The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data

J. Achan; I.I. Adam; E. Arinaitwe; E.A. Ashley; G.R. Awab; M.S. Ba; K.I. Barnes; Q. Bassat; S. Borrmann; T. Bousema; P. Dahal; U. D'Alessandro; Timothy Davis; A.M. Dondorp; G. Dorsey; C.J. Drakeley; C.I. Fanello; B.F. Faye; J.A. Flegg; O.H. Gaye; P.W. Gething; R. González; P.J. Guérin; S.I. Hay; T.T. Hien; B. Janssens; M.R. Kamya; C. Karema; H.A. Karunajeewa; M.W. Koné; B. Lell; K. Marsh; M. Mayxay; C. Menéndez; P.F. Mens; M.M. Meremikwu; C. Moreira; I. Müeller; C. Nabasumba; M. Nambozi; J.L.A. Ndiaye; P.N. Newton; T.N. Nguyen; F. Nosten; C. Nsanzabana; S.A. Omar; J.B. Ouédraogo; L.K. Pénali; M. Pene; A. Phyo; P. Piola; R.N. Price; P. Sasithon; P.J. Rosenthal; A. Samè-Ekobo; P. Sawa; H.D.F.H. Schallig; S.A. Shekalaghe; C.H. Sibley; J. Smith; F.M. Smithuis; A.F. Somé; K. Stepniewska; A.O. Talisuna; J. Tärning; E. Tjitra; R.C.K. Tine; H. Tinto; N. Valecha; M. Van Herp; M. Van Vugt; N.J. White; C.J. Woodrow; W. Yavo; A. Yeka; I. Zongo

doi:10.1371/journal.pmed.1001564

The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data

J. Achan, I.I. Adam, E. Arinaitwe, E.A. Ashley, G.R. Awab, M.S. Ba, K.I. Barnes, Q. Bassat, S. Borrmann, T. Bousema, P. Dahal, U. D'Alessandro, Timothy Davis, A.M. Dondorp, G. Dorsey, C.J. Drakeley, C.I. Fanello, B.F. Faye, J.A. Flegg, O.H. GayeP.W. Gething, R. González, P.J. Guérin, S.I. Hay, T.T. Hien, B. Janssens, M.R. Kamya, C. Karema, H.A. Karunajeewa, M.W. Koné, B. Lell, K. Marsh, M. Mayxay, C. Menéndez, P.F. Mens, M.M. Meremikwu, C. Moreira, I. Müeller, C. Nabasumba, M. Nambozi, J.L.A. Ndiaye, P.N. Newton, T.N. Nguyen, F. Nosten, C. Nsanzabana, S.A. Omar, J.B. Ouédraogo, L.K. Pénali, M. Pene, A. Phyo, P. Piola, R.N. Price, P. Sasithon, P.J. Rosenthal, A. Samè-Ekobo, P. Sawa, H.D.F.H. Schallig, S.A. Shekalaghe, C.H. Sibley, J. Smith, F.M. Smithuis, A.F. Somé, K. Stepniewska, A.O. Talisuna, J. Tärning, E. Tjitra, R.C.K. Tine, H. Tinto, N. Valecha, M. Van Herp, M. Van Vugt, N.J. White, C.J. Woodrow, W. Yavo, A. Yeka, I. Zongo

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Abstract

Background:Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy.Methods and Findings:A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan-Meier survival estimates were 97.7% (95% CI 97.3%-98.1%) at day 42 and 97.2% (95% CI 96.7%-97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3-2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%-96.2%], p

Original language	English
Pages (from-to)	1-17
Journal	PLoS Medicine
Volume	10
Issue number	12
DOIs	https://doi.org/10.1371/journal.pmed.1001564
Publication status	Published - 2013

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Achan, J., Adam, I. I., Arinaitwe, E., Ashley, E. A., Awab, G. R., Ba, M. S., Barnes, K. I., Bassat, Q., Borrmann, S., Bousema, T., Dahal, P., D'Alessandro, U., Davis, T., Dondorp, A. M., Dorsey, G., Drakeley, C. J., Fanello, C. I., Faye, B. F., Flegg, J. A., ... Zongo, I. (2013). The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data. PLoS Medicine, 10(12), 1-17. https://doi.org/10.1371/journal.pmed.1001564

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title = "The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data",

abstract = "Background:Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy.Methods and Findings:A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan-Meier survival estimates were 97.7% (95% CI 97.3%-98.1%) at day 42 and 97.2% (95% CI 96.7%-97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3-2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%-96.2%], p",

author = "J. Achan and I.I. Adam and E. Arinaitwe and E.A. Ashley and G.R. Awab and M.S. Ba and K.I. Barnes and Q. Bassat and S. Borrmann and T. Bousema and P. Dahal and U. D'Alessandro and Timothy Davis and A.M. Dondorp and G. Dorsey and C.J. Drakeley and C.I. Fanello and B.F. Faye and J.A. Flegg and O.H. Gaye and P.W. Gething and R. Gonz{\'a}lez and P.J. Gu{\'e}rin and S.I. Hay and T.T. Hien and B. Janssens and M.R. Kamya and C. Karema and H.A. Karunajeewa and M.W. Kon{\'e} and B. Lell and K. Marsh and M. Mayxay and C. Men{\'e}ndez and P.F. Mens and M.M. Meremikwu and C. Moreira and I. M{\"u}eller and C. Nabasumba and M. Nambozi and J.L.A. Ndiaye and P.N. Newton and T.N. Nguyen and F. Nosten and C. Nsanzabana and S.A. Omar and J.B. Ou{\'e}draogo and L.K. P{\'e}nali and M. Pene and A. Phyo and P. Piola and R.N. Price and P. Sasithon and P.J. Rosenthal and A. Sam{\`e}-Ekobo and P. Sawa and H.D.F.H. Schallig and S.A. Shekalaghe and C.H. Sibley and J. Smith and F.M. Smithuis and A.F. Som{\'e} and K. Stepniewska and A.O. Talisuna and J. T{\"a}rning and E. Tjitra and R.C.K. Tine and H. Tinto and N. Valecha and {Van Herp}, M. and {Van Vugt}, M. and N.J. White and C.J. Woodrow and W. Yavo and A. Yeka and I. Zongo",

year = "2013",

doi = "10.1371/journal.pmed.1001564",

language = "English",

volume = "10",

pages = "1--17",

journal = "PLoS Medicine",

issn = "1549-1277",

publisher = "Public Library of Science (PLoS)",

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Achan, J, Adam, II, Arinaitwe, E, Ashley, EA, Awab, GR, Ba, MS, Barnes, KI, Bassat, Q, Borrmann, S, Bousema, T, Dahal, P, D'Alessandro, U, Davis, T, Dondorp, AM, Dorsey, G, Drakeley, CJ, Fanello, CI, Faye, BF, Flegg, JA, Gaye, OH, Gething, PW, González, R, Guérin, PJ, Hay, SI, Hien, TT, Janssens, B, Kamya, MR, Karema, C, Karunajeewa, HA, Koné, MW, Lell, B, Marsh, K, Mayxay, M, Menéndez, C, Mens, PF, Meremikwu, MM, Moreira, C, Müeller, I, Nabasumba, C, Nambozi, M, Ndiaye, JLA, Newton, PN, Nguyen, TN, Nosten, F, Nsanzabana, C, Omar, SA, Ouédraogo, JB, Pénali, LK, Pene, M, Phyo, A, Piola, P, Price, RN, Sasithon, P, Rosenthal, PJ, Samè-Ekobo, A, Sawa, P, Schallig, HDFH, Shekalaghe, SA, Sibley, CH, Smith, J, Smithuis, FM, Somé, AF, Stepniewska, K, Talisuna, AO, Tärning, J, Tjitra, E, Tine, RCK, Tinto, H, Valecha, N, Van Herp, M, Van Vugt, M, White, NJ, Woodrow, CJ, Yavo, W, Yeka, A & Zongo, I 2013, 'The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data', PLoS Medicine, vol. 10, no. 12, pp. 1-17. https://doi.org/10.1371/journal.pmed.1001564

TY - JOUR

T1 - The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data

AU - Achan, J.

AU - Adam, I.I.

AU - Arinaitwe, E.

AU - Ashley, E.A.

AU - Awab, G.R.

AU - Ba, M.S.

AU - Barnes, K.I.

AU - Bassat, Q.

AU - Borrmann, S.

AU - Bousema, T.

AU - Dahal, P.

AU - D'Alessandro, U.

AU - Davis, Timothy

AU - Dondorp, A.M.

AU - Dorsey, G.

AU - Drakeley, C.J.

AU - Fanello, C.I.

AU - Faye, B.F.

AU - Flegg, J.A.

AU - Gaye, O.H.

AU - Gething, P.W.

AU - González, R.

AU - Guérin, P.J.

AU - Hay, S.I.

AU - Hien, T.T.

AU - Janssens, B.

AU - Kamya, M.R.

AU - Karema, C.

AU - Karunajeewa, H.A.

AU - Koné, M.W.

AU - Lell, B.

AU - Marsh, K.

AU - Mayxay, M.

AU - Menéndez, C.

AU - Mens, P.F.

AU - Meremikwu, M.M.

AU - Moreira, C.

AU - Müeller, I.

AU - Nabasumba, C.

AU - Nambozi, M.

AU - Ndiaye, J.L.A.

AU - Newton, P.N.

AU - Nguyen, T.N.

AU - Nosten, F.

AU - Nsanzabana, C.

AU - Omar, S.A.

AU - Ouédraogo, J.B.

AU - Pénali, L.K.

AU - Pene, M.

AU - Phyo, A.

AU - Piola, P.

AU - Price, R.N.

AU - Sasithon, P.

AU - Rosenthal, P.J.

AU - Samè-Ekobo, A.

AU - Sawa, P.

AU - Schallig, H.D.F.H.

AU - Shekalaghe, S.A.

AU - Sibley, C.H.

AU - Smith, J.

AU - Smithuis, F.M.

AU - Somé, A.F.

AU - Stepniewska, K.

AU - Talisuna, A.O.

AU - Tärning, J.

AU - Tjitra, E.

AU - Tine, R.C.K.

AU - Tinto, H.

AU - Valecha, N.

AU - Van Herp, M.

AU - Van Vugt, M.

AU - White, N.J.

AU - Woodrow, C.J.

AU - Yavo, W.

AU - Yeka, A.

AU - Zongo, I.

PY - 2013

Y1 - 2013

N2 - Background:Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy.Methods and Findings:A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan-Meier survival estimates were 97.7% (95% CI 97.3%-98.1%) at day 42 and 97.2% (95% CI 96.7%-97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3-2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%-96.2%], p

AB - Background:Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy.Methods and Findings:A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan-Meier survival estimates were 97.7% (95% CI 97.3%-98.1%) at day 42 and 97.2% (95% CI 96.7%-97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3-2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%-96.2%], p

U2 - 10.1371/journal.pmed.1001564

DO - 10.1371/journal.pmed.1001564

M3 - Article

C2 - 24311989

SN - 1549-1277

VL - 10

SP - 1

EP - 17

JO - PLoS Medicine

JF - PLoS Medicine

IS - 12

ER -

The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data

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