Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy

Ann Intern Med. 1999 Aug 3;131(3):174-81. doi: 10.7326/0003-4819-131-3-199908030-00003.


Background: Previous studies on the effect of interferon therapy on the incidence of hepatocellular carcinoma have not sufficiently assessed degree of liver fibrosis, a major risk factor for hepatocellular carcinoma.

Objective: To evaluate the effect of interferon therapy on incidence of hepatocellular carcinoma, adjusting for risk factors, including the degree of liver fibrosis.

Design: Retrospective cohort study.

Setting: Seven university hospitals and one regional core hospital in Japan.

Patients: 2890 patients with chronic hepatitis C who had undergone liver biopsy since 1986. Of these patients, 2400 received interferon and 490 were untreated.

Measurements: The degree of liver fibrosis was assessed from stage F0 (no fibrosis) to stage F4 (cirrhosis). Response to interferon was determined virologically and biochemically. Screening for development of hepatocellular carcinoma was performed periodically during an average follow-up of 4.3 years. Effect of interferon therapy on the risk for hepatocellular carcinoma was analyzed by using Cox proportional hazards regression.

Results: Hepatocellular carcinoma developed in 89 interferon-treated patients and in 59 untreated patients. Among untreated patients, the annual incidence of hepatocellular carcinoma increased with the degree of liver fibrosis, from 0.5% among patients with stage F0 or F1 fibrosis to 7.9% among patients with stage F4 fibrosis. The cumulative incidence in treated and untreated patients differed significantly for patients with stage F2 fibrosis (P = 0.0128) and for those with stage F3 fibrosis (P = 0.0011). In multivariate analysis, interferon therapy was associated with a reduced risk for hepatocellular carcinoma (adjusted risk ratio, 0.516 [95% CI, 0.358 to 0.742]; P < 0.001), especially among patients with sustained virologic response (risk ratio, 0.197 [CI, 0.099 to 0.392]), among those with persistently normal serum alanine aminotransferase levels (risk ratio, 0.197 [CI, 0.104 to 0.375]), and among those with alanine aminotransferase levels less than two times the upper limit of normal (risk ratio, 0.358 [CI, 0.206 to 0.622]).

Conclusions: Interferon therapy significantly reducesthe risk for hepatocellular carcinoma, especially among virologic or biochemical responders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Antineoplastic Agents / therapeutic use*
  • Antiviral Agents / therapeutic use*
  • Carcinoma, Hepatocellular / epidemiology
  • Carcinoma, Hepatocellular / prevention & control*
  • Data Interpretation, Statistical
  • Female
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / enzymology
  • Humans
  • Incidence
  • Interferons / therapeutic use*
  • Japan / epidemiology
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / enzymology
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / epidemiology
  • Liver Neoplasms / prevention & control*
  • Male
  • Middle Aged
  • Population Surveillance
  • Retrospective Studies


  • Antineoplastic Agents
  • Antiviral Agents
  • Interferons
  • Alanine Transaminase