The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria

A meta-analysis of individual patient data

Martin A. Adjuik, Richard Allan, Anupkumar R. Anvikar, Elizabeth A. Ashley, Mamadou S. Ba, Hubert Barennes, 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 & 87 others Meghna Desai, Graciela Diap, Abdoulaye A. Djimde, Grant Dorsey, Ogobara K. Doumbo, Emmanuelle Espié, Jean Francois Etard, Caterina I. Fanello, Jean François Faucher, Babacar Faye, Jennifer A. Flegg, Oumar Gaye, Peter W. Gething, Raquel González, Francesco Grandesso, Philippe J. Guerin, Jean Paul Guthmann, Sally Hamour, Armedy Ronny Hasugian, Simon I. Hay, Georgina S. Humphreys, Vincent Jullien, Elizabeth Juma, Moses R. Kamya, Corine Karema, Jean R. Kiechel, Peter G. Kremsner, Sanjeev Krishna, Valérie Lameyre, Laminou M. Ibrahim, Sue J. Lee, Bertrand Lell, Andreas Martensson, Achille Massougbodji, Hervé Menan, Didier Ménard, Clara Menéndez, Martin Meremikwu, Clarissa Moreira, Carolyn Nabasumba, Michael Nambozi, Jean Louis Ndiaye, Frederic Nikiema, Christian Nsanzabana, Francine Ntoumi, Bernhards R. Ogutu, Piero Olliaro, Lyda Osorio, Jean Bosco Ouédraogo, Louis K. Penali, Mbaye Pene, Loretxu Pinoges, Patrice Piola, Ric N. Price, Cally Roper, Philip J. Rosenthal, Claude Emile Rwagacondo, Albert Same-Ekobo, Birgit Schramm, Amadou Seck, Bhawna Sharma, Carol Hopkins Sibley, Véronique Sinou, Sodiomon B. Sirima, Jeffery J. Smith, Frank Smithuis, Fabrice A. Somé, Doudou Sow, Sarah G. Staedke, Kasia Stepniewska, Todd D. Swarthout, Khadime Sylla, Ambrose O. Talisuna, Joel Tarning, Walter R J Taylor, Emmanuel A. Temu, Julie I. Thwing, Emiliana Tjitra, Roger C K Tine, Halidou Tinto, Michel T. Vaillant, Neena Valecha, Ingrid Van den Broek, Nicholas J. White, Adoke Yeka, Issaka Zongo, The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.


Original languageEnglish
Article number66
Pages (from-to)1-19
Number of pages19
JournalBMC Medicine
Volume13
DOIs
Publication statusPublished - 31 Mar 2015

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Malaria
Meta-Analysis
Confidence Intervals
Antimalarials
Amodiaquine
Therapeutics
Recurrence
Parasitemia
Falciparum Malaria
Treatment Failure
Proportional Hazards Models
Tablets
artesunate drug combination amodiaquine

Cite this

Adjuik, M. A., Allan, R., Anvikar, A. R., Ashley, E. A., Ba, M. S., Barennes, H., ... The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group (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, 1-19. [66]. https://doi.org/10.1186/s12916-015-0301-z
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 ; Martensson, 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 ; The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group. / The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : A meta-analysis of individual patient data. In: BMC Medicine. 2015 ; Vol. 13. pp. 1-19.
@article{fd2f936dbe9040d3a4b5c8107b72db8b,
title = "The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: A meta-analysis of individual patient data",
abstract = "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.",
keywords = "amodiaquine, age, anemia, Article, body weight, diarrhea, drug dose comparison, drug efficacy, genotyping technique, human, malaria falciparum, meta analysis, neutropenia, neutrophil count, parasitemia, vomiting",
author = "Adjuik, {Martin A.} 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 Anders Bj{\"o}rkman and Fran{\cc}ois 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 Espi{\'e} and Etard, {Jean Francois} and Fanello, {Caterina I.} and Faucher, {Jean Fran{\cc}ois} and Babacar Faye and Flegg, {Jennifer A.} and Oumar Gaye and Gething, {Peter W.} and Raquel Gonz{\'a}lez and Francesco Grandesso and Guerin, {Philippe J.} and Guthmann, {Jean Paul} 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.} and Corine Karema and Kiechel, {Jean R.} and Kremsner, {Peter G.} and Sanjeev Krishna and Val{\'e}rie Lameyre and Ibrahim, {Laminou M.} and Lee, {Sue J.} and Bertrand Lell and Andreas Martensson and Achille Massougbodji and Herv{\'e} Menan and Didier M{\'e}nard and Clara Men{\'e}ndez and Martin Meremikwu and Clarissa Moreira and Carolyn Nabasumba and Michael Nambozi and Ndiaye, {Jean Louis} and Frederic Nikiema and Christian Nsanzabana and Francine Ntoumi and Ogutu, {Bernhards R.} and Piero Olliaro and Lyda Osorio and Ou{\'e}draogo, {Jean Bosco} and Penali, {Louis K.} and Mbaye Pene and Loretxu Pinoges and Patrice Piola and Price, {Ric N.} and Cally Roper and Rosenthal, {Philip J.} and Rwagacondo, {Claude Emile} and Albert Same-Ekobo and Birgit Schramm and Amadou Seck and Bhawna Sharma and Sibley, {Carol Hopkins} and V{\'e}ronique Sinou and Sirima, {Sodiomon B.} and Smith, {Jeffery J.} and Frank Smithuis and Som{\'e}, {Fabrice A.} and Doudou Sow and Staedke, {Sarah G.} and Kasia Stepniewska and Swarthout, {Todd D.} and Khadime Sylla and Talisuna, {Ambrose O.} and Joel Tarning and Taylor, {Walter R J} and Temu, {Emmanuel A.} and Thwing, {Julie I.} and Emiliana Tjitra and Tine, {Roger C K} and Halidou Tinto and Vaillant, {Michel T.} and Neena Valecha and {Van den Broek}, Ingrid and White, {Nicholas J.} and Adoke Yeka and Issaka Zongo and {The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group}",
year = "2015",
month = "3",
day = "31",
doi = "10.1186/s12916-015-0301-z",
language = "English",
volume = "13",
pages = "1--19",
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, Björkman, A, 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, Espié, E, Etard, JF, Fanello, CI, Faucher, JF, Faye, B, Flegg, JA, Gaye, O, Gething, PW, González, R, Grandesso, F, Guerin, PJ, Guthmann, JP, Hamour, S, Hasugian, AR, Hay, SI, Humphreys, GS, Jullien, V, Juma, E, Kamya, MR, Karema, C, Kiechel, JR, Kremsner, PG, Krishna, S, Lameyre, V, Ibrahim, LM, Lee, SJ, Lell, B, Martensson, A, Massougbodji, A, Menan, H, Ménard, D, Menéndez, C, Meremikwu, M, Moreira, C, Nabasumba, C, Nambozi, M, Ndiaye, JL, Nikiema, F, Nsanzabana, C, Ntoumi, F, Ogutu, BR, Olliaro, P, Osorio, L, Ouédraogo, JB, Penali, LK, Pene, M, Pinoges, L, Piola, P, Price, RN, Roper, C, Rosenthal, PJ, Rwagacondo, CE, Same-Ekobo, A, Schramm, B, Seck, A, Sharma, B, Sibley, CH, Sinou, V, Sirima, SB, Smith, JJ, Smithuis, F, Somé, FA, Sow, D, Staedke, SG, Stepniewska, K, Swarthout, TD, Sylla, K, Talisuna, AO, Tarning, J, Taylor, WRJ, Temu, EA, Thwing, JI, Tjitra, E, Tine, RCK, Tinto, H, Vaillant, MT, Valecha, N, Van den Broek, I, White, NJ, Yeka, A, Zongo, I & The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group 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, pp. 1-19. https://doi.org/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. / 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; Martensson, 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; The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group.

In: BMC Medicine, Vol. 13, 66, 31.03.2015, p. 1-19.

Research output: Contribution to journalArticleResearchpeer-review

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 - Ibrahim, Laminou M.

AU - Lee, Sue J.

AU - Lell, Bertrand

AU - Martensson, Andreas

AU - Massougbodji, Achille

AU - Menan, Hervé

AU - Ménard, Didier

AU - Menéndez, Clara

AU - Meremikwu, Martin

AU - Moreira, Clarissa

AU - Nabasumba, Carolyn

AU - Nambozi, Michael

AU - Ndiaye, Jean Louis

AU - Nikiema, Frederic

AU - Nsanzabana, Christian

AU - Ntoumi, Francine

AU - Ogutu, Bernhards R.

AU - Olliaro, Piero

AU - Osorio, Lyda

AU - Ouédraogo, Jean Bosco

AU - Penali, Louis K.

AU - Pene, Mbaye

AU - Pinoges, Loretxu

AU - Piola, Patrice

AU - Price, Ric N.

AU - Roper, Cally

AU - Rosenthal, Philip J.

AU - Rwagacondo, Claude Emile

AU - Same-Ekobo, Albert

AU - Schramm, Birgit

AU - Seck, Amadou

AU - Sharma, Bhawna

AU - Sibley, Carol Hopkins

AU - Sinou, Véronique

AU - Sirima, Sodiomon B.

AU - Smith, Jeffery J.

AU - Smithuis, Frank

AU - Somé, Fabrice A.

AU - Sow, Doudou

AU - Staedke, Sarah G.

AU - Stepniewska, Kasia

AU - Swarthout, Todd D.

AU - Sylla, Khadime

AU - Talisuna, Ambrose O.

AU - Tarning, Joel

AU - Taylor, Walter R J

AU - Temu, Emmanuel A.

AU - Thwing, Julie I.

AU - Tjitra, Emiliana

AU - Tine, Roger C K

AU - Tinto, Halidou

AU - Vaillant, Michel T.

AU - Valecha, Neena

AU - Van den Broek, Ingrid

AU - White, Nicholas J.

AU - Yeka, Adoke

AU - Zongo, Issaka

AU - The WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group

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 - age

KW - anemia

KW - Article

KW - body weight

KW - diarrhea

KW - drug dose comparison

KW - drug efficacy

KW - genotyping technique

KW - human

KW - malaria falciparum

KW - meta analysis

KW - neutropenia

KW - neutrophil count

KW - parasitemia

KW - vomiting

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

VL - 13

SP - 1

EP - 19

JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

M1 - 66

ER -