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.
Drug: Interferon alpha
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.