scholarly journals Naturally occurring hepatitis C virus (HCV) NS3/4A protease inhibitor resistance-related mutations in HCV genotype 1-infected subjects in Italy

2012 ◽  
Vol 67 (4) ◽  
pp. 984-987 ◽  
Author(s):  
I. Vicenti ◽  
A. Rosi ◽  
F. Saladini ◽  
G. Meini ◽  
F. Pippi ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Genotype 1 ◽  
Hcv Genotype ◽  
Protease Inhibitor Resistance ◽  
Naturally Occurring ◽  
Hcv Genotype 1 ◽  
Inhibitor Resistance

scholarly journals Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032)

2012 ◽  
Vol 56 (10) ◽  
pp. 5387-5396 ◽  
Author(s):  
Fiona McPhee ◽  
Amy K. Sheaffer ◽  
Jacques Friborg ◽  
Dennis Hernandez ◽  
Paul Falk ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Cysteine Proteases ◽  
Synergistic Activity ◽  
Significant Activity ◽  
Genotype 1 ◽  
Hcv Genotype ◽  
Hcv Genotype 1 ◽  
Ns3 Protease

ABSTRACTAsunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients chronically infected with HCV genotype 1 when combined with alfa interferon and/or the NS5A replication complex inhibitor daclatasvir. ASV competitively binds to the NS3/4A protease complex, withKivalues of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. Selectivity was demonstrated by the absence of any significant activity against the closely related GB virus-B NS3 protease and a panel of human serine or cysteine proteases. In cell culture, ASV inhibited replication of HCV replicons representing genotypes 1 and 4, with 50% effective concentrations (EC50s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC50, 67 to 1,162 nM). Selectivity was again demonstrated by the absence of activity (EC50, >12 μM) against a panel of other RNA viruses. ASV exhibited additive or synergistic activity in combination studies with alfa interferon, ribavirin, and/or inhibitors specifically targeting NS5A or NS5B. Plasma and tissue exposuresin vivoin several animal species indicated that ASV displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥110-fold above the inhibitor EC50s observed with HCV genotype-1 replicons. Based on these virologic and exposure properties, ASV holds promise for future utility in a combination with other anti-HCV agents in the treatment of HCV-infected patients.

Baseline prevalence and emergence of protease inhibitor resistance mutations following treatment in chronic HCV genotype 1-infected individuals

2015 ◽  
Vol 20 (8) ◽  
pp. 865-869 ◽  
Author(s):  
Linh Thuy Nguyen ◽  
Emma Gray ◽  
Jonathan Dean ◽  
Michael Carr ◽  
Jeff Connell ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Genotype 1 ◽  
Resistance Mutations ◽  
Hcv Genotype ◽  
Protease Inhibitor Resistance ◽  
Hcv Genotype 1 ◽  
Chronic Hcv ◽  
Inhibitor Resistance

scholarly journals Effects of 12-week treatment with Sovodak in patients infected by genotype 1 hepatitis C virus

2019 ◽  
Vol 7 (1) ◽  
pp. 1-6
Author(s):  
Hosein Mehdipour ◽  
Yaghoub Moaddab ◽  
Khalil Azizian ◽  
Morteza Ghojazadeh ◽  
Mohammad Hossein Somi
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
High Rate ◽  
Genotype 1 ◽  
Hcv Genotype ◽  
Definitive Evidence ◽  
Single Pill ◽  
Treatment Naïve ◽  
Hcv Genotype 1 ◽  
Rate Of Success

Introduction: It has been shown that the combination therapy of Sofosbuvir-Daclatasvir (Sof/Dac) has a high rate of success in the treatment of patients. For the first time, a single pill of Sof/Dac has been formulated in Iran (Sovodak). In this regard, the present study was carried out aiming to investigate the safety and efficacy of Sovodak for 12 weeks during treatment of patients infected by genotype 1 hepatitis C virus (HCV). Methods: In this study, 50 patients (25 and 25 treatment-naïve and treatment-experienced patients, respectively) infected by HCV genotype 1 received Sovodak (1pill per day) for 12 weeks. Ribavirin was added for patients who had definitive evidence of liver cirrhosis. The sustained virological response (SVR12) was investigated 12 weeks after the end of the therapy. Results: All 50 patients completed the treatment period. The mean age of patients was 54.40 ± 11.69 years, in addition, 60% and 90% of the patients were male and infected by HCV genotype 1b, respectively. After 4 and 12 weeks of treatment with Sovodak, the HCV ribonucleic acid (RNA) titer was undetectable in 82% and 100 % of the patients, respectively and 100% of them achieved SVR12. None of the subjects reported treatment discontinuation because of adverse events, however, 3 patients reported transient side effects including foot swelling, headache, and vomiting. Conclusion: The results of this study showed that once-daily Sovodak single-pill for 12 weeks is an effective and safe medicine for treating patients infected by HCV genotype 1

scholarly journals In VitroActivity and Resistance Profile of Dasabuvir, a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

2014 ◽  
Vol 59 (3) ◽  
pp. 1505-1511 ◽  
Author(s):  
Warren Kati ◽  
Gennadiy Koev ◽  
Michelle Irvin ◽  
Jill Beyer ◽  
Yaya Liu ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Clinical Isolates ◽  
Genotype 1 ◽  
Subgenomic Replicon ◽  
Hcv Genotype ◽  
Genotype 1A ◽  
Treatment Naïve ◽  
Hcv Genotype 1 ◽  
Hcv Ns5b

ABSTRACTDasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC50) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC50) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC50s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC50resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections.

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