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
South Africa, Cape Town
University of Cape Town
Lima, María Angeles
Switzerland, Geneva
Medecins Sans Frontieres
Adam, Ishag I.
Sudan, Khartoum
Khartoum University
Gadalla, Nahla B.
Sudan, Khartoum
National Center for Research Sudan
United Kingdom, London
London School of Hygiene & Tropical Medicine
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Malik, Elfatih Mohamed
Sudan, Khartoum
Federal Ministry of Health Sudan
Bjǒrkman, Anders B.
Sweden, Stockholm
Karolinska Institutet
Mårtensson, Andreas A.
Sweden, Stockholm
Karolinska Institutet
Ngasala, Billy E.
Sweden, Stockholm
Karolinska Institutet
Tanzania, Dar es Salaam
Muhimbili University of Health and Allied Sciences
Rombo, Lars
Sweden, Stockholm
Karolinska Institutet
Aliu, P.
Switzerland, Basel
Novartis International ag
Duparc, Stephan
Switzerland, Geneva
Medicines for Malaria Venture
Filler, Scott J.
Switzerland, Geneva
Fonds Mondial de Lutte Contre le Sida, la Tuberculose et le Paludisme
Genton, Blaise
Switzerland, Allschwil
Swiss Tropical and Public Health Institute Swiss Tph
Switzerland, Lausanne
Centre Hospitalier Universitaire Vaudois
Hodel, Eva Maria
Switzerland, Allschwil
Swiss Tropical and Public Health Institute Swiss Tph
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Olliaro, Piero L.
United States, Washington, D.c.
The World Bank, Usa
United Kingdom, Oxford
University of Oxford
Abdulla, Salim Mohammed K.
Tanzania, Ifakara
Ifakara Health Institute
Kamugisha, Erasmus
Tanzania, Mwanza
Catholic University of Health and Allied Sciences
Premji, Zulfiqarali G.
Tanzania, Dar es Salaam
Muhimbili University of Health and Allied Sciences
Shekalaghe, Seif Abdallah
Tanzania, Moshi
Kilimanjaro Clinical Research Institute
Tanzania, Ifakara
Ifakara Health Institute
Ashley, Elizabeth A.
Thailand, Nakhon Pathom
Mahidol University
Carrara, Verena Ilona
Thailand, Nakhon Pathom
Mahidol University
McGready, R. M.
Thailand, Nakhon Pathom
Mahidol University
United Kingdom, Oxford
University of Oxford
Nosten, François Henry
Thailand, Nakhon Pathom
Mahidol University
United Kingdom, Oxford
University of Oxford
Faiz, Mohammad Abul
Thailand, Nakhon Pathom
Mahidol University
Lee, Sue J.
Thailand, Nakhon Pathom
Mahidol University
United Kingdom, Oxford
University of Oxford
White, Nicholas J.
Thailand, Nakhon Pathom
Mahidol University
United Kingdom, Oxford
University of Oxford
Dondorp, A. M.
Thailand, Nakhon Pathom
Mahidol University
United Kingdom, Oxford
University of Oxford
Smith, Jeffery J.
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
Tarning, Joel
Thailand, Bangkok
Mahidol Oxford Tropical Medicine Research Unit
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
United Kingdom, Oxford
University of Oxford
Achan, Jane
Uganda, Kampala
Uganda Malaria Surveillance Project
Bukirwa, Hasifa
Uganda, Kampala
Uganda Malaria Surveillance Project
Yeka, Adoke
Uganda, Kampala
Uganda Malaria Surveillance Project
Arinaitwe, Emmanuel S.
Uganda, Kampala
Infectious Diseases Research Collaboration
Staedke, Sarah G.
Uganda, Kampala
Infectious Diseases Research Collaboration
United Kingdom, London
London School of Hygiene & Tropical Medicine
Kamya, Moses Robert K.
Uganda, Kampala
Makerere University
Kironde, Fred Alexander Sekaza
Uganda, Kampala
Makerere University
Drakeley, Chris J.
United Kingdom, London
London School of Hygiene & Tropical Medicine
Oguike, Mary Chiaka
United Kingdom, London
London School of Hygiene & Tropical Medicine
Sutherland, Colin J.
United Kingdom, London
London School of Hygiene & Tropical Medicine
Checchi, Francesco
United Kingdom, London
Save the Children Fund
Dahal, Prabin
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
United Kingdom, Oxford
University of Oxford
Flegg, Jennifer A.
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
United Kingdom, Oxford
University of Oxford
Guérin, Philippe Jean Jean
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
United Kingdom, Oxford
University of Oxford
Moreira, Clarissa M.
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
United Kingdom, Oxford
University of Oxford
Nsanzabana, Christian
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
United Kingdom, Oxford
University of Oxford
Sibley, Carol Hopkins
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
United States, Seattle
University of Washington
Stepniewska, Kasia
United Kingdom, Oxford
Worldwide Antimalarial Resistance Network
Gething, Peter W.
United Kingdom, Oxford
University of Oxford
Hay, Simon I.
United Kingdom, Oxford
University of Oxford
Greenwood, Brian M.
United Kingdom, London
London School of Hygiene & Tropical Medicine
Ward, Stephen Andrew
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Winstanley, Peter A.
United Kingdom, Coventry
University of Warwick
Dorsey, Grant M.
United States, San Francisco
University of California, San Francisco
Greenhouse, Bryan R.
United States, San Francisco
University of California, San Francisco
Rosenthal, Philip Jon
United States, San Francisco
University of California, San Francisco
Grivoyannis, Anastasia D.
United States, Seattle
University of Washington
Hamed, Kamal A.
Switzerland, Basel
Novartis International ag
Hwang, Jimee
United States, Atlanta
Centers for Disease Control and Prevention
United States, San Francisco
University of California, San Francisco
Kachur, Patrick S.
United States, Atlanta
Centers for Disease Control and Prevention
Nambozi, Michael
Zambia, Ndola
Tropical Diseases Research Centre
Statistics
Citations: 68
Authors: 134
Affiliations: 81
Identifiers
Doi:
10.1016/S1473-3099(15)70024-1
ISSN:
14733099
Research Areas
Health System And Policy
Infectious Diseases
Maternal And Child Health
Study Design
Case-Control Study
Study Approach
Systematic review