Introduction

The hepatitis C virus (HCV) specific protease inhibitors are a class of agents that block the enzymatic activity of the HCV NS3 protease region that is necessary for protein processing required for viral replication. The combination of an HCV protease inhibitor with other antiviral agents with activity against HCV (such as peginterferon, ribavirin, and the direct acting agents that block the NS5A and NS5B regions of the virus) leads to marked decrease in HCV replication and eradication of the infection in a high proportion of patients with chronic hepatitis C. At least four HCV protease inhibitors have been approved for use in the United States (boceprevir, glecaprevir, grazoprevir, paritaprevir, simeprevir, telaprevir), and others were evaluated in clinical studies (asunaprevir, danoprevir, faldaprevir, sovaprevir, vedroprevir). The HCV protease inhibitors are approved for use only in combination with other specified anti-HCV agents. The initially approved protease inhibitors had activity only against HCV genotype 1, the most common genotype strain found in the United States and most of the world. Currently approved agents, in contrast, have broad specificity against multiple HCV genotypes.

Background

The hepatitis C virus is a small RNA virus that is a major cause of acute and chronic hepatitis in the United States as well as worldwide. A striking feature of HCV infection is that the majority of affected persons (50% to 70%) develop chronic infection, which can lead to chronic liver injury, cirrhosis, end stage liver disease and hepatocellular carcinoma. An estimated 3.2 million Americans (~1.2%) are chronically infected with HCV, and up to one-third of them will develop cirrhosis or liver cancer as a result of this virus infection. Various approaches to antiviral therapy of chronic hepatitis C have been developed, starting in the 1980s with interferon alfa, which was replaced in the 1990s by long acting pegylated forms of interferon (peginterferon) to which was added the oral nucleoside analogue, ribavirin. Between 2010 and 2015, several potent direct acting anti-HCV agents were developed and combinations of these were found to have marked activity against the virus. When given in combination for 8, 12 or 24 weeks, these regimens can result in eradication of the viral infection and cure of the liver disease in 90% to 100% of patients without the need for peginterferon. These oral direct acting agents target various components of HCV, most commonly the NS3 region (viral protease) and the NS5 region (viral polymerase), which includes a structural region (NS5A) and the active polymerase enzyme region (NS5B).

The HCV protease inhibitors block the activity of the viral encoded protease that is essential in the post-translational modification of the viral polypeptide that is cleaved into a series of structural and nonstructural (enzyme) regions. The HCV proteases that have been developed are polypeptide-like molecules, modified amino acids that act as competitive inhibitors of the viral serine protease, resembling the specific amino acid sequence that the protease cleaves. At least seven HCV protease inhibitors (-previrs) have been approved for use in the United States (boceprevir [2012], telaprevir [2012], simeprevir [2013], paritaprevir [2014]) and grazoprevir [2015], and several more are in various stages of preclinical and clinical development.

The HCV protease inhibitors are generally well tolerated, but common adverse events include headache, dizziness, nausea, diarrhea, abdominal discomfort and rash. Liver injury has been reported with several of the HCV protease inhibitors, particularly asunaprevir which has been linked to acute hepatitis with immunoallergic features, sometimes as a part of a generalized hypersensitivity reaction. The onset of injury was within 4 to 12 weeks and was usually accompanied by fever, rash and eosinophilia. Serum enzyme elevations are typically hepatocellular and jaundice is mild-to-moderate in severity. At least one fatal instance of liver injury has been reported with asunaprevir. While asunaprevir has generally been given in combination with daclatasvir and sometimes with ribavirin, the liver injury has convincingly been attributed to asunaprevir in most cases.

The eight HCV protease inhibitors described in LiverTox are listed below with specific links. Many of these have been voluntarily discontinued by the sponsor because of the availability of more effective and better tolerated regimens of oral direct acting agents for hepatitis C. Three of the withdrawn agents are discussed separately including boceprevir, simeprevir and telaprevir, as they were available individually and were generally combined with other available agents with activity against HCV. Paritaprevir is discussed only in relation to the other antiviral agents with which it was combined, either in the product known as Viekira Pak (dasabuvir, ombitasvir and raritaprevir with ritonavir: D-O-P/r) or as Technive (ombitasvir and paritaprevir with ritonavir: O-P/r) both of which were withdrawn in 2018. Grazoprevir is discussed only in relation to elbasvir with which it is combined in a product known as Zepatier. Glecaprevir is discussed only in relation to pibrentasvir with which it is combined in a product known as Mavyret.

HCV Protease Inhibitors

• Asunaprevir [approved in some countries but never in the US, subsequently withdrawn]
• Boceprevir [approved in the US in 2012, withdrawn 2015]
• Glecaprevir: Mavyret [approved in the US in 2017]
• Grazoprevir: Zepatier [approved in the US in 2016]
• Paritaprevir: Technive, Viekira Pak [approved in the US in 2015, withdrawn 2018]
• Simeprevir [approved in the US in 2013, withdrawn 2018]
• Telaprevir [approved in the US in 2012, withdrawn 2015]
• Voxilaprevir: Vosevi [approved in the US in 2017]

Drug Class: Antiviral Agents, Hepatitis C Agents