TY - JOUR
T1 - The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria
T2 - A meta-analysis of individual patient data
AU - Adjuik, Martin A.
AU - Allan, Richard
AU - Anvikar, Anupkumar R.
AU - Ashley, Elizabeth A.
AU - Ba, Mamadou S.
AU - Barennes, Hubert
AU - Barnes, Karen I.
AU - Bassat, Quique
AU - Baudin, Elisabeth
AU - Björkman, Anders
AU - Bompart, François
AU - Bonnet, Maryline
AU - Borrmann, Steffen
AU - Brasseur, Philippe
AU - Bukirwa, Hasifa
AU - Checchi, Francesco
AU - Cot, Michel
AU - Dahal, Prabin
AU - D'Alessandro, Umberto
AU - Deloron, Philippe
AU - Desai, Meghna
AU - Diap, Graciela
AU - Djimde, Abdoulaye A.
AU - Dorsey, Grant
AU - Doumbo, Ogobara K.
AU - Espié, Emmanuelle
AU - Etard, Jean Francois
AU - Fanello, Caterina I.
AU - Faucher, Jean François
AU - Faye, Babacar
AU - Flegg, Jennifer A.
AU - Gaye, Oumar
AU - Gething, Peter W.
AU - González, Raquel
AU - Grandesso, Francesco
AU - Guerin, Philippe J.
AU - Guthmann, Jean Paul
AU - Hamour, Sally
AU - Hasugian, Armedy Ronny
AU - Hay, Simon I.
AU - Humphreys, Georgina S.
AU - Jullien, Vincent
AU - Juma, Elizabeth
AU - Kamya, Moses R.
AU - Karema, Corine
AU - Kiechel, Jean R.
AU - Kremsner, Peter G.
AU - Krishna, Sanjeev
AU - Lameyre, Valérie
AU - Vaillant, Michel T.
AU - The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group
N1 - Publisher Copyright:
© The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group; licensee BioMed Central.
PY - 2015/3/31
Y1 - 2015/3/31
N2 - Background: Artesunate-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. 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.
AB - Background: Artesunate-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. 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.
KW - Amodiaquine
KW - Artesunate
KW - Dosing
KW - Drug resistance
KW - Efficacy
KW - Malaria
KW - Plasmodium falciparum
UR - http://www.scopus.com/inward/record.url?scp=84928776445&partnerID=8YFLogxK
U2 - 10.1186/s12916-015-0301-z
DO - 10.1186/s12916-015-0301-z
M3 - Article
C2 - 604003796
AN - SCOPUS:84928776445
SN - 1741-7015
VL - 13
JO - BMC Medicine
JF - BMC Medicine
IS - 1
M1 - 66
ER -