September 29, 2012

Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C

Subject Category: Liver

Am J Gastroenterol 2012; 107:1388–1398; doi:10.1038/ajg.2012.137; published online 12 June 2012

Chihiro Morishima MD1, Mitchell L Shiffman MD2, Jules L Dienstag MD3,4, Karen L Lindsay MD, MMM5, Gyongyi Szabo MD, PhD6, Gregory T Everson MD7, Anna S Lok MD8, Adrian M Di Bisceglie MD9, Marc G Ghany MD, MHSc10, Deepa Naishadham MA, MS11, Timothy R Morgan MD12,13 and Elizabeth C Wright PhD10,14 for the HALT-C Trial Group15

  1. 1Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
  2. 2Liver Institute of Virginia, Bon Secours Health System, Newport News, Virginia, USA
  3. 3Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  4. 4Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
  5. 5Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  6. 6Department of Medicine, Division of Gastroenterology, Hepatology and Liver Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  7. 7Section of Hepatology, Division of Gastroenterology and Hepatology, University of Colorado Denver School of Medicine, Aurora, Colorado, USA
  8. 8Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
  9. 9Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
  10. 10Department of Health and Human Services, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
  11. 11New England Research Institutes, Watertown, Massachusetts, USA
  12. 12Division of Gastroenterology, University of California—Irvine, Irvine, California, USA
  13. 13Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, California, USA
  14. 14Department of Health and Human Services, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA

Correspondence: Chihiro Morishima, MD, Research Associate Professor, Department of Laboratory Medicine, University of Washington, Box 358050, 850 Republican Street, Seattle, Washington 98109, USA. E-mail:

15The HALT-C Trial was registered with (#NCT00006164).

Received 14 December 2011; Accepted 17 April 2012
Advance online publication 12 June 2012


During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation.


Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥2-point difference in HAI or Ishak fibrosis score between biopsies.


Among 657 patients who received full-dose peginterferon/ribavirin “lead-in” therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3–4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups.


Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.


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