Mohammad S. HossainRobert J. CommonsNicholas M. DouglasKamala ThriemerBereket H. AlemayehuChanaki AmaratungaAnupkumar R. AnvikarElizabeth A. AshleyPuji B.S. AsihVerena I. CarraraChanthap LonUmberto D’AlessandroTimothy M.E. DavisArjen M. DondorpMichael D. EdsteinRick M. FairhurstMarcelo U. FerreiraJimee HwangBart JanssensHarin KarunajeewaJean R. KiechelSimone Ladeia-AndradeMoses LamanMayfong MayxayRose McGreadyBrioni R. MooreIvo MuellerPaul N. NewtonNguyen T. Thuy-NhienHarald NoedlFrancois NostenAung P. PhyoJeanne R. PoespoprodjoDavid L. SaundersFrank SmithuisMichele D. SpringKasia StepniewskaSeila SuonYupin SuputtamongkolDin SyafruddinHien T. TranNeena ValechaMichel van HerpMichele van VugtNicholas J. WhitePhilippe J. GuerinJulie A. SimpsonRic N. PriceOxford University Clinical Research UnitMelbourne Medical SchoolMelbourne School of Population and Global HealthMedecins Sans Frontieres, BrusselsPapua New Guinea Institute of Medical ResearchEijkman Institute for Molecular BiologyHasanuddin UniversityUniversitas Gadjah MadaShoklo Malaria Research UnitThe University of Western AustraliaCurtin UniversitySunshine HospitalColumbia University Irving Medical CenterWalter and Eliza Hall Institute of Medical ResearchUniversity of MelbourneFundacao Oswaldo CruzMenzies School of Health ResearchNational Institute of Malaria Research IndiaUniversity of California, San FranciscoCenters for Disease Control and PreventionNational Institute of Allergy and Infectious Diseases (NIAID)Armed Forces Research Institute of Medical Sciences, ThailandMahosot Hospital, LaoMahidol UniversityBallarat Health ServicesFaculty of Medicine, Siriraj Hospital, Mahidol UniversityInternational Centre for Diarrhoeal Disease Research BangladeshSlotervaart HospitalNuffield Department of MedicineUnited States ArmyUniversidade de Sao Paulo - USPInstitut Pasteur, ParisDrugs for Neglected Diseases initiative (DNDi)LSTMHMyanmar Oxford Clinical Research UnitUniversity of Health SciencesAustralian Defence Force Malaria and Infectious Disease InstituteMARIBMimika District HospitalMinistry of Health of BrazilMedical Action MyanmarArmed Forces Research Institute of Medical SciencesPapuan Health and Community Development FoundationWorldWide Antimalarial Resistance Network (WWARN)National Center for Parasitology, Entomology and Malaria Control2020-12-282020-12-282020-11-19PLoS Medicine. Vol.17, No.11 (2020)15491676154912772-s2.0-85096458934https://repository.li.mahidol.ac.th/handle/20.500.14594/60552© 2020 Public Library of Science. All rights reserved. Background There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. Methods and findings A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0–29.0 years; range = 0–80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9–33.4) after AL, 14.1% (95% CI 10.8–18.3) after AA, 7.4% (95% CI 6.7–8.1) after AM, and 4.5% (95% CI 3.9–5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6–43.3), 42.4% (95% CI 34.7–51.2), 22.8% (95% CI 21.2–24.4), and 12.8% (95% CI 11.4–14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0–19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6–8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4–3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0–1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4–2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. Conclusions In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.Mahidol UniversityMedicineArticleSCOPUS10.1371/journal.pmed.1003393