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 language | English |
|---|---|
| Article number | e02205-18 |
| Number of pages | 12 |
| Journal | Antimicrobial Agents and Chemotherapy |
| Volume | 63 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 1 Apr 2019 |
Keywords
- Genotype 6
- HCV
- NS3
- NS5A
- NS5B
- Ombitasvir
- Polymorphism
- Resistance
- Sofosbuvir
- Velpatasvir
Cite this
}
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 journal › Article › Research › peer-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
UR - http://www.scopus.com/inward/record.url?scp=85063686119&partnerID=8YFLogxK
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 -