The hepatitis C virus (HCV) is a small RNA virus belonging to the family flaviviridae and genus hepacivirus. The virion is approximately 50 nm in diameter and has an outer lipid associated envelop (E1 and E2) and inner nucleocapsid (Core). Within the nucleocapsid is a single molecule of single-stranded RNA of positive polarity approximately 9.5 kilobases in length. The RNA is transcribed into a large polyprotein that is subsequently cleaved into multiple polypeptides, labeled from the 5’ to 3’ end: core, envelope 1 and 2, and nonstructural proteins NS2, NS3, NS4 and NS5A and NS5B. The NS3 region encodes a viral helicase and protease. The NS5A region encodes a polypeptide that is essential for production and maintenance of the replicative complex. The NS5B region encodes a viral RNA dependent, RNA polymerase that is essential for replication. The NS3, NS5A and NS5B regions have been targeted with direct acting antiviral agents.
The initial agents used to treat chronic hepatitis C were interferon alfa, peginterferon and ribavirin. The antiviral activity of interferon and peginterferon is based upon their ability to stimulate interferon stimulated genes (ISGs) that have endogenous antiviral activities. Ribavirin is a nucleoside analogue that potentiates the effects of interferon against hepatitis C by as yet undefined mechanisms. Until 2010, the standard therapy of chronic hepatitis C was the combination of peginterferon and ribavirin given for 24 or 48 weeks. This combination led to sustained clearance of HCV and remission in disease in 40% to 50% of patients. Response rates were higher with certain HCV genotypes, so that response rates in patients with genotypes 2 and 3 were as high as 70% to 80%. Importantly, these remissions in disease have been shown to represent cure of the chronic viral infection, in that long term follow up demonstrated lack of HCV replication and resolution of disease activity in over 98% of patients. The shortcomings of peginterferon-ribavirin therapy were significant, most importantly the poor tolerance and side effects of this regimen. Thus, a high proportion of patients was intolerant or had contraindications to treatment. In 2010, three HCV-specific protease inhibitors were approved for use and introduced into practice: boceprevir, telaprevir and simeprevir. All three of these were specific to genotype 1 HCV and had little or no activity against genotypes 2 or 3 or the lesser common genotypes 4, 5 and 6. Triple therapy with peginterferon, ribavirin and a HCV-specific protease inhibitor (boceprevir, telaprevir or simeprevir) increased the response rate in patients with chronic hepatitis C, genotype 1 from 40%-45% to 65%-75%. A persistent difficulty, however, was the continued need to combine these agents with peginterferon and the considerable side effects which were worsened by these protease inhibitors.
An important advance in therapy of hepatitis C came in 2013 with the approval of an HCV specific RNA polymerase inhibitor, sofosbuvir. Sofosbuvir not only increased the response rate when combined with peginterferon and ribavirin, but also allowed for interferon-free treatment when combined with ribavirin, HCV protease inhibitors or a new class of agents that antagonized HCV NS5A activity. In 2014, all-oral HCV specific antiviral regimens were approved that yielded response rates in excess of 95% in patients with genotype 1. Furthermore, successful therapy required only 8 to 12 weeks of treatment in most patients and were extremely well tolerated. These all-oral regimens revolutionized therapy of hepatitis C, allowing treatment of virtually all patients regardless of severity of illness or co-morbid conditions with few side effects and durations of therapy of 8, 12 or 24 weeks. Other all oral regimens, including treatments for the less common genotypes of hepatitis C began to become available in 2015, 2016 and 2017. The several classes of agents that are combined in either a two-, three- or four-drug regimens include HCV RNA polymerase inhibitors (nucleoside and nonnucleoside), HCV NS5A antagonists and the HCV protease inhibitors. Several of these drug combinations have been formulated as single tablet or co-packaged regimens. These combination products made therapy easier to apply, but also resulted in the withdrawal of less successful agents, including boceprevir, telaprevir, daclatasvir, simeprevir and the four-drug combination of ombitasvir, dasabuvir, paritaprevir and ritonavir (Viekira Pak). Most currently used regimens are given for 8 to 12 weeks and yield response rates of 98% or more (Epclusa, Mavyret and Zepatier). Widespread application of these therapies to patients with chronic hepatitis C will likely decrease the morbidity and mortality of this disease and make significant inroads into decreasing the burden of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide.