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Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies.
- Source :
-
Liver international : official journal of the International Association for the Study of the Liver [Liver Int] 2017 Apr; Vol. 37 (4), pp. 514-528. Date of Electronic Publication: 2017 Jan 20. - Publication Year :
- 2017
-
Abstract
- Background & Aims: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures.<br />Methods: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N=200) and whenever possible at baseline (N=70).<br />Results: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P<.001). Interestingly, 57.1% of DAA IFN-free non-responders had a misclassified genotype, and 3/4 sofosbuvir breakthroughs showed the major-RAS-S282T, while RAS-L159F was frequently found in sofosbuvir relapsers (18.2%). Notably, 9.0% of patients showed also extra target RASs, and 47.4% of patients treated with ≥2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure.<br />Conclusions: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring.<br /> (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Subjects :
- Aged
Drug Therapy, Combination
Female
Genotype
Hepacivirus drug effects
Humans
Interferons therapeutic use
Italy
Male
Middle Aged
Mutation
Recurrence
Ribavirin therapeutic use
Sequence Analysis, DNA
Sofosbuvir therapeutic use
Sustained Virologic Response
Treatment Failure
Antiviral Agents therapeutic use
Drug Resistance, Viral genetics
Hepacivirus genetics
Hepatitis C, Chronic drug therapy
Viral Nonstructural Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1478-3231
- Volume :
- 37
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Liver international : official journal of the International Association for the Study of the Liver
- Publication Type :
- Academic Journal
- Accession number :
- 28105744
- Full Text :
- https://doi.org/10.1111/liv.13327