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The aims of the study were to evaluate the long-term efficacy and tolerability of different doses of interferon-alpha (IFN alpha) and different durations of treatment in chronic hepatitis C by comparing 3 or 6 mega units (MUs) three times weekly given for either 12 or 24 months, and the possibility of obtaining a response in non-responder patients by increasing the dose or by administering IFN daily. A total of 504 patients with non-cirrhotic chronic hepatitis C enrolled in a multicentre study were consecutively assigned to receive either 3 (255 patients) or 6 MU (249 patients) of lymphoblastoid IFN alpha 3 times a week (tiw). At the 12th month of therapy, patients with normal aminotransferase (AMT) in both groups were either given IFN for an additional 12 months with an unmodified or halved dose, or else discontinued therapy. For patients with unmodified AMT levels after 6 months of therapy, the IFN dose was doubled in the 3-MU group, while it was administered at 3 MU daily in the 6-MU group. When no improvement was achieved, therapy was discontinued; otherwise it was prolonged until the 18th month. Patients were followed up for 12 months after discontinuing IFN. Of the 255 patients enrolled at 3 MU, therapy was stopped during the first 6 months in 36 patients (14.1%) because of side effects, and in 24 (9.4%) because of lack of cooperation. Of the remaining 195 patients at the 6th month of therapy, 119 (61%) had normal and 76 (39%) unmodified AMT levels; 14 of the 76 normalized AMT after doubling the dose of IFN, but only 5 (6.6%) had a sustained response. Of the 119 patients with normal AMT, 40 discontinued IFN at the 12th month (schedule A), 39 remained at 3 MU tiw (schedule B) and 40 were given a dose of 1.5 MU tiw (schedule C) for an additional 12 months. At the end of follow-up, 23/40 (57.5%) patients in schedule A, 31/39 (79.5%) on schedule B and 29/40 (72.5%) on schedule C still had normal AMT (A vs. B p = 0.04). In an intention-to-treat analysis, the sustained response rate for patients enrolled at 3 MUs, including the 5 initial non-responders, was 34.5%. Of the 249 patients enrolled at 6 MU, therapy was discontinued during the first 6 months for 39 (15.7%) because of side effects, and for 27 (10.8%) because of lack of cooperation. Of the remaining 183 patients at the 6th month of therapy, 110 (60%) had normal and 73 (40%) unmodified AMT levels. Of the 73 patients, 55 accepted the daily regimen and 8 of them (14.5%) showed a sustained response. Of the 110 patients with normal AMT, 32 (29.1%), despite normalization of AMT, spontaneously discontinued IFN or reduced the dose because of a poor quality of life, while 78 continued with 6 MU until the 12th month, when therapy was discontinued for 28 (schedule A1); 24 patients were given an unmodified dose (schedule B1) and 26 a halved dose (schedule C1) for an additional 12 months. At the end of follow-up, 18/28 (64.3%) patients on schedule A1, 19/24 (79.2%) on schedule B1 and 19/26 (73.1%) on C1 still had normal AMT (p = NS). In an intention-to-treat evaluation, the sustained response rate for patients enrolled at 6 MU, including the 8 from the daily treatment, was 25.7% (64/249). HCV viraemia was undetectable 1 year after discontinuation of IFN in 72.6% of patients with a sustained response. Sustained response was observed in 36.4% of patients with minimal, 46.6% of those with mild, and 33.3% with moderate or severe histological activity (p = NS). The rate of sustained response was lower in patients with genotype 1b (23.6%) than in those with genotype 2a (67.8%, p = 0.002) or genotype 3 (50%, p = 0.03), irrespective of the histological activity. In conclusion, 6 MU IFN alpha are no more effective than 3 MU in inducing a sustained response in treatments of both 12 and 24 months. A 24-month treatment is more effective than a 12-month treatment in maintaining a biochemical response after discontinuation of IFN. In terms of efficacy, compliance and cost, 3 MU for 24 months app