A randomized trial of prolonged high dose of interferon plus ribavirin for hepatitis C patients nonresponders to interferon alone.

Retreatment of chronic hepatitis C patients nonresponders to interferon (IFN) alone with the standard dose of IFN [3 million units (MU) thrice weekly (TIW)] plus ribavirin for 24 weeks has yielded low sustained virological response (SVR), averaging 8%. The aim of the present, open-labelled, randomized study was to evaluate the efficacy of IFN induction therapy followed by prolonged high dose of IFN plus ribavirin in nonresponders. One hundred and fifty-one patients were randomized to receive 5 MU daily of IFN alfa-2b (group 1, n = 73) or 5 MU TIW of IFN alfa 2b (group 2, n = 78) for 4 weeks followed by IFN (5 MU TIW) plus ribavirin (1000/1200 mg/daily) for 48 weeks in both groups. In an intention-to-treat analysis, the sustained virological response (SVR) at 24-week follow-up was 33 and 23% for group 1 and 2, respectively (P = 0.17). The overall SVR was 52 and 18% in patients with genotype 2/3 and 1/4, respectively. Among genotype 1/4 patients the SVR was 29 and 11% for age younger or older than 40 years. Compared with genotype 2/3 patients, the risk (95% confidence interval) of nonresponse to retreatment was 3.0-fold (1.17-8.0) in younger genotype 1/4 patients and 8.4-fold (3.0-23.29) in older genotype 1/4 patients. In conclusion these results suggest that retreatment with a reinforced regimen should be focused in nonresponder genotype 2/3 patients and younger genotype 1/4 patients, who are most likely to benefit. Induction therapy does not improve SVR.

Efficacy of prolonged 5 million units of interferon in combination with ribavirin for relapser patients with chronic hepatitis C.

summary. Retreatment of relapser patients with chronic hepatitis C with the standard dose of interferon (IFN) of 3 million units (MU) thrice weekly (tiw) plus ribavirin for 24 weeks achieves a sustained response in 30 and 73% of patients with genotype 1 and 2 or 3, respectively. The aim of this study was to evaluate the efficacy and safety of IFN alpha-2b induction therapy, followed by prolonged treatment with a high dose of IFN alpha-2b plus ribavirin in relapser patients. A total of 119 patients were randomized to receive IFN alpha-2b 5 MU daily (Group A: 59 patients) or IFN alpha-2b 5 MU tiw (Group B: 60 patients) for 4 weeks followed by IFN (5 MU tiw) and ribavirin (1000-1200 mg/day) for 48 weeks in both groups. The primary end point was hepatitis C virus (HCV)-RNA clearance at week 24 after the end of treatment. A sustained virological response (SVR) was achieved in 68 and 60% of Group A and B patients, respectively (P = 0.37). Logistic regression analysis identified genotype 2 or 3 as the only independent factor associated with response, whereas induction regimen and baseline viraemia levels did not affect the response. The overall SVR was 53 and 72% in patients with genotype 1 or 4 and 2 or 3, respectively. In conclusion, induction IFN therapy does not enhance the SVR to a 48-week combination therapy. Our study suggests that relapsed patients with genotype 1 or 4 may achieve significant response rates of approximately 50%, if retreated with 5 MU tiw IFN plus ribavirin for 48 weeks.

Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe.

The aim of this study was to evaluate the distribution and clinical significance of hepatitis C virus (HCV) genotypes in European patients with compensated cirrhosis due to hepatitis C (Child class A) seen at tertiary referral centres. HCV genotypes were determined by genotype-specific primer PCR in 255 stored serum samples obtained from cirrhotics followed for a median period of 7 years. Inclusion criteria were biopsy-proven cirrhosis, absence of complications of cirrhosis and exclusion of all other potential causes of chronic liver disease. The proportion of patients with types 1b, 2, 3a, 1a, 4 and 5 were 69%, 19%, 6%, 5%, 0.5% and 0.5%, respectively. Kaplan-Meier 5-year risk of hepatocellular carcinoma (HCC) was 6% and 4% for patients infected by type 1b and non-1b, respectively (P=0.8); the corresponding figures for decompensation were 18% and 7% (P=0.0009) and for event-free survival were 79% and 89% (P=0.09), respectively. After adjustment for baseline clinical and serological features, HCV type 1b did not increase the risk for HCC [adjusted relative risk=1.0 (95% confidence interval=0.47-2.34)], whereas it increased the risk for decompensation by a factor of 3 (1.2-7.4) and decreased event-free survival by a factor of 1.7 (0.9-3.10). In conclusion, type 1b and, to a lesser extent, type 2, are the most common HCV genotypes in European patients with cirrhosis. HCV type 1b is not associated with a greater risk for HCC, but increases the risk for decompensation by threefold in patients with cirrhosis.

Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep).

BACKGROUND: The effect of hepatitis delta virus (HDV) infection on the clinical course of cirrhosis type B is poorly defined. AIMS: To investigate the impact of HDV status on morbidity and mortality in cirrhosis type B. PATIENTS/METHODS: Retrospective cohort study of 200 Western European patients with compensated cirrhosis type B followed for a median period of 6.6 years. RESULTS: At diagnosis, 20% of patients had antibodies to HDV (anti-HDV); median age was lower in anti-HDV positive cirrhotics (34 v 48 years respectively). Kaplan-Meier five year probability of hepatocellular carcinoma (HCC) was 6, 10, and 9% in anti-HDV positive/HBeAg negative, anti-HDV negative/HBeAg negative, and anti-HDV negative/HBeAg positive cirrhotics respectively; the corresponding figures for decompensation were 22, 16, and 19% and for survival they were 92, 89, and 83% respectively. Cox regression analysis identified age, albumin concentration, gamma-globulin concentration, and HDV status as significant independent prognostic variables. After adjustment for clinical and serological differences at baseline, the risk (95% confidence interval) for HCC, decompensation, and mortality was increased by a factor of 3.2 (1.0 to 10), 2.2 (0.8 to 5.7), and 2.0 (0.7 to 5.7) respectively in anti-HDV positive relative to HDV negative cirrhotic patients. The adjusted estimated five year risk for HCC was 13, 4, and 2% for anti-HDV positive/HBeAg negative, anti-HDV negative/HBeAg negative, and anti-HDV negative/HBeAg positive cirrhotics respectively; the corresponding figures for decompensation were 18, 8, and 14% and for survival 90, 95, and 93% respectively. CONCLUSIONS: HDV infection increases the risk for HCC threefold and for mortality twofold in patients with cirrhosis type B.