Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

Abstract

The establishment of a robust hepatitis C virus (HCV) cell culture system and subsequent detailed characterization of the HCV life cycle was a key step toward the identification of putative antiviral targets and respective antiviral drugs. 1,2 These include direct-acting antiviral agents (DAAs) such as NS3/4A protease inhibitors, NS5A inhibitors, nucleos(t)ide and non-nucleoside polymerase inhibitors, as well as hosttargeting agents (HTAs) directed against cellular factors involved in viral entry or replication. 3 Trials investigating different drug classes with and without pegylated interferon (PegIFN) and/or ribavirin have rapidly evolved, yielding highly promising sustained virologic response (SVR) rates. 4,5 In regard to the enormous public health impact of HCV infection with an estimated 184 million anti-HCV positive persons worldwide, the recent advances in HCV drug development, together with implementation of improved HCV screening programs, have the potential to substantially reduce the burden of HCV-associated advanced liver disease including hepatocellular carcinoma. 6-9The first-in-class NS3/4A inhibitors telaprevir and boceprevir were approved in 2011. Addition of these drugs to the PegIFN/ribavirin backbone has considerably improved response rates in HCV therapy naïve and experienced patients compared with PegIFN/ribavirin alone. [10][11][12][13] The poor side-effect profile of these IFN-based therapies, however, limits the wide clinical applicability. Proof of the principle that viral clearance can be achieved with an IFN-free DAA combination has fast-tracked design and the conduct of clinical trials investigating IFN-free DAA combinations. 14 Different HCV genotypes and multiple subtypes result in a genotype and subtype-dependent efficacy of many available DAAs. 15,16 Furthermore, viral clearance is challenged by the presence and selection of resistance-associated variants (RAVs). 17,18 Thus, essential prerequisites for DAAs in clinical development comprise a high antiviral efficacy, a broad and at best pan-genotypic activity, as well as a high barrier to resistance. In this respect, nucleos(t)ide polymerase inhibitors display very favorable characteristics. [19][20][21] In addition to a high antiviral efficacy, binding to the highly conserved active site of the RNA-dependent RNA-polymerase (RdRp) and incorporation as active triphosphates into the growing HCV RNA chain terminating its elongation, confers a pan-genotypic activity. Also, the low replication fitness of emergent Keywords ► interferon-free HCV treatment ► direct-acting antiviral agents ► NS3/4A protease inhibitors ► NS5A inhibitors ► non-nucleoside polymerase inhibitors ► host-targeting agents AbstractThe identification of viral and host factors involved in hepatitis C virus (HCV) replication was a key prerequisite for the discovery and further exploration of antiviral drug targets. As of today, numerous direct-acting antiviral agents (DAAs), as well as host-targeting agents (HTAs), have been developed and entered clinical testing. The...

Daclatasvir, Simeprevir and Ribavirin as a Promising Interferon-Free Triple Regimen for HCV Recurrence after Liver Transplant

“…In patients with renal impairment, moderate anemia remains a residual problem related to RBV. Further studies will demonstrate whether RBV can be removed from the regimen without affecting its effectiveness [27]. …”

Completion of the Entire Hepatitis C Virus Life Cycle in Vero Cells Derived from Monkey Kidney

“…An interferon (IFN)-based therapy has been used both to control disease progression and to eradicate HCV ( 5 , 6 ). Novel direct-acting antiviral agents have been developed, and the number of patients in whom HCV has been eradicated has thus increased ( 7 – 9 ). However, these newly developed drugs are expensive and have associated side effects, and drug resistance is emerging.…”