Dynamics of HCV genotype 4 resistance-associated variants during virologic escape with pIFN/RBV+daclatasvir: A case study using ultra deep pyrosequencing

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Abstract

Background: Daclatasvir (DCV) is an approved NS5A inhibitor with potent anti-HCV activity and broad genotype coverage. DCV resistance-associated variants (RAVs) have been described for patients infected with genotype (GT) 1, but increased GT4 prevalence in European countries as a result of immigration has boosted interest in this genotype. Objectives: Establishment of NS5A variability in treatment-naive patients with HCV genotype 4 infection and a case study of the dynamics of resistance-associated variants in a virologic failure receiving pIFN/RBV. +. DCV, as assessed by ultra-deep sequencing. Study design: Five treatment-naïve GT4 patients (GT4a [n= 1], GT4d [n= 3], GT4o [n= 1]) were evaluated for inclusion in the COMMAND-4 study and treatment with pIFN/RBV ± DCV. Results: Patient (Pt) 1 received pIFN/RBV; Pts2-4 received pIFN/RBV + DCV; Pt5 was a screening failure. Pt1 relapsed; Pt2 experienced breakthrough at Wk4; Pts3 and 4 achieved a sustained virologic response. No substitutions associated with DCV-resistance were detected at baseline. In terms of viremic time points for Pts1 and 2, the extent of NS5A diversity pre-treatment was not significantly related to viral load (r = -0568; p = 0.035). In Pt2, multiple substitutions associated with DCV-resistance were observed after breakthrough at NS5A amino acid positions 28, 31 and 93. These substitutions were frequently observed on the same haplotype (L28S + M31I = 55.52, 82.50, and 99.36% at Wk4, 8 and 9; L28S + M31I + Y93H = 11.77, 5.01 and

Original languageEnglish
Pages (from-to)38-43
Number of pages6
JournalJournal of Clinical Virology
Volume66
DOIs
Publication statusPublished - May 1 2015

Fingerprint

Genotype
High-Throughput Nucleotide Sequencing
Emigration and Immigration
Therapeutics
BMS-790052
Viral Load
Haplotypes
Amino Acids
Infection

Keywords

  • Daclatasvir
  • Genotype 4
  • Hepatitis c virus
  • NS5A
  • UDPS

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases
  • Medicine(all)

Cite this

@article{3c5005d8ec6a4e76a530d14bed362480,
title = "Dynamics of HCV genotype 4 resistance-associated variants during virologic escape with pIFN/RBV+daclatasvir: A case study using ultra deep pyrosequencing",
abstract = "Background: Daclatasvir (DCV) is an approved NS5A inhibitor with potent anti-HCV activity and broad genotype coverage. DCV resistance-associated variants (RAVs) have been described for patients infected with genotype (GT) 1, but increased GT4 prevalence in European countries as a result of immigration has boosted interest in this genotype. Objectives: Establishment of NS5A variability in treatment-naive patients with HCV genotype 4 infection and a case study of the dynamics of resistance-associated variants in a virologic failure receiving pIFN/RBV. +. DCV, as assessed by ultra-deep sequencing. Study design: Five treatment-na{\"i}ve GT4 patients (GT4a [n= 1], GT4d [n= 3], GT4o [n= 1]) were evaluated for inclusion in the COMMAND-4 study and treatment with pIFN/RBV ± DCV. Results: Patient (Pt) 1 received pIFN/RBV; Pts2-4 received pIFN/RBV + DCV; Pt5 was a screening failure. Pt1 relapsed; Pt2 experienced breakthrough at Wk4; Pts3 and 4 achieved a sustained virologic response. No substitutions associated with DCV-resistance were detected at baseline. In terms of viremic time points for Pts1 and 2, the extent of NS5A diversity pre-treatment was not significantly related to viral load (r = -0568; p = 0.035). In Pt2, multiple substitutions associated with DCV-resistance were observed after breakthrough at NS5A amino acid positions 28, 31 and 93. These substitutions were frequently observed on the same haplotype (L28S + M31I = 55.52, 82.50, and 99.36{\%} at Wk4, 8 and 9; L28S + M31I + Y93H = 11.77, 5.01 and",
keywords = "Daclatasvir, Genotype 4, Hepatitis c virus, NS5A, UDPS",
author = "Barbara Bartolini and Raffaella Lionetti and Emanuela Giombini and Catia Sias and Chiara Taibi and Marzia Montalbano and D'Offizi Gianpiero and Fiona McPhee and Hughes, {Eric A.} and Nannan Zhou and Giuseppe Ippolito and Garbuglia, {Anna Rosa} and Capobianchi, {Maria R.}",
year = "2015",
month = "5",
day = "1",
doi = "10.1016/j.jcv.2015.02.001",
language = "English",
volume = "66",
pages = "38--43",
journal = "Journal of Clinical Virology",
issn = "1386-6532",
publisher = "Elsevier",

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TY - JOUR

T1 - Dynamics of HCV genotype 4 resistance-associated variants during virologic escape with pIFN/RBV+daclatasvir

T2 - A case study using ultra deep pyrosequencing

AU - Bartolini, Barbara

AU - Lionetti, Raffaella

AU - Giombini, Emanuela

AU - Sias, Catia

AU - Taibi, Chiara

AU - Montalbano, Marzia

AU - Gianpiero, D'Offizi

AU - McPhee, Fiona

AU - Hughes, Eric A.

AU - Zhou, Nannan

AU - Ippolito, Giuseppe

AU - Garbuglia, Anna Rosa

AU - Capobianchi, Maria R.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Background: Daclatasvir (DCV) is an approved NS5A inhibitor with potent anti-HCV activity and broad genotype coverage. DCV resistance-associated variants (RAVs) have been described for patients infected with genotype (GT) 1, but increased GT4 prevalence in European countries as a result of immigration has boosted interest in this genotype. Objectives: Establishment of NS5A variability in treatment-naive patients with HCV genotype 4 infection and a case study of the dynamics of resistance-associated variants in a virologic failure receiving pIFN/RBV. +. DCV, as assessed by ultra-deep sequencing. Study design: Five treatment-naïve GT4 patients (GT4a [n= 1], GT4d [n= 3], GT4o [n= 1]) were evaluated for inclusion in the COMMAND-4 study and treatment with pIFN/RBV ± DCV. Results: Patient (Pt) 1 received pIFN/RBV; Pts2-4 received pIFN/RBV + DCV; Pt5 was a screening failure. Pt1 relapsed; Pt2 experienced breakthrough at Wk4; Pts3 and 4 achieved a sustained virologic response. No substitutions associated with DCV-resistance were detected at baseline. In terms of viremic time points for Pts1 and 2, the extent of NS5A diversity pre-treatment was not significantly related to viral load (r = -0568; p = 0.035). In Pt2, multiple substitutions associated with DCV-resistance were observed after breakthrough at NS5A amino acid positions 28, 31 and 93. These substitutions were frequently observed on the same haplotype (L28S + M31I = 55.52, 82.50, and 99.36% at Wk4, 8 and 9; L28S + M31I + Y93H = 11.77, 5.01 and

AB - Background: Daclatasvir (DCV) is an approved NS5A inhibitor with potent anti-HCV activity and broad genotype coverage. DCV resistance-associated variants (RAVs) have been described for patients infected with genotype (GT) 1, but increased GT4 prevalence in European countries as a result of immigration has boosted interest in this genotype. Objectives: Establishment of NS5A variability in treatment-naive patients with HCV genotype 4 infection and a case study of the dynamics of resistance-associated variants in a virologic failure receiving pIFN/RBV. +. DCV, as assessed by ultra-deep sequencing. Study design: Five treatment-naïve GT4 patients (GT4a [n= 1], GT4d [n= 3], GT4o [n= 1]) were evaluated for inclusion in the COMMAND-4 study and treatment with pIFN/RBV ± DCV. Results: Patient (Pt) 1 received pIFN/RBV; Pts2-4 received pIFN/RBV + DCV; Pt5 was a screening failure. Pt1 relapsed; Pt2 experienced breakthrough at Wk4; Pts3 and 4 achieved a sustained virologic response. No substitutions associated with DCV-resistance were detected at baseline. In terms of viremic time points for Pts1 and 2, the extent of NS5A diversity pre-treatment was not significantly related to viral load (r = -0568; p = 0.035). In Pt2, multiple substitutions associated with DCV-resistance were observed after breakthrough at NS5A amino acid positions 28, 31 and 93. These substitutions were frequently observed on the same haplotype (L28S + M31I = 55.52, 82.50, and 99.36% at Wk4, 8 and 9; L28S + M31I + Y93H = 11.77, 5.01 and

KW - Daclatasvir

KW - Genotype 4

KW - Hepatitis c virus

KW - NS5A

KW - UDPS

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