New Therapies, Markers and Therapeutic Targets in HCV Chronic Infection and HCV Extrahepatic Manifestations

A More than 180 millions of subjects in the world are infected by Hepatitis C Virus (HCV), and about 20% of them with HCV chronic infection progress to cirrhosis. Furthermore, numerous HCV extrahepatic manifestations have been reported in up to 74% of patients, as mixed cryoglobulinemia, lymphomas, rheumatic disorders, autoimmune thyroiditis, hypothyroidism, papillary thyroid cancer, and type 2 diabetes. Advances in understanding the HCV life cycle, and the inflammatory processes (involving a complex network of cytokines and chemokines) associated with HCV chronic infection, have led to substantial advancements in therapy. The combination of ribavirin and PEGylated interferon-a was the standard of therapy for HCV chronically infected patients in the last decades. However, interferon has limited effectiveness and is associated with severe adverse effects. Recently, direct-acting antivirals (DAAs) that act as inhibitors of N5SA, or polymerase, or protease have been shown to result in shorter duration of therapy, better efficacy and tolerance, with respect to ribavirin and PEGylated interferon-a. Circulating CXCL10 levels, and the interleukin(IL)-28B gene polymorphisms, are associated with the success of the therapy both with DAAs or ribavirin and PEGylated interferon-alpha. New DAAs targeting the HCV at various molecular levels have been developed to eradicate HCV. Moving to interferonfree therapies should offer new treatments for resistant HCV genotypes, and for ineligible patients or patients failing to respond to prior therapies. Many efforts have been made to understand the factors that are involved with clearance of HCV to personalize the therapy for each patient, with the aim to reduce side effects, increasing the sustained virologic response rate, and to prevent the progression of the disease.