Long-term lymphoblastoid interferon-alpha therapy for non-cirrhotic chronic hepatitis C: An Italian multicentre study on dose and duration of LFN alpha treatment

The aims of the study were to evaluate the long-term efficacy and tolerabil ity of different doses of interferon-alpha (IFN alpha) and different durati ons 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 dairy. A total of 504 patients with non-cirrhotic chr onic hepatitis C enrolled in a multicentre study were consecutively assigne d to receive either 3 (255 patients) or 6 MU (249 patients) of lymphoblasto id IFNa 3 times a week (tiw). At the 12th month of therapy, patients with n ormal aminotransferase (AMT) in both groups were either given IFN for an ad ditional 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 wer e followed up for 12 months after discontinuing IFN. Of the 255 patients en rolled at 3 MU, therapy was stopped during the first 6 months in 36 patient s (14.1%) because of side effects, and in 24 (9.4%) because of lack of coop eration. 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 A MT after doubting the dose of IFN, but only 5 (6.6%) had a sustained respon se. Of the 119 patients with normal AMT, 40 discontinued IFN at the 12th mo nth (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 t he 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%) becaus e 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 7 3 patients, 55 accepted the daily regimen and 8 of them (14.5%) showed a su stained response. Of the 110 patients with normal AMT, 32 (29.1%), despite normalization of AMT, spontaneously discontinued IFN or reduced the dose be cause of a poor quality of life, while 78 continued with 6 MU until the 12t h month, when therapy was discontinued for 28 (schedule Al); 24 patients we re 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%) patie nts on schedule Al, 19/24 (79.2%) on schedule B1 and 19/26 (73.1%) on C1 st ill had normal AMT (p = NS). In an intention-to-treat evaluation, the susta ined 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 a fter 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% o f those with mild, and 33.3% with moderate or severe histological activity (p = NS). The rate of sustained response was lower in patients with genotyp e Ib (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 trea tment is more effective than a 12-month treatment in maintaining a biochemi cal response after discontinuation of IFN. In terms of efficacy, compliance and cost, 3 MU for 24 months appears to be the best treatment schedule. Th e benefit of doubling the dose of IFN for the 3 MU non-responders is slight , while the daily administration of 3 MU IFN seems to be more effective.