Jane AchanIshag AdamEmmanuel ArinaitweElizabeth A. AshleyGhulam Rahim AwabMamadou S. BaKaren I. BarnesQuique BassatSteffen BorrmannTeun BousemaPrabin DahalUmberto D'AlessandroTimothy M.E. DavisArjen M. DondorpGrant DorseyChris J. DrakeleyCaterina I. FanelloBabacar FayeJennifer A. FleggOumar GayePeter W. GethingRaquel GonzálezPhilippe J. GuerinSimon I. HayTran T. HienBart JanssensMoses R. KamyaCorine KaremaHarin A. KarunajeewaMoussa KonéBertrand LellKevin MarshMayfong MayxayClara MenéndezPetra F. MensMartin MeremikwuClarissa MoreiraIvo MuellerCarolyn NabasumbaMichael NamboziJean Louis NdiayePaul N. NewtonThuy Nhien NguyenFrancois NostenChristian NsanzabanaSabah A. OmarJean Bosco OuédraogoLouis K. PenaliMbaye PeneAung Pyae PhyoPatrice PiolaRic N. PriceP. SasithonPhilip J. RosenthalAlbert Same-EkoboPatrick SawaHenk D.F.H. SchalligSeif A. ShekalagheCarol Hopkins SibleyJeff SmithFrank SmithuisAnyirékun Fabrice SoméKasia StepniewskaAmbrose O. TalisunaJoel TarningEmiliana TjitraRoger C.K. TineUganda Malaria Surveillance ProjectKhartoum UniversityInfectious Diseases Research CollaborationShoklo Malaria Research UnitMahidol UniversityMinistry of Public HealthUniversite Cheikh Anta DiopUniversity of Cape TownCentro de Investigação em Saúde de ManhiçaCentre de Recerca en Salut Internacional de Barcelona (CRESIB)Kenya Medical Research InstituteUniversitat HeidelbergLondon School of Hygiene &amp; Tropical MedicineRadboud University Nijmegen Medical CentreWorldWide Antimalarial Resistance Network (WWARN)Nuffield Department of Clinical MedicinePrins Leopold Instituut voor Tropische GeneeskundeMedical Research Council UnitUniversity of Western AustraliaChurchill HospitalUniversity of California, San FranciscoUniversity of OxfordUCLOxford University Clinical Research UnitMédecins Sans FrontièresMakerere UniversityMinistry of HealthDepartment of Parasitology and MycologyUniversitat TubingenCentre de Recherches Médicales de LambarénéMahosot HospitalNational University of LaosCentro de Investigação em Saúde de Manhiça (CISM)Royal Tropical Institute - KITAcademic Medical Centre, University of AmsterdamUniversity of CalabarInstitute of Tropical Diseases Research and PreventionKenya Medical Research InstitutePapua New Guinea Institute of Medical ResearchWalter and Eliza Hall Institute of Medical ResearchEpicentreTropical Diseases Research CentreWellcome Trust-Mahosot Hospital-Oxford University Tropical Medicine Research CollaborationInternational Centre for Insect Physiology and Ecology (Icipe)Institut de Recherche en Sciences de la SantéCentre MURAZWorldWide Antimalarial Resistance Network (WWARN)-West Africa Regional CentreInstitut Pasteur de MadagascarMenzies School of Health ResearchCentre Hospitalier et Universitaire de YaoundeKilimanjaro Christian Medical CentreIfakara Health InstituteUniversity of Washington, SeattleWorld Wide Antimalarial Resistance Network (WWARN)-Asia Regional CentreWorld Wide Antimalarial Resistance Network (WWARN)-East Africa Regional CentreWellcome Trust Research Laboratories NairobiBadan Penelitian Dan Pengembangan Kesehatan, Kementerian Kesehatan Republik IndonesiaInstitut de Recherche en Sciences de la SantéNational Institute of Malaria Research IndiaMedecins Sans Frontieres, BrusselsMahidol-Oxford University Tropical Medicine Research Unit (MORU)National Institute of Public Health2018-10-192018-10-192013-01-01PLoS Medicine. Vol.10, No.12 (2013), 1-1715491676154912772-s2.0-84892892177https://repository.li.mahidol.ac.th/handle/20.500.14594/32709Background: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. © 2013 Price et al.Mahidol UniversityMedicineArticleSCOPUS10.1371/journal.pmed.1001564