Resistance analysis in patients with genotype 1–6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies

Christophe Hezode, Nancy Reau, Evguenia S. Svarovskaia, Brian P. Doehle, Ragavi Shanmugam, Hadas Dvory-Sobol, Charlotte Hedskog, John McNally, Anu Osinusi, Diana M. Brainard, Michael D. Miller, Hongmei Mo, Stuart K. Roberts, Jacqueline G. O'Leary, Stephen D. Shafran, Stefan Zeuzem

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Abstract

Background & Aims: The fixed-dose combination of sofosbuvir/velpatasvir was highly efficacious in patients infected with genotype (GT)1–6 hepatitis C virus (HCV) in the ASTRAL studies. This analysis evaluated the impact of baseline resistance-associated substitutions (RASs) on treatment outcome and emergence of RASs in patients infected with HCV GT1-6 who were treated with sofosbuvir/velpatasvir. Methods: Non-structural protein 5A and 5B (NS5A and NS5B) deep sequencing was performed at baseline and at the time of relapse for all patients treated with sofosbuvir/velpatasvir for 12 weeks (n = 1,778) in the ASTRAL-1–3, ASTRAL-5 and POLARIS-2–3 studies. Results: Patients with 37 known and 19 novel HCV subtypes were included in these analyses. Overall, 28% (range 9% to 61% depending on genotype) had detectable NS5A class RASs at baseline, using a 15% sequencing assay cut-off. There was no significant effect of baseline NS5A class RASs on sustained virologic response at week 12 (SVR12) with sofosbuvir/velpatasvir; the SVR12 rate in the presence of NS5A class RASs was 100% and 97%, in patients with GT1a and GT1b infection, respectively, and 100% in patients with GT2 and GT4–6 infections. In GT3 infection, the SVR rate was 93% and 98% in patients with and without baseline NS5A class RASs, respectively. The overall virologic failure rate was low (20/1,778 = 1.1%) in patients treated with sofosbuvir/velpatasvir. Single NS5A class resistance was observed at virologic failure in 17 of the 20 patients. Conclusions: Sofosbuvir/velpatasvir taken for 12 weeks once daily resulted in high SVR rates in patients infected with GT1–6 HCV, irrespective of baseline NS5A RASs. NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients. Lay summary: Sofosbuvir/velpatasvir taken once daily for 12 weeks resulted in high sustained virologic response rates in patients infected with HCV, irrespective of the presence of NS5A resistance-associated variants prior to treatment. Single class NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients.

Original languageEnglish
Pages (from-to)895-903
Number of pages9
JournalJournal of Hepatology
Volume68
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • ASTRAL-1
  • ASTRAL-2
  • ASTRAL-3
  • ASTRAL-5
  • Direct-acting antivirals
  • POLARIS-2
  • POLARIS-3
  • Sofosbuvir/velpatasvir

Cite this

Hezode, C., Reau, N., Svarovskaia, E. S., Doehle, B. P., Shanmugam, R., Dvory-Sobol, H., ... Zeuzem, S. (2018). Resistance analysis in patients with genotype 1–6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies. Journal of Hepatology, 68(5), 895-903. https://doi.org/10.1016/j.jhep.2017.11.032
Hezode, Christophe ; Reau, Nancy ; Svarovskaia, Evguenia S. ; Doehle, Brian P. ; Shanmugam, Ragavi ; Dvory-Sobol, Hadas ; Hedskog, Charlotte ; McNally, John ; Osinusi, Anu ; Brainard, Diana M. ; Miller, Michael D. ; Mo, Hongmei ; Roberts, Stuart K. ; O'Leary, Jacqueline G. ; Shafran, Stephen D. ; Zeuzem, Stefan. / Resistance analysis in patients with genotype 1–6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies. In: Journal of Hepatology. 2018 ; Vol. 68, No. 5. pp. 895-903.
@article{a002c52f3fbb4eb293a86e96b8ed84c3,
title = "Resistance analysis in patients with genotype 1–6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies",
abstract = "Background & Aims: The fixed-dose combination of sofosbuvir/velpatasvir was highly efficacious in patients infected with genotype (GT)1–6 hepatitis C virus (HCV) in the ASTRAL studies. This analysis evaluated the impact of baseline resistance-associated substitutions (RASs) on treatment outcome and emergence of RASs in patients infected with HCV GT1-6 who were treated with sofosbuvir/velpatasvir. Methods: Non-structural protein 5A and 5B (NS5A and NS5B) deep sequencing was performed at baseline and at the time of relapse for all patients treated with sofosbuvir/velpatasvir for 12 weeks (n = 1,778) in the ASTRAL-1–3, ASTRAL-5 and POLARIS-2–3 studies. Results: Patients with 37 known and 19 novel HCV subtypes were included in these analyses. Overall, 28{\%} (range 9{\%} to 61{\%} depending on genotype) had detectable NS5A class RASs at baseline, using a 15{\%} sequencing assay cut-off. There was no significant effect of baseline NS5A class RASs on sustained virologic response at week 12 (SVR12) with sofosbuvir/velpatasvir; the SVR12 rate in the presence of NS5A class RASs was 100{\%} and 97{\%}, in patients with GT1a and GT1b infection, respectively, and 100{\%} in patients with GT2 and GT4–6 infections. In GT3 infection, the SVR rate was 93{\%} and 98{\%} in patients with and without baseline NS5A class RASs, respectively. The overall virologic failure rate was low (20/1,778 = 1.1{\%}) in patients treated with sofosbuvir/velpatasvir. Single NS5A class resistance was observed at virologic failure in 17 of the 20 patients. Conclusions: Sofosbuvir/velpatasvir taken for 12 weeks once daily resulted in high SVR rates in patients infected with GT1–6 HCV, irrespective of baseline NS5A RASs. NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients. Lay summary: Sofosbuvir/velpatasvir taken once daily for 12 weeks resulted in high sustained virologic response rates in patients infected with HCV, irrespective of the presence of NS5A resistance-associated variants prior to treatment. Single class NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients.",
keywords = "ASTRAL-1, ASTRAL-2, ASTRAL-3, ASTRAL-5, Direct-acting antivirals, POLARIS-2, POLARIS-3, Sofosbuvir/velpatasvir",
author = "Christophe Hezode and Nancy Reau and Svarovskaia, {Evguenia S.} and Doehle, {Brian P.} and Ragavi Shanmugam and Hadas Dvory-Sobol and Charlotte Hedskog and John McNally and Anu Osinusi and Brainard, {Diana M.} and Miller, {Michael D.} and Hongmei Mo and Roberts, {Stuart K.} and O'Leary, {Jacqueline G.} and Shafran, {Stephen D.} and Stefan Zeuzem",
year = "2018",
month = "5",
day = "1",
doi = "10.1016/j.jhep.2017.11.032",
language = "English",
volume = "68",
pages = "895--903",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier",
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Hezode, C, Reau, N, Svarovskaia, ES, Doehle, BP, Shanmugam, R, Dvory-Sobol, H, Hedskog, C, McNally, J, Osinusi, A, Brainard, DM, Miller, MD, Mo, H, Roberts, SK, O'Leary, JG, Shafran, SD & Zeuzem, S 2018, 'Resistance analysis in patients with genotype 1–6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies', Journal of Hepatology, vol. 68, no. 5, pp. 895-903. https://doi.org/10.1016/j.jhep.2017.11.032

Resistance analysis in patients with genotype 1–6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies. / Hezode, Christophe; Reau, Nancy; Svarovskaia, Evguenia S.; Doehle, Brian P.; Shanmugam, Ragavi; Dvory-Sobol, Hadas; Hedskog, Charlotte; McNally, John; Osinusi, Anu; Brainard, Diana M.; Miller, Michael D.; Mo, Hongmei; Roberts, Stuart K.; O'Leary, Jacqueline G.; Shafran, Stephen D.; Zeuzem, Stefan.

In: Journal of Hepatology, Vol. 68, No. 5, 01.05.2018, p. 895-903.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Resistance analysis in patients with genotype 1–6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies

AU - Hezode, Christophe

AU - Reau, Nancy

AU - Svarovskaia, Evguenia S.

AU - Doehle, Brian P.

AU - Shanmugam, Ragavi

AU - Dvory-Sobol, Hadas

AU - Hedskog, Charlotte

AU - McNally, John

AU - Osinusi, Anu

AU - Brainard, Diana M.

AU - Miller, Michael D.

AU - Mo, Hongmei

AU - Roberts, Stuart K.

AU - O'Leary, Jacqueline G.

AU - Shafran, Stephen D.

AU - Zeuzem, Stefan

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Background & Aims: The fixed-dose combination of sofosbuvir/velpatasvir was highly efficacious in patients infected with genotype (GT)1–6 hepatitis C virus (HCV) in the ASTRAL studies. This analysis evaluated the impact of baseline resistance-associated substitutions (RASs) on treatment outcome and emergence of RASs in patients infected with HCV GT1-6 who were treated with sofosbuvir/velpatasvir. Methods: Non-structural protein 5A and 5B (NS5A and NS5B) deep sequencing was performed at baseline and at the time of relapse for all patients treated with sofosbuvir/velpatasvir for 12 weeks (n = 1,778) in the ASTRAL-1–3, ASTRAL-5 and POLARIS-2–3 studies. Results: Patients with 37 known and 19 novel HCV subtypes were included in these analyses. Overall, 28% (range 9% to 61% depending on genotype) had detectable NS5A class RASs at baseline, using a 15% sequencing assay cut-off. There was no significant effect of baseline NS5A class RASs on sustained virologic response at week 12 (SVR12) with sofosbuvir/velpatasvir; the SVR12 rate in the presence of NS5A class RASs was 100% and 97%, in patients with GT1a and GT1b infection, respectively, and 100% in patients with GT2 and GT4–6 infections. In GT3 infection, the SVR rate was 93% and 98% in patients with and without baseline NS5A class RASs, respectively. The overall virologic failure rate was low (20/1,778 = 1.1%) in patients treated with sofosbuvir/velpatasvir. Single NS5A class resistance was observed at virologic failure in 17 of the 20 patients. Conclusions: Sofosbuvir/velpatasvir taken for 12 weeks once daily resulted in high SVR rates in patients infected with GT1–6 HCV, irrespective of baseline NS5A RASs. NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients. Lay summary: Sofosbuvir/velpatasvir taken once daily for 12 weeks resulted in high sustained virologic response rates in patients infected with HCV, irrespective of the presence of NS5A resistance-associated variants prior to treatment. Single class NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients.

AB - Background & Aims: The fixed-dose combination of sofosbuvir/velpatasvir was highly efficacious in patients infected with genotype (GT)1–6 hepatitis C virus (HCV) in the ASTRAL studies. This analysis evaluated the impact of baseline resistance-associated substitutions (RASs) on treatment outcome and emergence of RASs in patients infected with HCV GT1-6 who were treated with sofosbuvir/velpatasvir. Methods: Non-structural protein 5A and 5B (NS5A and NS5B) deep sequencing was performed at baseline and at the time of relapse for all patients treated with sofosbuvir/velpatasvir for 12 weeks (n = 1,778) in the ASTRAL-1–3, ASTRAL-5 and POLARIS-2–3 studies. Results: Patients with 37 known and 19 novel HCV subtypes were included in these analyses. Overall, 28% (range 9% to 61% depending on genotype) had detectable NS5A class RASs at baseline, using a 15% sequencing assay cut-off. There was no significant effect of baseline NS5A class RASs on sustained virologic response at week 12 (SVR12) with sofosbuvir/velpatasvir; the SVR12 rate in the presence of NS5A class RASs was 100% and 97%, in patients with GT1a and GT1b infection, respectively, and 100% in patients with GT2 and GT4–6 infections. In GT3 infection, the SVR rate was 93% and 98% in patients with and without baseline NS5A class RASs, respectively. The overall virologic failure rate was low (20/1,778 = 1.1%) in patients treated with sofosbuvir/velpatasvir. Single NS5A class resistance was observed at virologic failure in 17 of the 20 patients. Conclusions: Sofosbuvir/velpatasvir taken for 12 weeks once daily resulted in high SVR rates in patients infected with GT1–6 HCV, irrespective of baseline NS5A RASs. NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients. Lay summary: Sofosbuvir/velpatasvir taken once daily for 12 weeks resulted in high sustained virologic response rates in patients infected with HCV, irrespective of the presence of NS5A resistance-associated variants prior to treatment. Single class NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients.

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KW - ASTRAL-2

KW - ASTRAL-3

KW - ASTRAL-5

KW - Direct-acting antivirals

KW - POLARIS-2

KW - POLARIS-3

KW - Sofosbuvir/velpatasvir

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U2 - 10.1016/j.jhep.2017.11.032

DO - 10.1016/j.jhep.2017.11.032

M3 - Article

VL - 68

SP - 895

EP - 903

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 5

ER -