June 27, 2011

J Viral Hepat. 2011 Apr;18(4):252-61. doi: 10.1111/j.1365-2893.2010.01292.x.

Tillmann HL, Wiese M, Braun Y, Wiegand J, Tenckhoff S, Mössner J, Manns MP, Weissenborn K.

Medizinische Hochschule Hannover, Abteilung für Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany. Hans.Tillmann@duke.edu

Abstract

Little is known comparing and contrasting quality of life (QoL) in patients with hepatitis C, compared to patients with other liver diseases. We performed two independent prospective cross-sectional studies including 511 and 284 patients with different forms of liver diseases. SF-36 was used in both studies. Fatigue Impact Score, WHO-BREF and Hospital Anxiety and Depression Scale (HADS) were used in either study only. In both studies, HCV-positive patients scored worse in the mental aspects of health-related QoL compared to other liver diseases, except for HBV in one study. Surprisingly, in both studies, quality of life was also significantly impaired in patients with viral clearance after interferon therapy but not after spontaneous clearance. Furthermore, patients with primary biliary cirrhosis showed significantly better mental health but significantly worse physical well-being. Liver diseases differ in their form of impaired QoL. In HCV, this impairment might not always return to normal after treatment-induced viral clearance. This may suggest that HCV either may not be involved in QoL impairment or may induce a process which persists after viral clearance in some patients.

© 2010 Blackwell Publishing Ltd.
 
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Hepatology
Volume 54, Issue 1, pages 50–59, July 2011

Frank Wagner 1,‡, Robert Thompson 2, Constantino Kantaridis 3, Paul Simpson 4, Philip J. F. Troke 4, Shyla Jagannatha 5, Srividya Neelakantan 5, Vivek S. Purohit 5, Jennifer L. Hammond 5,*,§

Article first published online: 24 JUN 2011
DOI: 10.1002/hep.24342
Copyright © 2011 American Association for the Study of Liver Diseases

Author Information
1 Charité Research Organisation, Charité Universitätsmedizin Berlin, Berlin, Germany
2 University of Florida, Center for Clinical Trials Research, FL
3 Pfizer Clinical Research Unit, Pfizer, Brussels, Belgium
4 Pfizer Global Research, Sandwich, Kent, UK
5 Pfizer Worldwide Biopharmaceuticals, New London, CT

Email: Jennifer L. Hammond (jennifer.hammond@pfizer.com)

* Correspondence: Jennifer L. Hammond, Worldwide Biopharmaceuticals, Specialty Care, Pfizer, Inc., 50 Pequot Avenue, New London, CT 06320

Abstract

More effective and better-tolerated therapies are needed for chronic hepatitis C virus (HCV) infection. Among the direct-acting anti-HCV agents in development is the nonstructural 5B protein (NS5B polymerase) non-nucleoside inhibitor filibuvir. We investigated the antiviral activity, pharmacokinetics, safety, and tolerability of multiple doses of filibuvir in treatment-naive and treatment-experienced patients who were chronically infected with HCV genotype 1 in two phase 1b clinical studies (study 1 was a randomized, placebo-controlled dose escalation study and study 2 was a nonrandomized, open-label study). The filibuvir doses evaluated ranged from 200-1400 mg daily, and the duration of dosing ranged from 3-10 days. Genotypic changes in the NS5B nucleotide sequence following short-term filibuvir therapy were also assessed. Filibuvir potently inhibited viral replication in a dose-dependent manner. Mean maximum HCV RNA change from baseline ranged from −0.97 log10 IU/mL with filibuvir given at 100 mg twice daily to −2.30 log10 IU/mL with filibuvir given at 700 mg twice daily in treatment-naive patients. In treatment-experienced patients, an HCV RNA reduction of 2.20 log10 IU/mL was achieved with filibuvir given at 450 mg twice daily. Filibuvir was well tolerated in both studies. Adverse events were mild or moderate in severity. No discontinuations, serious adverse events, or deaths were reported. NS5B sequencing identified residue 423 as the predominant site of mutation after filibuvir dosing. Conclusion: Filibuvir administration resulted in significant reductions in HCV RNA concentrations at doses that were well tolerated in patients infected with HCV genotype 1. Filibuvir is currently being evaluated in combination with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients. (Hepatology 2011;)

Source
Eur J Gastroenterol Hepatol. 2011 Jun 17. [Epub ahead of print]

Shoeb D, Rowe IA, Freshwater D, Mutimer D, Brown A, Moreea S, Sood R, Marley R, Sabin CA, Foster GR.

aThe Liver Unit, Blizard Institute for Cellular and Molecular Science, Queen Mary University of London bThe Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham cSt Mary's Hospital, Imperial College London dBradford Teaching Hospitals Foundation Trust, Bradford eResearch Department of Infection and Population Health, University College London Medical School, Royal Free Campus, London, UK.

Abstract

BACKGROUND AND AIMS: We completed a retrospective analysis of patients with genotype 3 hepatitis C virus (HCV) undergoing therapy in four UK centres with large populations of patients from the Indian subcontinent.

MATERIALS AND METHODS: Notes on all patients treated with pegylated interferon and ribavirin were reviewed and factors that influenced the response were examined.

RESULTS: Six hundred and four patients with genotype 3 HCV were studied, of whom 299 were Asians. Median age was 43 years, 65% were men and 24% had cirrhosis. Overall, 457 (76%) patients achieved sustained virological response (SVR). By multivariable analysis it was found that ethnicity was not associated with an impaired response but age, cirrhosis and diabetes were significantly associated with a reduced SVR, the likelihood of a response was reduced by 25% per 10-year increment in age, by 59% among individuals with cirrhosis and by 62% among individuals with diabetes mellitus. Most patients who did not achieve an SVR relapsed (15%) rather than failing to achieve an end of treatment response.

CONCLUSION: The response to antiviral therapy in genotype 3 HCV is not affected by South Asian (vs. Caucasian) ethnicity, but age, cirrhosis and diabetes reduce the response. Treatment failure most often is due to relapse.

PMID: 21691208 [PubMed - as supplied by publisher]
 
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Reported by Jules Levin
6th International Workshop on Hepatitis C, Resistance
and New Compounds. Cambridge, MA, June 24th, 2011

"Phase III study with DEB025 commenced recently with previously untreated patients infected by the most common form of hepatitis C virus....DEB025 is the first in a new class of drugs called cyclophilin inhibitors. Unlike other compounds in development that target the virus directly, DEB025 is a host targeting antiviral (HTA) that targets so-called host proteins which are essential for the replication of HCV.....Phase II study with the first-in-class antiviral DEB025 (alisporivir) met its primary endpoint for achieving viral cure (24 weeks after stopping treatment) in 76% of patients with chronic hepatitis C[1]. The study involved nearly 300 previously untreated patients infected with the most common form of hepatitis C virus (HCV), the genotype 1 (G1)[1].".....The findings show that 76% of G1 chronic hepatitis C patients treated with DEB025 plus standard of care (pegylated-interferon alfa 2a/ribavirin) achieved superior viral cure (known as sustained viral response, or SVR) compared to 55% of patients on standard of care alone (p=0.008)[1]. Treatment with DEB025 demonstrated a low incidence of adverse events, with discontinuation rates comparable between treatment groups[1]."

EASL: Once daily alisporivir (DEB025) plus Peg-IFN-alfa-2A/ ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment-naïve patients - The ESSENTIAL study - (03/31/11)

EASL: Once daily alisporivir (DEB025) plus Peg-IFN-alfa-2A/ ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment-naïve patients - The ESSENTIAL study - (03/31/11)

New HCV Drugs at EASL Apr 3, 2011 Ð TMC435 & BI201335 are in phase 3. ... EASL: Once daily alisporivir (DEB025) plus Peg-IFN-alfa-2A/ ribavirin results in superior sustained ... www.natap.org/2011/EASL/EASL_109.htm

"For all DAAs discovered to date, a single mutation can confer high-level resistance: Resistance develops quickly both in vitro and in patients (except nucs); Thus, it may take ≥3 DAA's to completely suppress resistance in an IFN-free regimen.....A complementary approach is to target host factors that are essential for viral replication, which may present a higher genetic barrier to resistance.....Resistance clones were selected in vitro using gen 1b (con 1) or 1a (H77) replicon: Replicon cells were incubated with increasing concentrations of DEB025 to 750 nM for gen 1a or 675 nM (7.5xEC90) for gen 1b for three weeks.....D320E in NS5A was the only mutation consistently selected in both gen 1a (H77) and gen 1b (con 1) replicons.....Only 2.65-fold EC50 increase with D320E and 4.76-fold with entire mutant NS5A: No significant effect on fitness with the substitutions; Fully sensitive to NS5A inhibitor (targeting domain I), NS3 inhibitor, or IFN-a....D320E was identified in three patients receiving alisporivir 1000 mg monotherapy for four weeks by population and clonal sequencing; However, D320E alone does not appear to be sufficient to cause viral breakthrough.....No change in sensitivity to NS3 protease inhibitor (BILN2061) or IFN-a, [or NSB5 (polymerase)].....Alisporivir is fully active against DAA resistant mutants (protease156, 168)"

Continue Reading ...
J Gastroenterol. 2011 Jun 17. [Epub ahead of print]

Hiramatsu N, Kurosaki M, Sakamoto N, Iwasaki M, Sakamoto M, Suzuki Y, Sugauchi F, Tamori A, Kakinnuma S, Matsuura K, Izumi N.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.

Abstract

BACKGROUND: This study aimed to develop a model to predict the development of severe anemia during pegylated interferon alpha-2b plus ribavirin combination therapy.

METHODS: Data were collected from 1081 genotype 1b chronic hepatitis C patients who were treated at 6 hospitals in Japan. These patients were randomly assigned to a model-building group (n = 691) or an internal validation group (n = 390). Factors predictive of severe anemia (hemoglobin, Hb < 8.5 g/dl) were explored using data-mining analysis.

RESULTS: Hb values at baseline, creatinine clearance (Ccr), and an Hb concentration decline by 2 g/dl at week 2 were used to build a decision-tree model, in which the patients were divided into 5 subgroups based on variable rates of severe anemia ranging from 0.4 to 11.8%. The reproducibility of the model was confirmed by the internal validation group (r (2) = 0.96). The probability of severe anemia was high in patients whose Hb value was <14 g/dl before treatment (6.5%), especially (a) in those whose Ccr was <80 ml/min (11.8%) and (b) those whose Ccr was ≥80 ml/min but whose Hb concentration decline at week 2 was ≥2 g/dl (11.5%). The probability of severe anemia was low in the other patients (0.4-2.5%).

CONCLUSIONS: The decision-tree model that included Hb values at baseline, Ccr, and an Hb concentration decline by 2 g/dl at week 2 was useful for predicting the probability of severe anemia, and has the potential to support clinical decisions regarding early dose reduction of ribavirin.

PMID: 21681410 [PubMed - as supplied by publisher]
 
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Cholesterol and chronic hepatitis C virus infection

Hepatol Res. 2011 Jun 17. doi: 10.1111/j.1872-034X.2011.00838.x. [Epub ahead of print]

Honda A, Matsuzaki Y.

Department of Gastroenterology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.

Abstract

Cholesterol is an essential molecule for the life cycle of the hepatitis C virus (HCV). This review focuses on the roles of cholesterol in HCV infection and introduces HCV events related to cholesterol metabolism and applications for cholesterol metabolism as a therapeutic target. HCV appears to alter host lipid metabolism into its preferable state, which is clinically recognized as steatosis and hypocholesterolemia. While hepatic fatty acid and triglyceride syntheses are upregulated in chronic hepatitis C patients, no direct evidence of increased hepatic de novo cholesterol biosynthesis has been obtained. Impaired VLDL secretion from hepatocytes is suggested to increase intracellular cholesterol concentrations, which may lead to hypocholesterolemia. Clinically, lower serum cholesterol levels are associated with lower rates of sustained virological responses (SVR) to pegylated-interferon plus ribavirin therapy, but the reason remains unclear. Clinical trials targeting HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, are being conducted using statins. Anti-HCV actions by statins appear to be caused by the inhibition of geranylgeranyl pyrophosphate synthesis rather than their cholesterol lowering effects. Other compounds that block various steps of cholesterol metabolic pathways have also been studied to develop new strategies for the complete eradication of this virus.

© 2011 The Japan Society of Hepatology.

Source
Journal of Hepatology

Articles in Press

Dominique Thabuta, Marika Rudlera, Didier Lebrecbc

Received 24 February 2011; received in revised form 11 May 2011; accepted 12 May 2011. published online 27 June 2011.
Accepted Manuscript

Abstract

Background
Patients with cirrhosis in Child-Pugh class C or those in class B who have persistent bleeding at endoscopy are at high risk for treatment failure and a poor prognosis, even if they have undergone rescue treatment with a transjugular intrahepatic portosystemic shunt (TIPS). This study evaluated the earlier use of TIPS in such patients.

Methods
We randomly assigned, within 24 hours after admission, a total of 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy to treatment with a polytetrafluoroethylene-covered stent within 72 hours after randomization (early-TIPS group, 32 patients) or continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapy-EBL group, 31 patients).

Results
During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapy-EBL group as compared with 1 patient in the early-TIPS group (P=0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapy-EBL group versus 97% in the early-TIPS group (P<0.001). Sixteen patients died (12 in the pharmacotherapy-EBL group and 4 in the early-TIPS group, P=0.01). The 1-year actuarial survival was 61% in the pharmacotherapy-EBL group versus 86% in the early-TIPS group (P<0.001). Seven patients in the pharmacotherapy-EBL group received TIPS as rescue therapy, but four died. The number of days in the intensive care unit and the percentage of time in the hospital during follow-up were significantly higher in the pharmacotherapy-EBL group than in the early-TIPS group. No significant differences were observed between the two treatment groups with respect to serious adverse events.

Conclusions
In these patients with cirrhosis who were hospitalized for acute variceal bleeding and at high risk for treatment failure, the early use of TIPS was associated with significant reductions in treatment failure and in mortality. (Current Controlled Trials number, ISRCTN58150114.)

Abbreviations: TIPS, Transjugular intrahepatic portosystemic shunt, HVPG, hepatic venous pressure gradient

Keywords: Child-Pugh score

No full text is available. To read the body of this article, please view the PDF online.

a Université Pierre et Marie Curie, Service d’hépato-gastroentérologie, Hôpital de la Pitié-Salpêtrière (AP-HP), Paris, France
b INSERM, Unité 773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Paris and Clichy, France Université Denis Diderot-Paris 7, site Bichat, Paris, France
c Service d’Hépatologie, Hôpital Beaujon, Clichy, France

PII: S0168-8278(11)00496-X
doi:10.1016/j.jhep.2011.05.013
© 2011 Published by Elsevier Inc.

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