{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:10:51Z","timestamp":1778803851651,"version":"3.51.4"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic hepatitis C (CHC) infection remains a global health burden, contributing to the risk of long-term complications such as progressive fibrosis, cirrhosis, and hepatocellular carcinoma, particularly in undiagnosed or untreated individuals. Novel biomarkers for the assessment of disease progression and prognosis are required for fibroinflammatory chronic liver disease. Our study population from the Hepatitis C Antiviral Long Term Treatment Against Cirrhosis (HALT-C) trial was used to investigate the association of neoepitope fibroinflammatory biomarkers with clinical outcomes in patients with CHC infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Baseline serum samples from 339 patients with advanced CHC from the HALT-C cohort were included and assessed for liver-related clinical outcomes. We assessed the fibrogenesis marker nordicPRO-C3\u2122 and the neutrophil activity marker nordicCPa9-HNE\u2122.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The active fibrogenesis marker PRO-C3 was associated with disease progression and liver-related outcomes in patients with CHC, with a 4-fold increased hazard (95% CI: 1.91\u20138.30) of liver-related outcomes in patients with high compared with low PRO-C3 levels at baseline. Grouping patients with a combination of high or low active fibrogenesis, PRO-C3, and high and low neutrophil activity, CPa9-HNE, revealed that the patient endotype with high fibrogenesis and low neutrophil activity had the highest risk of developing liver-related outcomes in patients with CHC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>PRO-C3 was associated with the risk of liver-related outcomes in patients with CHC infection in our HALT-C subpopulation. Grouping patients based on neoepitope biomarkers reflecting active fibrogenesis and neutrophil activity could provide fibroinflammatory disease endotype classification that may be applicable to other chronic liver diseases with appropriate validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiaf552","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T13:06:38Z","timestamp":1761743198000},"page":"831-839","source":"Crossref","is-referenced-by-count":0,"title":["Serum Markers of Fibroinflammatory Activity PRO-C3 and CPa9-HNE Are Associated with Liver-Related Outcomes in Patients with Chronic Hepatitis C"],"prefix":"10.1093","volume":"233","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3875-488X","authenticated-orcid":false,"given":"Emilie Toft","family":"Skovgaard","sequence":"first","affiliation":[{"name":"Nordic Bioscience, Biomarkers & Research , Herlev ,","place":["Denmark"]},{"name":"Department of Biomedical Sciences, University of Copenhagen, Copenhagen ,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6030-5556","authenticated-orcid":false,"given":"Thomas","family":"Wiggers","sequence":"additional","affiliation":[{"name":"Nordic Bioscience, Biomarkers & Research , Herlev ,","place":["Denmark"]},{"name":"Department of Biomedical Sciences, University of Copenhagen, Copenhagen ,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5026-8740","authenticated-orcid":false,"given":"Morten","family":"Karsdal","sequence":"additional","affiliation":[{"name":"Nordic Bioscience, Biomarkers & Research , Herlev ,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens Peter","family":"Goetze","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Copenhagen, Copenhagen ,","place":["Denmark"]},{"name":"Department of Clinical Biochemistry, Diagnostic Center, Rigshospitalet , Copenhagen ,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana Julie","family":"Leeming","sequence":"additional","affiliation":[{"name":"Nordic Bioscience, Biomarkers & Research , Herlev ,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keyur","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, University Health Network Toronto, Toronto General Hospital , Toronto, Ontario ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"2026051419571918500_jiaf552-B1"},{"key":"2026051419571918500_jiaf552-B2","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of liver diseases in the world","volume":"70","author":"Asrani","year":"2019","journal-title":"J Hepatol"},{"key":"2026051419571918500_jiaf552-B3","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1055\/s-2007-991517","article-title":"Hepatic fibrogenesis","volume":"27","author":"Guo","year":"2007","journal-title":"Semin Liver Dis"},{"key":"2026051419571918500_jiaf552-B4","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3389\/fphar.2014.00123","article-title":"Fibroblasts in fibrosis: novel roles and mediators","volume":"5","author":"Kendall","year":"2014","journal-title":"Front Pharmacol"},{"key":"2026051419571918500_jiaf552-B5","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1089\/ars.2013.5697","article-title":"Extracellular matrix and liver disease","volume":"21","author":"Arriazu","year":"2014","journal-title":"Antioxid Redox Signal"},{"key":"2026051419571918500_jiaf552-B6","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/j.clinbiochem.2011.08.1135","article-title":"Protein fingerprints\u2014relying on and understanding the information of serological protein measurements","volume":"44","author":"Karsdal","year":"2011","journal-title":"Clin Biochem"},{"key":"2026051419571918500_jiaf552-B7","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.clinbiochem.2010.03.015","article-title":"Novel combinations of Post-Translational Modification (PTM) neo-epitopes provide tissue-specific biochemical markers\u2014are they the cause or the consequence of the disease?","volume":"43","author":"Karsdal","year":"2010","journal-title":"Clin Biochem"},{"key":"2026051419571918500_jiaf552-B8","doi-asserted-by":"crossref","first-page":"100743","DOI":"10.1016\/j.jhepr.2023.100743","article-title":"PRO-C3 is a predictor of clinical outcomes in distinct cohorts of patients with advanced liver disease","volume":"5","author":"Nielsen","year":"2023","journal-title":"JHEP Reports"},{"key":"2026051419571918500_jiaf552-B9","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1111\/liv.15595","article-title":"Validation of scores of PRO-C3 to predict liver-related events in alcohol-related liver disease","volume":"43","author":"Johansen","year":"2023","journal-title":"Liver International"},{"key":"2026051419571918500_jiaf552-B10","doi-asserted-by":"crossref","first-page":"100841","DOI":"10.1016\/j.isci.2020.100841","article-title":"Principles of cell circuits for tissue repair and fibrosis","volume":"23","author":"Adler","year":"2020","journal-title":"iScience"},{"key":"2026051419571918500_jiaf552-B11","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.jhep.2025.02.039","article-title":"Hot and cold fibrosis: the role of Serum biomarkers to assess the immune mechanisms and ECM-cell interactions in human fibrosis","volume":"83","author":"de Zawadzki","year":"2025","journal-title":"J Hepatol"},{"key":"2026051419571918500_jiaf552-B12","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1093\/ecco-jcc\/jjac047","article-title":"A specific calprotectin neo-epitope [CPa9-HNE] in Serum from inflammatory bowel disease patients is associated with neutrophil activity and endoscopic severity","volume":"16","author":"Mortensen","year":"2022","journal-title":"J Crohns Colitis"},{"key":"2026051419571918500_jiaf552-B13","doi-asserted-by":"crossref","first-page":"e1000639","DOI":"10.1371\/journal.ppat.1000639","article-title":"Neutrophil extracellular traps contain calprotectin, a cytosolic protein Complex involved in host defense against Candida albicans","volume":"5","author":"Urban","year":"2009","journal-title":"PLoS Pathog"},{"key":"2026051419571918500_jiaf552-B14","doi-asserted-by":"crossref","first-page":"8137","DOI":"10.3390\/ijms23158137","article-title":"Serological biomarkers of extracellular matrix turnover and neutrophil activity are associated with long-term use of vedolizumab in patients with Crohn's disease","volume":"23","author":"Alexdottir","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2026051419571918500_jiaf552-B15","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s13075-024-03332-7","article-title":"Investigating protease-mediated peptides of inflammation and tissue remodeling as biomarkers associated with flares in psoriatic arthritis","volume":"26","author":"Groen","year":"2024","journal-title":"Arthritis Res Ther"},{"key":"2026051419571918500_jiaf552-B16","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1016\/j.dld.2025.03.033","article-title":"The heterogeneity of cirrhosis\u2014systemically assessed endotypes described by fibrosis, apoptosis, and immunoregulatory-related biomarkers","volume":"57","author":"Skovgaard","year":"2025","journal-title":"Dig Liver Dis"},{"key":"2026051419571918500_jiaf552-B17","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s10238-022-00799-z","article-title":"Liver biopsy for assessment of chronic liver diseases: a synopsis","volume":"23","author":"Chowdhury","year":"2023","journal-title":"Clin Exp Med"},{"key":"2026051419571918500_jiaf552-B18","doi-asserted-by":"crossref","first-page":"475","DOI":"10.3748\/wjg.v20.i2.475","article-title":"Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis.","volume":"20","author":"Sumida","year":"2014","journal-title":"World J Gastroenterol"},{"key":"2026051419571918500_jiaf552-B19","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1056\/NEJMoa0707615","article-title":"Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon","volume":"359","author":"Di Bisceglie","year":"2008","journal-title":"Ne Engl J Med"},{"key":"2026051419571918500_jiaf552-B20","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1002\/hep.22099","article-title":"Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C","volume":"47","author":"Fontana","year":"2008","journal-title":"Hepatology"},{"key":"2026051419571918500_jiaf552-B21","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/S1665-2681(19)31818-6","article-title":"Hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial","volume":"8","author":"Haque","year":"2009","journal-title":"Ann Hepatol"},{"key":"2026051419571918500_jiaf552-B22","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1002\/hep.23211","article-title":"Fibrosis progression in chronic hepatitis C: morphometric image analysis in the HALT-C trial","volume":"50","author":"Goodman","year":"2009","journal-title":"Hepatology"},{"key":"2026051419571918500_jiaf552-B23","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1053\/j.gastro.2009.09.007","article-title":"Predicting clinical and histologic outcomes based on standard laboratory tests in advanced chronic hepatitis C","volume":"138","author":"Ghany","year":"2010","journal-title":"Gastroenterology"},{"key":"2026051419571918500_jiaf552-B24","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1002\/hep.24370","article-title":"A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C","volume":"54","author":"Dienstag","year":"2011","journal-title":"Hepatology"},{"key":"2026051419571918500_jiaf552-B25","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1002\/hep.23315","article-title":"Prognostic value of ishak fibrosis stage: findings from the hepatitis C antiviral long-term treatment against cirrhosis trial","volume":"51","author":"Everhart","year":"2010","journal-title":"Hepatology"},{"key":"2026051419571918500_jiaf552-B26","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1053\/j.gastro.2011.06.007","article-title":"Rate of progression of hepatic fibrosis in patients with chronic hepatitis C: results from the HALT-C trial","volume":"141","author":"Hoefs","year":"2011","journal-title":"Gastroenterology"},{"key":"2026051419571918500_jiaf552-B27","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cct.2004.08.003","article-title":"Evolution of the HALT-C trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon nonresponders","volume":"25","author":"Lee","year":"2004","journal-title":"Control Clin Trials"},{"key":"2026051419571918500_jiaf552-B28","first-page":"303","article-title":"The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters","volume":"5","author":"Nielsen","year":"2013","journal-title":"Am J Transl Res"},{"key":"2026051419571918500_jiaf552-B29","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1097\/HEP.0000000000000845","article-title":"AASLD practice guideline on blood-based noninvasive liver disease assessment of hepatic fibrosis and steatosis","volume":"81","author":"Sterling","year":"2025","journal-title":"Hepatology"},{"key":"2026051419571918500_jiaf552-B30","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1136\/gut.2010.207423","article-title":"Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C","volume":"59","author":"Fontana","year":"2010","journal-title":"Gut"},{"key":"2026051419571918500_jiaf552-B31","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1097\/HEP.0000000000000927","article-title":"Estimating hepatitis C prevalence in the United States, 2017\u20132020","volume":"81","author":"Hall","year":"2025","journal-title":"Hepatology"},{"key":"2026051419571918500_jiaf552-B32","doi-asserted-by":"crossref","first-page":"100317","DOI":"10.1016\/j.jhepr.2021.100317","article-title":"Determining a healthy reference range and factors potentially influencing PRO-C3\u2014a biomarker of liver fibrosis","volume":"3","author":"Erhardtsen","year":"2021","journal-title":"JHEP Reports"},{"key":"2026051419571918500_jiaf552-B33","doi-asserted-by":"crossref","first-page":"e0137302","DOI":"10.1371\/journal.pone.0137302","article-title":"Markers of collagen remodeling detect clinically significant fibrosis in chronic hepatitis C patients","volume":"10","author":"Nielsen","year":"2015","journal-title":"PLoS One"},{"key":"2026051419571918500_jiaf552-B34","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/liv.12700","article-title":"Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C","volume":"35","author":"Nielsen","year":"2015","journal-title":"Liver Int"},{"key":"2026051419571918500_jiaf552-B35","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1111\/apt.16567","article-title":"Progressive alcohol-related liver fibrosis is characterised by imbalanced collagen formation and degradation","volume":"54","author":"Thiele","year":"2021","journal-title":"Aliment Pharmacol Ther"},{"key":"2026051419571918500_jiaf552-B36","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1002\/hep.30163","article-title":"ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis","volume":"69","author":"Daniels","year":"2019","journal-title":"Hepatology"},{"key":"2026051419571918500_jiaf552-B37","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/bjc.2013.352","article-title":"Impact of liver fibrosis on prognosis following liver resection for hepatitis B-associated hepatocellular carcinoma","volume":"109","author":"Wang","year":"2013","journal-title":"Br J Cancer"},{"key":"2026051419571918500_jiaf552-B38","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41392-024-01979-x","article-title":"Cold and hot tumors: from molecular mechanisms to targeted therapy","volume":"9","author":"Wu","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"2026051419571918500_jiaf552-B39","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/ni.2691","article-title":"Immune surveillance by the liver","volume":"14","author":"Jenne","year":"2013","journal-title":"Nat Immunol"},{"key":"2026051419571918500_jiaf552-B40","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nri3623","article-title":"Liver fibrosis and repair: immune regulation of wound healing in a solid organ","volume":"14","author":"Pellicoro","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"2026051419571918500_jiaf552-B41","doi-asserted-by":"crossref","first-page":"5203","DOI":"10.3390\/ijms21155203","article-title":"The roles of immune cells in the pathogenesis of fibrosis","volume":"21","author":"Huang","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2026051419571918500_jiaf552-B42","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1002\/hep.22865","article-title":"Evolution of hepatic steatosis in patients with advanced hepatitis C","volume":"49","author":"Lok","year":"2009","journal-title":"Hepatology"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiaf552\/65045014\/jiaf552.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/233\/5\/831\/65045014\/jiaf552.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/233\/5\/831\/65045014\/jiaf552.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T23:57:29Z","timestamp":1778803049000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/233\/5\/831\/8307141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,31]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,10,31]]},"published-print":{"date-parts":[[2026,5,15]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiaf552","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5,15]]},"published":{"date-parts":[[2025,10,31]]}}}