Significance of Mutations in the Region Coding for NS3/4 Protease in Patients Infected with HCV Genotype 1b

2016 ◽  
Vol 64 (2) ◽  
pp. S527
Author(s):  
T.W. Lapinski ◽  
J. Nikolajuk-Stasiuk ◽  
M. Rogalska-Plonska ◽  
O. Kowalczuk ◽  
J. Kisluk ◽  
...  
Keyword(s):  
Hcv Genotype ◽  
Genotype 1B ◽  
Region Coding

scholarly journals Significance of mutations in the region coding for NS3/4 protease in patients infected with HCV genotype 1b.

2018 ◽  
Vol 27 (11) ◽  
pp. 1593-1600
Author(s):  
Tadeusz Łapiński ◽  
Magdalena Rogalska-Plonska ◽  
Oksana Kowalczuk ◽  
Joanna Kiśluk ◽  
Joanna Zurnowska ◽  
...  
Keyword(s):  
Hcv Genotype ◽  
Genotype 1B ◽  
Region Coding

scholarly journals Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 743
Author(s):  
Mohammad Alkhatib ◽  
Velia Di Maio ◽  
Valentina De Murtas ◽  
Ennio Polilli ◽  
Martina Milana ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multivariable Analysis ◽  
Viral Fitness ◽  
Cellular Proteins ◽  
Genetic Determinants ◽  
Hcv Genotype ◽  
Genotype 1B ◽  
Oncogenic Pathways ◽  
Cirrhotic Patients ◽  
Cycle Regulation

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC-group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell-cycle regulation (p53, p85-PIK3, and β-catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.

scholarly journals Resistance Analysis of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir

2012 ◽  
Vol 56 (7) ◽  
pp. 3670-3681 ◽  
Author(s):  
Fiona McPhee ◽  
Jacques Friborg ◽  
Steven Levine ◽  
Chaoqun Chen ◽  
Paul Falk ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Clinical Studies ◽  
Replication Capacity ◽  
Replication Complex ◽  
Hcv Genotype ◽  
Genotype 1A ◽  
Genotype 1B ◽  
Ns3 Protease

ABSTRACTAsunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor demonstrating efficacy in alfa interferon-sparing, direct-acting antiviral dual-combination regimens (together with the NS5A replication complex inhibitor daclatasvir) in patients chronically infected with HCV genotype 1b. Here, we describe a comprehensivein vitrogenotypic and phenotypic analysis of asunaprevir-associated resistance against genotypes 1a and 1b using HCV replicons and patient samples obtained from clinical studies of short-term asunaprevir monotherapy. During genotype 1a resistance selection using HCV replicons, the primary NS3 protease substitutions identified were R155K, D168G, and I170T, which conferred low- to moderate-level asunaprevir resistance (5- to 21-fold) in transient-transfection susceptibility assays. For genotype 1b, a higher level of asunaprevir-associated resistance was observed at the same selection pressures, ranging from 170- to 400-fold relative to the wild-type control. The primary NS3 protease substitutions identified occurred predominantly at amino acid residue D168 (D168A/G/H/V/Y) and were associated with high-level asunaprevir resistance (16- to 280-fold) and impaired replication capacity. In asunaprevir single-ascending-dose and 3-day multiple-ascending-dose studies in HCV genotype 1a- or 1b-infected patients, the predominant pre-existing NS3 baseline polymorphism was NS3-Q80K. This substitution impacted initial virologic response rates in a single-ascending-dose study, but its effects after multiple doses were more ambiguous. Interestingly, for patient NS3 protease sequences containing Q80 and those containing K80, susceptibilities to asunaprevir were comparable when tested in an enzyme assay. No resistance-associated variants emerged in these clinical studies that significantly impacted susceptibility to asunaprevir. Importantly, asunaprevir-resistant replicons remained susceptible to an NS5A replication complex inhibitor, consistent with a role for asunaprevir in combination therapies.

scholarly journals Efficacy and safety of 12 weeks of daclatasvir, asunaprevir plus ribavirin for HCV genotype-1b infection without NS5A resistance-associated substitutions

2019 ◽  
Vol 118 (2) ◽  
pp. 556-564 ◽  
Author(s):  
Ming-Lung Yu ◽  
Chao-Hung Hung ◽  
Yi-Hsiang Huang ◽  
Cheng-Yuan Peng ◽  
Chun-Yen Lin ◽  
...  
Keyword(s):  
Efficacy And Safety ◽  
Hcv Genotype ◽  
Genotype 1B

scholarly journals Genotype-specific versus pangenotypic regimens in patients infected with HCV genotype 1b in real-world settings

2021 ◽  
Author(s):  
Paweł Pabjan ◽  
Michał Brzdęk ◽  
Magdalena Chrapek ◽  
Kacper Dziedzic ◽  
Piotr M. Stępień ◽  
...  
Keyword(s):  
Real World ◽  
Hcv Genotype ◽  
Genotype 1B

scholarly journals Efficacy and safety of narlaprevir/ritonavir and daclatasvir non interferon combination in population of Russian patients with chronic hepatitis C

2019 ◽  
Vol 91 (8) ◽  
pp. 67-74
Author(s):  
E A Klimova ◽  
E Z Burnevich ◽  
V P Chulanov ◽  
D A Gusev ◽  
O O Znoyko ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Efficacy And Safety ◽  
Hcv Genotype ◽  
Genotype 1B ◽  
Safety Population ◽  
Viral Hepatitis C ◽  
Treatment Naïve ◽  
The Mean ◽  
Almost All ◽  
Direct Acting

Aim. Evaluate efficacy and safety of a combination of direct - acting antivirals narlaprevir/ritonavir with daclatasvir in patients with viral hepatitis C. Materials and methods. The study enrolled adult patients with HCV genotype 1b infection without demonstrated NS5A resistance - associated substitutions Y93C/H/N/S and/or L31F/M/V/I. Patients were treated with narlaprevir 200 mg QD, ritonavir 100 mg QD and daclatasvir 60 mg QD. Treatment duration was 12 weeks. Proportion of patients achieving sustained virological response 12 weeks after treatment (SVR12) was the primary efficacy endpoint. Results and discussion. In total, 105 (75.0%) patients were treatment with the study combination. Patients’ age varied from 21 to 69 years, the mean age being 43.2±10.9 years. There were slightly more women (55.2%), and 69 patients (65.7%) had comorbidities. SVR 12 was 89.5% (95% CI 82.0-94.7%). In 10 of 11 patients with treatment failures NS5A resistance - associated substitutions in residues 31 and/or 93 were found, as well as less clinically relevant substitutions L28M, P58S, R30Q, Q62K. Adverse events (AEs) were found in less than one half of patients (45 patients, or 42.9% in the safety population). Almost all recorded AEs were mild to moderate. Conclusion. Efficacy of treatment with a combination of narlaprevir/ritonavir and daclatasvir in treatment - naïve patients with HCV genotype 1b was close to 90%. This combination was found to be safe and well - tolerated.

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