13 The high rate of emergence of the protease resistant variant, R155K, in genotype 1a–infected, but not in genotype 1b–infected, patients selleck chemicals llc has also been described previously with this class of agent and is reflective of single-nucleotide change required for the development of resistance in genotype 1a patients, but two-nucleotide changes in the majority of genotype 1b patients. 27 It is of note that single-nucleotide change is required for both mutations at NS3 R155 and D168 in genotype
1a patients; however, a mutation at only R155, and not D168, was identified in genotype 1a patients by population sequencing. The R155 nucleotide sequence may be more susceptible to change than D168, or the R155K may be more fit than mutations at D168 in this genotype. Mutations at D168 were commonly selected in genotype
1b–infected patients, consistent with genotype 1b replicon data. The Y448H mutation observed with selleck chemicals tegobuvir has been observed frequently in monotherapy studies and is consistent with in vitro mutational data, indicating the tegobuvir interaction likely involves the β-hairpin in the thumb subdomain of the NS5B polymerase. 20 In the present study, 7 of 8 genotype 1a patients developed dual-class resistance: R155K against the NS3 protease inhibitor and Y448H for the NS5B polymerase inhibitor. However, with the addition of RBV, the incidence of resistance was significantly reduced, with none of genotype 1a patients (n = 3) exhibiting drug-resistant variants. Though RBV has been shown to have modest antiviral activity, 28 its ability to significantly reduce the development of resistance highlights a distinct mechanism of action. This may indicate
a broader mutational effect of RBV on viral fitness, which renders a proportion of virus noninfectious, regardless of oral antiviral-resistance mutations. Although similar trials have been reported on, 29 the present study is the first report of an IFN-free NS5B polymerase/NS3 protease combination both with and without RBV, thus allowing for a prospective evaluation medchemexpress of the contribution of RBV to the antiviral effect of the regimen. The emergence of various classes of DAAs for treating chronic HCV infection has enabled an evaluation of multiple combination approaches either with or without Peg-IFN and RBV. 19, 30, 31 Specifically, the strategy of quadruple therapy with a non-nucleoside analog, a protease inhibitor, and Peg-IFN and RBV has been supported by results from a recently reported study, in which the non-nucleoside NS5B polymerase inhibitor, VX-222, telaprevir, and peg-IFN/RBV resulted in RVR in 51 of 59 (86%) of treatment-naïve patients, 19 which is higher than those reported with telaprevir and Peg-IFN/RBV. 6, 9 In this study, 100% of patients receiving quadruple therapy achieved RVR at week 4, and a high proportion of patients (71%) had HCV RNA below 25 IU/mL at week 2.