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 MD^3,4, 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 MD^12,13 and Elizabeth C Wright PhD^10,14 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: chihiro@u.washington.edu

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

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

Abstract

OBJECTIVES:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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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