Direct-acting antivirals for the treatment of hepatitis C virus infection
- Paul J Pockros, MD
Paul J Pockros, MD
- Director, Liver Disease Center, Scripps Clinic
- Clinical Director of Research, Scripps Translational Science Institute
A greater understanding of the hepatitis C virus (HCV) genome and proteins has enabled efforts to improve efficacy and tolerability of HCV treatment. Notably, this has led to the development of multiple direct-acting antivirals (DAAs), which are medications targeted at specific steps within the HCV life cycle (figure 1). DAAs are molecules that target specific nonstructural proteins of the virus and results in disruption of viral replication and infection. There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target. The four classes are nonstructural proteins 3/4A (NS3/4A) protease inhibitors (PIs), NS5B nucleoside polymerase inhibitors (NPIs), NS5B non-nucleoside polymerase inhibitors (NNPIs), and NS5A inhibitors .
This topic reviews the mechanism of action, pharmacology, and spectrum of use of these various agents. Other important issues related to the treatment of chronic HCV infection, including patient evaluation, selection of treatment regimen, and other management issues are discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection" and "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults" and "Overview of the management of chronic hepatitis C virus infection".)
Many direct-acting antivirals are in various stages of development and are not yet available. These are discussed in detail elsewhere.
VIRAL LIFE CYCLE AND REPLICATION
The main targets of the direct-acting antiviral agents are the HCV-encoded proteins that are vital to the replication of the virus (figure 1). The infectious viral structure is comprised of envelope glycoproteins in a lipid bilayer that contain the viral core protein and RNA . After cell entry, the viral RNA is translated through host machinery into a polyprotein, which is cleaved during and after translation by both host and viral-encoded proteases into 10 mature viral proteins, including a number of nonstructural (NS) proteins. One of the viral proteases involved in this post-translational processing is a heterodimeric complex of the NS3 and NS4A proteins (NS3/NS4A). NS3 possesses the proteolytic activity and NS4 is a membrane protein that acts as a cofactor. Synthesis of new viral RNA occurs in a highly structured replication complex that consists of NS3, NS4A, NS4B, NS5A, and NS5B. NS5B is an RNA-dependent RNA polymerase that is essential for viral replication. NS5A has a presumptive role in the organization of the replication complex and in regulating replication. It is also involved in assembly of the viral particle that is released from the host cell.
Direct-acting antivirals are inhibitors of the NS3/4A protease, the NS5A protein, and the NS5B polymerase.
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- VIRAL LIFE CYCLE AND REPLICATION
- NS3/4A PROTEASE INHIBITORS
- NS5A INHIBITORS
- NS5B RNA-DEPENDENT RNA POLYMERASE INHIBITORS
- Nucleot(s)ide polymerase inhibitors (NPIs)
- - Sofosbuvir
- Non-nucleoside polymerase inhibitors (NNPIs)
- - Dasabuvir
- FIXED-DOSE COMBINATIONS
- Ombitasvir-paritaprevir-ritonavir with or without dasabuvir