18 Months Interferon+Ribivarin Reduces Relapse Rate Compared to 6 Months Treatment

LOW RELAPSE RATE IN CHRONIC HEPATITIS C TREATED WITH 18 MONTHS INTERFERON-ALPHA AND RIBAVIRIN AS COMPARED TO 6 MONTHS COMBINATION THERAPY AND TO 18 MONTHS MONOTHERAPY. A BENELUX STUDY IN 300 PATIENTS.
     Johannes T Brouwer, Dept Hepatogastroenterology, Acad Hosp Rotterdam, Rotterdam Netherlands; Bettina E Hansen, Erasmus Univ Rotterdam, Rotterdam Netherlands; Solko W Schalm, Dept Hepatogastroenterology, Acad Hosp Rotterdam, Rotterdam Netherlands

This is an interesting study in patients with biopsy proven chronic hepatitis C, elevated LFTs and detectable HCV RNA from 25 centers in Belgium, Netherlands, and Luxembourg. The study purpose was to see if prolonging therapy to 18 months improves the relapse rate, and it did. As well, the suatained virologic response (SVR) was better after 18 months combination therapy compared to 6 months (43% vs 34%). Individuals with compensated cirrhosis had a better SVR than after 18 months combination treatment compared to individuals receiving 6 month treatment (57% vs 29%). Unfortunately, this study did not compare 18 to 12 months treatment to see if the additional 6 months would appreciably improve relapse and SVR rates.

Treatment of chronic viral hepatitis C (HCV) with Interferon is hampered by two biological phenomena: incomplete efficacy of interferon in blocking viral replication, resulting in a limited initial response, and incomplete immune-mediated removal of virus infected hepatocytes, leading to frequent relapses after treatment withdrawal. In this study, we aimed to improve the initial response rate by combining Interferon with Ribavirin, and to reduce the relapse rate by prolonging the treatment to 18 months.

TREATMENT REGIMENS

Patients were randomized to-

• 18 months combination therapy
  (IFNa2b 3 MU 3 times/week + RBV 1000-12-- mg/day),

• combination therapy for 6 months
  (IFNa2b 3 MU 3 times/week + RBV 1000-1200 mg/day), or

• monotherapy for 18 months
  (IFNa2b 3 MU 3 times per week).

STUDY DESIGN
 All 295 patients who received at least one dose of treatment were included in the intention to treat analysis. In addition, a per-protocol (pp) analysis was performed on the 238 patients who did not withdraw from treatment prematurely. A third analysis called 80% approximation was performed on individuals who took at least 80% of allocated dose & duration. The study was double blinded, placebo controlled. After 6 months, an envelope was opened disclosing the assigned duration (6 or 18 months). Treatment was withdrawn after 6 months in case of insufficient response (detectable HCV-RNA [sensitivity to 100 copies/ml NGI test] and ALT levels >1.5 x upper limit of normal).

PATIENT CHARACTERISTIC
70% genotype 1 (70% 18 months IFN+RBV, 66% IFN+RBV 6 mo. 75% IFN monotherapy 18 mos.); 53% HCV-RNA >2 million copies/ml. 50-55% had >3 million copies/ml HCV-RNA; male: 63% IFN+RBV 18 mos and 6 mos, 46% IFN monotherapy 18 mos. Age: about 46 years in all 3 groups.

RESULTS
During the first 6 months 5% of patients on mono- and 10% of those on combination therapy withdrew due to side effects or incompliance. Of the patients allocated to 18 months therapy, 10% on combination therapy and 28% on monotherapy stopped after the initial 6 months due to insufficient response, and 13% on combination and 20% on mono therapy withdrew from treatment before month 18.