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 language | English |
|---|---|
| Pages (from-to) | 38-43 |
| Number of pages | 6 |
| Journal | Journal of Clinical Virology |
| Volume | 66 |
| DOIs | |
| Publication status | Published - May 1 2015 |
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Keywords
- Daclatasvir
- Genotype 4
- Hepatitis c virus
- NS5A
- UDPS
ASJC Scopus subject areas
- Virology
- Infectious Diseases
- Medicine(all)
Cite this
Dynamics of HCV genotype 4 resistance-associated variants during virologic escape with pIFN/RBV+daclatasvir : A case study using ultra deep pyrosequencing. / Bartolini, Barbara; Lionetti, Raffaella; Giombini, Emanuela; Sias, Catia; Taibi, Chiara; Montalbano, Marzia; Gianpiero, D'Offizi; McPhee, Fiona; Hughes, Eric A.; Zhou, Nannan; Ippolito, Giuseppe; Garbuglia, Anna Rosa; Capobianchi, Maria R.
In: Journal of Clinical Virology, Vol. 66, 01.05.2015, p. 38-43.Research output: Contribution to journal › Article
}
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
UR - http://www.scopus.com/inward/record.url?scp=84926622123&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84926622123&partnerID=8YFLogxK
U2 - 10.1016/j.jcv.2015.02.001
DO - 10.1016/j.jcv.2015.02.001
M3 - Article
C2 - 25866334
AN - SCOPUS:84926622123
VL - 66
SP - 38
EP - 43
JO - Journal of Clinical Virology
JF - Journal of Clinical Virology
SN - 1386-6532
ER -