Two Distinct Hepatitis C Virus Genotype 1a Clades Have Different Geographical Distribution and Association With Natural Resistance to NS3 Protease Inhibitors

Luca, Andrea De; Giambenedetto, Simona Di; Presti, Alessandra Lo; Sierra, Saleta; Prosperi, Mattia; Cella, Eleonora; Giovanetti, Marta; Torti, Carlo; Caudai, Cinzia; Vicenti, Ilaria; Saladini, Francesco; Almi, P; Grima, Pierfrancesco; Blanc, Pierluigi; Fabbiani, Massimiliano; Rossetti, Barbara; Gagliardini, Roberta; Kaiser, Rolf; Ciccozzi, Massimo; Zazzi, Maurizio

doi:10.1093/ofid/ofv043

Cited by 37 publications

(54 citation statements)

References 45 publications

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“…Indeed, a single patient showed NS3 sequences harboring Q80K at a frequency higher than 15%, and all NS3 sequences from this patient belonged to clade I. Interestingly, the 2 patients showing the Q80K RAS at a frequency higher than 5% had a mixed infection with both clade I and clade II sequences. In this context, our results from phylogenetic analysis demonstrates that both clade I and II cocirculate with an approximately similar prevalence in our geographic area -in accordance with data from other Italian and European regions [31,32] -and that a mixed infection with both clades is quite a frequent event.…”

Section: Discussionsupporting

confidence: 92%

NS3 Variability in Hepatitis C Virus Genotype 1A Isolates from Liver Tissue and Serum Samples of Treatment-Naïve Patients with Chronic Hepatitis C

D’Aliberti

Cacciola²,

Musolino³

et al. 2018

Intervirology

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Background: Hepatitis C virus (HCV) NS3 resistance-associated substitutions (RASs) reduce HCV susceptibility to protease inhibitors. Little is known about NS3 RASs in viral isolates from the liver of chronic hepatitis C (CHC) patients infected with HCV genotype-1a (G1a). Aim: The objective of this work was to study NS3 variability in isolates from the serum and liver of HCV-G1a-infected patients naïve to direct-acting antivirals (DAAs). Methods: NS3 variability of HCV-G1a isolates from the serum and liver of 11 naïve CHC patients, and from sera of an additional 20 naïve CHC patients, was investigated by next-generation sequencing. Results: At a cutoff of 1%, NS3 RASs were detected in all the samples examined. At a cutoff of 15%, they were found in 54.5% (6/11) and 27.3% (3/11) of the paired liver and serum samples, respectively, and in 22.5% (7/31) of the overall serum samples examined. Twenty-six out of thirty-one (84%) patients showed NS3 variants with multiple RASs. Phylogenetic analysis showed that NS3 sequences clustered within 2 clades, with 10/31 (32.2%) patients infected by clade I, 15/31 (48.8%) by clade II, and 6/31 (19.3%) by both clades. Conclusions: Though the number of patients examined was limited, NS3 variants with RASs appear to be major components of both intrahepatic and circulating viral quasispecies populations in DAA-naïve patients.

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Section: Discussionsupporting

confidence: 92%

NS3 Variability in Hepatitis C Virus Genotype 1A Isolates from Liver Tissue and Serum Samples of Treatment-Naïve Patients with Chronic Hepatitis C

D’Aliberti

Cacciola²,

Musolino³

et al. 2018

Intervirology

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“…A different distribution of naturally occurring amino acid substitutions exist between clades. The Q80K polymorphism is only found in clade 1 and not clade 2 (48.9% versus 0%; n = 293 sequences) (De Luca et al, 2013). The Q80K polymorphism is believed to have originated in the US, with 96% of HCV infections in an international cohort of 677 patients with Q80K present analysed descending from a single lineage originating in the 1940s (McCloskey et al, 2014).…”

Section: Discussionmentioning

confidence: 93%

Prevalence of the hepatitis C virus NS3 polymorphism Q80K in genotype 1 patients in the European region

et al. 2015

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Hepatitis C virus (HCV) NS3 polymorphism Q80K is mainly found in patients with HCV genotype (G) 1a, and has been associated with a reduced treatment response to simeprevir with pegylated interferon (P) and ribavirin (R). Prevalence of Q80K among G1 patients may vary geographically. Q80K prevalence in the North-American G1 population in a recent study was 34%. We conducted a post hoc meta-analysis of Q80K polymorphism prevalence among HCV G1-infected patients enrolled in simeprevir and telaprevir Phase II/III studies. Baseline HCV NS3/4A protease sequences were analysed by population sequencing to determine Q80K prevalence. Overall, of 3349 patients from 25 countries in the European region analysed, 35.8%, 63.8% and 0.3% of patients had G1a, G1b and other/unknown HCV G1 subtypes, respectively. Q80K was detected at baseline in 7.5% of HCV G1 patients overall. Examination by subtype showed that 19.8%, 0.5% and 18.2% of patients with G1a, G1b and other/unknown HCV G1 subtypes had the Q80K polymorphism, respectively. Among countries in the European region with sequencing data available for either ⩾20 patients with G1a and/or ⩾40 G1 patients overall, the Q80K prevalence in G1 ranged from 0% in Bulgaria to 18.2% in the UK. Q80K prevalence also varied within G1a across different countries. HCV subtype 1a was correctly determined in 99% of patients by the LiPA v2 assay. A low overall prevalence of Q80K was observed in HCV G1-infected patients in the European region, compared with North America. However, the prevalence varied by country, due to differing ratios of G1a/G1b and differing Q80K prevalence within the G1a populations.

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“…The substitution event took place in the United States of America. The majority of HCV isolates with Q80K substitution (96%) originated from the same lineage, which indicates that this substitution is highly transmissible (26 (27).…”

Section: Discussionmentioning

confidence: 98%

High Prevalence of Q80K Among NS3 Resistance-Associated Substitutions in Subtype 1a Patients with Chronic Hepatitis C Prior to Treatment with Direct Acting Antivirals: The Croatian Data

et al. 2017

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Background: Therapy for chronic hepatitis C is based on direct-acting antiviral drugs (DAA) that include protease inhibitors, polymerase inhibitors, as well as inhibitors of NS5A protein. Resistance-associated substitutions (RAS) can be associated with inadequate treatment outcomes with DAA. People with HCV subtype 1a infection carrying Q80K polymorphism could have a reduced treatment response to a protease inhibitor simeprevir. The data on the prevalence of Q80K polymorphism and other RAS worldwide are quite variable. Objectives:The study goal was to analyze the frequency of Q80K polymorphism and other substitutions associated with HCV resistance to NS3 inhibitors in patients previously not treated with simeprevir infected with HCV subtype 1a from Croatia. Methods: The study included 136 people with chronic hepatitis C and infected with HCV subtype 1a receiving clinical care at the department of viral hepatitis of the University hospital for infectious diseases, Zagreb and Croatian reference center for viral hepatitis from July 2015 to April 2016. All participants were not previously treated with simeprevir and not co-infected with HIV. Detection of Q80K polymorphism and other substitutions associated with resistance to NS3 inhibitors was performed by population-based sequencing on ABI PRISM ® 3100 genetic analyzer. Phylogenetic tree was constructed using the Maximum Likelihood method and

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Two Distinct Hepatitis C Virus Genotype 1a Clades Have Different Geographical Distribution and Association With Natural Resistance to NS3 Protease Inhibitors

Cited by 37 publications

References 45 publications

NS3 Variability in Hepatitis C Virus Genotype 1A Isolates from Liver Tissue and Serum Samples of Treatment-Naïve Patients with Chronic Hepatitis C

NS3 Variability in Hepatitis C Virus Genotype 1A Isolates from Liver Tissue and Serum Samples of Treatment-Naïve Patients with Chronic Hepatitis C

Prevalence of the hepatitis C virus NS3 polymorphism Q80K in genotype 1 patients in the European region

High Prevalence of Q80K Among NS3 Resistance-Associated Substitutions in Subtype 1a Patients with Chronic Hepatitis C Prior to Treatment with Direct Acting Antivirals: The Croatian Data

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