The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine

A Pooled Analysis of Individual Patient Data

Jane Achan, Ishag Adam, Emmanuel Arinaitwe, Elizabeth Ashley, Ghulam Awab, Mamadou Ba, Karen I Barnes, Quique Bassat, Steffen Borrmann, Teun Bousema, Prabin Dahal, Umberto D'Alessandro, Timothy Davis, Arjen Dondorp, Grant Dorsey, Chris Drakeley, Caterina Fanello, Babacar Faye, J Flegg, Oumar Gaye & 1 others Ric Price

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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 Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis.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<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.
    Original languageEnglish
    Article numbere1001564
    Pages (from-to)1-17
    Number of pages17
    JournalPLoS Medicine
    Volume10
    Issue number12
    DOIs
    Publication statusPublished - Dec 2013

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    dihydroartemisinin
    Antimalarials
    Treatment Failure
    Parasites
    Recurrence
    piperaquine
    Proportional Hazards Models

    Cite this

    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 ; Dorsey, Grant ; Drakeley, Chris ; Fanello, Caterina ; Faye, Babacar ; Flegg, J ; Gaye, Oumar ; Price, Ric. / The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine : A Pooled Analysis of Individual Patient Data. In: PLoS Medicine. 2013 ; Vol. 10, No. 12. pp. 1-17.
    @article{2415988d8d734903afb84815047ecf50,
    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<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.",
    keywords = "artecan, dihydroartemisinin, dihydroartemisinin plus piperaquine, piperaquine, unclassified drug, anemia, anorexia, antimalarial activity, arm disease, article, aspiration pneumonia, body weight, clinical trial (topic), convulsion, diarrhea, disease association, disease duration, disease transmission, drug dose regimen, drug efficacy, drug treatment failure, encephalitis, fever, follow up, gametocyte, genotype, human, malaria, malaria falciparum, meta analysis (topic), methodology, multicenter study (topic), parasite clearance, parasitemia, polymerase chain reaction, pyelonephritis, pyomyositis, rash, recurrent disease, reinfection, risk factor, skin disease, survival rate, vomiting",
    author = "Jane Achan and Ishag Adam and Emmanuel Arinaitwe and Elizabeth Ashley and Ghulam Awab and Mamadou Ba and Barnes, {Karen I} and Quique Bassat and Steffen Borrmann and Teun Bousema and Prabin Dahal and Umberto D'Alessandro and Timothy Davis and Arjen Dondorp and Grant Dorsey and Chris Drakeley and Caterina Fanello and Babacar Faye and J Flegg and Oumar Gaye and Ric Price",
    year = "2013",
    month = "12",
    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)",
    number = "12",

    }

    Achan, J, Adam, I, Arinaitwe, E, Ashley, E, Awab, G, Ba, M, Barnes, KI, Bassat, Q, Borrmann, S, Bousema, T, Dahal, P, D'Alessandro, U, Davis, T, Dondorp, A, Dorsey, G, Drakeley, C, Fanello, C, Faye, B, Flegg, J, Gaye, O & Price, R 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, e1001564, pp. 1-17. https://doi.org/10.1371/journal.pmed.1001564

    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; Dorsey, Grant; Drakeley, Chris; Fanello, Caterina; Faye, Babacar; Flegg, J; Gaye, Oumar; Price, Ric.

    In: PLoS Medicine, Vol. 10, No. 12, e1001564, 12.2013, p. 1-17.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine

    T2 - A Pooled Analysis of Individual Patient Data

    AU - Achan, Jane

    AU - Adam, Ishag

    AU - Arinaitwe, Emmanuel

    AU - Ashley, Elizabeth

    AU - Awab, Ghulam

    AU - Ba, Mamadou

    AU - Barnes, Karen I

    AU - Bassat, Quique

    AU - Borrmann, Steffen

    AU - Bousema, Teun

    AU - Dahal, Prabin

    AU - D'Alessandro, Umberto

    AU - Davis, Timothy

    AU - Dondorp, Arjen

    AU - Dorsey, Grant

    AU - Drakeley, Chris

    AU - Fanello, Caterina

    AU - Faye, Babacar

    AU - Flegg, J

    AU - Gaye, Oumar

    AU - Price, Ric

    PY - 2013/12

    Y1 - 2013/12

    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<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.

    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<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.

    KW - artecan

    KW - dihydroartemisinin

    KW - dihydroartemisinin plus piperaquine

    KW - piperaquine

    KW - unclassified drug

    KW - anemia

    KW - anorexia

    KW - antimalarial activity

    KW - arm disease

    KW - article

    KW - aspiration pneumonia

    KW - body weight

    KW - clinical trial (topic)

    KW - convulsion

    KW - diarrhea

    KW - disease association

    KW - disease duration

    KW - disease transmission

    KW - drug dose regimen

    KW - drug efficacy

    KW - drug treatment failure

    KW - encephalitis

    KW - fever

    KW - follow up

    KW - gametocyte

    KW - genotype

    KW - human

    KW - malaria

    KW - malaria falciparum

    KW - meta analysis (topic)

    KW - methodology

    KW - multicenter study (topic)

    KW - parasite clearance

    KW - parasitemia

    KW - polymerase chain reaction

    KW - pyelonephritis

    KW - pyomyositis

    KW - rash

    KW - recurrent disease

    KW - reinfection

    KW - risk factor

    KW - skin disease

    KW - survival rate

    KW - vomiting

    U2 - 10.1371/journal.pmed.1001564

    DO - 10.1371/journal.pmed.1001564

    M3 - Article

    VL - 10

    SP - 1

    EP - 17

    JO - PLoS Medicine

    JF - PLoS Medicine

    SN - 1549-1277

    IS - 12

    M1 - e1001564

    ER -