New horizons in hepatitis C antiviral therapy with direct-acting antivirals

Abstract

Most direct-acting antivirals (DAAs) that are being developed as therapy against hepatitis C virus target the NS3/4A protease, the NS5A protein, and the NS5B polymerase. The latter enzyme offers different target sites: the catalytic domain for nucleos(t)ide analogues as well as a number of allosteric sites for nonnucleos(t)ide inhibitors. Two NS3/ 4A protease inhibitors have been approved recently, and more than 40 new NS3/4A, NS5A, or NS5B inhibitors are in development. These agents can achieve very high cure rates when combined with pegylated interferon-a and ribavirin and show promising clinical results when administered in all-oral combinations. In addition to the more canonical drug targets, new alternative viral targets for small-molecule drug development are emerging, such as p7 or NS4B and viral entry. Future research will need to define well-tolerated and cost-effective DAA combinations that provide the highest rates of viral eradication in all patients (including those with advanced liver disease), the broadest spectrum of action on viral genotypes showing minimal or no clinical resistance, and the shortest treatment duration. (HEPATOLOGY 2013;58:428-438) F or more than a decade, the standard treatment of chronic hepatitis C virus (HCV) infection has been based on the combination of pegylated interferon-a (PEG-IFN) and ribavirin (RBV) administered for 24 or 48 weeks. These regimens eradicate infection in 40% to 50% of treated patients with genotype 1 (HCV-1) infection and 80% of treated patients with genotype 2 (HCV-2) and 3 (HCV-3) infection. In addition, PEG-IFN/RBV regimens are poorly tolerated and contraindicated in a high percentage of patients. In order to address the shortcomings of PEG-IFN/RBV therapy, new direct-acting antivirals (DAAs) are being developed that target specific HCV functions. The recent approval of the first two NS3/4A oral protease inhibitors (PIs), boceprevir (BOC) and telaprevir (TVR), for use in combination with the PEG-IFN/RBV backbone has represented a dramatic advance in the efficacy of pharmacotherapy against chronic hepatitis C. With this new triple therapy regimen, patient cure rates for chronic HCV-1 infection have increased to 70% to 80% while significantly reducing treatment duration. However, these recently approved DAA regimens are poorly tolerated, are associated with a high pill burden and an inconvenient dosing frequency, and are not indicated for genotypes other than HCV-1. Moreover, selection of DAA-resistant viral variants occurs in patients who respond poorly to the PEG-IFN/RBV component of combination therapy. In light of these limitations, newer DAAs are being developed to identify regimens that are more convenient and efficacious, are better tolerated, are pan-genotypic, and have a low propensity to develop viral resistance. These are primarily targeted at the NS3/4A protease, NS5A protein, or NS5B RNA-dependent RNA polymerase. In addition, other less-studied viral proteins (e.g., NS4B or p7) or the virus entry steps have been recently demonstrated t...

NS5A Inhibitors Impair NS5A–Phosphatidylinositol 4-Kinase IIIα Complex Formation and Cause a Decrease of Phosphatidylinositol 4-Phosphate and Cholesterol Levels in Hepatitis C Virus-Associated Membranes

“…These new drugs offer the promise of well-tolerated interferonfree oral regimens that are able to cure the majority of infected patients (1).…”

Increased Replicative Fitness Can Lead to Decreased Drug Sensitivity of Hepatitis C Virus

“…Directly acting antiviral agents (DAAs)-some currently in use and others under development-offer great promise for control of HCV either as a substitute for or complement of the standard-of-care (SOC) therapy based on treatment using a combination of pegylated alpha interferon (IFN-␣) and ribavirin (30)(31)(32)(33)(34)(35)(36). Combinations that include the polymerase inhibitor sofosbuvir have produced sustained viral responses that in some cases have been higher than 90% in clinical trials (37)(38)(39)(40), but the possible impact of resistance mutations is not known; sofosbuvir resistance substitution S282T in NS5B is present in the sequence of HCV reference isolate ED43 of genotype 4a and L159F is present in the mutant spectrum of HCV quasispecies following treatment of HCV p100 with ribavirin (I. Gallego, E. Domingo, and C. Perales, unpublished results).…”

An a priori prediction model of response to peginterferon plus ribavirin dual therapy in naïve patients with genotype 1 chronic hepatitis C

“…First, even though guidelines will gravitate towards these newer preferred treatments, the universal use of present or future triple therapies is certainly an overtreatment for the subset of patients with favourable clinical, genetic, and virological profiles [12,13,30]. Several scientific societies issued position papers stating that treatment-naïve patients with favourable baseline and on-treatment predictive features do not necessarily deserve triple therapy [11,12], a recommendation which has undergone a formal validation in a recent clinical trial [13].…”