1229 GENOTYPIC AND PHENOTYPIC CHARACTERIZATION OF NS3 VARIANTS SELECTED IN HCV-INFECTED PATIENTS TREATED WITH ABT-450

Abstract

Background: This study monitored for resistance for up to 12 weeks of treatment with danoprevir (DNV) plus low-dose ritonavir (r) in combination with PegIFNa-2a/RBV in genotype (GT) 1 treatmentnaive patients and prior null responders. Materials and Methods: Three cohorts of treatment-naive HCV GT1 patients were randomised to receive DNV/r (n = 31) or placebo/r + PegIFNa-2a/RBV (n =3) for 15 days with DNV/r regimens of 100/100mg q12h (cohort 1), 200/100mg q24h (cohort 2), and 200/100mg q12h (cohort 3). A fourth cohort (n = 24) included prior null responder GT1 patients who received 100/100mg q12h DNV/r or placebo/r + PegIFNa-2a/RBV for 12 weeks. The NS3/4A and/or NS3 protease coding region was amplified and population sequence was performed on all baseline samples. Population sequence and phenotypic analyses were performed on on-treatment and follow up samples from DNV/r/PegIFNa-2a/RBV-treated patients that experienced: i. viral load rebound, ii. non response or iii. partial response. Results: Low-dose DNV/r + PegIFNa-2a/RBV provided robust virological response in all cohorts. No viral breakthrough was observed in treatment-naive patients (cohorts 1–3, 22 GT1a and 9 GT1b) after 2 weeks of DNV combination therapy. Of the 24 (8 GT1a and 16 GT1b) prior null responder patients treated with DNV/r for up to 12 weeks, four GT1a patients experienced a viral breakthrough (two patients by week 3, one by week 4 and one by week 8 of treatment). This was associated with the selection of R155K in the NS3 protease region and ~250-fold EC50 shift compared to the baseline samples. The R155K resistance mutation persisted for up to 12 weeks after cessation of therapy. Viral breakthrough was observed in one GT1b patient. Population sequence of the NS3/4A region of 58 patients at baseline did not show any DNV resistance mutations. Conclusions: DNV/r + PegIFNa-2a/RBV provided a robust virological response in GT1b and GT1a treatment-naive patients with no viral breakthrough observed. In prior null responders, robust response was observed in GT1b patients whereas resistance related viral breakthrough was observed in 4/8 GT1a patients. R155K mutation persisted for 12 weeks after the cessation of therapy, emphasising the need for a second direct-acting antiviral agent in this population.