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In therapy with standard interferon and ribavirin, five independent risk factors (RF) were predictive of relapse. The aim was to prospectively validate an a la carte regimen of pegylated interferon (PEG-IFN) alpha2b 1.5 microg/kg and ribavirin 11 mg/kg [PEG-IFN-ribavirin (PEG-IFN-R)], taking into account these five risk factors in order to determine whether to continue an additional 24 weeks of treatment in polymerase chain reaction (PCR) negative patients after 24 weeks. Treatment was stopped after 24 weeks in PCR positive patients. The same regimen was continued in PCR negative patients for an additional 24 weeks if patients had two or more RF. FibroTest and ActiTest assessed the impact of treatment on the histological features from baseline to end of follow-up. A total of 96 patients were included; 84 (87.5%) had at least two RF and 12 (12.5%) had no or one RF. A total of 70 patients were sustained virologic response (SVR; 73%), 19 were nonresponders (20%) and seven were relapsers (7%). The SVR in genotypes 2 or 3 was 85% (34/40) vs 64% in other genotypes (36/56; P = 0.02). There was a decrease (P = 0.003) in fibrosis as estimated by FibroTest, from 0.38 +/- 0.03 (mean +/- SE) at baseline to 0.33 +/- 0.03 at the 12-week follow-up, and a decrease in activity as estimated by ActiTest, from 0.49 +/- 0.02 to 0.19 +/- 0.03 (P < 0.0001). Improvement in activity was already significant at 12 weeks, even in virologic nonresponders. This study confirms that an a la carte regimen which takes into account not only genotype but also baseline viral load, fibrosis stage, gender and age, is efficient for the PEG-IFN-R combination. It achieves a 73% SVR and a significant decrease in fibrosis and activity as estimated by biochemical markers.

Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.

Background/aim: Fifty percent of patients infected with hepatitis C virus (HCV) show no response to alpha-interferon, and no alternative therapy has thus far proven to be effective. Therapeutic combination with ribavirin and alpha-interferon has shown promising results in naive patients and in relapsers, but based on limited series, it was reported to be inefficient in non-responders. The aim of our study was therefore to explore and compare, in a randomized trial, the tolerance and potential efficacy of alpha-interferon alone with a sequential combination of ribavirin and the same alpha-interferon regimen in those patients., Methods: Sixty-four non-responder patients were randomized in the alpha2b-interferon group (a 6-month course at a dosage of 6 MU followed by a 6-month course of 3 MU three times weekly subcutaneously) and 62 in the "combination" group (sequential combination of the same alpha2b-interferon therapy preceded by a 2-month course of ribavirin which was then associated for 2 months with alpha2b-interferon at a daily dosage of 1.0 or 1.2 g)., Results: Treatment withdrawal was necessary for six patients from the alpha-interferon and eight patients from the combination group. Normalization of aminotransferase activities was significantly more frequent after the 4-month course of ribavirin with 2 months of interferon than after 2 months of interferon alone (52.8 vs. 26.2%, p<0.01), but this difference was not maintained after ribavirin withdrawal. Disappearance of serum HCV RNA (PCR) was significantly more frequent at the end of treatment in the combination group (24.5 vs. 7.7%, p=0.02), but did not differ 6 months after the end of therapy (9.8 and 8.3%, respectively). The long-term response was not associated with liver status (cirrhosis vs. absence of cirrhosis) or genotype. Mean viremia was significantly lower in long-term responders than in non-responders or relapsers in both groups (p<0.001 for the interferon group and p<0.05 for the combination group), but the large extent of viral load precluded reliable prediction. The pre- and post-treatment hepatitis activity index did not differ between the two groups. While a crude histopathological improvement in the hepatitis activity index for a given patient was more frequently observed in the combination group (69.2 vs. 35.9%, p<0.01), improvement as defined by a decrease of at least 2 in the hepatitis activity index was significant only for lobular necrosis and degeneration., Conclusions: This study demonstrates the efficacy of the combination of ribavirin/alpha-interferon in non-responders. Indeed, (i) it is fairly tolerated; (ii) it increases the rate of the initial biological response, and of the virological response by decreasing breakthrough, though this benefit is not sustained; and (iii) it induces a significant histological improvement in necrosis. A simultaneous and prolonged combination of ribavirin/alpha-interferon should be further evaluated in non-responders.

Aim: To assess the benefit risk ratio of interferon and ribavirin in the treatment of patients with post hepatitis C cirrhosis we summarize the spontaneous over mortality of this disease, and made an overview of the randomized trials and of other controlled studies., Results: In comparison to controls, patients with post hepatitis C cirrhosis have a 17 fold increase risk of dying from a liver disease that a control population, and a 6 fold increase from primary liver cancer. In France the hepatitis C epidemic which start in the sixties explains now the observed dramatic increase in mortality by primary liver cancer, both in men and women. Meta-analysis of randomized trials and controlled retrospective studies showed that interferon treatment is associated with a significant increase in ALT response at the end of the treatment, with a decrease in hepatocellular incidence as well as a decrease in mortality in comparison with controls. Very few data are published concerning ribavirin alone or in combination with interferon in patients with cirrhosis. Preliminary data suggest that this combination during 48 weeks permit to obtain in patients with compensated cirrhosis 20% of sustained virological response. The safety was acceptable but patients with low initial blood cells count must be carefully followed. In conclusion this overview clearly demonstrates a benefit-risk ratio in favor of treatment in patients with post hepatitis C cirrhosis by interferon.

Chronic hepatitis C is a major health care problem throughout the world. The disease may progress to cirrhosis, with complications such as hepatocellular carcinoma. The usual primary goal of therapy is viral eradication, as patients with long-term remission are generally regarded as unlikely to develop cirrhosis or hepatocellular carcinoma. Another primary goal should be the reduction in liver fibrosis progression. Interferon-alpha (IFN-alpha) is the only drug approved for the treatment of hepatitis C in Europe and North America. Its effectiveness appears to be related to dose and duration of therapy. The best efficacy/risk ratio seems to be in favour of 3 million units (MU) IFN-alpha three times per week on a 12-month schedule. With this regimen, a sustained alanine aminotransferase (ALT) response is achieved in nearly 35% of patients. Ribavirin has emerged as potentially the second most effective drug. While it appears unsatisfactory when given alone, it seems much more effective in combination with IFN. Combining them seems to exert a synergistic effect between the two drugs and sustained remission might be achieved in nearly 50% of patients with combination therapy. Controversy persists concerning the long-term benefit of therapy in transient responders and non-responders. It is possible that IFN therapy, in comparison to natural history, might reduce liver fibrosis progression and prevent hepatocellular carcinoma, even in non-responders, and have greater efficacy if used in long-term treatment. Whatever the treatment schedule, prolonged viral eradication may not be achieved in all patients and new drugs should be sought to improve the results of therapy.

To determine adverse events of ribavirin in the treatment of chronic hepatitis C, 41 patients (18 with cirrhosis), treated with ribavirin at an initial dose of 600-1200mg day(-1), were analysed retrospectively (six patients were treated twice because adverse effects during the first treatment necessitated cessation of ribavirin). Indications for ribavirin included a contraindication (n = 15) an intolerance (n = 11) or a non-response (n = 15) to interferon (IFN). Ribavirin was combined with IFN 3 million units (MU) three times weekly for 15 patients and with azathioprine for six patients (five of whom were transplant patients). No cirrhotics and only one patient treated with ribavirin + IFN received azathioprine. The mean duration of treatment was 5 months (range 1-18 months). Sixteen of 47 treatments (34%) with ribavirin were stopped: four because of vomiting (8.5%), two for psychiatric disorder, one for dry cough, one for an unrelated cause, and eight (at 1-2 months) because of a fall in the level of haemoglobin (Hb) of 4.6 g dl(-1) (range 2.7-5.9 g dl[-1]); however, according to the rules of international protocol, we would have expected only four treatments (two in patients receiving azathioprine) with Hb < 8.5 g dl(-1) to be stopped. The decrease in Hb level occurred more slowly in patients treated with IFN plus ribavirin than in patients treated with ribavirin alone and was of lower clinical significance in patients with cirrhosis than in patients without cirrhosis. After exclusion of patients receiving azathioprine, there was no significant difference in the fall of Hb level between cirrhotic and non-cirrhotic patients and between patients treated with IFN plus ribavirin and patients treated with ribavirin alone. Interestingly, the platelet count of patients treated with IFN plus ribavirin fell less than in patients treated with IFN alone. The most important and expected adverse event associated with ribavirin was haemolysis. Anaemia < 8.5 g dl(-1), requiring cessation of ribavirin therapy, was present in 9% of patients and was worsened by azathioprine. Abdominal discomfort and dry cough were other, potentially important, clinical adverse events found in our study.