Hepatitis C Treatment and Atherosclerosis

Hepatitis C virus (HCV) infection is associated with changes in lipid metabolism in the liver
and the peripheral blood. Patients with chronic hepatitis C infection tend to have low levels
of cholesterol and LDL-cholesterol. These levels increase in many patients after treatment
and successful eradication of the virus. However, it is not known whether this increase is
associated with increased cardiovascular risk and thus may increase their risk for
atherosclerotic disease. To determine whether eradication of HCV affects atherosclerosis
progression, we propose to examine up to 200 patients with chronic hepatitis C for markers of
atherosclerosis and the risk of its complications. Up to 100 patients who have cleared HCV
and recovered will be matched and compared to patients who failed to respond and continue to
have chronic hepatitis C. The atherosclerosis assessment will include careful history for
cardiovascular risk factors, a battery of blood tests for lipid levels and relevant
biomarkers followed by specialized imaging tests of the carotid and coronary arteries,
including ultrasound imaging of intima-media thickness of the carotid arteries and
computerized axial tomography of the heart and coronary arteries. The primary end point in
the assessment will be differences in maximal carotid intima media thickness and secondary
end points will include differences in coronary artery calcium score, Framingham risk scores
and other measurements or atherosclerosis. This cross-sectional study will set the stage for
a more formal prospective assessment of cardiovascular risk factors and evidence of coronary
and cerebrovascular disease among patients being treated with antiviral agents.

- INCLUSION CRITERIA:

Age equal to or greater than 30 years, male or female

Written informed consent

All ethnicities

Viral hepatitis status:

- Cases:

- History of chronic hepatitis C defined by past positivity for serum HCV-RNA, HCV
antibody and elevated serum alanine or aspartate aminotransferase levels for at
least 6 months before start of treatment

- Genotype 1, 2 or 3

- Absence of detectable serum HCV-RNA by PCR on screening visit and on a previous
test, at least 3 months apart. Both tests have to be performed at least 24 weeks
after cessation of therapy

- Past treatment with interferon alfa (standard or pegylated) for at least 12 weeks

- At least 12 months after end of interferon treatment

- Normal liver enzymes on screening visit

- Genotype 1 controls:

- Detectable serum HCV-RNA on screening visit

- Past treatment with interferon alfa (standard or pegylated) for at least 12 weeks

- At least 12 months after end of interferon treatment

- Age (difference less than or equal to 3 years), sex and race-matched with
genotype 1 cases

- Genotype 2 and 3 controls:

- Detectable serum HCV-RNA on screening visit

- If previously treated with interferon alfa (standard or pegylated) - at least 12
months elapsed from the end of treatment

- Age (difference less than or equal to 3 years), sex, race and genotype-matched
with genotype 2 and 3 cases

EXCLUSION CRITERIA:

Pregnancy or lactation

History of clinical atherosclerotic disease manifest as:

- Ischemic cerebrovascular accident (CVA), transient ischemic accident (TIA) or
radiological evidence of stroke.

- Proven coronary artery disease history of myocardial infarction, need for coronary
angioplasty or coronary artery bypass graft, anginal syndrome with confirmatory stress
test or cardiac imaging.

- Symptomatic peripheral vascular disease, history of angioplasty or surgical bypass.

- History of carotid artery surgery or angioplasty

- Patients with overt atherosclerotic disease can be included if the first manifestation
of that disease appeared at least 3 years after cessation of interferon treatment.
Control patients who were never treated in the past will not be included if there is
an overt manifestation of atherosclerosis.

Diabetes mellitus unless fasting blood sugar can be maintained within normal limits and
HBA1C less than 7 without the need for pharmacologic intervention

Hypertension unless blood pressures can be maintained for greater than 6 months within
normal limits without the need for pharmacologic intervention

Current treatment with cholesterol lowering medications

Chronic renal failure (creatinine clearance less than 50 ml)

Known HIV infection

HCV genotype 4, 5, 6 or mixed infection.

Other causes of liver disease apart from hepatitis C (hepatitis B, alcoholic liver disease,
NASH, autoimmune hepatitis, PBC etc.). Bland, non-alcoholic hepatic steatosis will not
constitute an exclusion criterion

History of trauma to the neck, surgery or deformity precluding sonographic visualization of
the carotid arteries

Inability to sign or understand the informed consent form

A contraindication or unwillingness to undergo the coronary calcium score CT scan will not
be an exclusion criterion, as this is not a primary end-point, as long as the participant
is willing to undergo an IMT measurement.