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Viruses 2017, 9(8), 212; doi:10.3390/v9080212

Characterization of Naturally Occurring NS5A and NS5B Polymorphisms in Patients Infected with HCV Genotype 3a Treated with Direct-Acting Antiviral Agents

1
National Institute for Infectious Diseases “L. Spallanzani”, Via Portuense 292, 00149 Rome, Italy
2
Bristol-Myers Squibb Research and Development, Wallingford, CT 06492, USA
3
Laboratory of Virology, National Institute for Infectious Diseases “L. Spallanzani”, Via Portuense 292, 00149 Rome, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Curt Hagedorn
Received: 28 June 2017 / Revised: 27 July 2017 / Accepted: 31 July 2017 / Published: 7 August 2017
(This article belongs to the Section Antivirals & Vaccines)
View Full-Text   |   Download PDF [2310 KB, uploaded 16 August 2017]   |  

Abstract

Hepatitis C virus (HCV) genotype (GT)3 is associated with increased risk of steatosis, development of cirrhosis and hepatocellular carcinoma. Limited data are available regarding genetic variability and use of direct-acting antiviral agents in these patients. non-structural protein 5A (NS5A) and non-structural protein 5B (NS5B) sequencing was performed on 45 HCV GT3-infected Italian patients subsequently treated with sofosbuvir ± daclatasvir (SOF ± DCV). Novel GT3a polymorphisms were observed by Sanger sequencing in three NS5A (T79S, T107K, and T107S) and three NS5B (G166R, Q180K, and C274W) baseline sequences in patients who achieved sustained virological response (SVR). Baseline NS5A resistance-associated substitutions A30K and Y93H were detected in 9.5% of patients; one patient with A30K did not achieve SVR. Phylogenetic analyses of sequences showed no distinct clustering. Genetic heterogeneity of NS5A and NS5B was evaluated using ultra-deep pyrosequencing (UDPS) in samples longitudinally collected in patients not achieving SVR. Some novel NS5A and NS5B polymorphisms detected at baseline may not impact treatment outcome, as they were not enriched in post-failure samples. In contrast, the novel L31F NS5A variant emerged in one treatment failure, and I184T, G188D and N310S, located on the same NS5B haplotype, became predominant after failure. These findings suggest a potential impact of these novel substitutions on the treatment outcome; however, their significance requires further investigation. View Full-Text
Keywords: HCV; Genotype3; genetic variability; NS5A; NS5B; polymorphism; resistance-associated substitutions; ultra-deep pyrosequencing HCV; Genotype3; genetic variability; NS5A; NS5B; polymorphism; resistance-associated substitutions; ultra-deep pyrosequencing
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Bartolini, B.; Giombini, E.; Taibi, C.; Lionetti, R.; Montalbano, M.; Visco-Comandini, U.; D’Offizi, G.; Capobianchi, M.R.; McPhee, F.; Garbuglia, A.R. Characterization of Naturally Occurring NS5A and NS5B Polymorphisms in Patients Infected with HCV Genotype 3a Treated with Direct-Acting Antiviral Agents. Viruses 2017, 9, 212.

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