Gastroenterology

Gastroenterology

Volume 136, Issue 1, January 2009, Pages 138-148
Gastroenterology

Clinical Advances in Liver, Pancreas, and Biliary Tract
Incidence of Hepatocellular Carcinoma and Associated Risk Factors in Hepatitis C-Related Advanced Liver Disease

https://doi.org/10.1053/j.gastro.2008.09.014Get rights and content

Background & Aims

Although the incidence of hepatocellular carcinoma (HCC) is increasing in the United States, data from large prospective studies are limited. We evaluated the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) cohort for the incidence of HCC and associated risk factors.

Methods

Hepatitis C virus-positive patients with bridging fibrosis or cirrhosis who did not respond to peginterferon and ribavirin were randomized to groups that were given maintenance peginterferon for 3.5 years or no treatment. HCC incidence was determined by Kaplan–Meier analysis, and baseline factors associated with HCC were analyzed by Cox regression.

Results

1,005 patients (mean age, 50.2 years; 71% male; 72% white race) were studied; 59% had bridging fibrosis, and 41% had cirrhosis. During a median follow-up of 4.6 years (maximum, 6.7 years), HCC developed in 48 patients (4.8%). The cumulative 5-year HCC incidence was similar for peginterferon-treated patients and controls, 5.4% vs 5.0%, respectively (P = .78), and was higher among patients with cirrhosis than those with bridging fibrosis, 7.0% vs 4.1%, respectively (P = .08). HCC developed in 8 (17%) patients whose serial biopsy specimens showed only fibrosis. A multivariate analysis model comprising older age, black race, lower platelet count, higher alkaline phosphatase, esophageal varices, and smoking was developed to predict the risk of HCC.

Conclusions

We found that maintenance peginterferon did not reduce the incidence of HCC in the HALT-C cohort. Baseline clinical and laboratory features predicted risk for HCC. Additional studies are required to confirm our finding of HCC in patients with chronic hepatitis C and bridging fibrosis.

Section snippets

Patients and Methods

The design of the HALT-C Trial has been described previously.18, 19 Briefly, patients with detectable HCV RNA at 10 clinical centers had to meet the following criteria for enrollment: failure to have achieved a sustained virologic response after previous interferon treatment with or without ribavirin, the presence of advanced hepatic fibrosis on liver biopsy (Ishak fibrosis score, ≥3), no history of hepatic decompensation or HCC, and the absence of defined exclusion criteria (eg, liver disease

Results

A total of 1050 patients were randomized between January 2001 and August 2004. Forty-five patients were excluded for the following reasons: (1) prevalent HCC, defined as HCC diagnosed within 12 months after enrollment (n = 5); (2) patients who had less than 12 months follow-up after enrollment (n = 38); and (3) patients with a diagnosis of presumed HCC who were followed for at least 24 months and did not show radiologic or clinical progression of their liver masses (n = 2). The characteristics

Discussion

The major objective of the HALT-C Trial was to determine whether long-term treatment with peginterferon would reduce progression of hepatitis C, including the development of HCC. Support for the possibility that maintenance therapy might inhibit disease progression had come from a 2-year study of interferon maintenance therapy in a US population.23 Additionally, several early reports suggested that interferon therapy reduced the development of HCC in Japanese and Italian patients with chronic

References (54)

  • C.T. Wai et al.

    A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C

    Hepatology

    (2003)
  • M.L. Shiffman et al.

    A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia

    Gastroenterology

    (1999)
  • A. Craxi et al.

    Prevention of hepatocellular carcinoma

    Clin Liver Dis

    (2005)
  • J.A. Davila et al.

    Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study

    Gastroenterology

    (2004)
  • K. Kiyosawa et al.

    Hepatocellular carcinoma: recent trends in Japan

    Gastroenterology

    (2004)
  • J. Bruix et al.

    Clinical management of hepatocellular carcinomaConclusions of the Barcelona-2000 EASL Conference

    J Hepatol

    (2001)
  • A.S. Befeler et al.

    Liver transplantation for hepatocellular carcinoma

    Gastroenterology

    (2005)
  • M.C. Yu et al.

    Environmental factors and risk for hepatocellular carcinoma

    Gastroenterology

    (2004)
  • A. Said et al.

    The prevalence of alcohol-induced liver disease and hepatitis C and their interaction in a tertiary care setting

    Clin Gastroenterol Hepatol

    (2004)
  • J.A. Marrero et al.

    NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States

    Hepatology

    (2002)
  • S. Kubo et al.

    Correlation between low platelet count and multicentricity of hepatocellular carcinoma in patients with chronic hepatitis C

    Hepatol Res

    (2004)
  • E.G. Giannini et al.

    Prevalence and prognostic significance of the presence of esophageal varices in patients with hepatocellular carcinoma

    Clin Gastroenterol Hepatol

    (2006)
  • P.A. Bonis et al.

    A predictive model for the development of hepatocellular carcinoma, liver failure, or liver transplantation for patients presenting to clinic with chronic hepatitis C

    Am J Gastroenterol

    (1999)
  • N. Ganne-Carrie et al.

    Predictive score for the development of hepatocellular carcinoma and additional value of liver large cell dysplasia in Western patients with cirrhosis

    Hepatology

    (1996)
  • R.F. Velazquez et al.

    Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis

    Hepatology

    (2003)
  • J.L. Rodriguez-Diaz et al.

    Clinical and pathological factors associated with the development of hepatocellular carcinoma in patients with hepatitis virus-related cirrhosis: a long-term follow-up study

    Clin Oncol (R Coll Radiol)

    (2007)
  • S.L. Chen et al.

    The natural history of hepatitis C virus (HCV) infection

    Int J Med Sci

    (2006)
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    H.L.B.'s current address is Carolinas Medical Center, Charlotte, North Carolina.

    The authors disclose the following: Financial relationships of the authors with Hoffmann–La Roche, Inc, are as follows: A. S. Lok is a consultant; T. R. Morgan is a consultant, on the speaker's bureau, and receives research support; A. M. Di Bisceglie is a consultant, on the speaker's bureau, and receives research support; R. K. Sterling is a consultant, on the speaker's bureau, and receives research support; G. T. Everson is a consultant, on the speaker's bureau, and receives research support; K. L. Lindsay is a consultant and receives research support; W. M. Lee receives research support; H. L. Bonkovsky receives research support. Authors with no financial relationships related to this project are L. B. Seeff, T. M. Curto, J. L. Dienstag, M. G. Ghany, C. Morishima, and Z. D. Goodman. Potential investigator conflict of interest was disclosed to study participants.

    Supported by the National Institute of Diabetes and Digestive and Kidney Diseases (contract numbers are listed in Appendix 1); the National Institute of Allergy and Infectious Diseases (NIAID); the National Cancer Institute; the National Center for Minority Health and Health Disparities; General Clinical Research Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed in Appendix 1); and by Hoffman–La Roche, Inc, through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health.

    This is publication No. 34 from the HALT-C Trial Group.

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

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