Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon

Abstract

Background: In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain.

Methods: We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 microg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points.

Results: We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81 to 1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07).

Conclusions: Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164.)

Figure 1. Enrollment, Randomization, and Follow-up of Study Participants

Patients were enrolled either in the lead-in cohort of patients who underwent another course of antiviral treatment with peginterferon and ribavirin within the study or in the express cohort of patients who were initially treated outside the study. They were then randomly assigned to either the treatment or the control group and were followed up to monitor for clinical outcomes and histologic evidence of progression of liver disease.

Figure 2. Kaplan–Meier Analysis of Time to the Primary Outcome and the First Clinical Outcome

Panel A shows the time to the first primary outcome (death, hepatic decompensation, hepatocellular carcinoma, or histologic progression) according to group assignment (treatment or control). The large steps in the plot reflect liver biopsies performed for the study. Panel B shows the time to the first clinical outcome (death, hepatic decompensation, or hepatocellular carcinoma) according to group assignment and with patients stratified according to the presence or absence of cirrhosis.

Figure 3. Changes in Dose or Discontinuation of Peginterferon among Patients in the Treatment Group

The figure shows the proportion of patients who had a clinical outcome and stopped treatment, received a full dose of peginterferon (90 μg per week), decreased their dose of peginterferon (to either 45 to 89 μg or 22 to 44 μg per week), withdrew from the study, or stopped treatment but continued to be followed for assessment of outcomes.