scholarly journals MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants

2012 ◽  
Vol 56 (8) ◽  
pp. 4161-4167 ◽  
Author(s):  
Vincenzo Summa ◽  
Steven W. Ludmerer ◽  
John A. McCauley ◽  
Christine Fandozzi ◽  
Christine Burlein ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Selective Pressure ◽  
Pegylated Interferon ◽  
Therapeutic Agents ◽  
Hepatitis C Virus Infection ◽  
Dosing Regimen ◽  
Once Daily ◽  
Hcv Genotypes

ABSTRACTHCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.

scholarly journals Pleuro-Pulmonary Nocardiosis as Opportunistic Infection in a Patient with Chronic Hepatitis C under Combination Treatment with Pegylated Interferon, Ribavirin, and Boceprevir

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Csilla Putz-Bankuti ◽  
Harald H. Kessler ◽  
Thomas Valentin ◽  
Eva Leitner ◽  
Emina Talakic ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Pulmonary Infection ◽  
Antiviral Treatment ◽  
Pegylated Interferon ◽  
Hepatitis C Virus Infection ◽  
Chronic Hepatitis C Virus ◽  
Aerobic Actinomycetes

Nocardiosis is an infrequent but serious pulmonary infection caused by Gram-positive aerobic actinomycetes. In this paper, we report on a 48-year-old patient with pleuropulmonary nocardiosis and cirrhosis due to chronic hepatitis C virus infection treated with triple antiviral treatment complicated by prolonged neutropenia.

Prospective study of hepatitis C virus infection in hemodialysis patients by monthly analysis of HCV RNA and antibodies

2003 ◽  
Vol 49 (8) ◽  
pp. 503-507 ◽  
Author(s):  
Regina Moreira ◽  
João Renato Rebello Pinho ◽  
Jorge Fares ◽  
Isabel Takano Oba ◽  
Maria Regina Cardoso ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hemodialysis Patients ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Hepatitis C Virus Infection ◽  
Serum Samples ◽  
Hcv Genotypes ◽  
High Prevalence ◽  
Time Required

The aims of this study were to (i) evaluate the prevalence and the incidence of hepatitis C virus (HCV) infection in hemodialysis patients in two different centers in São Paulo (Brazil), (ii) determine the time required to detect HCV infection among these patients by serology or PCR, (iii) establish the importance of alanine aminotransferase determination as a marker of HCV infection, and (iv) identify the HCV genotypes in this population. Serum samples were collected monthly for 1 year from 281 patients admitted to hospital for hemodialysis. Out of 281 patients, 41 patients (14.6%) were HCV positive; six patients seroconverted during this study (incidence = 3.1/1000 person-month). In 1.8% (5/281) of cases, RNA was detected before the appearance of antibodies (up to 5 months), and in 1.1% (3/281) of cases, RNA was the unique marker of HCV infection. The genotypes found were 1a, 1b, 3a, and 4a. The presence of genotype 4a is noteworthy, since it is a rare genotype in Brazil. These data pointed out the high prevalence and incidence of HCV infection at hemodialysis centers in Brazil and showed that routine PCR is fundamental for improving the detection of HCV carriers among patients undergoing hemodialysis.Key words: HCV genotypes, hemodialysis, hepatitis C, PCR, prevalence, incidence.

scholarly journals Quantification of Different Human Alpha Interferon Subtypes and Pegylated Interferon Activities by Measuring MxA Promoter Activation

2005 ◽  
Vol 49 (9) ◽  
pp. 3770-3775 ◽  
Author(s):  
Catherine François ◽  
Isabelle Bernard ◽  
Sandrine Castelain ◽  
Bryan Charleston ◽  
Martin D. Fray ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Biological Samples ◽  
Pegylated Interferon ◽  
Biologically Active ◽  
Enzyme Linked Immunosorbent Assay ◽  
Hepatitis C Virus Infection ◽  
Promoter Activation ◽  
Antiviral Protein

ABSTRACT Alpha interferons (α-IFNs) are potent biologically active proteins synthesized and secreted by somatic cells during viral infection. Quantification of α-IFN concentrations in biological samples is used for diagnosis. More recently, recombinant IFNs have been used as antiviral, antiproliferative, and immunomodulatory therapeutic agents, and particularly for the treatment of chronic hepatitis C virus infection. For this purpose, IFN has recently been coupled to polyethylene glycol (PEG) to improve the pharmacokinetic properties. The measure of α-IFN in biological samples from treated patients could be useful to ensure compliance to therapy and the true IFN activity in relation to viral decay during follow-up. In particular, it could be used to monitor the PEG-IFN concentration in patients treated for hepatitis C virus infection. The most frequently used test is a bioassay based on the antiviral property of the IFN, but the assay is not highly reproducible. Here, we present a reporter test based on MxA promoter activation of chloramphenicol acetyltransferase expression (Mx-CAT). MxA is an antiviral protein induced and tightly regulated by α-IFN. The Mx-CAT assay showed good reproducibility of 15% and was suitable to quantify PEG-IFN and numerous other α-IFN subtypes as well, despite a differential MxA promoter activation in relation with the subtype. A good correlation was obtained with the reporter assay and a commercial enzyme-linked immunosorbent assay on samples from treated patients. This test could be useful for monitoring IFN therapy of chronically infected hepatitis C virus-infected patients treated with the standard IFN, PEG-IFN, and probably forthcoming recombinant IFNs.

scholarly journals Correction to Discovery of Ledipasvir (GS-5885): A Potent, Once-Daily Oral NS5A Inhibitor for the Treatment of Hepatitis C Virus Infection

2016 ◽  
Vol 59 (16) ◽  
pp. 7696-7696 ◽  
Author(s):  
John O. Link ◽  
James G. Taylor ◽  
Lianhong Xu ◽  
Michael Mitchell ◽  
Hongyan Guo ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Hepatitis C Virus Infection ◽  
Once Daily ◽  
Ns5a Inhibitor
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