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Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C
  1. Robert J Fontana1,
  2. Jules L Dienstag2,
  3. Herbert L Bonkovsky3,
  4. Richard K Sterling4,
  5. Deepa Naishadham5,
  6. Zachary D Goodman6,
  7. Anna S F Lok1,
  8. Elizabeth C Wright7,
  9. Grace L Su1,
  10. the HALT-C Trial Group
  1. 1Department of Internal Medicine, University of Michigan Medical School, Michigan, USA
  2. 2Gastrointestinal Unit (Medical Services), Massachusetts General Hospital and the Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
  3. 3Departments of Medicine and Molecular & Structural Biology and The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, Connecticut, USA
  4. 4Hepatology Section, Virginia Commonwealth University Medical Center, Virginia, USA
  5. 5New England Research Institutes, Massachusetts, USA
  6. 6Armed Forces Institute of Pathology, Division of Hepatic Pathology and Veterans Administration Special Reference Laboratory for Pathology, Washington, USA
  7. 7Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Maryland, USA
  1. Correspondence to Robert J Fontana, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, Ann Arbor, Michigan, USA; rfontana{at}


Objectives The aim of this study was to explore the association of serum fibrosis marker levels with the risk of clinical and histological disease progression in a large cohort of patients with chronic hepatitis C (CHC).

Methods 462 prior non-responders to peginterferon and ribavirin enrolled in the randomised phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial had baseline and annual serum samples tested for hyaluronic acid (HA), N-terminal peptide of procollagen type 3, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and YKL-40. All patients underwent a pretreatment liver biopsy and follow-up biopsies at years 2 and 4. Histological progression was defined as a ≥2 point increase in Ishak fibrosis score in patients without cirrhosis. Clinical outcomes included development of decompensation, hepatocellular cancer, death or an increase in the CTP (Child–Turcotte–Pugh) score to ≥7.

Results Mean patient age was 49.5 years and 39% had histological cirrhosis at entry. Baseline HA, YKL-40 and TIMP-1 levels combined with other laboratory parameters were all significantly associated with clinical outcomes in the 69 (15%) patients with disease progression (p<0.0001). The best multivariate model to predict clinical outcomes included baseline bilirubin, albumin, international normalised ratio (INR) and YKL-40 levels. All of the baseline serum fibrosis marker levels were also significantly associated with histological fibrosis progression that developed in 70 (33%) of the 209 patients with cirrhosis (p <0.0001). However, baseline HA and platelet counts were best at predicting histological progression (area under the curve (AUC)=0.663).

Conclusion Pretreatment serum fibrosis marker levels are significantly increased in patients with CHC at risk of clinical and histological disease progression. If validated in additional cohorts, measurement of these markers could help identify patients with CHC who would benefit from more frequent and intensive monitoring.

Trial Registration Number NCT00006164.

  • Cirrhosis
  • non-invasive markers
  • liver fibrosis
  • natural history
  • viral hepatitis
  • fibrogenesis
  • Hepatitis C
  • liver biopsy
  • liver cirrhosis
  • staging

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  • This is publication #49 of the HALT-C Trial.

  • Funding This study was supported by the National Institute of Diabetes & Digestive & Kidney Diseases (contract numbers are listed below). Additional support was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed below). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health. In addition to the authors of this manuscript, the following individuals were instrumental in the planning, conduct and/or care of patients enrolled in this study at each of the participating institutions as follows: University of Massachusetts Medical Center, Worcester, Massachusetts (contract N01-DK-9-2326), Gyongyi Szabo, Barbara F Banner, Maureen Cormier, Donna Giansiracusa; University of Connecticut Health Center, Farmington, Connecticut (grant M01RR-06192), Gloria Borders, Michelle Kelley; Massachusetts General Hospital, Boston, Massachusetts (contract N01-DK-9-2319, grant M01RR-01066; grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center), Raymond T Chung, Andrea E Reid, Atul K Bhan, Wallis A Molchen, Cara C Gooch; University of Michigan Medical Center, Ann Arbor, Michigan (contract N01-DK-9-2323, grant M01RR-00042, grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research), Joel K Greenson, Pamela A Richtmyer, R Tess Bonham; Virginia Commonwealth University Health System, Richmond, Virginia (contract N01-DK-9-2322, grant M01RR-00065), Mitchell L Shiffman, Melissa J Contos, A Scott Mills, Charlotte Hofmann, Paula Smith; National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, Maryland, James E. Everhart, Leonard B Seeff, Patricia R Robuck, Jay H Hoofnagle; New England Research Institutes, Watertown, Massachusetts (contract N01-DK-9-2328), Kristin K Snow, Margaret C Bell, Teresa M Curto; Armed Forces Institute of Pathology, Washington, DC, Fanny Monge, Michelle Parks; Data and Safety Monitoring Board Members: (Chair) Gary L. Davis, Guadalupe Garcia-Tsao, Michael Kutner, Stanley M. Lemon, Robert P. Perrillo.

  • Competing interests We are enclosing two sections relating to disclosures of potential conflicts of interest. Disclosures that pertain to the industrial sponsors who have partnered with the NIDDK to support this study, which are also listed in the text of the manuscript, are listed in section A. In addition, many of the HALT-C Trial investigators have other associations with industry relating to the area of hepatitis C, and, to achieve the highest level of disclosure, we list these for you as well in section B. Authors with no financial relationships related to this project are: DN, JLD, ZDG, ECW, GLS, Section A. The following are disclosures that pertain to the industrial sponsors who have partnered with the NIDDK to support this study, which are also listed in the text of the manuscript. Financial relationships of the authors with Hoffmann-La Roche, Inc., are as follows: RJF is on the speaker's bureau; HLB receives research support; RKSt is a consultant, receives research support, ASL is a consultant. Section B. In addition, many of the HALT-C Trial investigators have other associations with industry relating to the area of hepatitis C, and, to achieve the highest level of disclosure, we list these for you as well. RJF: Bristol-Meyers Squibb–Speaker’s bureau and consultant. Abbott Pharmaceuticals–Consultant. Bayer/Siemens–Consultant. JLD: Vertex Pharmaceuticals–receives research support. Serves on a Data Monitoring Committee for Schering-Plough Research Institute and Human Genome Sciences. HLB: Merck—receives research support. Novartis Pharmaceuticals–consultant and receives research support. Lundbeck Pharmaceuticals—consultant and on speakers’ bureau. Vertex Pharmaceuticals–receives research support. RKS: WAKO Diagnostics–consultant and receives research support. Schering-Plough Corporation–consultant and speaker's bureau. Glaxo Smith Kline–speaker's bureau. Vertex Pharmaceuticals–Advisory Board. ZDG: Research support from Schering-Plough and Novartis. ASL: Schering-Plough Corporation–consultant and receives research support. Vertex Pharmaceuticals–consultant. Novartis Pharmaceuticals–receives research support.

  • Ethics approval This study was conducted with the approval of the ethics committess at all of the participating sites.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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