Robert J. CommonsJulie A. SimpsonKamala ThriemerGeorgina S. HumphreysTesfay AbrehaSisay G. AlemuArletta AñezNicholas M. AnsteyGhulam R. AwabJ. Kevin BairdBridget E. BarberIsabelle Borghini-FuhrerCindy S. ChuUmberto D'AlessandroPrabin DahalAndré DaherPeter J. de VriesAnnette ErhartMargarete S.M. GomesLilia Gonzalez-CeronMatthew J. GriggAliehsan HeidariJimee HwangPiet A. KagerTsige KetemaWasif A. KhanMarcus V.G. LacerdaToby LeslieBenedikt LeyKartini LidiaWuelton M. MonteiroFrancois NostenDhelio B. PereiraGiao T. PhanAung P. PhyoMark RowlandKavitha SaravuCarol H. SibleyAndré M. SiqueiraKasia StepniewskaInge SutantoWalter R.J. TaylorGuy ThwaitesBinh Q. TranHien T. TranNeena ValechaJosé Luiz F. VieiraSonam WangchukTimothy WilliamCharles J. WoodrowLina Zuluaga-IdarragaPhilippe J. GuerinNicholas J. WhiteRic N. PriceMelbourne School of Population and Global HealthHealth Works, AmsterdamAlborz University of Medical SciencesTergooiziekenhuizenCho Ray HospitalJimma UniversityArmauer Hansen Research InstituteAddis Ababa UniversityUniversitas IndonesiaUniversidad de AntioquiaUniversity of LondonLondon School of Hygiene &amp; Tropical MedicinePrins Leopold Instituut voor Tropische GeneeskundeRoyal Brisbane and Women's HospitalFundacao Oswaldo CruzMenzies School of Health ResearchFundacao Universidade Federal de RondoniaNational Institute of Malaria Research IndiaUniversity of California, San FranciscoCenters for Disease Control and PreventionLiverpool School of Tropical MedicineUniversidade Federal do AmapaManipal Academy of Higher EducationKasturba Medical College, ManipalUniversity of Washington, SeattleUniversiteit AntwerpenMahidol UniversityNuffield Department of Clinical MedicineUniversidade do Estado do AmazonasUniversidade Federal do ParaUniversitat de BarcelonaAmsterdam UMC - University of AmsterdamMedicines for Malaria VentureNangarhar UniversityWorldWide Antimalarial Resistance NetworkNusa Cendana UniversityQueen Elizabeth HospitalMedical Research Council UnitNational Institute for Public HealthInfectious Diseases Society Sabah-Menzies School of Health Research Clinical Research UnitOrganización Panamericana de SaludWorldWide Antimalarial Resistance NetworkColumbia University Mailman School of Public HealthInternational Centre for Diarrheal Diseases and ResearchEijkman-Oxford Clinical Research UnitMinistry of HealthSecretaria de Saúde do Estado do AmapáOxford University Clinical Research UnitCentro de Pesquisa em Medicina Tropical2019-08-232019-08-232018-09-01The Lancet Infectious Diseases. Vol.18, No.9 (2018), 1025-103414744457147330992-s2.0-85053837530https://repository.li.mahidol.ac.th/handle/20.500.14594/46424© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings. Methods: A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310. Findings: Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8–35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69–0·97; p=0·021) and in children younger than 5 years (0·59, 0·41–0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1–7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05–0·17; p<0·0001). Interpretation: Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax. Funding: Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.Mahidol UniversityMedicineArticleSCOPUS10.1016/S1473-3099(18)30348-7