{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T02:03:18Z","timestamp":1792634598973,"version":"4.5.0"},"reference-count":29,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T00:00:00Z","timestamp":1605052800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>The widespread use of primaquine (PQ) radical cure for <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic>, is constrained by concerns over its safety. We used routinely collected patient data to compare the overall morbidity and mortality in patients treated with and without PQ without prior testing of Glucose-6-Phosphate-Dehydrogenase (G6PD) deficiency in Papua, Indonesia, where there is a low prevalence of G6PD deficiency. Records were collated from patients older than 1 year, with <jats:italic>P<\/jats:italic>. vivax infection, who were treated with an artemisinin combination therapy (ACT). The risks of re-presentation, hospitalization, major fall in haemoglobin and death within 30 days were quantified and compared between patients treated with and without PQ using a Cox regression model. In total 26,216 patients with <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> malaria presented to the hospital with malaria during the study period. Overall 27.56% (95% Confidence Interval (95%CI): 26.96\u201328.16) of 21,344 patients treated with PQ re-presented with any illness within 30 days and 1.69% (1.51\u20131.88) required admission to hospital. The corresponding risks were higher in the 4,872 patients not treated with PQ; Adjusted Hazard Ratio (AHR) = 0.84 (0.79\u20130.91; p&lt;0.001) and 0.54 (0.41\u20130.70; p&lt;0.001) respectively. By day 30, 14.15% (12.45\u201316.05) of patients who had received PQ had a fall in haemoglobin (Hb) below 7g\/dl compared to 20.43% (16.67\u201324.89) of patients treated without PQ; AHR = 0.66 (0.45\u20130.97; p = 0.033). A total of 75 (0.3%) patients died within 30 days of treatment with a mortality risk of 0.27% (0.21\u20130.35) in patients treated with PQ, compared to 0.38% (0.24\u20130.60) without PQ; AHR = 0.79 (0.43\u20131.45; p = 0.448). In Papua, Indonesia routine administration of PQ radical cure without prior G6PD testing, was associated with lower risk of all cause hospitalization and other serious adverse clinical outcomes. In areas where G6PD testing is not available or cannot be delivered reliably, the risks of drug induced haemolysis should be balanced against the potential benefits of reducing recurrent <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> malaria and its associated morbidity and mortality.<\/jats:p>","DOI":"10.1371\/journal.pntd.0008838","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T18:33:15Z","timestamp":1605119595000},"page":"e0008838","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["The risk of adverse clinical outcomes following treatment of Plasmodium vivax malaria with and without primaquine in Papua, Indonesia"],"prefix":"10.1371","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7536-7497","authenticated-orcid":true,"given":"Kamala","family":"Thriemer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne-Rini","family":"Poespoprodjo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enny","family":"Kenangalem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas M.","family":"Douglas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulus","family":"Sugiarto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas M.","family":"Anstey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2660-2013","authenticated-orcid":true,"given":"Julie Anne","family":"Simpson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ric N.","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,11,11]]},"reference":[{"key":"pntd.0008838.ref001","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/1475-2875-11-135","article-title":"The anaemia of Plasmodium vivax malaria","volume":"11","author":"NM Douglas","year":"2012","journal-title":"Malaria journal"},{"issue":"6","key":"pntd.0008838.ref002","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.pt.2020.03.009","article-title":"Plasmodium vivax in the Era of the Shrinking P. falciparum Map","volume":"36","author":"RN Price","year":"2020","journal-title":"Trends in parasitology"},{"issue":"5","key":"pntd.0008838.ref003","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.pt.2009.02.003","article-title":"The pathophysiology of vivax malaria","volume":"25","author":"NM Anstey","year":"2009","journal-title":"Trends in parasitology"},{"issue":"1827","key":"pntd.0008838.ref004","first-page":"20160048","article-title":"Variation in relapse frequency and the transmission potential of Plasmodium vivax malaria","volume":"283","author":"MT White","year":"2016","journal-title":"Proc Biol Sci"},{"issue":"1","key":"pntd.0008838.ref005","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s12936-017-1784-1","article-title":"Challenges for achieving safe and effective radical cure of Plasmodium vivax: a round table discussion of the APMEN Vivax Working Group","volume":"16","author":"K Thriemer","year":"2017","journal-title":"Malaria journal"},{"key":"pntd.0008838.ref006","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/1475-2875-12-112","article-title":"Review of key knowledge gaps in glucose-6-phosphate dehydrogenase deficiency detection with regard to the safe clinical deployment of 8-aminoquinoline treatment regimens: a workshop report","volume":"12","author":"L von Seidlein","year":"2013","journal-title":"Malaria journal"},{"key":"pntd.0008838.ref007","author":"WHO","year":"2015","journal-title":"Guidelines for the treatment of malaria"},{"issue":"10","key":"pntd.0008838.ref008","doi-asserted-by":"crossref","first-page":"e0165340","DOI":"10.1371\/journal.pone.0165340","article-title":"Submicroscopic and Asymptomatic Plasmodium Parasitaemia Associated with Significant Risk of Anaemia in Papua, Indonesia","volume":"11","author":"Z Pava","year":"2016","journal-title":"PloS one"},{"issue":"5","key":"pntd.0008838.ref009","doi-asserted-by":"crossref","first-page":"e1002815","DOI":"10.1371\/journal.pmed.1002815","article-title":"Malaria morbidity and mortality following introduction of a universal policy of artemisinin-based treatment for malaria in Papua, Indonesia: A longitudinal surveillance study","volume":"16","author":"E Kenangalem","year":"2019","journal-title":"PLoS medicine"},{"issue":"1","key":"pntd.0008838.ref010","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1186\/s12936-016-1588-8","article-title":"Treatment-seeking behaviour and associated costs for malaria in Papua, Indonesia","volume":"15","author":"M Karyana","year":"2016","journal-title":"Malaria journal"},{"issue":"12","key":"pntd.0008838.ref011","doi-asserted-by":"crossref","first-page":"e1001575","DOI":"10.1371\/journal.pmed.1001575","article-title":"Major burden of severe anemia from non-falciparum malaria species in Southern Papua: a hospital-based surveillance study","volume":"10","author":"NM Douglas","year":"2013","journal-title":"PLoS medicine"},{"issue":"1","key":"pntd.0008838.ref012","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s12916-020-1497-0","article-title":"The risk of morbidity and mortality following recurrent malaria in Papua, Indonesia: a retrospective cohort study","volume":"18","author":"S Dini","year":"2020","journal-title":"BMC medicine"},{"key":"pntd.0008838.ref013","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/1475-2875-7-148","article-title":"Malaria morbidity in Papua Indonesia, an area with multidrug resistant Plasmodium vivax and Plasmodium falciparum","volume":"7","author":"M Karyana","year":"2008","journal-title":"Malar J"},{"issue":"8","key":"pntd.0008838.ref014","doi-asserted-by":"crossref","first-page":"e1002379","DOI":"10.1371\/journal.pmed.1002379","article-title":"Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study","volume":"14","author":"NM Douglas","year":"2017","journal-title":"PLoS medicine"},{"issue":"4","key":"pntd.0008838.ref015","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.trstmh.2006.06.008","article-title":"Therapeutic response of multidrug-resistant Plasmodium falciparum and P. vivax to chloroquine and sulfadoxine-pyrimethamine in southern Papua, Indonesia","volume":"101","author":"A Ratcliff","year":"2007","journal-title":"Transactions of the Royal Society of Tropical Medicine and Hygiene"},{"issue":"9563","key":"pntd.0008838.ref016","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/S0140-6736(07)60160-3","article-title":"Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison","volume":"369","author":"A Ratcliff","year":"2007","journal-title":"Lancet"},{"issue":"8","key":"pntd.0008838.ref017","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1086\/512677","article-title":"Dihydroartemisinin-piperaquine versus artesunate-amodiaquine: superior efficacy and posttreatment prophylaxis against multidrug-resistant Plasmodium falciparum and Plasmodium vivax malaria","volume":"44","author":"AR Hasugian","year":"2007","journal-title":"Clinical infectious diseases: an official publication of the Infectious Diseases Society of America"},{"issue":"7223","key":"pntd.0008838.ref018","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1136\/bmj.319.7223.1492","article-title":"Calculating the number needed to treat for trials where the outcome is time to an event","volume":"319","author":"DG Altman","year":"1999","journal-title":"Bmj"},{"key":"pntd.0008838.ref019","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/s12916-014-0217-z","article-title":"Mortality attributable to Plasmodium vivax malaria: a clinical audit from Papua, Indonesia","volume":"12","author":"NM Douglas","year":"2014","journal-title":"BMC medicine"},{"issue":"10","key":"pntd.0008838.ref020","doi-asserted-by":"crossref","first-page":"e1001891","DOI":"10.1371\/journal.pmed.1001891","article-title":"Strategies for Understanding and Reducing the Plasmodium vivax and Plasmodium ovale Hypnozoite Reservoir in Papua New Guinean Children: A Randomised Placebo-Controlled Trial and Mathematical Model","volume":"12","author":"LJ Robinson","year":"2015","journal-title":"PLoS Med"},{"issue":"5","key":"pntd.0008838.ref021","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1093\/infdis\/jit261","article-title":"Gametocyte dynamics and the role of drugs in reducing the transmission potential of Plasmodium vivax","volume":"208","author":"NM Douglas","year":"2013","journal-title":"The Journal of infectious diseases"},{"key":"pntd.0008838.ref022","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1186\/1475-2875-13-418","article-title":"Primaquine: the risks and the benefits","volume":"13","author":"EA Ashley","year":"2014","journal-title":"Malaria journal"},{"issue":"2","key":"pntd.0008838.ref023","doi-asserted-by":"crossref","first-page":"e1002224","DOI":"10.1371\/journal.pmed.1002224","article-title":"Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens","volume":"14","author":"CS Chu","year":"2017","journal-title":"PLoS medicine"},{"issue":"1","key":"pntd.0008838.ref024","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1186\/s12936-017-1981-y","article-title":"Barriers to routine G6PD testing prior to treatment with primaquine","volume":"16","author":"B Ley","year":"2017","journal-title":"Malaria journal"},{"issue":"12","key":"pntd.0008838.ref025","first-page":"e500","volume":"3","author":"K Maitland","year":"2006"},{"issue":"1","key":"pntd.0008838.ref026","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s12916-019-1386-6","article-title":"The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis","volume":"17","author":"RJ Commons","year":"2019","journal-title":"BMC medicine"},{"key":"pntd.0008838.ref027","article-title":"Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial","author":"WRJ Taylor","year":"2019","journal-title":"Lancet"},{"issue":"1","key":"pntd.0008838.ref028","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s12936-019-2745-7","article-title":"Safety of primaquine in infants with Plasmodium vivax malaria in Papua, Indonesia","volume":"18","author":"A Setyadi","year":"2019","journal-title":"Malaria journal"},{"issue":"2","key":"pntd.0008838.ref029","doi-asserted-by":"crossref","first-page":"543","DOI":"10.4269\/ajtmh.17-0680","article-title":"Treatment-Seeking Behavior after the Implementation of a Unified Policy of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Malaria in Papua, Indonesia","volume":"98","author":"A Devine","year":"2018","journal-title":"The American journal of tropical medicine and hygiene"}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0008838","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T18:34:14Z","timestamp":1605119654000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0008838"}},"subtitle":[],"editor":[{"given":"Hans-Peter","family":"Fuehrer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2020,11,11]]},"references-count":29,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0008838","relation":{},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,11]]}}}