Could the presence of Mixed Cryoglobulinemia influence the outcome of standard peg-IFN plus ribavirin anti-HCV therapy?

Background. HCV infection is closely related to the development of mixed cryoglobulinemia (MC). Although MC is present in the majority of HCV patients, only a minority, ranging from 5% to 30% in different studied manifests a MC syndrome (MCS). The possible influence of MC/MCS on the results of anti-HCV treatment is still matter of debate. Being MC/MCS an elusive condition (i.e., the diagnosis of MCS is not well standardized and the MC impossible to determine in stored samples), the possibility that retrospective studies may include MC/MCS patients in the MC-negative control group cannot be ruled out. The aim of this study was to prospectively analyze whether the presence of MC influences the response to the standard peg-IFN+ribavirin therapy (SoC) in HCV+ patients. Patients. 425 HCV-positive patients were consecutively treated with SoC PegIFN and ribavirin therapy and were evaluated for the enrollment. These included: 121 (28.5%) patients with MCS (HCV+MCS), 132 (31.1%) with MC without MCS (HCV+MC) and 159 (37.3%) without MCS nor MC or other autoimmune/lymphoproliferative disorders (HCV). 13 patients (3.1%) resulted of uncertain classification and were excluded from the study. MC/MCS data and virological response were regularly assessed during treatment and in a 6-month post-treatment follow-up. The IL28B genotype was detected by allele-specific real-time PCR. Results. The univariate statistical analysis showed that HCV+MCS group was associated with older age (p=0.0151), more severe liver disease (p=0.02), female sex (p<0.00005) and re-treatment (p=0.0168). No differences were observed in viral genotype distribution, pre-treatment viral load, IL28B allele distribution. During treatment, no significant differences were observed for both RVR and EVR. However, when SVR was considered, a statistically significant difference was observed between HCV+MCS vs. HCV patients (p=0.012) and also HCV+MC vs HCV (p=0.045). The logistic regression analysis showed that HCV+MCS was an independent risk factor of non-response (O.R. 2.48; CI 1.24-6.3; p=0.013). Conclusions. In the present study, for the first time, the virological response of a large number of HCV+ patients with and without MC/MCS was prospectively studied. Results strongly suggest that MCS represents a negative prognostic factors of response to anti-HCV SoC. This does not appear related to a significantly modified early viral kinetics. It may be hypothesized that the higher prevalence of persisting infection in lymphatic reservoirs, previously shown in MCS+ vs. MCS- patients, plays a role.