Resistance-associated substitutions after sofosbuvir/velpatasvir/voxilaprevir triple therapy failure.
Aged
Aminoisobutyric Acids
Antiviral Agents
/ therapeutic use
Carbamates
Cyclopropanes
Drug Resistance, Viral
Drug Therapy, Combination
Genotype
Hepacivirus
/ genetics
Hepatitis C, Chronic
/ drug therapy
Heterocyclic Compounds, 4 or More Rings
Humans
Lactams, Macrocyclic
Leucine
/ analogs & derivatives
Male
Middle Aged
Proline
/ analogs & derivatives
Quinoxalines
Sofosbuvir
/ therapeutic use
Sulfonamides
Treatment Failure
Viral Nonstructural Proteins
/ genetics
RAS
RAS-guided salvage treatment
deep sequencing
hepatitis C virus
treatment failure
triple therapy
Journal
Journal of viral hepatitis
ISSN: 1365-2893
Titre abrégé: J Viral Hepat
Pays: England
ID NLM: 9435672
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
03
03
2021
received:
23
12
2020
accepted:
04
03
2021
pubmed:
16
3
2021
medline:
5
10
2021
entrez:
15
3
2021
Statut:
ppublish
Résumé
Direct-acting antivirals (DAAs) resolve chronic HCV infection in >95% of patients, but a small percentage do not respond to DAA-based therapy. These may be difficult to treat because of resistance-associated substitutions (RAS) emerging after treatment failure. Triple therapy with sofosbuvir (SOF)/velpatasvir (VEL)/voxilaprevir (VOX) is the recommended retreatment after DAA-based failure. However, in rare cases, failure to triple therapy occurs, and there is little information characterizing the viruses that relapse. To determine the RAS profile after failing SOF/VEL/VOX, and seek suitable alternatives for retreatment, samples from 5 patients were analysed using MiSeq Illumina deep sequencing before and after triple therapy. All patients were men, aged 59-78 years, 2 HCV genotype (G) 1b and 3 G3a. The most prevalent NS3 substitutions after SOF/VEL/VOX failure were Y56F and A166T. Four patients had the NS5A RAS, Y93H, after triple failure, and Y93H was observed in both G1b patients before retreatment and after SOF/ledipasvir failure. In 2 G3a patients, Y93H appeared at triple failure, and on the other G3a, A30K persisted in 100% of viral genomes. Finally, G1b patients showed C316N in NS5B, associated with SOF failure, but G3a patients had no known NS5B substitutions. HCV RAS analysis identified the following substitutions present at higher rates after triple failure: Y56F in NS3 (G1b), A166T in NS3 (G3a), A30K or Y93H in NS5A, and C316N in NS5B (G1b). A RAS-based salvage treatment (SOF + glecaprevir/pibrentasvir + RBV) was successfully used in one G3a patient.
Substances chimiques
Aminoisobutyric Acids
0
Antiviral Agents
0
Carbamates
0
Cyclopropanes
0
Heterocyclic Compounds, 4 or More Rings
0
Lactams, Macrocyclic
0
Quinoxalines
0
Sulfonamides
0
Viral Nonstructural Proteins
0
voxilaprevir
0570F37359
Proline
9DLQ4CIU6V
Leucine
GMW67QNF9C
velpatasvir
KCU0C7RS7Z
Sofosbuvir
WJ6CA3ZU8B
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1319-1324Subventions
Organisme : Ministerio de Sanidad, Consumo y Bienestar Social
Organisme : European Regional Development Fund
Organisme : Instituto de Salud Carlos III
Organisme : Centre for Industrial Technological Development
Informations de copyright
© 2021 John Wiley & Sons Ltd.
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