scholarly journals Persistence of Resistant Variants in Hepatitis C Virus-Infected Patients Treated with the NS5A Replication Complex Inhibitor Daclatasvir

2013 ◽  
Vol 57 (5) ◽  
pp. 2054-2065 ◽  
Author(s):  
Chunfu Wang ◽  
Jin-Hua Sun ◽  
Donald R. O'Boyle ◽  
Peter Nower ◽  
Lourdes Valera ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Fitness ◽  
Viral Rna ◽  
Wild Type Virus ◽  
Replication Complex ◽  
Resistance Patterns

ABSTRACTDaclatasvir (DCV; BMS-790052) is a hepatitis C virus (HCV) NS5A replication complex inhibitor (RCI) with picomolar to low nanomolar potency and broad genotypic coveragein vitro. Viral RNA declines have been observed in the clinic for both alpha interferon-ribavirin (IFN-α–RBV) and IFN-RBV-free regimens that include DCV. Follow-up specimens (up to 6 months) from selected subjects treated with DCV in 14-day monotherapy studies were analyzed for genotype and phenotype. Variants were detected by clonal sequencing in specimens from baseline and were readily detected by population sequencing following viral RNA breakthrough and posttreatment. The major amino acid substitutions generating resistancein vivowere at residues M28, Q30, L31, and Y93 for genotype 1a (GT-1a) and L31 and Y93 for GT-1b, similar to the resistance substitutions observed with thein vitroreplicon system. The primary difference in the resistance patterns observedin vitroandin vivowas the increased complexity of linked variant combinations observed in clinical specimens. Changes in the percentage of individual variants were observed during follow-up; however, the overall percentage of variants in the total population persisted up to 6 months. Our results suggest that during the 14-day monotherapy, most wild-type virus was eradicated by DCV. After the end of DCV treatment, viral fitness, rather than DCV resistance, probably determines which viral variants emerge as dominant in populations.

scholarly journals Preclinical Profile and Clinical Efficacy of a Novel Hepatitis C Virus NS5A Inhibitor, EDP-239

2016 ◽  
Vol 60 (10) ◽  
pp. 6207-6215 ◽  
Author(s):  
Christopher M. Owens ◽  
Bradley B. Brasher ◽  
Alex Polemeropoulos ◽  
Michael H. J. Rhodin ◽  
Nicole McAllister ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonstructural Protein ◽  
Viral Rna ◽  
Controlled Clinical Trial ◽  
Genotype 1A ◽  
Pharmacokinetic Properties ◽  
Direct Acting

ABSTRACTEDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigatedin vitroandin vivo. EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistancein vitro. Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC50s) equivalent to those for the wild type. In a phase I, single-ascending-dose, placebo-controlled clinical trial, EDP-239 demonstrated excellent pharmacokinetic properties that supported once daily dosing. A single 100-mg dose of EDP-239 resulted in reductions in HCV genotype 1a viral RNA of >3 log10IU/ml within the first 48 h after dosing and reductions in genotype 1b viral RNA of >4-log10IU/ml within 96 h. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.)

scholarly journals Modeling Subgenomic Hepatitis C Virus RNA Kinetics during Treatment with Alpha Interferon

2009 ◽  
Vol 83 (13) ◽  
pp. 6383-6390 ◽  
Author(s):  
Harel Dahari ◽  
Bruno Sainz ◽  
Alan S. Perelson ◽  
Susan L. Uprichard
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Rna ◽  
Alpha Interferon ◽  
Hcv Rna ◽  
Second Phase ◽  
Inhibition Kinetics ◽  
Rna Levels

ABSTRACT Although replicons have been used to demonstrate hepatitis C virus (HCV) inhibition by alpha interferon (IFN-α), the detailed inhibition kinetics required to mathematically model HCV RNA decline have been lacking. Therefore, we measured genotype 1b subgenomic replicon (sg1b) RNA levels under various IFN-α concentrations to assess the inhibition kinetics of intracellular HCV RNA. During nine days of IFN-α treatment, sg1b RNA decreased in a biphasic, dose-dependent manner. Using frequent measurements to dissect these phases during IFN-α treatments of 100 and 250 U/ml revealed that the first-phase sg1b RNA decline began ∼12 h posttreatment, continued for 2 to 4 days, and then exhibited a distinct flat or slower second phase. Based on these data, we developed a mathematical model of IFN-α-induced intracellular sg1b RNA decline, and we show that the mechanism(s) mediating IFN-α inhibition of HCV acts primarily by reducing sg1b RNA amplification, with an additional effect on HCV RNA stability/degradation detectable at a dose of 250 U/ml IFN-α. While the extremely slow or flat second phase of viral RNA inhibition observed in vitro, in which there is little or no cell death, supports the in vivo modeling prediction that the more profound second-phase decline observed in IFN-α-treated patients reflects immune-mediated death/loss of productively infected cells, the second-phase decline in viral RNA with a dose of 250 U/ml IFN-α suggests that a further inhibition of intracellular HCV RNA levels may contribute as well. As such, dissection of HCV IFN-α inhibition kinetics in vitro has brought us closer to understanding the mechanism(s) by which IFN-α may be inhibiting HCV in vivo.

Funktion von CEACAM-1 im Rahmen der Therapie der Hepatitis C-Virus Infektion mit Interferon-alpha in vivo und in vitro

2006 ◽  
Vol 44 (08) ◽  
Author(s):  
P Hilgard ◽  
R Bröring ◽  
M Trippler ◽  
S Viazov ◽  
G Gerken ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Interferon Alpha

scholarly journals Mass Balance, Metabolite Profile, andIn Vitro-In VivoComparison of Clearance Pathways of Deleobuvir, a Hepatitis C Virus Polymerase Inhibitor

2014 ◽  
Vol 59 (1) ◽  
pp. 25-37 ◽  
Author(s):  
Lin-Zhi Chen ◽  
John P. Sabo ◽  
Elsy Philip ◽  
Lois Rowland ◽  
Yan Mao ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Mass Balance ◽  
Metabolite Profile ◽  
Fecal Samples ◽  
Acyl Glucuronide ◽  
Polymerase Inhibitor ◽  
Main Components

ABSTRACTThe pharmacokinetics, mass balance, and metabolism of deleobuvir, a hepatitis C virus (HCV) polymerase inhibitor, were assessed in healthy subjects following a single oral dose of 800 mg of [14C]deleobuvir (100 μCi). The overall recovery of radioactivity was 95.2%, with 95.1% recovered from feces. Deleobuvir had moderate to high clearance, and the half-life of deleobuvir and radioactivity in plasma were ∼3 h, indicating that there were no metabolites with half-lives significantly longer than that of the parent. The most frequently reported adverse events (in 6 of 12 subjects) were gastrointestinal disorders. Two major metabolites of deleobuvir were identified in plasma: an acyl glucuronide and an alkene reduction metabolite formed in the gastrointestinal (GI) tract by gut bacteria (CD 6168), representing ∼20% and 15% of the total drug-related material, respectively. Deleobuvir and CD 6168 were the main components in the fecal samples, each representing ∼30 to 35% of the dose. The majority of the remaining radioactivity found in the fecal samples (∼21% of the dose) was accounted for by three metabolites in which deleobuvir underwent both alkene reduction and monohydroxylation. In fresh human hepatocytes that form biliary canaliculi in sandwich cultures, the biliary excretion for these excretory metabolites was markedly higher than that for deleobuvir and CD 6168, implying that rapid biliary elimination upon hepatic formation may underlie the absence of these metabolites in circulation. The lowin vitroclearance was not predictive of the observedin vivoclearance, likely because major deleobuvir biotransformation occurred by non-CYP450-mediated enzymes that are not well represented in hepatocyte-basedin vitromodels.

scholarly journals Characterization of Resistance to the Nonnucleoside NS5B Inhibitor Filibuvir in Hepatitis C Virus-Infected Patients

2011 ◽  
Vol 56 (3) ◽  
pp. 1331-1341 ◽  
Author(s):  
Philip J. F. Troke ◽  
Marilyn Lewis ◽  
Paul Simpson ◽  
Katrina Gore ◽  
Jennifer Hammond ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Site Directed Mutagenesis ◽  
Phenotypic Resistance ◽  
Number Of Patients ◽  
Chronic Hcv ◽  
Selection Of

ABSTRACTFilibuvir (PF-00868554) is an investigational nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural 5B (NS5B) RNA-dependent RNA polymerase currently in development for treating chronic HCV infection. The aim of this study was to characterize the selection of filibuvir-resistant variants in HCV-infected individuals receiving filibuvir as short (3- to 10-day) monotherapy. We identified amino acid M423 as the primary site of mutation arising upon filibuvir dosing. Through bulk cloning of clinical NS5B sequences into a transient-replicon system, and supported by site-directed mutagenesis of the Con1 replicon, we confirmed that mutations M423I/T/V mediate phenotypic resistance. Selection in patients of an NS5B mutation at M423 was associated with a reduced replicative capacityin vitrorelative to the pretherapy sequence; consistent with this, reversion to wild-type M423 was observed in the majority of patients following therapy cessation. Mutations at NS5B residues R422 and M426 were detected in a small number of patients at baseline or the end of therapy and also mediate reductions in filibuvir susceptibility, suggesting these are rare but clinically relevant alternative resistance pathways. Amino acid variants at position M423 in HCV NS5B polymerase are the preferred pathway for selection of viral resistance to filibuvirin vivo.

Circulating and inducible IL-32α in chronic hepatitis C virus infection

2019 ◽  
Vol 2 (1) ◽  
pp. 23-30
Author(s):  
Mark Collister ◽  
Julia Rempel ◽  
Jiaqi Yang ◽  
Kelly Kaita ◽  
Zach Raizman ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Chronic Hepatitis C Virus ◽  
Chronic Hcv

Background: Interleukin 32 (IL-32) is a recently described pro-inflammatory cytokine implicated in chronic hepatitis C virus (HCV)-related inflammation and fibrosis. IL-32α is the most abundant IL-32 isoform. Methods: Circulating IL-32α levels were documented in patients with chronic HCV infections ( n = 31) and compared with individuals who spontaneously resolved HCV infection ( n = 14) and HCV-naive controls ( n = 20). In addition, peripheral blood mononuclear cells (PBMC) from the chronic HCV ( n = 12) and HCV-naive ( n = 9) cohorts were investigated for responses to HCV core and non-structural (NS)3 protein induced IL-32α production. Finally, correlations between IL-32α levels, hepatic fibrosis and subsequent responses to interferon-based therapy were documented in patients with chronic HCV. Results: Circulating IL-32α levels in patients with chronic HCV were similar to those of spontaneously resolved and HCV-naive controls. HCV protein induced IL-32α responses were similar in chronic HCV patients and HCV-naive controls. In patients with chronic HCV, serum IL-32α levels correlated with worsening METAVIR fibrosis (F) scores from F0 to F3 ( r = 0.596, P < 0.001) as did NS3 induced IL-32α responses ( r = 0.837, P < 0.05). However, these correlations were not sustained with the inclusion of IL-32α levels at F4 scores, suggesting events at F4 interfere with IL-32α synthesis or release. In chronic HCV patients who underwent treatment ( n = 28), baseline in vivo and in vitro induced IL-32α concentrations were not predictive of therapeutic outcomes. Conclusions: IL-32α activity is associated with worsening fibrosis scores in non-cirrhotic, chronic HCV patients.

Inhibition of hepatitis C virus gene expression by adenoviral vectors encoding antisense RNA in vitro and in vivo

2011 ◽  
Vol 55 (1) ◽  
pp. 19-28 ◽  
Author(s):  
Maria A. González-Carmona ◽  
Annabelle Vogt ◽  
Thomas Heinicke ◽  
Maria Quasdorff ◽  
Per Hoffmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antisense Rna ◽  
Adenoviral Vectors ◽  
Virus Gene ◽  
Virus Gene Expression
Sign in / Sign up

Export Citation Format

Share Document