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

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    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

    Fingerprint

    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 -