{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:28:29Z","timestamp":1793413709878,"version":"4.5.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T00:00:00Z","timestamp":1611014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100004396","name":"Thailand Research Fund","doi-asserted-by":"publisher","award":["RDG59D0011"],"award-info":[{"award-number":["RDG59D0011"]}],"id":[{"id":"10.13039\/501100004396","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Faculty of Medicine Siriraj Hospital","award":["R015936007"],"award-info":[{"award-number":["R015936007"]}],"id":[{"id":"https:\/\/ror.org\/0331zs648","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004397","name":"Ministry of Public Health","doi-asserted-by":"publisher","award":["R015745005 and R015845009"],"award-info":[{"award-number":["R015745005 and R015845009"]}],"id":[{"id":"10.13039\/501100004397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004156","name":"Mahidol University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004156","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Dengue is the most significant mosquito-borne viral disease; there are no specific therapeutics. The antiparasitic drug ivermectin efficiently inhibits the replication of all 4 dengue virus serotypes in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted 2 consecutive randomized, double-blind, placebo-controlled trials in adult dengue patients to evaluate safety and virological and clinical efficacies of ivermectin. After a phase 2 trial with 2 or 3 days of 1 daily dose of 400 \u00b5g\/kg ivermectin, we continued with a phase 3, placebo-controlled trial with 3 days of 400 \u00b5g\/kg ivermectin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The phase 2 trial showed a trend in reduction of plasma nonstructural protein 1 (NS1) clearance time in the 3-day ivermectin group compared with placebo. Combining phase 2 and 3 trials, 203 patients were included in the intention to treat analysis (100 and 103 patients receiving ivermectin and placebo, respectively). Dengue hemorrhagic fever occurred in 24 (24.0%) of ivermectin-treated patients and 32 (31.1%) patients receiving placebo (P = .260). The median (95% confidence interval [CI]) clearance time of NS1 antigenemia was shorter in the ivermectin group (71.5 [95% CI 59.9\u201384.0] hours vs 95.8 [95% CI 83.9\u2013120.0] hours, P = .014). At discharge, 72.0% and 47.6% of patients in the ivermectin and placebo groups, respectively had undetectable plasma NS1 (P = .001). There were no differences in the viremia clearance time and incidence of adverse events between the 2 groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A 3-day 1 daily dose of 400 \u00b5g\/kg oral ivermectin was safe and accelerated NS1 antigenemia clearance in dengue patients. However, clinical efficacy of ivermectin was not observed at this dosage regimen.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciaa1332","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T08:21:38Z","timestamp":1606292498000},"page":"e586-e593","source":"Crossref","is-referenced-by-count":63,"title":["Ivermectin Accelerates Circulating Nonstructural Protein 1 (NS1) Clearance in Adult Dengue Patients: A Combined Phase 2\/3 Randomized Double-blinded Placebo Controlled Trial"],"prefix":"10.1093","volume":"72","author":[{"given":"Yupin","family":"Suputtamongkol","sequence":"first","affiliation":[{"name":"Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0053-3045","authenticated-orcid":false,"given":"Panisadee","family":"Avirutnan","sequence":"additional","affiliation":[{"name":"Division of Dengue Hemorrhagic Fever Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"name":"Siriraj Center of Research Excellence in Dengue & Emerging Pathogens, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"name":"Molecular Biology of Dengue and Flaviviruses Research Team, Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dumrong","family":"Mairiang","sequence":"additional","affiliation":[{"name":"Division of Dengue Hemorrhagic Fever Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"name":"Siriraj Center of Research Excellence in Dengue & Emerging Pathogens, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"name":"Molecular Biology of Dengue and Flaviviruses Research Team, Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasikarn","family":"Angkasekwinai","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kannika","family":"Niwattayakul","sequence":"additional","affiliation":[{"name":"Medical Department, Loei Hospital, Ministry of Public Health, Loei, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eakkawit","family":"Yamasmith","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadhil A-hamad","family":"Saleh-arong","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adisak","family":"Songjaeng","sequence":"additional","affiliation":[{"name":"Division of Dengue Hemorrhagic Fever Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"name":"Siriraj Center of Research Excellence in Dengue & Emerging Pathogens, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanapan","family":"Prommool","sequence":"additional","affiliation":[{"name":"Molecular Biology of Dengue and Flaviviruses Research Team, Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nattaya","family":"Tangthawornchaikul","sequence":"additional","affiliation":[{"name":"Molecular Biology of Dengue and Flaviviruses Research Team, Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunya","family":"Puttikhunt","sequence":"additional","affiliation":[{"name":"Division of Dengue Hemorrhagic Fever Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"name":"Siriraj Center of Research Excellence in Dengue & Emerging Pathogens, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"name":"Molecular Biology of Dengue and Flaviviruses Research Team, Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saowalak","family":"Hunnangkul","sequence":"additional","affiliation":[{"name":"Research Group and Research Network Division, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chulaluk","family":"Komoltri","sequence":"additional","affiliation":[{"name":"Research Group and Research Network Division, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suwich","family":"Thammapalo","sequence":"additional","affiliation":[{"name":"Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prida","family":"Malasit","sequence":"additional","affiliation":[{"name":"Division of Dengue Hemorrhagic Fever Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"name":"Siriraj Center of Research Excellence in Dengue & Emerging Pathogens, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"name":"Molecular Biology of Dengue and Flaviviruses Research Team, Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"key":"2021051810402262000_CIT0001","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"2021051810402262000_CIT0002","volume-title":"Dengue haemorrhagic fever: diagnosis, treatment, prevention, and control. 2nd ed","author":"World Health Organization","year":"1997"},{"key":"2021051810402262000_CIT0003","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1086\/315215","article-title":"Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity","volume":"181","author":"Vaughn","year":"2000","journal-title":"J Infect Dis"},{"key":"2021051810402262000_CIT0004","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1086\/343813","article-title":"High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever","volume":"186","author":"Libraty","year":"2002","journal-title":"J Infect Dis"},{"key":"2021051810402262000_CIT0005","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1086\/500949","article-title":"Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement","volume":"193","author":"Avirutnan","year":"2006","journal-title":"J Infect Dis"},{"key":"2021051810402262000_CIT0006","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/jac\/34.2.195","article-title":"Ivermectin in human medicine","volume":"34","author":"Ottesen","year":"1994","journal-title":"J Antimicrob Chemother"},{"key":"2021051810402262000_CIT0007","doi-asserted-by":"crossref","first-page":"e0004051","DOI":"10.1371\/journal.pntd.0004051","article-title":"African program for onchocerciasis control 1995\u20132010: impact of annual ivermectin mass treatment on off-target infectious diseases","volume":"9","author":"Krotneva","year":"2015","journal-title":"PLoS Negl Trop Dis"},{"key":"2021051810402262000_CIT0008","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1042\/BJ20120150","article-title":"Ivermectin is a specific inhibitor of importin alpha\/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus","volume":"443","author":"Wagstaff","year":"2012","journal-title":"Biochem J"},{"key":"2021051810402262000_CIT0009","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1093\/jac\/dks147","article-title":"Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug","volume":"67","author":"Mastrangelo","year":"2012","journal-title":"J Antimicrob Chemother"},{"key":"2021051810402262000_CIT0010","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.antiviral.2013.06.002","article-title":"Nuclear localization of dengue virus (DENV) 1\u20134 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin","volume":"99","author":"Tay","year":"2013","journal-title":"Antiviral Res"},{"key":"2021051810402262000_CIT0011","volume-title":"Dengue: guidelines for diagnosis, treatment, prevention, and control. New ed","author":"Special Programme for Research and Training in Tropical Diseases, World Health Organization","year":"2009"},{"key":"2021051810402262000_CIT0012","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1086\/657063","article-title":"Use of high-dose, twice-yearly albendazole and ivermectin to suppress Wuchereria bancrofti microfilarial levels","volume":"51","author":"Dembele","year":"2010","journal-title":"Clin Infect Dis"},{"key":"2021051810402262000_CIT0013","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.trstmh.2003.10.018","article-title":"Adverse systemic reactions to treatment of onchocerciasis with ivermectin at normal and high doses given annually or three-monthly","volume":"98","author":"Kamgno","year":"2004","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"2021051810402262000_CIT0014","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.trstmh.2004.04.003","article-title":"A randomized, double-blind, controlled trial of the effects of ivermectin at normal and high doses, given annually or three-monthly, against Onchocerca volvulus: ophthalmological results","volume":"99","author":"Fobi","year":"2005","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"2021051810402262000_CIT0015","first-page":"131","article-title":"The chemotherapy of onchocerciasis. XIX: the clinical and laboratory tolerance of high dose ivermectin","volume":"46","author":"Awadzi","year":"1995","journal-title":"Trop Med Parasitol"},{"key":"2021051810402262000_CIT0016","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1177\/009127002401382731","article-title":"Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects","volume":"42","author":"Guzzo","year":"2002","journal-title":"J Clin Pharmacol"},{"key":"2021051810402262000_CIT0017","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1093\/cid\/cis655","article-title":"Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized, placebo-controlled trial","volume":"55","author":"Tam","year":"2012","journal-title":"Clin Infect Dis"},{"key":"2021051810402262000_CIT0018","doi-asserted-by":"crossref","first-page":"e785","DOI":"10.1371\/journal.pntd.0000785","article-title":"A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults","volume":"4","author":"Tricou","year":"2010","journal-title":"PLoS Negl Trop Dis"},{"key":"2021051810402262000_CIT0019","first-page":"468","article-title":"Lovastatin for the treatment of adult patients with dengue: a randomized, double-blind, placebo-controlled trial","volume":"62","author":"Whitehorn","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2021051810402262000_CIT0020","doi-asserted-by":"crossref","first-page":"446","DOI":"10.4269\/ajtmh.12-0023","article-title":"Determination of viremia and concentration of circulating nonstructural protein 1 in patients infected with dengue virus in Mexico","volume":"88","author":"de la Cruz-Hernandez","year":"2013","journal-title":"Am J Trop Med Hyg"},{"key":"2021051810402262000_CIT0021","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1186\/s12879-014-0570-8","article-title":"Dengue NS1 antigen as a marker of severe clinical disease","volume":"14","author":"Paranavitane","year":"2014","journal-title":"BMC Infect Dis"},{"key":"2021051810402262000_CIT0022","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1093\/infdis\/jis470","article-title":"A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients","volume":"207","author":"Nguyen","year":"2013","journal-title":"J Infect Dis"},{"key":"2021051810402262000_CIT0023","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/S1473-3099(14)70730-3","article-title":"Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial","volume":"14","author":"Low","year":"2014","journal-title":"Lancet Infect Dis"},{"key":"2021051810402262000_CIT0024","doi-asserted-by":"crossref","first-page":"e51335","DOI":"10.1371\/journal.pone.0051335","article-title":"Dengue viral RNA levels in peripheral blood mononuclear cells are associated with disease severity and preexisting dengue immune status","volume":"7","author":"Srikiatkhachorn","year":"2012","journal-title":"PLoS One"},{"key":"2021051810402262000_CIT0025","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1006\/viro.2002.1704","article-title":"High levels of plasma dengue viral load during defervescence in patients with dengue hemorrhagic fever: implications for pathogenesis","volume":"305","author":"Wang","year":"2003","journal-title":"Virology"},{"key":"2021051810402262000_CIT0026","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1086\/507635","article-title":"Slower rates of clearance of viral load and virus-containing immune complexes in patients with dengue hemorrhagic fever","volume":"43","author":"Wang","year":"2006","journal-title":"Clin Infect Dis"},{"key":"2021051810402262000_CIT0027","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-virology-101416-041848","article-title":"The good, the bad, and the shocking: the multiple roles of dengue virus nonstructural protein 1 in protection and pathogenesis","volume":"5","author":"Glasner","year":"2018","journal-title":"Annu Rev Virol"},{"key":"2021051810402262000_CIT0028","doi-asserted-by":"crossref","first-page":"304ra141","DOI":"10.1126\/scitranslmed.aaa3787","article-title":"Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination","volume":"7","author":"Beatty","year":"2015","journal-title":"Sci Transl Med"},{"key":"2021051810402262000_CIT0029","doi-asserted-by":"crossref","first-page":"304ra142","DOI":"10.1126\/scitranslmed.aaa3863","article-title":"Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity","volume":"7","author":"Modhiran","year":"2015","journal-title":"Sci Transl Med"},{"key":"2021051810402262000_CIT0030","doi-asserted-by":"crossref","first-page":"e1005738","DOI":"10.1371\/journal.ppat.1005738","article-title":"Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability","volume":"12","author":"Puerta-Guardo","year":"2016","journal-title":"PLoS Pathog"},{"key":"2021051810402262000_CIT0031","doi-asserted-by":"crossref","first-page":"e1006673","DOI":"10.1371\/journal.ppat.1006673","article-title":"Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components","volume":"13","author":"Glasner","year":"2017","journal-title":"PLoS Pathog"},{"key":"2021051810402262000_CIT0032","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.celrep.2019.01.036","article-title":"Flavivirus NS1 triggers tissue-specific vascular endothelial dysfunction reflecting disease tropism","volume":"26","author":"Puerta-Guardo","year":"2019","journal-title":"Cell Rep"},{"key":"2021051810402262000_CIT0033","doi-asserted-by":"crossref","first-page":"5242","DOI":"10.1038\/s41467-018-07667-z","article-title":"Role of NS1 antibodies in the pathogenesis of acute secondary dengue infection","volume":"9","author":"Jayathilaka","year":"2018","journal-title":"Nat Commun"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciaa1332\/35922728\/ciaa1332.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/72\/10\/e586\/37950651\/ciaa1332.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/72\/10\/e586\/37950651\/ciaa1332.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T06:58:20Z","timestamp":1621321100000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/72\/10\/e586\/6104252"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,19]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,1,19]]},"published-print":{"date-parts":[[2021,5,18]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciaa1332","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,5,15]]},"published":{"date-parts":[[2021,1,19]]}}}