{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:20:15Z","timestamp":1789755615472,"version":"4.0.1"},"reference-count":26,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T00:00:00Z","timestamp":1623715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shin Poong Pharmaceutical"},{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"crossref","award":["INV-007155"],"award-info":[{"award-number":["INV-007155"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"\n Background<\/jats:title>\n In Phase II\/III randomized controlled clinical trials for the treatment of acute uncomplicated malaria, pyronaridine\u2013artesunate demonstrated high efficacy and a safety profile consistent with that of comparators, except that asymptomatic, mainly mild-to-moderate transient increases in liver aminotransferases were reported for some patients. Hepatic safety, tolerability, and effectiveness have not been previously assessed under real-world conditions in Africa.<\/jats:p>\n <\/jats:sec>\n \n Methods and findings<\/jats:title>\n \n This single-arm, open-label, cohort event monitoring study was conducted at 6 health centers in Cameroon, Democratic Republic of Congo, Gabon, Ivory Coast, and Republic of Congo between June 2017 and April 2019. The trial protocol as closely as possible resembled real-world clinical practice for the treatment of malaria at the centers. Eligible patients were adults or children of either sex, weighing at least 5 kg, with acute uncomplicated malaria who did not have contraindications for pyronaridine\u2013artesunate treatment as per the summary of product characteristics. Patients received fixed-dose pyronaridine\u2013artesunate once daily for 3 days, dosed by body weight, without regard to food intake. A tablet formulation was used in adults and adolescents and a pediatric granule formulation in children and infants under 20 kg body weight. The primary outcome was the hepatic event incidence, defined as the appearance of the clinical signs and symptoms of hepatotoxicity confirmed by a >2\u00d7 rise in alanine aminotransferase\/aspartate aminotransferase (ALT\/AST) versus baseline in patients with baseline ALT\/AST >2\u00d7 the upper limit of normal (ULN). As a secondary outcome, this was assessed in patients with ALT\/AST >2\u00d7 ULN prior to treatment versus a matched cohort of patients with normal baseline ALT\/AST. The safety population comprised 7,154 patients, of mean age 13.9 years (standard deviation (SD) 14.6), around half of whom were male (3,569 [49.9%]). Patients experienced 8,560 malaria episodes; 158 occurred in patients with baseline ALT\/AST elevations >2\u00d7ULN. No protocol-defined hepatic events occurred following pyronaridine\u2013artesunate treatment of malaria patients with or without baseline hepatic dysfunction. Thus, no cohort comparison could be undertaken. Also, as postbaseline clinical chemistry was only performed where clinically indicated, postbaseline ALT\/AST levels were not systematically assessed for all patients. Adverse events of any cause occurred in 20.8% (1,490\/7,154) of patients, most frequently pyrexia (5.1% [366\/7,154]) and vomiting (4.2% [303\/7,154]). Adjusting for\n Plasmodium falciparum<\/jats:italic>\n reinfection, clinical effectiveness at day 28 was 98.6% ([7,369\/7,746] 95% confidence interval (CI) 98.3 to 98.9) in the per-protocol population. There was no indication that comorbidities or malnutrition adversely affected outcomes. The key study limitation was that postbaseline clinical biochemistry was only evaluated when clinically indicated.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Pyronaridine\u2013artesunate had good tolerability and effectiveness in a representative African population under conditions similar to everyday clinical practice. These findings support pyronaridine\u2013artesunate as an operationally useful addition to the management of acute uncomplicated malaria.<\/jats:p>\n <\/jats:sec>\n \n Trial registration<\/jats:title>\n \n ClinicalTrials.gov<\/jats:ext-link>\n NCT03201770<\/jats:ext-link>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1371\/journal.pmed.1003669","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T13:22:59Z","timestamp":1623763379000},"page":"e1003669","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":30,"title":["Pyronaridine\u2013artesunate real-world safety, tolerability, and effectiveness in malaria patients in 5 African countries: A single-arm, open-label, cohort event monitoring study"],"prefix":"10.1371","volume":"18","author":[{"given":"Gaston","family":"Tona Lutete","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2658-8706","authenticated-orcid":true,"given":"Ghyslain","family":"Mombo-Ngoma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge-Brice","family":"Assi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7206-3308","authenticated-orcid":true,"given":"Jude D.","family":"Bigoga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Koukouikila-Koussounda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2929-9301","authenticated-orcid":true,"given":"Nsengi Y.","family":"Ntamabyaliro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francine","family":"Ntoumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4693-4207","authenticated-orcid":true,"given":"Selidji T.","family":"Agnandji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7375-3685","authenticated-orcid":true,"given":"Mirjam","family":"Groger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jangsik","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Borghini-Fuhrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0352-5307","authenticated-orcid":true,"given":"Sarah","family":"Arbe-Barnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6675-249X","authenticated-orcid":true,"given":"Stephen J.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter G.","family":"Kremsner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9649-4847","authenticated-orcid":true,"given":"Stephan","family":"Duparc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9259-1885","authenticated-orcid":true,"given":"Michael","family":"Ramharter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the CANTAM study group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,15]]},"reference":[{"key":"pmed.1003669.ref001","volume-title":"World malaria report","year":"2020"},{"key":"pmed.1003669.ref002","volume-title":"World Malaria Report","year":"2019"},{"key":"pmed.1003669.ref003","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/S1473-3099(19)30391-3","article-title":"Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study","volume":"19","author":"RW van der Pluijm","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"pmed.1003669.ref004","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1038\/s41591-020-1005-2","article-title":"Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda","volume":"26","author":"A Uwimana","year":"2020","journal-title":"Nat Med"},{"key":"pmed.1003669.ref005","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s40249-019-0577-x","article-title":"Declining responsiveness of childhood Plasmodium falciparum infections to artemisinin-based combination treatments ten years following deployment as first-line antimalarials in Nigeria","volume":"8","author":"A Sowunmi","year":"2019","journal-title":"Infect Dis Poverty"},{"key":"pmed.1003669.ref006","first-page":"CD006404","article-title":"Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria","volume":"1","author":"J Pryce","year":"2019","journal-title":"Cochrane Database Syst Rev"},{"key":"pmed.1003669.ref007","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1093\/cid\/ciz583","article-title":"Pyronaridine-artesunate shows promise as an effective and well-tolerated treatment for artemisinin-resistant Plasmodium falciparum malaria","volume":"70","author":"J Okombo","year":"2020","journal-title":"Clin Infect Dis"},{"key":"pmed.1003669.ref008","first-page":"e02242","article-title":"Efficacy and Safety of pyronaridine-artesunate plus single-dose primaquine for treatment of uncomplicated Plasmodium falciparum malaria in eastern Cambodia","volume":"63","author":"R Leang","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"pmed.1003669.ref009","first-page":"e01273","article-title":"Pyronaridine-artesunate plus single-dose primaquine efficacy and safety for the treatment of malaria in western Cambodia","volume":"63","author":"R Leang","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"pmed.1003669.ref010","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1093\/cid\/ciz580","article-title":"Pyronaridine-artesunate efficacy and safety in uncomplicated Plasmodium falciparum malaria in areas of artemisinin-resistant falciparum in Viet Nam (2017\u20132018)","volume":"70","author":"P Bui Quang","year":"2020","journal-title":"Clin Infect Dis"},{"key":"pmed.1003669.ref011","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/S0140-6736(18)30291-5","article-title":"Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b\/4 trial","volume":"391","author":"West African Network for Clinical Trials of Antimalarial Drugs","year":"2018","journal-title":"Lancet"},{"key":"pmed.1003669.ref012","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1186\/s12936-018-2340-3","article-title":"Pyronaridine-artesunate and artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a randomized controlled non-inferiority trial","volume":"17","author":"JM Roth","year":"2018","journal-title":"Malar J"},{"key":"pmed.1003669.ref013","doi-asserted-by":"crossref","first-page":"3884","DOI":"10.1128\/AAC.00039-16","article-title":"Efficacy and safety of pyronaridine-artesunate for treatment of uncomplicated Plasmodium falciparum malaria in western Cambodia","volume":"60","author":"R Leang","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"key":"pmed.1003669.ref014","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/1475-2875-12-70","article-title":"Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials","volume":"12","author":"S Duparc","year":"2013","journal-title":"Malar J."},{"key":"pmed.1003669.ref015","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1056\/NEJMoa1007125","article-title":"Pyronaridine-artesunate versus mefloquine plus artesunate for malaria","volume":"366","author":"R Rueangweerayut","year":"2012","journal-title":"N Engl J Med"},{"key":"pmed.1003669.ref016","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1186\/1475-2875-11-364","article-title":"Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial","volume":"11","author":"K Kayentao","year":"2012","journal-title":"Malar J"},{"key":"pmed.1003669.ref017","doi-asserted-by":"crossref","first-page":"e14501","DOI":"10.1371\/journal.pone.0014501","article-title":"Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial","volume":"6","author":"Y Poravuth","year":"2011","journal-title":"PLoS ONE"},{"key":"pmed.1003669.ref018","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/S0140-6736(10)60322-4","article-title":"Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial","volume":"375","author":"AK Tshefu","year":"2010","journal-title":"Lancet"},{"key":"pmed.1003669.ref019","volume-title":"Pyramax: Product information","author":"European Medicines Agency","year":"2017"},{"key":"pmed.1003669.ref020","volume-title":"A practical handbook on the pharmacovigilance of antimalarial medicines","author":"World Health Organization","year":"2007"},{"key":"pmed.1003669.ref021","volume-title":"Frequently asked questions about the use of cohort event monitoring (CEM) for active pharmacovigilance in TB treatment","author":"World Health Organization","year":"2015"},{"key":"pmed.1003669.ref022","volume-title":"Methods for surveillance of antimalarial drug efficacy","author":"World Health Organization","year":"2009"},{"key":"pmed.1003669.ref023","volume-title":"Methods and techniques for clinical trials on antimalarial drug efficacy: genotyping to identify parasite populations","author":"World Health Organization","year":"2008"},{"key":"pmed.1003669.ref024","volume-title":"Growth reference 5\u201319 years","author":"World Health Organization","year":"2007"},{"key":"pmed.1003669.ref025","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S1473-3099(15)00318-7","article-title":"Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial","volume":"16","author":"I Sagara","year":"2016","journal-title":"Lancet Infect Dis"},{"key":"pmed.1003669.ref026","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1086\/591096","article-title":"Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon","volume":"198","author":"M Ramharter","year":"2008","journal-title":"J Infect Dis"}],"container-title":["PLOS Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1003669","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T13:23:34Z","timestamp":1623763414000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1003669"}},"subtitle":[],"editor":[{"given":"Elizabeth A.","family":"Ashley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,6,15]]},"references-count":26,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pmed.1003669","relation":{},"ISSN":["1549-1676"],"issn-type":[{"value":"1549-1676","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,15]]}}}