Current issues of ACP Journal Club are published in Annals of Internal Medicine


Interferon-α decreased the incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis

ACP J Club. 1996 Mar-April;124:32. doi:10.7326/ACPJC-1996-124-2-032

Source Citation

Nishiguchi S, Kuroki T, Nakatani S, et al. Randomised trial of effects of interferon-α on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 1995 Oct 21;346:1051-5. [PubMed ID: 7564784]



To determine the effectiveness of interferon-α in preventing hepatic carcinogenesis in patients with chronic active hepatitis C and cirrhosis.


Randomized controlled trial with 2- to 7-year (mean 5-y) follow-up.


Outpatient clinic at Osaka City University Hospital in Japan.


90 patients (mean age 56 y, 57% men) with a clinical diagnosis of type C cirrhosis who had had abnormal serum alanine aminotransferase levels for ≥ 1 year, were HBsAg negative, and had no reason for chronic liver disease apart from hepatitis C virus (HCV) infection. Other inclusion criteria were compensated cirrhosis of grade A as judged by the Child-Pugh score, no severe thrombocytopenia, anti-HIV negativity, HCV RNA positivity, and no hepatocellular carcinoma (HCC) or suspicious-looking lesion by imaging techniques.


45 patients were allocated to intramuscular injection of human lymphoblastoid interferon-α, 6 MIU 3 times/wk for 12 to 24 weeks. 10 patients had their daily dose decreased to 3 MIU because of side effects. 45 patients were allocated to the control group and received dietary advice and therapy to treat the symptoms of ascites.

Main Outcome Measures

Development of HCC and disappearance of HCV RNA. Other outcomes were changes in serum alanine aminotransferase level, serum albumin level, and histologic activity.

Main Results

12 to 24 weeks of interferon-α led to fewer cases of HCC at a mean follow-up of 5 years than did symptomatic treatment alone (P = 0.002) (Table). The mean change in serum alanine aminotransferase level did not differ between the 2 groups (P = 0.89). HCV RNA disappeared in 7 patients who received interferon-α compared with 0 patients in the control group (P = 0.018). The mean change in serum albumin level favored the interferon-α group (P < 0.001) (Table). Histologic activity was improved in patients in the interferon-α group (P = 0.03).


Human lymphoblastoid interferon-α decreased the incidence of hepatocellular carcinoma and improved liver function in patients with chronic active hepatitis C and cirrhosis.

Source of funding: In part, Ministry of Welfare, Japan.

For article reprint: Dr. S. Nishiguchi, 4-7-7, Asahimachi Abenoku, Osaka, JAPAN. FAX 81-666461433.

Table. Human lymphoblastoid interferon-α in chronic active hepatitis C with cirrhosis*

Outcomes at mean 5 y Interferon-α Control RRR (95% CI) NNT (CI)
Development of HCC 4% 38% 88% (58 to 97) 3 (2 to 6)
Disappearance of HCV RNA 16% 0% Infinity 7

*HCC = hepatocellular carcinoma, HCV = hepatitis C virus. Other abbreviations defined in Glossary; RRR, RBI, NNT, and CI calculated from data in article.


The incidence of HCC in patients who are anti-HCV positive ranges from 39% to 77%, particularly in geographic areas endemic for HCV infection, such as Japan and southern Europe. Although patients with cirrhosis of any cause are at risk for HCC, the precise role of HCV in the genesis of HCC is not known (1). In the study by Nishiguchi and colleagues, 15% of the patients considered for the study had HCC at initial evaluation and comprised 57% of those excluded. This percentage is high enough to wonder whether the study participants were derived from patients with suspected HCC who were referred to the clinic for management. The patients in the control and treatment groups had long-standing HCV infection and established cirrhosis, both large risk factors for HCC (2). Because active HCV status was determined retrospectively in some patients and prospectively in others, an important question is how patients were selected for this study.

The lower frequency of HCC in the interferon group compared with the control group is reason for cautious excitement. This salutary effect was achieved without a significant mean change in serum aminotransferase levels, but histologic index and serum albumin levels improved and α-fetoprotein levels were lower in treated patients. An important point is that HCV RNA did not disappear in any of the patients in the control group compared with only 16% of patients in the treatment group. It is difficult to relate the success of a reduced frequency of HCC to this effect of interferon on HCV replication. Because interferon is an immune-modulatory agent, could these results be caused by the direct antitumor effects of interferon rather than by direct effects on the virus?

Several questions remain about the mechanism of interferon, the dose, and the duration of therapy. The small number of patients who were willing to receive additional interferon treatments during follow-up confirms the reluctance that some patients have about experiencing the frequent, sometimes disabling, side effects of this drug.

Most certainly, the results of this study should provide the impetus and enthusiasm to confirm these findings in larger, carefully designed, controlled trials. Is there hope for a hopeless disease? Time will tell.

Jacob Korula, MD
University of Southern California School of MedicineLos Angeles, California, USA


1. Takano S, Yokosuka, Imazeki F, et al. Incidence of hepatocellular carcinoma in chronic hepatitis B and C: a prospective study of 251 patients. Hepatology. 1995;21:650-5.

2. Okuda K, Nakashima T, Kojiro M, et al. Hepatocellular carcinoma without cirrhosis in Japanese patients. Gastroenterology. 1989;97:140-6.