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

Achan, Jane, Adam, Ishag, Arinaitwe, Emmanuel, Ashley, Elizabeth, Awab, Ghulam, Ba, Mamadou, Barnes, Karen I., Bassat, Quique, Borrmann, Steffen, Bousema, Teun, Dahal, Prabin, D'Alessandro, Umberto, Davis, Timothy, Dondorp, Arjen M., Dorsey, Grant, Drakeley, Chris, Fanello, Caterina, Faye, Babacar, Flegg, J., Price, Ric N. and et al. (2013). The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data. PLoS Medicine,10(12):e1001564-1-e1001564-17.

Document type: Journal Article
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IRMA ID cmartelxPUB88
Title The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data
Author Achan, Jane
Adam, Ishag
Arinaitwe, Emmanuel
Ashley, Elizabeth
Awab, Ghulam
Ba, Mamadou
Barnes, Karen I.
Bassat, Quique
Borrmann, Steffen
Bousema, Teun
Dahal, Prabin
D'Alessandro, Umberto
Davis, Timothy
Dondorp, Arjen M.
Dorsey, Grant
Drakeley, Chris
Fanello, Caterina
Faye, Babacar
Flegg, J.
Price, Ric N.
et al.
Journal Name PLoS Medicine
Publication Date 2013
Volume Number 10
Issue Number 12
Scopus ID 2-s2.0-84892892177
Start Page e1001564-1
End Page e1001564-17
Total Pages 17
Place of Publication United States of America
Publisher Public Library of Science
HERDC Category C1 - Journal Article (DIISR)
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 Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis.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<0.001). After adjusting for confounding factors, the mg/kg dose of piperaquine was found to be a significant predictor for recrudescence, the risk increasing by 13% (95% CI 5.0%–21%) for every 5 mg/kg decrease in dose; p = 0.002. In a multivariable model increasing the target minimum total dose of piperaquine in children aged 1 to 5 years old from 48 mg/kg to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of patients; such an increment was not associated with gastrointestinal toxicity in the ten studies in which this could be assessed.

Conclusions
DP demonstrates excellent efficacy in a wide range of transmission settings; however, treatment failure is associated with a lower dose of piperaquine, particularly in young children, suggesting potential for further dose optimisation.

Please see later in the article for the Editors' Summary

DOI http://dx.doi.org/10.1371/journal.pmed.1001564   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
Additional Notes This is an Open Access article distributed under the terms of the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Description for Link Link to CC Attribution 4.0 License
URL https://creativecommons.org/licenses/by/4.0/au/legalcode


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