Status of Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection and Remaining Challenges

Abstract

Chronic infection with hepatitis C virus is a major cause of liver disease and hepatocellular carcinoma worldwide. After the discovery of hepatitis C virus 3 decades ago, the identification of the structure of the viral proteins, combined with high-throughput replicon models, enabled the discovery and development of direct-acting antivirals. These agents have revolutionized patient care, with cure rates of more than 90%. We review the status of direct-acting antiviral therapies for hepatitis C virus infection and discuss remaining challenges. We highlight licensed compounds, discuss the potential to shorten therapy even further, and review different options for treatment failure and resistance. We also provide an overview of clinical experience with generic agents and evidence for their efficacy. Finally, we discuss the need for new drugs and outline promising targets for future therapies.

Keywords: Direct-Acting Antivirals; Hepatitis C; Resistance; Treatment Failure.

Figure 1.. Hepatocyte Targets and the HCV viral life cycle.

In a simplified model of the HCV cycle human hepatocytes, agents inhibit virus cell entry, replication, assembly, and release. HCV lipoviroparticles (LVPs) circulating in the blood bind to hepatocyte cell surface receptors such as heparan sulfate proteoglycans, low density lipoproteins (LDL), and SR-B1. HCV is transferred to the claudin 1 and CD81 co-receptor complex and occludin. Following clathrin-mediated endocytosis and uncoating, the positive strand virus RNA is translated into a single polyprotein that is processed into at least 10 proteins, which are anchored in the endoplasmic reticulum. Virus replication occurs in membranes derived from the endoplasmic reticulum (ER), called the membranous web, and requires cyclophilins and MIR122. The assembly process is induced by core protein trafficking to lipid droplets (LD). Morphogenesis of the virus is associated with synthesis of ver low densty lipoproteins (VLDL). New virions are transported and maturated through the Golgi before being released as LVPs. Assembly and egress requires factors such as apolipoproteins (APOB and APOE), diglyceride acyltransferase (DGAT), and microsomal triglyceride transfer protein (MTTP). Entry and replication inhibitors have been tested in clinical trials. (figure modified from ref .).