The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data

Martin Alhassan Adjuik; Richard Allan; Anupkumar R Anvikar; Elizabeth A Ashley; Mamadou S Ba; Hubert Barennes; Karen I Barnes; Quique Bassat; Elisabeth Baudin; Anders B Bjorkman; Francois 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 A Djimde; Grant Dorsey; Ogobara K Doumbo; Emmanuelle Espie; Jean-Francois Etard; Caterina I Fanello; Jean-Francois Faucher; Babacar Faye; Jennifer Anne Flegg; Oumar Gaye; Peter W Gething; Raquel Gonzalez; Francesco Grandesso; Philippe Jean Guerin; Jean-Paul Guthmann; Sally Hamour; Armedy Ronny Hasugian; Simon I Hay; Georgina S Humphreys; Vincent Jullien; Elizabeth Juma; Moses R K Kamya; Corine Kakizi Karema; Jean-Rene Kiechel; Peter G Kremsner; Sanjeev Krishna; Valerie Lameyre; Maman Laminou Ibrahim

doi:10.1186/s12916-015-0301-z

The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data

Martin Alhassan Adjuik, Richard Allan, Anupkumar R Anvikar, Elizabeth A Ashley, Mamadou S Ba, Hubert Barennes, Karen I Barnes, Quique Bassat, Elisabeth Baudin, Anders B Bjorkman, Francois Bompart, Maryline Bonnet, Steffen Borrmann, Philippe Brasseur, Hasifa Bukirwa, Francesco Checchi, Michel Cot, Prabin Dahal, Umberto D'Alessandro, Philippe DeloronMeghna Desai, Graciela Diap, Abdoulaye A Djimde, Grant Dorsey, Ogobara K Doumbo, Emmanuelle Espie, Jean-Francois Etard, Caterina I Fanello, Jean-Francois Faucher, Babacar Faye, Jennifer Anne Flegg, Oumar Gaye, Peter W Gething, Raquel Gonzalez, Francesco Grandesso, Philippe Jean Guerin, Jean-Paul Guthmann, Sally Hamour, Armedy Ronny Hasugian, Simon I Hay, Georgina S Humphreys, Vincent Jullien, Elizabeth Juma, Moses R K Kamya, Corine Kakizi Karema, Jean-Rene Kiechel, Peter G Kremsner, Sanjeev Krishna, Valerie Lameyre, Maman Laminou Ibrahim

School of Mathematics

Research output: Contribution to journal › Article › Research › peer-review

35 Citations (Scopus)

Abstract

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.

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.

Original language	English
Article number	66
Number of pages	19
Journal	BMC Medicine
Volume	13
DOIs	https://doi.org/10.1186/s12916-015-0301-z
Publication status	Published - 2015

Keywords

Malaria
Plasmodium falciparum
Drug resistance
Artesunate
Amodiaquine
Dosing
Efficacy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Adjuik, M. A., Allan, R., Anvikar, A. R., Ashley, E. A., Ba, M. S., Barennes, H., Barnes, K. I., Bassat, Q., Baudin, E., Bjorkman, A. B., Bompart, F., Bonnet, M., Borrmann, S., Brasseur, P., Bukirwa, H., Checchi, F., Cot, M., Dahal, P., D'Alessandro, U., ... Ibrahim, M. L. (2015). The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data. BMC Medicine, 13, Article 66. https://doi.org/10.1186/s12916-015-0301-z

@article{751c7f43a10444788ad122045e25a9b8,

title = "The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data",

abstract = "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.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.",

keywords = "Malaria, Plasmodium falciparum, Drug resistance, Artesunate, Amodiaquine, Dosing, Efficacy",

author = "Adjuik, {Martin Alhassan} and Richard Allan and Anvikar, {Anupkumar R} and Ashley, {Elizabeth A} and Ba, {Mamadou S} and Hubert Barennes and Barnes, {Karen I} and Quique Bassat and Elisabeth Baudin and Bjorkman, {Anders B} and Francois Bompart and Maryline Bonnet and Steffen Borrmann and Philippe Brasseur and Hasifa Bukirwa and Francesco Checchi and Michel Cot and Prabin Dahal and Umberto D'Alessandro and Philippe Deloron and Meghna Desai and Graciela Diap and Djimde, {Abdoulaye A} and Grant Dorsey and Doumbo, {Ogobara K} and Emmanuelle Espie and Jean-Francois Etard and Fanello, {Caterina I} and Jean-Francois Faucher and Babacar Faye and Flegg, {Jennifer Anne} and Oumar Gaye and Gething, {Peter W} and Raquel Gonzalez and Francesco Grandesso and Guerin, {Philippe Jean} and Jean-Paul Guthmann and Sally Hamour and Hasugian, {Armedy Ronny} and Hay, {Simon I} and Humphreys, {Georgina S} and Vincent Jullien and Elizabeth Juma and Kamya, {Moses R K} and Karema, {Corine Kakizi} and Jean-Rene Kiechel and Kremsner, {Peter G} and Sanjeev Krishna and Valerie Lameyre and Ibrahim, {Maman Laminou}",

year = "2015",

doi = "10.1186/s12916-015-0301-z",

language = "English",

volume = "13",

journal = "BMC Medicine",

issn = "1741-7015",

publisher = "BioMed Central",

}

Adjuik, MA, Allan, R, Anvikar, AR, Ashley, EA, Ba, MS, Barennes, H, Barnes, KI, Bassat, Q, Baudin, E, Bjorkman, AB, Bompart, F, Bonnet, M, Borrmann, S, Brasseur, P, Bukirwa, H, Checchi, F, Cot, M, Dahal, P, D'Alessandro, U, Deloron, P, Desai, M, Diap, G, Djimde, AA, Dorsey, G, Doumbo, OK, Espie, E, Etard, J-F, Fanello, CI, Faucher, J-F, Faye, B, Flegg, JA, Gaye, O, Gething, PW, Gonzalez, R, Grandesso, F, Guerin, PJ, Guthmann, J-P, Hamour, S, Hasugian, AR, Hay, SI, Humphreys, GS, Jullien, V, Juma, E, Kamya, MRK, Karema, CK, Kiechel, J-R, Kremsner, PG, Krishna, S, Lameyre, V & Ibrahim, ML 2015, 'The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data', BMC Medicine, vol. 13, 66. https://doi.org/10.1186/s12916-015-0301-z

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 Alhassan

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 - Bjorkman, Anders B

AU - Bompart, Francois

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 - Espie, Emmanuelle

AU - Etard, Jean-Francois

AU - Fanello, Caterina I

AU - Faucher, Jean-Francois

AU - Faye, Babacar

AU - Flegg, Jennifer Anne

AU - Gaye, Oumar

AU - Gething, Peter W

AU - Gonzalez, Raquel

AU - Grandesso, Francesco

AU - Guerin, Philippe Jean

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 K

AU - Karema, Corine Kakizi

AU - Kiechel, Jean-Rene

AU - Kremsner, Peter G

AU - Krishna, Sanjeev

AU - Lameyre, Valerie

AU - Ibrahim, Maman Laminou

PY - 2015

Y1 - 2015

N2 - 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.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.

AB - 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.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.

KW - Malaria

KW - Plasmodium falciparum

KW - Drug resistance

KW - Artesunate

KW - Amodiaquine

KW - Dosing

KW - Efficacy

U2 - 10.1186/s12916-015-0301-z

DO - 10.1186/s12916-015-0301-z

M3 - Article

C2 - 25888957

SN - 1741-7015

VL - 13

JO - BMC Medicine

JF - BMC Medicine

M1 - 66

ER -