Role of Heme Oxygenase in the Pathogenesis of Hepatocellular Injury in Chronic Hepatitis C Virus (HCV) Infection
Primary Purpose
Chronic HCV Infection, Nonalcoholic Steatohepatitis
Status
Unknown status
Phase
Not Applicable
Locations
Czech Republic
Study Type
Interventional
Intervention
pegylated interferon
Ribavarin
Sponsored by
About this trial
This is an interventional basic science trial for Chronic HCV Infection focused on measuring hepatitis C, NASH, Hem Oxygenase, Gene polymorphism
Eligibility Criteria
Inclusion Criteria:
- chronic HCV infection
- must undergo liver biopsy
- must undergo antiviral treatment
Exclusion Criteria:
- liver sample not obtained
- blood samples for HCV testing not obtained in specified time points during antiviral therapy
Sites / Locations
- Cetral Military HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
No Intervention
Arm Label
1 HCV positive pts
2 Other liver disease
Arm Description
Patients with chronic HCV infection undergoing liver biopsy followed by antiviral treatment. peg-IFN alfa 2a 180ug s.c. QW + ribavirin 1000-1200mg p.o. daily 48weeks or peg-IFN alfa 2b 1.5 ug/kg s.c. QW + ribavirin 100-1200mg p.o. daily 48 weeks
pts. with NASH (or other liver disease) undergoing liver biopsy.
Outcomes
Primary Outcome Measures
1. the relation between HO activity and basic virologic and histologic parameters in chronic HCV patients. 2. changes of HO activity within antiviral treatment 3. relation of HO gene polymorphisms to the course of disease
Secondary Outcome Measures
Relation of HO gene polymorphisms and UGT1A1*28 polymorphism.
Full Information
NCT ID
NCT00842205
First Posted
February 11, 2009
Last Updated
February 11, 2009
Sponsor
Charles University, Czech Republic
Collaborators
IGA MZ, Czech Republic
1. Study Identification
Unique Protocol Identification Number
NCT00842205
Brief Title
Role of Heme Oxygenase in the Pathogenesis of Hepatocellular Injury in Chronic Hepatitis C Virus (HCV) Infection
Official Title
Role of Heme Oxygenase in the Pathogenesis od Hepatocellular Injury in Chronic HCV Infection
Study Type
Interventional
2. Study Status
Record Verification Date
February 2009
Overall Recruitment Status
Unknown status
Study Start Date
January 2007 (undefined)
Primary Completion Date
June 2009 (Anticipated)
Study Completion Date
December 2009 (Anticipated)
3. Sponsor/Collaborators
Name of the Sponsor
Charles University, Czech Republic
Collaborators
IGA MZ, Czech Republic
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
In the presented project, the role of heme oxygenase 1 and 2 in the procesess associated with fibroproduction in the chronic HCV infection will be studied. Heme oxygenase expression will be evaluated by the techniques of molecular genetics and immunohistochemistry, both in the liver tissue and in peripheral blood mononuclear cells. These parameters will be correlated with basic virological and clinical characteristics of the chronic HCV infection. The investigators' expected results may help in understanding the mechanisms of fibroproduction in chronic HVC infection and, therefore, contribute to explain individual differences in the development of chronic HCV infection.
Detailed Description
Hepatitis C virus (HCV) is a single stranded positive RNA virus belonging to the Flaviviridae family. HCV is a major cause of chronic hepatitis and progressive liver fibrosis leading to cirrhosis. Currently, the mechanisms responsible for hepatocellular injury are not fully understood. Oxidative damage has been hypothesized to play a role in HCV-induced liver disease, with reactive oxygen species (ROS), generated from HCV-infected hepatocytes and infiltrating immune cells. Persistence of recurrent hepatocellular injury leads to wound-healing process in which oxidative stress, inflammatory response mediated by immune cells and/or cytokines, and activation of hepatic stellate cells (HSCs) contribute to cascade of fibrogenesis. HCV can infect peripheral blood mononuclear cells (PBMC) of patients with chronic HCV infection . PBMC play key roles both in innate and adaptive antigen-specific immunity and they constitute critical components of the immune response.Heme oxygenase (HO) is the rate-limiting enzyme in the heme catabolic pathway. It cleaves pro-oxidant heme into equimolar amounts of carbon monoxide (CO), free iron, and biliverdin, which is rapidly metabolized to bilirubin by biliverdin reductase.The human HO-1 gene is located at chromosome 22q12 and a variable number of tandem repeat polymorphism (VNTR) was identified in the proximal promoter region. It is suggested that these highly polymorphic (GT)n repeats could alter the transcriptional activity. In recent years, enhanced HO enzymatic activity has been reported - probably through its formation of bioactive products - to possess antioxidant, cytoprotective, and neurotransmitter activity and to play a role in anti-inflammatory functions . AIMS: AIM 1.To characterize HO expression in liver biopsies in patients with chronic hepatitis C comparing to expression in patients with other types of hepatitis (esp. autoimmune) and to normal liver tissue. To investigate the relationship between HO expression and hepatitis C virus concentration, duration of infection, level of fibrosis and inflammation, ALT, AST activities, bilirubin levels, response to the standard treatment and a level of apoptosis. AIM 2. To characterize HO expression in PBMC in patients with chronic hepatitis C before, in the week 12 and after the standard treatment (PEG-IFN+RBV). To correlate HO expression in PBMC with viral concentration in sera and a response to the standard treatment.AIM 3. To investigate HO polymorphisms in patients with chronic hepatitis C. AIM 4. To investigate UGT1A1 28 polymorphism which is responsible for benign hyperbilirubinemia. Expected results: 1. This study could elucidate a relationship between development of liver fibrosis and inflammation and HO expression. 2. This project may, for the first time, show the relationship between chronic HCV infection and regulation of HO expression in PBMC. 3.This project will answer the question whether genetic predisposition, length polymorphism in HO promoter responsible for its lower transcriptional activity, could be a risk factor for fibrosis/cirrhosis development in patients infected with hepatitis C virus. UGT1A1 28 polymorphism is connected with low prevalence of diseases in which the oxidative stress is increased. We suggest that HCV infected persons might have low prevalence of this polymorphism or this polymorphism might be connected to low efficacy of antiviral treatment in these persons.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic HCV Infection, Nonalcoholic Steatohepatitis
Keywords
hepatitis C, NASH, Hem Oxygenase, Gene polymorphism
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Enrollment
150 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
1 HCV positive pts
Arm Type
Active Comparator
Arm Description
Patients with chronic HCV infection undergoing liver biopsy followed by antiviral treatment.
peg-IFN alfa 2a 180ug s.c. QW + ribavirin 1000-1200mg p.o. daily 48weeks or peg-IFN alfa 2b 1.5 ug/kg s.c. QW + ribavirin 100-1200mg p.o. daily 48 weeks
Arm Title
2 Other liver disease
Arm Type
No Intervention
Arm Description
pts. with NASH (or other liver disease) undergoing liver biopsy.
Intervention Type
Drug
Intervention Name(s)
pegylated interferon
Other Intervention Name(s)
Pegasys, Pegintron
Intervention Description
peg-IFN alfa 2a 180ug s.c. QW or peg-IFN alfa 2b 1.5 ug/kg s.c. QW
Intervention Type
Drug
Intervention Name(s)
Ribavarin
Other Intervention Name(s)
Copegus, Rebetol
Intervention Description
ribavirin 1000-1200mg p.o. daily 48weeks or ribavirin 100-1200mg p.o. daily 48 weeks
Primary Outcome Measure Information:
Title
1. the relation between HO activity and basic virologic and histologic parameters in chronic HCV patients. 2. changes of HO activity within antiviral treatment 3. relation of HO gene polymorphisms to the course of disease
Time Frame
from HCV transmission in each individual patient to the time of liver biopsy and begining of antiviral treatment
Secondary Outcome Measure Information:
Title
Relation of HO gene polymorphisms and UGT1A1*28 polymorphism.
Time Frame
3 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
chronic HCV infection
must undergo liver biopsy
must undergo antiviral treatment
Exclusion Criteria:
liver sample not obtained
blood samples for HCV testing not obtained in specified time points during antiviral therapy
Facility Information:
Facility Name
Cetral Military Hospital
City
Prague
ZIP/Postal Code
16202
Country
Czech Republic
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Petr Urbanek, Doc., MD, CSc
Phone
+420973203049
Email
petr.urbanek@uvn.cz
First Name & Middle Initial & Last Name & Degree
Petr Urbanek, Doc., MD, CSc
12. IPD Sharing Statement
Citations:
PubMed Identifier
21911884
Citation
Urbanek P, Lenicek M, Muchova L, Subhanova I, Dusek L, Kasprikova N, Hrabal P, Bruha R, Vitek L. No association of promoter variations of HMOX1 and UGT1A1 genes with liver injury in chronic hepatitis C. Ann Hepatol. 2011 Oct-Dec;10(4):445-51.
Results Reference
derived
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Role of Heme Oxygenase in the Pathogenesis of Hepatocellular Injury in Chronic Hepatitis C Virus (HCV) Infection
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