Chronic hepatitis C patients (472 patients) were treated with consensus interferon (CIFN) or interferon (IFN) alfa-2b for 6 months in a large multicenter trial. Efficacy was assessed by clearance of hepatitis C virus (HCV) RNA using reverse transcription polymerase chain reaction (RT-PCR) (F100 copies/mL), normalization of serum alanine aminotransferase (ALT), and histological improvement. The purpose of these analyses was to compare these efficacy parameters in nonfibrotics, fibrotics, and cirrhotics. Patients with chronic HCV and cirrhosis showed the same benefit from IFN treatment as noncirrhotic patients when efficacy was assessed by clearance of serum HCV RNA or by histological benefit. Sustained HCV RNA response rates were similar when measured among nonfibrotic (11%), fibrotic (13%), and cirrhotic (11%) patients. Improvement in histologic activity index (HAI) scores was noted among all 3 groups. Cirrhotic patients had a lower sustained ALT response rate (12%) than did nonfibrotic patients (23%). Ninety percent of nonfibrotics, but only 71% of fibrotics and 67% of cirrhotics, who sustained a virological response normalized their ALT. This suggests that cirrhotic patients may clear the hepatitis C virus without normalization of ALT levels. The pattern of both HCV RNA clearance over time and ALT decrease was similar among nonfibrotics, fibrotics, and cirrhotics. Tolerability to IFN therapy was similar among the 3 groups except that more cirrhotics required dose reduction because of thrombocytopenia. In patients with cirrhosis, ALT levels may be a less appropriate endpoint in the measurement of response to therapy. We conclude that liver cirrhosis should not be a reason for excluding patients from therapy because both cirrhotic and fibrotic HCV patients benefit from IFN therapy not only by clearance of virus but by improvements in liver histology. (HEPATOLOGY 1999;30:271-276.)
Hepatitis C virus (HCV) is a leading cause of chronic liver disease in the United States. By 1996, it was the major indication for orthotopic liver transplantation. Currently, 8,000 to 10,000 deaths each year are a result of HCV, and by the year 2010, it is estimated that 30,000 to 40,000 patients will die annually of HCV-related chronic liver disease. Although the incidence of new cases of HCV is declining, an increasing number of HCV patients are identified with cirrhosis and will face its complications of liver failure and cancer. Existing literature suggests that interferon (IFN) therapy is less effective in cirrhotic patients, the group with the greatest need for medical rescue.
IFN therapy, alone or in combination with ribavirin, is currently the only approved treatment for patients with chronic HCV infection. Patients with chronic infection, who have varying degrees of inflammatory changes and fibrosis, may develop pronounced fibrotic changes, cirrhosis, and hepatocellular carcinoma if left untreated. Progression from the acute infection to cirrhosis may take several years, 1,2 and up to 20% of patients may develop cirrhosis after 20 years of infection. Some patients exhibit a benign stable course over decades, whereas others progress rapidly. Factors such as viral genotype, viral load, immune responsiveness, age at infection, alcohol consumption, male gender, or other host factors play a role in disease progression. Morbidity and mortality in chronic HCV infection is primarily associated with decompensated liver cirrhosis or hepatocellular carcinoma. Decompensated liver cirrhosis is a contraindication for IFN therapy resulting from the risk of severe complications. 6 However, many have suggested that even patients with compensated cirrhosis should be denied IFN therapy, 7 mainly because of the disappointing sustained response rates in patients with pre-existing cirrhosis. Response rates in earlier studies were defined biochemically as a normalization of serum alanine aminotransferase (ALT) concentrations. However, recently developed sensitive methods of detecting viral responses by measuring HCV RNA have become available. Because chronic HCV is a viral disease, the ultimate goal should be elimination of the virus. Serum ALT is a surrogate marker for liver cell damage, which may be a consequence of the viral infection, but elevation of serum ALT can also be caused by fatty liver, fibrosis, cirrhosis, other causes of hepatitis, or even by agents used to treat viral hepatitis, such as IFNs.