We have prospectively studied patients with type II cryoglobulinemia since 1985 to assess the efficacy of treatment with interferon-α at cumulative doses ranging from 234 to 849 MU. In the present study we retrospectively evaluated in this cohort parameters associated with complete response to therapy in 31 consecutive patients with type II cryoglobulinemia associated with hepatitis C virus (HCV) infection. Prevalence of complete response of cryoglobulinemia (disappearance of symptoms and signs of vasculitis and decrease of cryocrit below 10% of the initial value) was 62%, with a median response duration of 33 months and a range of 3 to 100 months. Three patients were putatively cured, as they remained in complete remission for more than 5 years off therapy. Eighteen patients (58%) had liver disease evidenced by histopathology and/or raised transaminase levels. Prevalence of normalization of transaminase levels was 100%, with a median response duration of 36 months. Relapse of hypertransaminasemia occurred in 100% and 8% of patients receiving less than or greater than 621 MU, respectively. By logistic regression analysis, the only pretherapy parameter that associated significantly (P = .0393) with complete response of cryoglobulinemia was the solitary anti-C22 (HCV core) antibody pattern, which was observed in 29% of patients. Association with older age and low cryocrit approached statistical significance (P = .06), while no significant correlations were found with serum IgM levels, duration of disease, HCV genotype, NS5a gene mutations, liver histology, HLA-DR phenotype, or WA cross-idiotype. Complete responses were also associated, on univariate statistical analysis, with low pretherapy HCV viremia. Responses were accompanied by decrease of viremia, of anti-HCV antibody levels and cryocrit. The usefulness of a high dose regimen is underscored by the higher rates of sustained responses of cryoglobulinemia and transaminase levels compared with previous studies.

SUMMARYA number of trials have demonstrated that IFN-is effective in chronic hepatitis C virus infection. It is known, however, that a number of chronic hepatitis C patients experience, after an initial response to IFN, disease reactivation or relapse (also called 'breakthrough') while IFN therapy is still ongoing. Since in a number of clinical conditions a significant correlation between development of antibodies to IFN and failure of therapy has been established, we addressed the possibility that the development of antibodies to IFN may take part in the relapse occurring in hepatitis C patients during recombinant IFN-(rIFN-) therapy. The prevalence of neutralizing (NA) and binding antibodies (BA) to rIFN-2 has been evaluated in 45 patients with chronic hepatitis C treated with rIFN-2a who first normalized aminotransferase (ALT) levels, and subsequently showed disease reactivation while on treatment. The presence of NA and BA was tested before therapy, during the response to IFN treatment, and at the time when ALT started to rise again to abnormal levels. The results showed that no patients had detectable antibodies to IFN before therapy and during the period of response to the therapy, while most of them (88 . 9%) developed NA and/or BA to IFN-2 concomitantly with disease reactivation. In particular, in 29 of the 45 patients (64 . 4%) ALT normalized on treatment and rose to abnormal levels when NA appeared in their serum, while in 11 of the 16 (68 . 8%) remaining patients the relapse was associated with BA development. The frequency of seroconversion in these patients is significantly higher than that observed in the control group. These data indicate that antibodies to IFN may be responsible for breakthrough in the majority of patients showing disease reactivation while rIFN-therapy is still ongoing.

SUMMARYIt is known that IFN therapy can induce the development of anti-IFN antibodies. In order to evaluate the biological and clinical significance of both neutralizing (NA) and non-neutralizing (binding) antibodies, 123 patients with chronic hepatitis C treated with recombinant IFN-fi were examined. Among them. 15 were positive for NA and 24 for binding antibodies. The kinetics of NA appearance show that, in general, they develop early during the first 3 months of treatment. Moreover. NA seem to be clinically relevant, since they may be responsible for non-responsiveness to treatment in 53% of patients who develop them. The evaluation of the clinical significance of binding antibodies is more difficult. They appear significantly earlier in non-responders than in responders, but no differences were observed in the overall percentage of seroconversion between responders and non-responders. Thus, it is not possible at the moment to establish their possible role in inducing non-responsiveness.