scholarly journals Antiviral Effect, Safety, and Pharmacokinetics of Five-Day Oral Administration of Deleobuvir (BI 207127), an Investigational Hepatitis C Virus RNA Polymerase Inhibitor, in Patients with Chronic Hepatitis C

2013 ◽  
Vol 57 (10) ◽  
pp. 4727-4735 ◽  
Author(s):  
Dominique Larrey ◽  
Ansgar W. Lohse ◽  
Christian Trepo ◽  
Jean-Pierre Bronowicki ◽  
Keikawus Arastéh ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Rna Polymerase ◽  
Hcv Rna ◽  
Genotype 1 ◽  
Double Blind ◽  
Hcv Genotype ◽  
Hcv Genotype 1 ◽  
Dose Dependent

ABSTRACTDeleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days' deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN;n= 15) and treatment-experienced (TE;n= 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n= 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log10(with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log10. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistancein vitrowere detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.

scholarly journals First-in-Human Study of the Pharmacokinetics and Antiviral Activity of IDX375, a Novel Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

2012 ◽  
Vol 56 (8) ◽  
pp. 4525-4528 ◽  
Author(s):  
J. de Bruijne ◽  
J. van de Wetering de Rooij ◽  
A. A. van Vliet ◽  
X. J. Zhou ◽  
M. F. Temam ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Human Study ◽  
Hcv Rna ◽  
Genotype 1 ◽  
Hcv Genotype ◽  
Clinical Investigations ◽  
Hcv Genotype 1 ◽  
Study Participants

ABSTRACTIDX375 is a potent and selective palm-binding nonnucleoside inhibitor of the hepatitis C virus (HCV) genotype 1 polymerase. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics of IDX375 in healthy volunteers, as well as its antiviral activity in HCV-infected patients. IDX375, as a choline salt, was administered for 1 day to 40 healthy male volunteers (25- to 200-mg IDX375-equivalent single ascending doses and a 200-mg twice-daily [BID] dose) and three patients chronically infected with HCV genotype 1 (200 mg BID only). IDX375 was well absorbed and well tolerated by all of the study participants. A single-day 200-mg BID dose resulted in exposure-related anti-HCV activity with maximal 0.5 to 1.1 log10reductions in plasma HCV RNA. These observations support further clinical investigations of IDX375.

scholarly journals Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of GSK2336805, an Inhibitor of Hepatitis C Virus (HCV) NS5A, in Healthy Subjects and Subjects Chronically Infected with HCV Genotype 1

2013 ◽  
Vol 57 (10) ◽  
pp. 5037-5044 ◽  
Author(s):  
D. A. Wilfret ◽  
J. Walker ◽  
K. K. Adkison ◽  
L. A. Jones ◽  
Y. Lou ◽  
...  
Keyword(s):  
Single Dose ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Healthy Subjects ◽  
Hcv Rna ◽  
Genotype 1 ◽  
Once Daily ◽  
Hcv Genotype ◽  
Hcv Genotype 1

ABSTRACTGSK2336805 is an orally bioavailable hepatitis C virus (HCV) inhibitor working through an NS5A-mediated mechanism. This first-time-in-human study was conducted to assess the safety, tolerability, pharmacokinetics, metabolism, and efficacy of GSK2336805 in healthy subjects and subjects infected with HCV genotype 1. We performed a three-part, randomized, double-blind, placebo-controlled study in 46 healthy subjects and 23 HCV-infected subjects. After an overnight fast, healthy subjects received GSK2336805 as 10 mg, 30 mg, 30 mg plus food, and 60 mg in a single dose and 10 mg (7 days), 30 mg (7 days), and 75 mg (14 days) in a once-daily multiple dose. Subjects with HCV received GSK2336805 as a 1- to 120-mg single dose. In subjects with HCV, reductions in HCV RNA were observed within 4 h and a single dose of GSK2336805 of ≥10 mg resulted in a statistically significant ≥2-log reduction in HCV RNA compared with placebo at 24 h postdose. GSK2336805 was readily absorbed in all subjects, and the half-life (t1/2) was suitable for once-daily dosing. Administration of GSK2336805 with food had no effect on plasma GSK2336805 exposure; however, absorption was delayed, with a mediantmax(time to maximum concentration of drug in serum) of 4.5 versus 2.0 h. Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. GSK2336805 was well tolerated and exhibited rapid, significant antiviral activity after a single dose in HCV-infected subjects. These results support the conduct of further studies evaluating GSK2336805 administered once daily for longer durations in combination with peginterferon, ribavirin, and other direct-acting antivirals. (This study has been registered at ClinicalTrials.gov under registration no. NCT01277692.)

scholarly journals Molecular epidemiology of Hepatitis C Virus (HCV) in liver disease patients in Sri Lanka

2014 ◽  
Vol 6 (3) ◽  
pp. 1-5
Author(s):  
D. B. Senevirathna ◽  
Y. Wahalathanthri ◽  
P. Thiyagarajah ◽  
A. Shani ◽  
S. Jayasinghe ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Sri Lanka ◽  
Hcv Rna ◽  
Sri Lankan ◽  
Genotype 1 ◽  
Hcv Genotype ◽  
Specific Amplification ◽  
Hcv Genotype 1

Background: Globally, hepatitis C virus (HCV) is an important cause of chronic liver disease. Genotypes of HCV are associated with different profiles of pathogenicity, infectivity, and antiviral therapy. The prevalence of HCV and distribution of HCV genotypes in Sri Lanka in comparison with the rest of Asia is not well known.Objective: The objective of the study was to investigate the presence of HCV and to genotype HCV in a group of Sri Lankan patients suspected to have liver disease.Methods: A total of 1933 samples were screened for HCV antibodies using ELISA and HCV RNA with RT-PCR methods. RNA positive samples were genotyped by type specific amplification and by DNA sequencing.Results: Out Of the 1933 liver disease patients tested 219 (11.33%) were detected to be positive for anti-HCV antibodies, out of which, 54 (24.66%) were positive for HCV RNA. Furthermore out of 49 positively tested patients, 24 (48.97%) were found to be categorised as HCV genotype 1.Conclusion: This result confirms previous observations that the contribution of HCV as a causative virus in liver disease patients is low in Sri Lanka. HCV genotype 1 was found to be the most predominant genotype in studied cohort of Sri Lankan liver disease patients. DOI: http://dx.doi.org/10.3126/ajms.v6i3.10741Asian Journal of Medical Sciences Vol.6(3) 2015 1-5

scholarly journals In VitroandIn VivoAntiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A

2014 ◽  
Vol 59 (2) ◽  
pp. 979-987 ◽  
Author(s):  
Preethi Krishnan ◽  
Jill Beyer ◽  
Neeta Mistry ◽  
Gennadiy Koev ◽  
Thomas Reisch ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Wild Type Virus ◽  
Hcv Rna ◽  
Sequencing Analysis ◽  
Genotype 1 ◽  
Resistant Variant ◽  
Hcv Genotype ◽  
Hcv Genotype 1

ABSTRACTOmbitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A.In vitroresistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluatedin vivoin a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log10IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. These data support clinical development of ombitasvir in combination with inhibitors targeting HCV NS3/4A protease (ABT-450 with ritonavir) and HCV NS5B polymerase (ABT-333, dasabuvir) for the treatment of chronic HCV genotype 1 infection. (Study M12-116 is registered at ClinicalTrials.gov under registration no. NCT01181427.)

scholarly journals Quantification of Hepatitis C Virus (HCV) RNA in a Multicenter Study: Implications for Management of HCV Genotype 1-Infected Patients

2009 ◽  
Vol 47 (9) ◽  
pp. 2931-2936 ◽  
Author(s):  
G. Pisani ◽  
K. Cristiano ◽  
F. Marino ◽  
F. Luciani ◽  
G. M. Bisso ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Multicenter Study ◽  
Hcv Rna ◽  
Genotype 1 ◽  
Hcv Genotype ◽  
Hcv Genotype 1

scholarly journals Preclinical Characterization of PF-00868554, a Potent Nonnucleoside Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase

2009 ◽  
Vol 53 (6) ◽  
pp. 2544-2552 ◽  
Author(s):  
Stephanie T. Shi ◽  
Koleen J. Herlihy ◽  
Joanne P. Graham ◽  
Jim Nonomiya ◽  
Sadayappan V. Rahavendran ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Rna Polymerase ◽  
Serum Proteins ◽  
Resistance Mutation ◽  
Hcv Rna ◽  
Genotype 1 ◽  
Genotype 1A

ABSTRACT PF-00868554 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, which exerts its inhibitory effect by binding to the thumb base domain of the protein. It is a potent and selective inhibitor, with a mean 50% inhibitory concentration of 0.019 μM against genotype 1 polymerases and a mean 50% effective concentration (EC50) of 0.075 μM against the genotype 1b-Con1 replicon. To determine the in vitro antiviral activity of PF-00868554 against various HCV strains, a panel of chimeric replicons was generated, in which polymerase sequences derived from genotype 1a and 1b clinical isolates were cloned into the 1b-Con1 subgenomic reporter replicon. Our results indicate that PF-00868554 has potent in vitro antiviral activity against a majority (95.8%) of genotype 1a and 1b replicons, with an overall mean EC50 of 0.059 μM. PF-00868554 showed no cytotoxic effect in several human cell lines, up to the highest concentration evaluated (320 μM). Furthermore, the antiviral activity of PF-00868554 was retained in the presence of human serum proteins. An in vitro resistance study of PF-00868554 identified M423T as the predominant resistance mutation, resulting in a 761-fold reduction in susceptibility to PF-00868554 but no change in susceptibility to alpha interferon and a polymerase inhibitor that binds to a different region. PF-00868554 also showed good pharmacokinetic properties in preclinical animal species. Our results demonstrate that PF-00868554 has potent and broad-spectrum antiviral activity against genotype 1 HCV strains, supporting its use as an oral antiviral agent in HCV-infected patients.

scholarly journals Quantification of Hepatitis C Virus (HCV) RNA in a Multicenter Study: Implications for Management of HCV Genotype 1-Infected Patients

2009 ◽  
Vol 47 (11) ◽  
pp. 3795-3795
Author(s):  
G. Pisani ◽  
K. Cristiano ◽  
F. Marino ◽  
F. Luciani ◽  
G. M. Bisso ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Multicenter Study ◽  
Hcv Rna ◽  
Genotype 1 ◽  
Hcv Genotype ◽  
Hcv Genotype 1

scholarly journals Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection

2015 ◽  
Vol 60 (3) ◽  
pp. 1546-1555 ◽  
Author(s):  
Eric J. Lawitz ◽  
William D. O'Riordan ◽  
Armen Asatryan ◽  
Bradley L. Freilich ◽  
Terry D. Box ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Viral Load ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Genotype 1 ◽  
Direct Acting Antivirals ◽  
Hcv Genotype ◽  
Compensated Cirrhosis ◽  
Hcv Genotype 1 ◽  
Direct Acting

ABT-493 is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530 is an HCV NS5A inhibitor. These direct-acting antivirals (DAAs) demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistancein vitro. In this open-label dose-ranging trial, antiviral activity and safety were assessed during 3 days of monotherapy with ABT-493 or ABT-530 in treatment-naive adults with HCV genotype 1 infection, with or without compensated cirrhosis. The presence of baseline resistance-associated variants (RAVs) was also evaluated. The mean maximal decreases in HCV RNA levels from baseline were approximately 4 log10IU/ml for all ABT-493 doses ranging from 100 mg to 700 mg and for ABT-530 doses of ≥40 mg. There were no meaningful differences in viral load declines for patients with versus without compensated cirrhosis. Twenty-four (50%) of the baseline samples from patients treated with ABT-493 had RAVs to NS3/4A protease inhibitors. Among 40 patients treated with ABT-530, 6 (15%) carried baseline RAVs to NS5A inhibitors. Viral load declines in patients with single baseline NS5A RAVs were similar to those in patients without RAVs. One patient harbored baseline RAVs at 3 NS5A positions and appeared to have a slightly less robust viral load decline on day 3 of monotherapy. No serious or grade 3 (severe) or higher adverse events and no clinically relevant laboratory abnormalities were observed with either compound. ABT-493 and ABT-530 demonstrated potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis. Based on these results, phase II studies assessing the combination of these DAAs for the treatment of chronic HCV infection in patients with or without compensated cirrhosis have been initiated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01995071.)

scholarly journals Optimizing Hepatitis C Therapy in HIV/hepatitis C Virus (HCV) Coinfected Patients: Analysis of HCV Viral Kinetics on Treatment

2012 ◽  
Vol 23 (1) ◽  
pp. 31-35 ◽  
Author(s):  
Paul Damien James ◽  
David KH Wong
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Pegylated Interferon ◽  
Hcv Rna ◽  
Genotype 1 ◽  
Viral Kinetics ◽  
Hcv Genotype ◽  
Hiv Coinfection ◽  
Genotype 2 ◽  
Hcv Genotype 1

INTRODUCTION: Hepatitis C virus (HCV) infection is potentially curable, but the sustained virological response (SVR) has been shown to be lower in patients coinfected HIV. A single-centre experience treating individuals with HCV and HIV coinfection is reported.METHODS: Twenty-one patients who received standard doses of pegylated interferon with weight-based dosing of ribavirin (mean 14.3 mg/kg) were retrospectively reviewed. Qualitative HCV polymerase chain reaction (PCR) was performed prospectively every four weeks if the patient remained HCV PCR positive. All patients with HCV genotype 1 were treated for 48 weeks. Patients with genotype 2 or 3 were treated for 24 weeks and 32 weeks to 36 weeks if their HCV RNA level was undetectable after four weeks (RVR4) or eight weeks (RVR8) of therapy, respectively. If RVR8 was not achieved, the treatment was continued for 48 weeks.RESULTS: There were no dropouts or dose reductions within the first 12 weeks of treatment. SVR status was available for 20 patients and adequate serum for viral kinetics analyses was available for 17 patients. Eighty per cent of the patients achieved SVR (50% genotype 1; 100% genotypes 2 and 3). The week 8 viral load remained elevated for all genotype 1 nonresponders.DISCUSSION: High effectiveness rates were seen, particularly in patients with HCV genotype 2 and 3 who were treated for shorter durations. HCV viral loads after eight weeks of therapy helped distinguish patients with HCV genotype 1 who would respond to therapy.

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