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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

2015; BioMed Central; Volume: 13; Issue: 1 Linguagem: Inglês

10.1186/s12916-015-0301-z

1741-7015

Martin Adjuik, Richard Allan, Anupkumar R. Anvikar, Elizabeth A. Ashley, Mamadou Fallou Ba, B. Hubert, Karen I. Barnes, Quique Bassat, Elisabeth Baudin, Anders Björkman, François Bompart, Maryline Bonnet, Steffen Borrmann, Philippe Brasseur, Hasifa Bukirwa, Francesco Checchi, Michel Cot, Prabin Dahal, Umberto D’Alessandro, Philippe Deloron, Meghna Desai, Graciela Diap, Abdoulaye Djimdé, Grant Dorsey, Ogobara K. Doumbo, Emmanuelle Espié, Jean-François Étard, Caterina Fanello, Jean‐François Faucher, Babacar Faye, Jennifer A. Flegg, Oumar Gaye, Peter W. Gething, Raquel González, Francesco Grandesso, Philippe J. Guérin, Jean‐Paul Guthmann, Sally Hamour, Armedy Ronny Hasugian, Simon I Hay, Georgina Humphreys, Vincent Jullien, Elizabeth Juma, Moses Kamya, Corine Karema, J.R. Kiechel, Peter G. Kremsner, Sanjeev Krishna, Valérie Lameyre, Laminou Ibrahim, Sue J. Lee, Bertrand Lell, Andreas Mårtensson, Achille Massougbodji, Hervé Ménan, Didier Ménard, Clara Menéndez, Martin Meremikwu, Clarissa Moreira, Carolyn Nabasumba, Michael Nambozi, Jean Louis Ndiaye, Frédéric Nikièma, Christian Nsanzabana, Francine Ntoumi, Bernhards Ogutu, Piero Olliaro, Lyda Osório, Jean‐Bosco Ouédraogo, Louis K. Pénali, Mbaye Pene, Loretxu Pinoges, Patrice Piola, Ric N. Price, Cally Roper, Philip J. Rosenthal, Claude Rwagacondo, A Samé‐Ekobo, Birgit Schramm, Amadou Seck, Bhawna Sharma, Carol Hopkins Sibley, Véronique Sinou, Sodiomon B. Sirima, Jeffery Smith, Frank Smithuis, Anyirékun Fabrice Somé, Doudou Sow, Sarah G. Staedke, Kasia Stepniewska, Todd D. Swarthout, Khadime Sylla, Ambrose Talisuna, Joel Tärning, Walter Taylor, Emmanuel A. Temu, Julie Thwing, Emiliana Tjitra, Roger Tine, Halidou Tinto, Michel Vaillant, Neena Valecha, Ingrid van den Broek, Nicholas J. White, Adoke Yeka, Issaka Zongo,

Drug-Induced Hepatotoxicity and Protection

BackgroundArtesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.MethodsIndividual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites.ResultsForty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites.ConclusionsThere was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.