Timing and Characteristics of Drug Resistance Mutations (DRMs) in Chronic Hepatitis C Patients During and After Treatment with Protease Inhibitor Therapy at a Single Centre

Introduction: We report the prevalence and characteristics of DRMs associated with virological failure (VF) in a prospective cohort of 59 patients with chronic HCV infection treated with telaprevir (TVR) or boceprevir (BOC) combined with pegylated interferon-alfa and ribavirin (PEG/R). Methods: All patients had baseline HCV RNA levels >10,000 IU/ml and evidence of at least bridging fibrosis. VF was defined as HCV RNA >1000 IU/ml at week 4 or 12 for TVR, or HCV RNA >100IU/ml at week 12 for BOC, or an increase of >1log10 VL from nadir. Genotypic resistance was detected using nested RT-PCR to amplify viral RNA and the first 181 amino acids of the NS3 protease were sequenced by population sequencing. Results: Forty seven patients (80%) were treated with TVR and 12 (20%) with BOC. Nineteen patients (32%) had VF (18 TVR, 1 BOC) of which DRMs were detected in 16 (84%). All patients who developed VF with DRMs had HCV genotype 1a and were treated with TVR. Mutations evolved at NS3 positions 155 and 36; Arginine to Lysine at 155 and/or Valine to Methionine, Leucine, Alanine or Valine/Methionine at 36, none of which were detected at baseline. Eight of fifteen DRMs were detected during TVR therapy, the remainder during PEG/R ‘tail’ of therapy (4 at week 4; 2 at week 8; 2 at week 12; 1 at week 15; 3 at week 24; 1 at week 36; 1 at week 48 and 1 at week 60). Those patients with VF without identifiable DRMs had breakthrough after week 12 with TVR (1 at week 22; 1 at week 24) and at week 8 with BOC. Of the VF/no DRM patients, all TVR patients had subtype 1b and severe fibrosis. The BOC treated patient had subtype 1a with moderate fibrosis. Conclusion: In this cohort treated with TVR, VF was associated with development of DRMs which were identified both before and during the PEG/R tail of therapy. Given the potential impact of DRMs on success of future therapy with protease inhibitors we suggest HCV protease sequencing for DRMs for all patients presenting with VF