Back HCV Treatment Long-term Maintenance Interferon Does Not Prevent Hepatocellular Carcinoma among Chronic Hepatitis C Patients in HALT-C Study

Long-term Maintenance Interferon Does Not Prevent Hepatocellular Carcinoma among Chronic Hepatitis C Patients in HALT-C Study

Current standard therapy for chronic hepatitis C virus (HCV) infection using pegylated interferon plus ribavirin produces a sustained virological response (SVR) in about half of treated patients, and researchers have explored other therapies that might slow, halt, or even reverse liver fibrosis progression and reduce the risk of cirrhosis and hepatocellular carcinoma (HCC) in people who do not clear the virus.

The HALT-C trial was designed to assess whether long-term, low-dose pegylated interferon maintenance monotherapy would improve outcomes in this population. While an interim analysis indicated that low-dose interferon produced improvements in ALT levels, HCV viral load, and necroinflammation, the study's primary analysis found no benefit with regard to reduced liver disease progression after 3.5 years.

HALT-C researchers also conducted several secondary analyses looking at specific aspects of disease progression. In the present study, published in the January 2009 issue of Gastroenterology, Anna Lok from the University of Michigan Medical Center and colleagues analyzed the HCC incidence rate and risk factors among HALT-C participants. (Results from a shorter duration of follow-up were previously presented at the April 2008 annual meeting of the European Association for the Study of the Liver [EASL]).

Briefly, HALT-C included more than 1000 participants with chronic hepatitis C and bridging fibrosis (Ishak stages F3-F4; 59%) or cirrhosis (stages F5-F6; 41%) at baseline. Those who did not achieve sustained response to standard combination therapy with pegylated interferon plus ribavirin were randomly assigned to receive either low-dose (90 mcg per week) pegylated interferon alfa-2a (Pegasys) monotherapy for 3.5 years or else no ongoing treatment. Most study participants (71%) were men, the mean age was 50 years, and 72% were white.


  • Over a median 4.6 years of follow-up (maximum 6.7 years), 48 out of 1005 patients (4.8%) developed HCC
  • The cumulative 5-year HCC incidence rate was similar in the maintenance therapy and untreated observation arms, at 5.4% and 5.0%, respectively (P = 0.78).
  • As expected, HCC was more likely to occur in patients with cirrhosis than in those with bridging fibrosis (7.0% vs 4.1%, respectively; P = .08).
  • However, HCC developed in 8 patients (17%) whose serial biopsy specimens showed only simple (non-bridging) fibrosis.
  • In a multivariate analysis, a model including older age, black race, lower platelet count, higher alkaline phosphatase level, presence of esophageal varices, and tobacco smoking was developed to predict the risk of HCC.
  • Over 5 years, the researchers calculated that the expected rate of HCC would be < 1% for patients the model classified as low-risk, about 5% for those classified as intermediate-risk, and approximately 20% for those considered high-risk.

Based on these results, the study investigators concluded, "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."

In an accompanying editorial, Morris Sherman from the University of Toronto presented an overview of HCC epidemiology in individuals with chronic hepatitis C.

He noted that the incidence HCC was "unexpectedly high" in HALT-C participants who had advanced fibrosis but not yet cirrhosis. Until this report, he wrote, "HCC developing in a noncirrhotic hepatitis C patient was considered uncommon."

The HALT-C findings led to an algorithm that can identify patients at greatest risk who can then be targeted for surveillance. But, Sherman stated, "the intensity of surveillance in the United States has to increase to a level that exists elsewhere in the world before HCC surveillance will result in mortality reduction."

Recent data suggest that regular surveillance (e.g., with ultrasonography) every 6 months is associated with better survival than every 12 months, since the shorter interval improves the chances of detecting small tumors at an earlier, more treatable stage.



AS Lok, LB Seeff, TR Morgan, and others. Incidence of Hepatocellular Carcinoma and Associated Risk Factors in Hepatitis C-Related Advanced Liver Disease. Gastroenterology 136(1): 138-148. January 2009. (Abstract).