Can cirrhosis or cancer be prevented with interferon/ribavirin in chronic viral hepatitis?

The incidence of hepatocellular cancer (liver cancer) is rising rapidly. According to Surveillance, Epidemiology and End Results (SEER) analyses, liver and intrahepatic biliary cancer rates are increasing at a faster rate than any other cancer-related death. Once a patient is diagnosed clinically, the average life expectancy is less than one year.

The major risk factors for hepatocellular cancer are chronic viral hepatitis (predominantly hepatitis B (HBV) in Asia and Africa and hepatitis C (HCV) in Japan and Western countries), alcohol-related liver disease, hemochromatosis, nonalcoholic steatohepatitis (NASH), and other less common causes of cirrhosis. In the United States, chronic HCV is the most common antecedent of hepatocellular cancer, which develops mostly in individuals with preexisting cirrhosis. The risk of hepatocellular cancer for people with HCV-related cirrhosis is 1%-4% per year. The current, marked increase in the incidence of hepatocellular cancer is a result of the high HCV infection rates of the mid-1960s and 1970s that resulted from the proliferation of illegal drug use and the long "incubation" period (20 to 40 years from initial infection to development of hepatocellular cancer worldwide, since it is endemic in the world’s most populous countries. It is less frequent in the United States, where it is more common among Asian immigrants. Hepatocellular cancer can arise in individuals with HBV infection who do not have cirrhosis.

Patients with HCV genotype I who are treated with pegylated interferon and ribavirin for 12 months have a sustained virologic response of 50%-55% (the loss of HCV RNA is sustained for at least six months after completion of treated), whereas patients with genotypes 2 and 3 who are treated for six months have a sustained virologic response of 75%-80%. Newer, effective drugs are available to treat people with HBV infection. Accordingly, the question arises as to whether treatment might prevent or reduce the frequency of hepatocellular cancer. With the long latency of the disease, it has been difficult to launch well-controlled studies to answer this question. Rather, the issue has been assessed by examining the results of prospective and retrospective treatment trials of individuals with and without cirrhosis.

The first report, from Japan, involved 90 patients with HCV-related cirrhosis, half of whom received lymphoblastoid interferon for three to six months and half of whom received no therapy. Although only 16 percent of treated patients had a sustained virologic response, hepatocellular cancer developed significantly less frequently in the treated patients (27%) than in the untreated patients (75%). These results were at first greeted with skepticism because of the high rate of hepatocellular cancer and the short duration of treatment. Three randomized trials from Europe failed to confirm these results.

Numerous efforts have been directed at assessing the effectiveness of treatment in reducing hepatocellular cancer for patients with either HCV or HBV infection. However, no studies were powered to specifically address the issue of treatment effect on the disease, none utilized the best treatment regimen (pegylated interferon and ribavirin), and most were of relatively short duration. Accordingly, several investigators performed meta-analyses hoping to make sense of the varied studies and results. All concluded, with differing degrees of confidence that treatment with interferon seems to reduce the frequency of development of hepatocellular cancer. One study indicated that the data were only "suggestive" and therefore interferon treatment could not be recommended for all individuals with HCV-related and HBV-related cirrhosis (Bffis et al. Ann Intern Med. 1999; 131-696-701). Another noted that the pooled data suggested a slight preventive effect but with a low magnitude confined to the individuals who had a sustained response, and that no effect was detectable in individuals with HBV-related cirrhosis (Camma et al. J Hepatol. 2001;34-593-602). The third study concluded that hepatocellular cancer was markedly less common for individuals with a sustained response and slightly less common for individuals who had no response.

Because most individuals with HCV infection in whom hepatocellular cancer develops have no cirrhosis, it is rational to treat the infection before cirrhosis develops. However, treatment efficacy in reducing hepatocellular cancer is difficult to assess for patients without cirrhosis because of the low rate of development of hepatocellular cancer. Accordingly, studies in Europe have been unable to demonstrate efficacy. But three retrospective evaluations in Japan have yielded supportive data. Yoshida et al. found a significant benefit for persons with marked portal or bridging fibrosis. Okanoue et al. also found a positive effect among patients with a sustained response with moderate fibrosis, but not in those with cirrhosis, and Imai et al. reported a significant reduction of hepatocellular cancer only in patients with a sustained response.

In summary, there is a suggestion that treatment of HCV infection, particularly before development of cirrhosis and especially in individuals with a sustained response, lowers the rate of development of hepatocellular cancer. Better powered studies are needed, and one major National Institutes of Health-supported study, the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial, is in progress.