Incidence of and Risk Factors for Hepatocellular Carcinoma in Hepatitis C Patients with Advanced Liver Disease: HALT-C Trial

By Liz Highleyman

Current standard combination therapy for chronic hepatitis C virus (HCV) infection using pegylated interferon plus ribavirin produces a cure, or sustained virological response (SVR), in about 50% of treated patients.

Researchers have therefore explored other therapies that might help slow, halt, or even reverse liver fibrosis progression and reduce the risk of cirrhosis and hepatocellular carcinoma (HCC) among individuals who do not clear the virus.

The HALT-C trial was designed to assess whether long-term, low-dose (90 mcg/week) pegylated interferon alfa-2a (Pegasys) maintenance monotherapy would improve outcomes in this population.

As previously reported, the study's primary analysis found no benefit to maintenance therapy in terms of reduced liver disease progression after 3.5 years, even though an interim analysis had indicated that low-dose interferon led to improvements in ALT level, HCV viral load, and necroinflammation.

As reported at the 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008) last month in Milan, the HALT-C investigators analyzed the HCC incidence rate and risk factors for liver cancer in the study population.

The 1043 participants were HCV positive, had bridging fibrosis (Ishak stages F3-F4; 59%) or cirrhosis (F5-F6; 41%) at baseline, and were non-responders to prior therapy with pegylated interferon plus ribavirin. The mean age was 50 years, 71% were men, and 72% were white.

Results

• During a median follow-up period of 4.2 years, 22 patients receiving maintenance therapy and 24 untreated control subjects were diagnosed with HCC (5 prevalent cases diagnosed within 12 months of enrollment were excluded).

• The cumulative 5-year incidence of HCC was 5.7% for treated patients and 5.1% for controls, not a statistically significant difference (P=0.91).

• Patients with cirrhosis had higher rates of HCC (7.2%) than those with bridging fibrosis (4.2%) (P=0.03).

• In a univariate analysis, the following factors were significantly associated with HCC (P<0.05):

• Older age;
• Lower BMI;
• Lower platelet count;
• Higher serum alkaline phosphatase (SAP);
• Higher des-gamma-carboxy prothrombin (DCP);
• Presence of esophageal varices;
• Decreased physical activity.

• Habitual tobacco smoking showed borderline significance (P=0.05).

• Sex, race, diabetes, alcohol consumption, type of treatment, and alfa-fetoprotein (AFP) levels were not significantly associated with HCC.

• A Cox proportional hazards model comprising age, sex, BMI, SAP, AST-platelet ratio index (APRI), DCP, esophageal varices, and smoking predicted that HCC development 5 years after study randomization would be:

• 0% for low-risk patients;
• 3.6% for intermediate-risk patients;
• 22% for high-risk patients.

Conclusion

"Maintenance [pegylated interferon] did not reduce the rate of HCC development in the HALT-C cohort," the investigators concluded.

"Although the incidence of HCC was substantial among those with bridging fibrosis, it was significantly lower than the incidence in those with cirrhosis," they added. "HCC development was significantly associated with older age, lower BMI, lesser physical activity, lower platelet count, higher DCP and SAP levels, and the presence of esophageal varices."

The researchers suggested that, "Modeling of risks based upon clinical and laboratory features can identify patients at highest risk of HCC who might warrant more intense surveillance."

Interestingly, AFP level did not show a significant association with HCC, which raises questions about its use as a common screening test for liver cancer.

Division Of Gastroenterology, University Of Michigan Medical Center, Ann Arbor, MI; Division Of Digestive Diseases And Nutrition, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Division of Gastroenterology, University of California Irvine, Irvine, CA; VA Long Beach Healthcare System, Long Beach, CA; Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO; Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA; New England Research Institutes, Watertown, MA.

5/16/08

Reference
AS Lok, LB Seeff, TR Morgan, and others. Incidence rates and risk factors associated with hepatocellular carcinoma (HCC) in patients with advanced liver disease due to hepatitis C: results of the HALT-C trial. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.