Treating hepatitis C: current standard of care and emerging direct‐acting antiviral agents

Abstract

Summary. During the late 1990s and early 2000s, major advances were made in the treatment of patients with chronic hepatitis C virus (HCV) infection. Interferon, combination interferon plus ribavirin (RBV) and pegylated interferon plus RBV increased sustained virologic response (SVR) rates from ~5% to ~40-80%, depending on the genotype of HCV infection. Advances in molecular biology have allowed investigators to begin to understand the mechanisms of HCV infection and replication. Advances in understanding of viral kinetics have provided tools to identify patients who are most likely to attain SVR. With the advances in the science of HCV infection, the first part of the 21st century has seen the development and early introduction of a number of direct-acting antiviral (DAA) drugs. These novel medications interfere with critical steps in HCV replication and have the potential to significantly increase SVR rates. This article will review the key elements of HCV replication and evaluate the various classes of new and investigational DAA that have the potential to create a revolution in the management of patients with chronic hepatitis C.

Hepatitis C virus resistance to new specifically-targeted antiviral therapy: A public health perspective

“…These promising results were reproduced with other PIs, such as Telaprevir (VX-950), Boceprevir [11,12] . Two of these have been approved recently for clinical use: Telaprevir and Boceprevir.…”

“…NS5A has been linked to interferon sensitivity, and includes a variable region (V3), and PKR and zinc binding domains [26] . NS5A replication complex inhibitors undergoing clinical trials include Daclatasvir (BMS-790052, Bristol-Myers Squibb) and ACH-2928 (Achillion) [12] . Daclastavir is a potent oral NS5A inhibitor, studied in combination with the NS3 PI Asunaprevir alone (n = 11), or plus Peg-IFNα + RBV (n = 10) for 24 wk in genotype-1 infected patients [58] .…”

“…Some of these compounds are in advanced clinical trials to be used either as an adjunct to Peg-IFNα + RBV, and/or combined with other DAAs. STAT-C drugs include inhibitors of the viral proteins NS3/4A, NS4B, NS5A, and NS5B [11,12] . The well-defined virusspecific enzymatic functions of the NS3/4A serine protease and the NS5B RNA-dependent RNA-polymerase (RdRp) made them the initial focus for drug development and represent the most advanced STAT-C drugs, showing potent antiviral efficacy in vitro and in vivo.…”

Chronic hepatitis C: This and the new era of treatment

“…There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target [75] ( Figure 2 and Table 1): (1) NS3/4A PIs; (2) NS5B nucleoside polymerase inhibitors (NPIs); (3) NS5B non NPIs (NNPIs); and (4) NS5A inhibitors.…”

“…The DAAs have a high barrier to resistance and ideally, they should also be active against all HCV genotypes. Furthermore, these drugs are well tolerated and have few drug interactions.There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target [75] ( Figure 2 and Table 1): (1) NS3/4A PIs; (2) NS5B nucleoside polymerase inhibitors (NPIs); (3) NS5B non NPIs (NNPIs); and (4) NS5A inhibitors. …”