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Войти в исследования The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.
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WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group, Adjuik Martin A, Allan Richard, Anvikar Anupkumar R, Ashley Elizabeth A, Ba Mamadou S, Barennes Hubert, Barnes Karen I, Bassat Quique, Baudin Elisabeth, Björkman Anders, Bompart François, Bonnet Maryline, Borrmann Steffen, Brasseur Philippe, Bukirwa Hasifa, Checchi Francesco, Cot Michel, Dahal Prabin, D'Alessandro Umberto, Deloron Philippe, Desai Meghna, Diap Graciela, Djimde Abdoulaye A, Dorsey Grant, Doumbo Ogobara K, Espié Emmanuelle, Etard Jean-Francois, Fanello Caterina I, Faucher Jean-François, Faye Babacar, Flegg Jennifer A, Gaye Oumar, Gething Peter W, González Raquel, Grandesso Francesco, Guerin Philippe J, Guthmann Jean-Paul, Hamour Sally, Hasugian Armedy Ronny, Hay Simon I, Humphreys Georgina S, Jullien Vincent, Juma Elizabeth, Kamya Moses R, Karema Corine, Kiechel Jean R, Kremsner Peter G, Krishna Sanjeev, Lameyre Valérie, Ibrahim Laminou M, Lee Sue J, Lell Bertrand, Mårtensson Andreas, Massougbodji Achille, Menan Hervé, Ménard Didier, Menéndez Clara, Meremikwu Martin, Moreira Clarissa, Nabasumba Carolyn, Nambozi Michael, Ndiaye Jean-Louis, Nikiema Frederic, Nsanzabana Christian, Ntoumi Francine, Ogutu Bernhards R, Olliaro Piero, Osorio Lyda, Ouédraogo Jean-Bosco, Penali Louis K, Pene Mbaye, Pinoges Loretxu, Piola Patrice, Price Ric N, Roper Cally, Rosenthal Philip J, Rwagacondo Claude Emile, Same-Ekobo Albert, Schramm Birgit, Seck Amadou, Sharma Bhawna, Sibley Carol Hopkins, Sinou Véronique, Sirima Sodiomon B, Smith Jeffery J, Smithuis Frank, Somé Fabrice A, Sow Doudou, Staedke Sarah G, Stepniewska Kasia, Swarthout Todd D, Sylla Khadime, Talisuna Ambrose O, Tarning Joel, Taylor Walter R J, Temu Emmanuel A, Thwing Julie I, Tjitra Emiliana, Tine Roger C K, Tinto Halidou, Vaillant Michel T, Valecha Neena, Van den Broek Ingrid, White Nicholas J, Yeka Adoke, Zongo Issaka
Аннотация
METHODS: Individual 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.
RESULTS: Forty-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.
CONCLUSIONS: There 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.