Hepatitis C in Clinically Discordant Hemophilic Siblings

Brief Title

Hepatitis C in Clinically Discordant Hemophilic Siblings

Official Title

Hepatitis C in Clinically Discordant Hemophilic Siblings

Brief Summary

      To define the natural history, immunologic, and genetic factors that influence the clinical
      outcome of hepatitis C in a cohort of hemophilic siblings.

Detailed Description

      BACKGROUND:

      The clinical spectrum of hepatitis C is variable and the factors responsible for these
      divergent outcomes with chronic hepatitis C infection remain unknown. Dr. Fried and his
      colleagues are studying a cohort of hemophilic siblings infected with hepatitis C to define
      the natural history, immunologic, and genetic factors that influence its clinical outcome.
      Patients with hemophilia have a prevalence rate of hepatitis C as high as 90 percent. The
      sex-linked pattern of inheritance of hemophilia allows them to identify a cohort of siblings
      both of who have been infected with hepatitis C. Hemophilic siblings are an attractive
      population to study because: 1) They are all males; 2) Siblings are relatively close in age;
      3) The mode of HCV acquisition is identical; 4) The age at acquisition of hepatitis C is
      similar 5) The date of acquisition can be confidently estimated upon their factor replacement
      history; 6) Hemophilic sibs share significant amounts of genetic material.

      The study is in response to a Request for Applications entitled "Hepatitis C: Natural
      History, Pathogenesis, Therapy and Prevention" issued by the National Institute of Diabetes
      and Digestive and Kidney Diseases

      DESIGN NARRATIVE:

      Hemophilic siblings with hepatitis C undergo a detailed clinical evaluation to stage their
      liver disease and to identify sibling pairs with clinically and/or histologically discordant
      levels of disease activity. These siblings pairs are further studied to define antigen
      recognition patterns of lymphocyte cells including peripheral CD8 plus cytotoxic T
      lymphocytes (CTL) and CD4 plus cells and determine their functional significance. Using
      peripheral blood mononuclear cells, CD8 plus cells are assayed for CTL activity against three
      overlapping vaccinia/hepatitis C virus (HCV) constructs covering the entire HCV genome
      followed by fine cloning to identify HCV-specific CTL epitopes. Peripheral CD4 plus cells are
      tested for their ability to proliferate to HCV antigens. Using stimulation index, Drs. Fried
      and colleagues are quantitating the presence and magnitude of this response. They are also
      trying to identify immunodominant regions targeted by cytotoxic T cells using HLA class I
      matched hemophilic siblings. Finally, they are identifying specific host genes that are
      preferentially expressed or repressed in patients with delayed progression of their HCV
      disease. They are quantitating the expression of mRNAs encoding host antiviral defense and
      immunoregulatory elements in peripheral blood mononuclear cells (PBMCs) and liver tissue from
      sibling pairs that have discordant chronic hepatitis C using mRNA libraries that are screened
      by high density oligonucleotide arrays. The expression levels of these genes (including, but
      not limited to, interferon alpha, beta, and gamma; IRF-1 and IRF-2; interferon induced
      protein kinase; the cellular protein activator of PKR (PACT) RNase L; interferon-inducible
      RNA-specific adenosine deaminase; a ribonuclease specific for inosine- containing RNA;
      chemokine receptors CCR1, CCR3, CCR5, and their signal transduction elements;
      2'-5'-oligoadenylate synthetase; tumor necrosis factor; FAS receptor; signal transduction
      components of these antiviral pathways, and both type 1 and 2 cytokines) are correlated with
      delayed progression and diminished pathogenesis in paired hemophilic siblings.

Study Type

Observational

Condition

Blood Disease

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Start Date

September 1999

Completion Date

August 2004

Primary Completion Date

August 2004

Eligibility Criteria

        No eligibility criteria

Gender

Male

Ages

N/A - 100 Years

Accepts Healthy Volunteers

No

Contacts

Michael Fried, ,

Administrative Informations

NCT ID

NCT00007371

Organization ID

Secondary IDs

R01HL064817

Responsible Party

Sponsor

Study Sponsor

University of North Carolina, Chapel Hill

Collaborators

 National Heart, Lung, and Blood Institute (NHLBI)

Study Sponsor

Michael Fried, Principal Investigator, University of North Carolina

Verification Date

January 2005