Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C.
ALT, alanine aminotransferase
AST, aspartate transaminase
ASV, asunaprevir
BCV, beclabuvir
CT, computed tomography
DAA, direct-acting antiviral
DCV, daclatasvir
Direct acting antiviral
EBR, elbasvir
FIB-4, Fibrosis-4
GLE, glecaprevir
GZR, grazoprevir
Hepatitis C virus
IFN, interferon
LDV, ledipasvir
MRI, magnetic resonance imaging
OBV, ombitasvir
OR, odds ratio
P32del
PI, protease inhibitor
PIB, pibrentasvir
PTV/r, paritaprevir/ritonavir
RAS, resistance-associated substitutions
RBV, ribavirin
Resistance-associated substitution
SOF, sofosbuvir
SVR, sustained virological response
VEL, velpatasvir
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
Oct 2020
Oct 2020
Historique:
received:
10
12
2019
revised:
29
05
2020
accepted:
05
06
2020
entrez:
21
8
2020
pubmed:
21
8
2020
medline:
21
8
2020
Statut:
epublish
Résumé
We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections. A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing. Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens ( Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV. Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.
Sections du résumé
BACKGROUND & AIMS
OBJECTIVE
We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections.
METHODS
METHODS
A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing.
RESULTS
RESULTS
Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (
CONCLUSIONS
CONCLUSIONS
Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV.
LAY SUMMARY
BACKGROUND
Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.
Identifiants
pubmed: 32817930
doi: 10.1016/j.jhepr.2020.100138
pii: S2589-5559(20)30072-0
pii: 100138
pmc: PMC7424232
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100138Informations de copyright
© 2020 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details.
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