Rheumatology to hepatology cross talk: An evidence based update on the treat to target strategy in hepatitis-C related extrahepatic autoimmune syndromes

Hepatitis C virus (HCV) is a universally identified major epidemiological health problem with an estimated reservoir of almost 200 million or 3% of the global population. In the year 2013, the WHO declared viral hepatitis as “a leading cause of death worldwide 1.46 million deaths, a toll higher than that from HIV, tuberculosis or malaria, and on the increase since 1990” with more than 90% of these deaths being related to the sequelae of the infection with either forms of hepatitis viruses (HBV-HCV). HCV is classically a hepatotropic virus with the liver cells providing the primary bed for viral replication with clinical evidences supporting an additionally significant viral lymphotropism. HCV is a linear single stranded RNA retrovirus, member of the genus hepacivirus of the flaviviridae family. It is a small virus comprised of a positive-sense 9.6 Kb single-stranded RNA genome embodied in a double layered glycosylated protein envelope, the viral genome protein is basically made up of structural and non-structural proteins. The viral enzymes- NS2-3 and NS3-4A proteases, NS3 helicase and NS5BRdRp— are essential contributors for HCV replication, the HCV serine protease NS3, and its cofactor NS4A, constitute a complex that directs polyprotein cleavage. HCV infected individuals are capable of producing 10-13 trillion virions/day with the majority coming primarily from viral replication within the hepatocytes with an unpredictable yet significant extrahepatic contributions that may lead to the development and modulation of systemic extrahepatic disease. The use of conventional antiviral therapy PEGylated interferon (Peg-IFN) and ribavirin (RBV) practically contributed to the disease burden with less than a 50% sustained viral response rates. A major challenge for interferon therapy comes from the Hepatitis C viral genome itself. The challenging draw backs to interferon based regimen in patients with autoimmune extrahepatic disease EHD demanded an evidence based revisit to the classic recommendations on the use of conventional antivirals with immunomodulatory drugs in this indication. It wasn’t until spring of 2011 when the FDA approved the first two directly acting antiviral drugs that the hepatologists experienced a revolutionary shift in Hepatitis C virus (HCV) treatment paradigm. Directly acting antiviral drugs (DAAs are drugs that target some of the main molecular components of HCV, including NS3/4A protease (first and second generation protease inhibitors), NS5B polymerase (nucleoside and non-nucleoside analogs) and NS5A protein. The recent era of DAAs established an additional need to modify treatment regimens in extrahepatic disease. In the year 2017 the international study group of HCV extrahepatic disease published evidence based recommendations on the use of antivirals for control of EHD. The treatment armamentarium in chronic HCV viremia with and without extrahepatic disease has experienced a revolution with the establishment of directly acting antiviral drugs. Interferon free directly acting antiviral drug regimens are currently considered as standard of care in patients with extrahepatic disease. Longitudinal studies are further requested to assess the unmet needs including drugs addressing other potential targets in the viral genome and life cycle.