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FOR THE HEPATITIS INTERVENTIONAL THERAPY GROUP 10This international, randomized, active-controlled, parallel-group, double-blind dose-finding study compared peginterferon alfa-2b (PegIntron ™ ) to interferon alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three-times-weekly (TIW) interferon alfa-2b dose (3 MIU) or the once-weekly (QW) peginterferon alfa-2b (0.5, 1.0, or 1.5 g/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 peginterferon alfa-2b doses significantly (P < .042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow-up, as compared with interferon alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not doserelated above 1.0 g/kg peginterferon alfa-2b because of a higher relapse rate among patients treated with 1.5 g/kg peginterferon alfa-2b, particularly among patients infected with genotype 1. All 3 peginterferon alfa-2b doses decreased liver inflammation to a greater extent than did interferon alfa-2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, peginterferon alfa-2b maintained (0.5 g/kg) or surpassed (1.0, 1.5 g/kg) the clinical efficacy of interferon alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 g/kg peginterferon alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation. (HEPATOLOGY 2001;34:395-403.)The current international standard of care treatment for chronic hepatitis C, interferon alfa-2b in combination with ribavirin, has proven highly effective, achieving sustained viral eradication in approximately 40% of patients. 1,2 Interferon alfa-2b is administered as a fixed dose 3 times per week, but this schedule is burdensome to patients and may be associated with virologic breakthrough infections. 3,4 To maintain constant pressure on the virus and reduce the frequency of drug administration, a pegylated formulation of interferon alfa-2b has been developed. The advantages of protein pegylation are well established, having been described for many clinically applicable proteins. [5][6][7][8] Covalently attached polyethylene glycol (peg) delays protein clearance and reduces immunogenicity. 8 The resulting longer plasma half-life increases exposure to the drug and therefore may improve efficacy and allow for less frequent dosing. Less frequent dosing, in turn, may improve patient compliance and quality of life.Peginterferon alfa-2b (PegIntron ™ ), a protein-conjugate containing a single straight-chain peg with a molecular weight of 12,000 daltons and interferon alfa-2b in a 1:1 ratio, maintains its antiviral activity but has an approximately 10-fold longer plasma half-life than interferon alfa-2b in humans (29-34 hours vs. 3.6 ho...

Background and Aims Although the incidence of hepatocellular carcinoma (HCC) is increasing in the United States, data from large prospective studies are limited. We evaluated the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) cohort for the incidence of HCC and associated risk factors. Methods HCV-positive patients with bridging fibrosis or cirrhosis that did not respond to peginterferon and ribavirin were randomized to groups that were given maintenance peginterferon for 3.5 years or no treatment. HCC incidence was determined by Kaplan-Meier analysis and baseline factors associated with HCC were analyzed by Cox regression. Results 1,005 patients (mean age 50.2 years, 71% male, 72% white) were studied; 59% had bridging fibrosis and 41% had cirrhosis. During a median follow-up of 4.6 years (maximum 6.7 years), HCC developed in 48 patients (4.8%). The cumulative 5-year HCC incidence was similar for peginterferon-treated patients and controls, 5.4% vs. 5.0% (p=0.78), and was higher among patients with cirrhosis than those with bridging fibrosis, 7.0% vs. 4.1% (p=0.08). HCC developed in eight (17%) patients whose serial biopsies showed only fibrosis. A multivariate analysis model comprising older age, black race, lower platelet count, higher alkaline phosphatase, esophageal varices, and smoking was developed to predict the risk of HCC. Conclusions 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. Additional studies are required to confirm our finding of HCC in patients with chronic hepatitis C and bridging fibrosis.