Racial Difference in HCV/Host Interactions

The University of Tennessee Health Science Center (UTHSC) Memphis Hepatitis C Cooperative
Research Center was established in 2000 to support clinical and basic research in
understanding the basis for chronic disease in hepatitis C (HCV) infection and response to
therapy in clinically infected patients. The primary research goal is to understand why
African American (AA) patients with chronic hepatitis C are more susceptible to chronic
infection and why their response rate to combination therapy is only 50 percent or less of
that for non AA patients. The present study will support this ongoing work by continuing to
provide clinical samples from patients with chronic hepatitis C who are undergoing treatment.
The specific aims for the 2005-2010 Hepatitis C Cooperative Research Center are: to determine
how human leukocyte antigen (HLA) class II-dependent immune regulation and T cell
specificities affect differences in immune responses to HCV and response to therapy in AA
patients compared to non AA patients; to determine if there is a difference in
interferon-induced signaling between patients that respond to therapy and those that do not;
and to measure and compare the sustained virologic response to standard treatment for
hepatitis C between AA and non AA patients. Researchers plan to continue enrollment of
patients to the "African American Response to Therapy for Hepatitis C" study (112 African
American patients and 20 Caucasian patients) in order to meet the current specific aims.
Participants will include adult African American and Caucasian patients with compensated
chronic hepatitis C who have not been previously treated with interferon and/or ribavirin.
Patients meeting the entry criteria will be enrolled. The total number of patients to be
enrolled is 260 over a 10-year period. In the next 5 years 132 subjects (112 African
American, 20 Caucasian) will be studied locally. Patients will be recruited primarily from
the clinical practices of the hepatologists at UTHSC. Patients will also be selected from
referrals at local Gastroenterology Hepatology clinics and the Memphis Department of Veterans
Affairs (VA) Hospital. Patients will be treated with weight based pegylated interferon
alfa-2b once weekly and weight based ribavirin twice a day. Duration of treatment with both
pegylated interferon alfa-2b and ribavirin will be for up to 72 weeks. Treatment will be
discontinued at 24 weeks if there is persistent viremia and the patient wishes to discontinue
therapy. Ribavirin will be administered orally at a dose of 13 +/- 2 mg/kg per day twice
daily, with 200 mg capsules. Pegylated interferon alpha-2b will be administered by the
subcutaneous route.

Inclusion Criteria:

- Adult, male or female, African-American or Caucasian, age 18 or older.

- Serum positive for hepatitis C virus by Polymerase Chain Reaction (PCR) or other
assays [e.g. Deoxyribonucleic acid, (BDNA)].

- Liver biopsy prior to entry to this protocol with a pathology report confirming that
the histological diagnosis is consistent with chronic hepatitis.

- Compensated liver disease with the following laboratory parameters at the Entry visit:

- Hemoglobin values of greater than or equal to 12 mg/dL

- Neutrophil count greater than or equal to 1,200/mm^3

- Platelets greater than or equal to 60,000/mm

- Albumin > 3.0 g/dL or within 20 percent of lower limit of normal (LLN)

- Serum creatinine less than or equal to 1.5 mg/dL

- Thyroid stimulating hormone (TSH) within normal limits or thyroid disease under
control

- Reconfirmation and documentation that sexually active female patients of childbearing
potential are practicing adequate contraception (intrauterine device, oral
contraceptives, progesterone implanted rods (Norplant), medroxyprogesterone acetate
(Depo-Provera), surgical sterilization, barrier method (diaphragm + spermicide), or
monogamous relationship with a male partner who has had a vasectomy or is using a
condom + spermicide) during the treatment period and for 6 months after
discontinuation of therapy. A urine pregnancy test obtained at entry prior to the
initiation of treatment must be negative. Female patients must not be breast-feeding.
Documentation that sexually active male patients are practicing acceptable methods of
contraception (vasectomy, use of a condom + spermicide, monogamous relationship with a
female partner who practices an acceptable method of contraception) during the
treatment period and for 6 months after discontinuation of therapy.

- Written informed consent specific for this protocol has been obtained prior to entry.

Exclusion Criteria:

- Hypersensitivity to interferon or ribavirin.

- Any cause for chronic liver disease other than chronic hepatitis C.

- Active hemolytic anemia.

- Evidence of advanced liver disease such as a history of or presence of ascites,
bleeding varices, or spontaneous encephalopathy.

- Any known preexisting medical condition that could interfere with the patient's
participation in the protocol including: (Central Nervous System) CNS trauma or
uncontrolled seizure disorders; poorly controlled diabetes mellitus; serious pulmonary
disease; immunologically-mediated diseases; gout' or any medical condition requiring,
or likely to require during the course of the study, chronic administration of
steroids.

- Patients with evidence of ischemia or stress testing, Electrocardiogram (ECG) evidence
of ischemia, a significant arrhythmia, cardiac failure, recent coronary surgery,
uncontrolled hypertension, angina or a myocardial infarction within 12 months.
Pretreatment stress test will be required for all participants greater than 50 years
of age or 45 years of age if diabetic.

- Patients with clinically significant retinal abnormalities.

- Substance abuse, such as alcohol (greater than 80 gm/day), intravenous (IV) drugs and
inhaled drugs. If the patient has a history of substance abuse, to be considered for
inclusion into the protocol, the patient must have abstained from using the abused
substance for at least 3 months.

- Patients with a history of organ transplantation will be excluded.

- Patients infected with human immunodeficiency virus.

- Preexisting psychiatric conditions; especially severe depression, or a history of
severe psychiatric disorder, such as major psychoses, active suicidal ideation and/or
suicidal attempt are excluded. Patients with a history of mild depression may enter
the protocol if they meet the following eligibility criterion and are monitored more
intensively. Mild depression includes either situational depression for a limited
period or depressive symptoms, which do not significantly interfere with the patient's
work or daily functions. All patients will complete the Center for Epidemiological
Studies Depression Scale (CES-D). The CES-D is a 20-item self-report scale designed to
measure depressive symptomatology experienced during the week prior to the interview.
The items are scored on a four-point scale (0-3), with the total score ranging from
zero to 60. CES-D scores of 16-20 suggest minor depression, and scores greater than 20
suggest major depression. The score can be determined in real time. A score of 16 or
higher should prompt further questioning and consideration of treatment or referral to
psychiatry. Detailed follow-up of each patient may be individualized according to
his/her need; this would usually include predetermined visits.