Enhancing our understanding of current therapies for hepatitis C virus (HCV)

Abstract

Great progress has been made in understanding the HCV genome and its molecular virology. This understanding has culminated in the development of direct-acting antiviral (DAA) agents targeting HCV viral proteins. Telaprevir (TVR) and boceprevir (BOC) were the first DAAs introduced for treatment of genotype 1 HCV in 2011; when used in combination with pegylated interferon (pegIFN) and ribavirin (RBV), these protease inhibitors improved efficacy in patients with chronic HCV infection compared to the traditional dual therapy. However, this combination was associated with adverse events that often led to early termination of therapy. In late 2013, the FDA approved a second wave of DAAs, sofosbuvir (SOF) and simeprevir (SMV). The use of SOF with SMV opened the door for IFN-free combination regimens. This combination was highly efficacious and well tolerated in patients with HCV genotype 1. Sofosbuvir and ledipasvir (LDV) fixed-dose oral combination (FDC) therapy, and paritaprevir/ritonavir, ombitasvir and dasabuvir ± RBV were recently approved, elevating sustained virologic response (SVR) rates to over 95 %. We are anticipating the approval of additional IFN-free regimens with comparable efficacy and tolerability but with the addition of pangenotypic coverage, fewer drug-drug interactions, and a high barrier to resistance. This review will summarize current management for chronic HCV infection.

Figure 1

HCV viral lifecycle, HCV polypeptide structure, and cleavage sites. (A) The HCV viral lifecycle. The virus circulates as a highly lipidated lipoviral particle (LVP). The LVP requires several cells surface receptors for entry (step 1) into the hepatocyte, including scavenger receptor class B1 (SR-B1), CD-81, claudin (CLDN1), and occludin (not pictured). Once internalized, the viral genome is uncoated, revealing the naked viral RNA and viral nucleocapsid. The viral RNA is translated by host ribosomes into the viral polypeptide (step 3), which is then cleaved by a combination of host and viral proteases into the 10 viral proteins. Replication occurs at an endoplasmic reticulum membrane derived replication complex (the membranous web), which includes the lipid droplet (LD) and nonstructural viral proteins NS4A NS5B (step 4). Viral replication is also dependent on the participation of key host factors, which include miR-122 and cyclophilin A (CypA). The newly synthesized viral RNA is assembled into new LVP by the Golgi apparatus and subsequently released by the cell (steps 5 and 6). (B) HCV viral genome. The viral genome is a positive-sense, single-stranded RNA genome. The 5′ untranslated region (UTR) contains 2 important domains. The internal ribosome entry site (IRES) directs translation in a cap-independent manner. The 5′ UTR also contains 2 recognition sites by miR-122 that are critical for viral replication. After translation, a single viral polypeptide is generated. The structural proteins are cleaved by host proteases. The NS2/3 autoprotease cleaves the NS2 NS3 junction. The NS3/4A protease initially serves as an autoprotease and separates NS3 NS4A, but then subsequently cleaves the remaining nonstructural proteins.