{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:33:34Z","timestamp":1790876014031,"version":"4.1.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2019,5,28]],"date-time":"2019-05-28T00:00:00Z","timestamp":1559001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,5,28]],"date-time":"2019-05-28T00:00:00Z","timestamp":1559001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:p>Progression of nonalcoholic steatohepatitis (NASH) is incompletely characterized. We analyzed data on longitudinal changes in liver histology, hepatic venous pressure gradient (HVPG), and serum markers of fibrosis in 475 patients with NASH with bridging fibrosis (F3) or compensated cirrhosis (F4) enrolled in two phase 2b, placebo\u2010controlled trials of simtuzumab. The trials were terminated after 96 weeks because of lack of efficacy, so data from treatment groups were combined. Liver biopsies and HVPG measurements (only for patients with F4 fibrosis) were collected at screening and at weeks 48 and 96. Patients were assessed for Ishak fibrosis stage, hepatic collagen content and alpha\u2010smooth muscle actin (by morphometry), NAFLD Activity Score (NAS), and serum markers of fibrosis. Associations with progression to cirrhosis (in patients with F3 fibrosis) and liver\u2010related clinical events (in patients with F4 fibrosis) were determined. Progression to cirrhosis occurred in 22% (48\/217) of F3 patients, and liver\u2010related clinical events occurred in 19% (50\/258) of patients with cirrhosis. Factors significantly associated with progression to cirrhosis included higher baseline values of and greater increases in hepatic collagen content, level of alpha\u2010smooth muscle actin, and Enhanced Liver Fibrosis score. Similar factors, plus lack of fibrosis stage improvement (hazard ratio, 9.30; 95% confidence interval, 1.28\u201067.37), higher HVPG at baseline, and greater increase in HVPG over time, were associated with an increased risk of liver\u2010related clinical events in patients with cirrhosis. Disease progression was not associated with the NAS at baseline or changes in NAS during treatment after adjustment for fibrosis stage. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: In patients with advanced fibrosis due to NASH, the primary determinant of clinical disease progression is fibrosis and its change over time.<\/jats:p>","DOI":"10.1002\/hep.30664","type":"journal-article","created":{"date-parts":[[2019,4,17]],"date-time":"2019-04-17T04:14:20Z","timestamp":1555474460000},"page":"1913-1927","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":350,"title":["The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials"],"prefix":"10.1097","volume":"70","author":[{"given":"Arun J.","family":"Sanyal","sequence":"first","affiliation":[{"name":"Virginia Commonwealth University,Richmond,VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Pinnacle Clinical Research,San Antonio,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlad","family":"Ratziu","sequence":"additional","affiliation":[{"name":"H\u00f4pital Universitaire Piti\u00e9\u2010Salp\u00eatri\u00e8re,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal F.","family":"Abdelmalek","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute,Durham,NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Mae","family":"Diehl","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute,Durham,NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Caldwell","sequence":"additional","affiliation":[{"name":"University of Virginia,Charlottesville,VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell L.","family":"Shiffman","sequence":"additional","affiliation":[{"name":"Liver Institute of Virginia,Richmond,VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul","family":"Aguilar Schall","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Jia","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"McColgan","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Stephen","family":"Djedjos","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"McHutchison","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Mani","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Myers","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zobair","family":"Younossi","sequence":"additional","affiliation":[{"name":"Inova Fairfax Hospital,Falls Church,VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Muir","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute,Durham,NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nezam H.","family":"Afdhal","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center, Harvard Medical 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