Gastroenterology
Volume 137, Issue 6 , Pages 1986-1994, December 2009

Effect of HCV RNA Suppression During Peginterferon Alfa-2a Maintenance Therapy on Clinical Outcomes in the HALT-C Trial

  • Mitchell L. Shiffman

      Affiliations

    • Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, Virginia
    • Corresponding Author InformationReprint requests Address requests for reprints to: Mitchell L. Shiffman, MD, Hepatology Section, VCU Health System, Box 980341, Richmond, Virginia 23298. fax: (804) 828-4945
    • ,
  • Chihiro Morishima

      Affiliations

    • Virology Division, Department of Laboratory Medicine, University of Washington, Seattle, Washington
    • ,
  • Jules L. Dienstag

      Affiliations

    • Gastrointestinal Unit (Medical Services), Massachusetts General Hospital and the Department of Medicine, Harvard Medical School, Boston, Massachusetts
    • ,
  • Karen L. Lindsay

      Affiliations

    • Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California
    • ,
  • John C. Hoefs

      Affiliations

    • Division of Gastroenterology, University of California-Irvine, Irvine, California
    • ,
  • William M. Lee

      Affiliations

    • Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
    • ,
  • Elizabeth C. Wright

      Affiliations

    • Office of the director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
    • ,
  • Deepa Naishadham

      Affiliations

    • New England Research Institutes, Watertown, Massachusetts
    • ,
  • Gregory T. Everson

      Affiliations

    • Section of Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado
    • ,
  • Anna S. Lok

      Affiliations

    • Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan
    • ,
  • Adrian M. Di Bisceglie

      Affiliations

    • Division of Gastroenterology and Hepatology, St. Louis University School of Medicine, St. Louis, Missouri
    • ,
  • Herbert L. Bonkovsky

      Affiliations

    • Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut
    • Department of Molecular and Structural Biology, University of Connecticut Health Center, Farmington, Connecticut
    • The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, Farmington, Connecticut
    • ,
  • Marc G. Ghany

      Affiliations

    • Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
    • ,
  • HALT-C Trial Group

Received 15 April 2009; accepted 31 August 2009. published online 11 September 2009.

Background & Aims

The Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial demonstrated that low-dose peginterferon maintenance therapy was ineffective in preventing clinical outcomes in patients with chronic hepatitis C, advanced fibrosis, and failure to achieve a sustained virologic response during lead-in phase treatment with standard dose peginterferon/ribavirin. This analysis was performed to determine whether suppressing HCV RNA during the trial was associated with a reduction in clinical outcomes.

Methods

Seven hundred sixty-four patients treated during the lead-in phase of HALT-C trial were randomized to either peginterferon alfa-2a (90 μg/week) maintenance therapy or no treatment (control) for 3.5 years. Clinical outcomes included an increase in Child–Turcotte–Pugh score, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma, and mortality.

Results

During the lead-in, ≥4-log10 decline in serum HCV RNA occurred in 178 patients; 82% of whom lost detectable HCV RNA and later broke through or relapsed. These patients had significantly (P = .003) fewer clinical outcomes whether randomized to maintenance therapy or control. Following randomization, serum HCV RNA increased significantly in all 90 control patients and in 58 of 88 receiving maintenance therapy. Only 30 patients had persistent suppression of HCV RNA by ≥4 log10 during maintenance therapy. No significant reduction in clinical outcomes was observed in these patients.

Conclusions

Viral suppression by ≥4 log10 with full-dose peginterferon/ribavirin is associated with a significant reduction in clinical outcomes. Continuing low-dose peginterferon maintenance therapy, even in patients with persistent viral suppression, does not lead to a further decline in clinical outcomes.

Abbreviations used in this paper: CO-PILOT, Colchicine Versus Pegintron Long-term Therapy, CTP, Child–Turcotte–Pugh, EPIC, Evaluation of Pegintron in Control of Hepatitis C Cirrhosis, HCC, hepatocellular carcinoma, SVR, sustained virologic response

 

 This article has an accompanying continuing medical education activity on page 2159. Learning Objective: Upon completion of reading this article, successful learners will be able to determine the role of peginterferon alfa-2b maintenance therapy on the management of patients with chronic HCV and advanced fibrosis.

 Conflicts of interest The authors disclose the following: M.L. Shiffman, G.T. Everson, A.S. Lok, and A.M. Di Bisceglie are consultants for Hoffmann-La Roche, Inc. M.L. Shiffman, J.C. Hoefs, G.T. Everson, and A.M. Di Bisceglie are on the speaker's bureau of Hoffmann-La Roche, Inc. M.L. Shiffman, W.M. Lee, G.T. Everson, A.M. Di Bisceglie, and H.L. Bonkovsky receive research support from Hoffmann-La Roche, Inc. K.L. Lindsay was a consultant and received research support during this study and is now an employee of Tibotec (a subsidiary of Johnson and Johnson), Yardsley, NJ. The remaining authors disclose no conflicts.

 Funding Supported by the National Institute of Diabetes and Digestive and Kidney Diseases (contract numbers listed above), the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute, the National Center for Minority Health and Health Disparities, and the General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, and National Institutes of Health (grant numbers are listed above). 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, Inc, through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health.

PII: S0016-5085(09)01561-3

doi:10.1053/j.gastro.2009.08.067

Gastroenterology
Volume 137, Issue 6 , Pages 1986-1994, December 2009