Interferon-Induced Gene Expression in Liver Cells and Peripheral Blood Lymphocytes
Condition: Hepatitis C
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis
Study type: Interventional
Phase: Phase 2

Summary: 
      This proposal seeks to use DNA analyses to understand how racial and genetic factors
      influence interferon (treatment) response in HCV infection in African Americans. A better
      understanding should allow rational design of new therapies or better use of existing
      therapies. Patients will provide medical history and undergo a physical exam, blood draws,
      electrocardiogram, possible chest x-ray, and abdominal ultrasound. Patients will be admitted
      to the hospital for 5 days and undergo 2 liver biopsies, sedation, and multiple blood draws.
      Twenty adult male volunteers (10 Caucasians,10 African Americans) ages 18 - 65 years will
      participate.
    

Detailed description: 
      This proposal uses sophisticated DNA microarray analyses of the transcriptional changes
      induced in hepatocytes (cellular locus of viral replication) and peripheral blood lymphocytes
      (one compartment of immune responder cells) in an effort to better understand how racial and
      host genetic factors influence interferon response in HCV infection. A better understanding
      of these underlying mechanisms should allow rational design of new therapies or better use of
      existing therapeutic modalities. The variables to be investigated are racial differences in
      interferon induced: 1) HCV viral kinetics and 2) intrahepatic and PBL transcriptional
      responses. Specific Aim 1: (a) To compare the phase 1 and early phase 2 decline of the viral
      titer in serum in African-Americans and Caucasians following a single dose of IFN-alpha (10
      MU sc). (b) To determine the hepatic HCV RNA abundance in both a baseline liver biopsy and in
      a repeat liver biopsy taken 24 hrs after administration of interferon, and to determine how
      this correlates with the HCV RNA decline in serum over the 24 hr period. (c) To compare the
      rates of viral decline in the liver and serum in African-Americans and Caucasians 24 hours
      after interferon, and to relate this to the pharmacokinetics (PK) of the initial dose of
      interferon. A total of 10 Caucasian and 10 African American patients with chronic hepatitis C
      and HCV genotype 1 will be enrolled in this study. All study patients will undergo a baseline
      percutaneous liver biopsy on day 1 of the study. On day 3, a single dose of IFN-alpha 2a (10
      MU sc) will be administered and a repeat liver biopsy will be done 24 hours after the
      injection. Specific Aim 2: (a) To utilize Affymetrix HG-U133A&B Human GeneChips® to determine
      global mRNA profiles in liver tissue collected from patients before and 24 hrs after a single
      10 MU dose of IFN-alpha and thereby assess the intrahepatic transcriptional response to
      IFN-alpha. (b) To characterize differences in the early intrahepatic transcriptional response
      to interferon in Caucasians and African Americans. Specific Aim 3: (a) To utilize Affymetrix
      HG-U133A&B Human GeneChips® to determine global transcription profiles in peripheral blood
      lymphocytes pre-treatment, 24hrs, and 48hrs after the initial dose of interferon and to
      compare these results in Caucasians and African Americans at these time points. (b) To
      compare global gene profiles in lymphocytes and liver at baseline and 24hrs after interferon,
      and determine whether lymphocytic transcriptional profiling is a valid surrogate for
      intrahepatic gene profiling. Specific Aim 4: To use sophisticated bioinformatics approaches
      and HCV kinetic modeling to determine whether differences in early intrahepatic or
      lymphocytic transcriptional profiles correlate with early changes in the level of viremia
      (observed antiviral response) in the period immediately following administration of the 10 MU
      dose of IFN-alpha.
    

Intervention name(s): Interferon alpha
Intervention type(s): Drug
Intervention MeSH terms: Interferons; Interferon-alpha
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Interferon, Gene Expression in Liver, Lymphocytes, High Density Oligonucleotide Microarray Expression Analysis, African American, Hepatitis C