Antiviral treatment of hepatitis C

Abstract

Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of cirrhosis and hepatocellular carcinoma. Although they are associated with toxicities and low sustained viral response rates, interferon alfa and ribavirin have been the mainstay of treatment until recently. New direct acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase) are now becoming available. The NS3/4A inhibitor simeprevir and NS5B inhibitor sofosbuvir have recently been licensed and can reduce the length of antiviral treatment, improve response rates, and allow for interferon-free regimens for some HCV genotypes. Several other newer direct acting antivirals have shown promise in clinical studies and are likely to be licensed soon. These agents seem to facilitate the use of shortened courses of combination interferon-free therapy, which are associated with high (>95%) sustained response rates and relatively few toxicities. These regimens have also been successful in patients who were previously difficult to treat, including those with cirrhosis, HIV coinfection, and those who have undergone liver transplantation. The high cost of these agents may be the biggest challenge to their implementation worldwide.

Fig 1

Life cycle of hepatitis C virus (HCV). HCV interacts with co-receptors on hepatocytes, which results in its endocytosis, then fusion of the virus with the endosome and uncoating of its RNA. This RNA is translated by host ribosomes into a polyprotein, which is cleaved by host and virally encoded proteases into 10 structural and non-structural proteins. The non-structural proteins form a replication complex on a “membranous web” derived from the endoplasmic reticulum that replicates HCV RNA. This in turn assembles with viral structural proteins in the Golgi into infectious viral particles, which are exocytosed from the cell

Fig 2

Hepatitis C virus (HCV) genome, protein products, and inhibitors. The HCV genome encodes three structural and seven non-structural proteins. Protein functions are listed in red. Direct acting antivirals can inhibit three major non-structural proteins—the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase. Direct acting antivirals in clinical use or development are listed in black. Those approved by the FDA are highlighted in bold