Publication:
The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data

Issued Date

2013-01-01

Resource Type

Article

ISSN

15491676
15491277

DOI

10.1371/journal.pmed.1001564

Other identifier(s)

2-s2.0-84892892177

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

PLoS Medicine. Vol.10, No.12 (2013), 1-17

Suggested Citation

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 The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data. PLoS Medicine. Vol.10, No.12 (2013), 1-17. doi:10.1371/journal.pmed.1001564 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/32709

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Title

The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data

Author(s)

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

Other Contributor(s)

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
 UCL
 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
 Epicentre
 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

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.

Keyword(s)

Medicine

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https://repository.li.mahidol.ac.th/handle/20.500.14594/32709

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