The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data
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 eff...
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Medicine 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 |
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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. |
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Uganda Malaria Surveillance Project |
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Uganda Malaria Surveillance Project 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 |
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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 |
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Jane Achan |
title |
The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data |
title_short |
The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data |
title_full |
The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data |
title_fullStr |
The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data |
title_full_unstemmed |
The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data |
title_sort |
effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin-piperaquine: a pooled analysis of individual patient data |
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2018 |
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https://repository.li.mahidol.ac.th/handle/123456789/32709 |
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1763494908829630464 |
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th-mahidol.327092018-10-19T12:40:32Z The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data 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 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 Medicine 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. 2018-10-19T05:40:32Z 2018-10-19T05:40:32Z 2013-01-01 Article PLoS Medicine. Vol.10, No.12 (2013), 1-17 10.1371/journal.pmed.1001564 15491676 15491277 2-s2.0-84892892177 https://repository.li.mahidol.ac.th/handle/123456789/32709 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84892892177&origin=inward |