Impact of preexisting hepatitis C virus genotype 6 NS3, NS5A, and NS5B polymorphisms on the in vitro potency of direct-acting antiviral agents

Fiona McPhee, Joseph Ueland, Vincent Vellucci, Scott Bowden, William Sievert, Nannan Zhou

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

HCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse, with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAA in vitro potency when evaluated in a GT-6a consensus replicon, and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the U.S. HCV database were compared, and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Preexisting resistance-associated substitutions (RASs) to NS3 protease (A156V and D168E) and NS5B nucleotide (L159F and S282C) inhibitors were rare (4%). Preexisting RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S). In vitro susceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (90% effective concentration [EC 90 ] range, 119 to 2,032 nM) compared with susceptibilities against a GT-6a consensus replicon (EC 90 range, 0.1 to 19 nM). These L28 RASs preexisted in combination with R30S (EC 90 [L28A-R30S] of 720 nM or EC 90 [L28T-R30S] of 128 nM against tested DAAs) or as L28T-L31I (EC 90 [tested DAAs] of 5,000 nM) and were detected in evaluated GT-6b and -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f, and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Therefore, monitoring SVR in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is suggested to confirm any association between noted NS5A polymorphisms and treatment failure.

Original languageEnglish
Article numbere02205-18
Number of pages12
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

Keywords

  • Genotype 6
  • HCV
  • NS3
  • NS5A
  • NS5B
  • Ombitasvir
  • Polymorphism
  • Resistance
  • Sofosbuvir
  • Velpatasvir

Cite this

@article{3911349e1a8e4cef97c8f6f2416aa5fd,
title = "Impact of preexisting hepatitis C virus genotype 6 NS3, NS5A, and NS5B polymorphisms on the in vitro potency of direct-acting antiviral agents",
abstract = "HCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse, with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAA in vitro potency when evaluated in a GT-6a consensus replicon, and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the U.S. HCV database were compared, and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Preexisting resistance-associated substitutions (RASs) to NS3 protease (A156V and D168E) and NS5B nucleotide (L159F and S282C) inhibitors were rare (4{\%}). Preexisting RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S). In vitro susceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (90{\%} effective concentration [EC 90 ] range, 119 to 2,032 nM) compared with susceptibilities against a GT-6a consensus replicon (EC 90 range, 0.1 to 19 nM). These L28 RASs preexisted in combination with R30S (EC 90 [L28A-R30S] of 720 nM or EC 90 [L28T-R30S] of 128 nM against tested DAAs) or as L28T-L31I (EC 90 [tested DAAs] of 5,000 nM) and were detected in evaluated GT-6b and -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f, and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Therefore, monitoring SVR in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is suggested to confirm any association between noted NS5A polymorphisms and treatment failure.",
keywords = "Genotype 6, HCV, NS3, NS5A, NS5B, Ombitasvir, Polymorphism, Resistance, Sofosbuvir, Velpatasvir",
author = "Fiona McPhee and Joseph Ueland and Vincent Vellucci and Scott Bowden and William Sievert and Nannan Zhou",
year = "2019",
month = "4",
day = "1",
doi = "10.1128/AAC.02205-18",
language = "English",
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journal = "Antimicrobial Agents and Chemotherapy",
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Impact of preexisting hepatitis C virus genotype 6 NS3, NS5A, and NS5B polymorphisms on the in vitro potency of direct-acting antiviral agents. / McPhee, Fiona; Ueland, Joseph; Vellucci, Vincent; Bowden, Scott; Sievert, William; Zhou, Nannan.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 4, e02205-18, 01.04.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Impact of preexisting hepatitis C virus genotype 6 NS3, NS5A, and NS5B polymorphisms on the in vitro potency of direct-acting antiviral agents

AU - McPhee, Fiona

AU - Ueland, Joseph

AU - Vellucci, Vincent

AU - Bowden, Scott

AU - Sievert, William

AU - Zhou, Nannan

PY - 2019/4/1

Y1 - 2019/4/1

N2 - HCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse, with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAA in vitro potency when evaluated in a GT-6a consensus replicon, and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the U.S. HCV database were compared, and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Preexisting resistance-associated substitutions (RASs) to NS3 protease (A156V and D168E) and NS5B nucleotide (L159F and S282C) inhibitors were rare (4%). Preexisting RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S). In vitro susceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (90% effective concentration [EC 90 ] range, 119 to 2,032 nM) compared with susceptibilities against a GT-6a consensus replicon (EC 90 range, 0.1 to 19 nM). These L28 RASs preexisted in combination with R30S (EC 90 [L28A-R30S] of 720 nM or EC 90 [L28T-R30S] of 128 nM against tested DAAs) or as L28T-L31I (EC 90 [tested DAAs] of 5,000 nM) and were detected in evaluated GT-6b and -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f, and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Therefore, monitoring SVR in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is suggested to confirm any association between noted NS5A polymorphisms and treatment failure.

AB - HCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse, with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAA in vitro potency when evaluated in a GT-6a consensus replicon, and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the U.S. HCV database were compared, and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Preexisting resistance-associated substitutions (RASs) to NS3 protease (A156V and D168E) and NS5B nucleotide (L159F and S282C) inhibitors were rare (4%). Preexisting RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S). In vitro susceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (90% effective concentration [EC 90 ] range, 119 to 2,032 nM) compared with susceptibilities against a GT-6a consensus replicon (EC 90 range, 0.1 to 19 nM). These L28 RASs preexisted in combination with R30S (EC 90 [L28A-R30S] of 720 nM or EC 90 [L28T-R30S] of 128 nM against tested DAAs) or as L28T-L31I (EC 90 [tested DAAs] of 5,000 nM) and were detected in evaluated GT-6b and -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f, and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Therefore, monitoring SVR in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is suggested to confirm any association between noted NS5A polymorphisms and treatment failure.

KW - Genotype 6

KW - HCV

KW - NS3

KW - NS5A

KW - NS5B

KW - Ombitasvir

KW - Polymorphism

KW - Resistance

KW - Sofosbuvir

KW - Velpatasvir

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U2 - 10.1128/AAC.02205-18

DO - 10.1128/AAC.02205-18

M3 - Article

VL - 63

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 1098-6596

IS - 4

M1 - e02205-18

ER -