Dual role of IL-12 in the therapeutic efficacy or failure during combined PEG-Interferon-α2A and ribavirin therapy in patients with chronic hepatitis C

Abstract

Several efforts have been made to establish novel biomarkers with relevant predictive values to monitor HCV-infected patients under pegilated Interferon-α2A-(PEG-IFN-α2A)/ribavirin therapy. The aim of this study was to monitor the kinetics of HCV viral load, serum levels of pro-inflammatory/regulatory cytokines and leukocyte activation status before and after PEG-IFN-α2A/ribavirin therapy in 52 volunteers, including 12 chronic HCV patients and 40 controls. The HCV viral load, serum levels of cytokines (IL-8/IL-6/TNF-α/IL-12/IFN-γ/IL-4/IL-10) and the phenotype of peripheral blood leukocytes were evaluated before and after 4, 12 and 24 weeks following the PEG-IFN-α2A/ribavirin therapy. Our results demonstrated that sustained virological response-(SVR) is associated with early decrease in the viral load after 4 weeks of treatment. The presence of a modulated pro-inflammatory profile at baseline favors SVR, whereas a strong inflammatory response at baseline predisposes to therapeutic failure. Furthermore, a time-dependent increase on serum IL-12 levels in patients under treatment is critical to support the SVR, while the early predominance of IL-10 correlates to late virological relapse. On the other hand, a broad but unguided “cytokine storm” is observed in the non-responder HCV patients after 12 weeks of treatment. Corroborating these findings, monocyte/lymphocyte activation at baseline is associated with the non-responders to therapy whereas high CD8+ T-cell numbers associate with SVR. All in all, these data suggest that the baseline pattern of serum pro-inflammatory/regulatory cytokines and the immunological activation status of chronic HCV patients undergoing PEG-IFN-α2A/ribavirin therapy are closely related with the therapeutic response.