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

Velazquez, C., Macartney, Malcolm, Irish, Dianne, Tanwar, Sudeep, Trembling, Paul, Hogan, Brian John, Catt, J., Glasgow, S., Ju, M., Moore, M.T., Hains, M., Smith, B., Suri, D., Jacobs, M. G., Oben, Jude A., Smith, P., Booth, C., Bridge, Simon, Garcia, Andre, McCormick, Adele, Nastouli, Eleni, Dusheiko, Geoffrey, Rosenberg, William and Haque, Tanzina (2013) 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. In: International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver, 24th - 28th April 2013, Amsterdam, Netherlands.

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Abstract

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.

Item Type:	Conference or Workshop Item (Poster)
Subjects:	B900 Others in Subjects allied to Medicine
Department:	Faculties > Health and Life Sciences > Applied Sciences
Depositing User:	Paul Burns
Date Deposited:	19 Jul 2019 10:27
Last Modified:	10 Oct 2019 16:48
URI:	http://nrl.northumbria.ac.uk/id/eprint/40094

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