Effects of Vitamin D on Inflammation in Liver Disease

Vitamin D appears to be a critical signaling molecule for macrophages because is needed for
activation and differentiation of monocytes/macrophages. From our Preliminary Studies( VA
Merit Review Grant), we propose that Vitamin D deficiency may alter the 'pro-inflammatory'
('classically activated') M1 macrophages , characterized by i] high expression of NOS2,
TNF-a, IL-1, IL-6, IL-8, TGF-a, CXCL10, and CCL19; and ii] minimal expression of arginase 1
and mannose R.

The clinical relevance of these findings is suggested by the presence of activated M1
macrophages in liver biopsies from patients with severe drug-induced liver injury
(unpublished observations).

Prospective vitamin D supplementation studies with appropriate endpoints are needed to
define the role of vitamin D on inflammation in patients with chronic liver diseases.

Inclusion Criteria:

- Men or women aged 18 or older

- Total 25-OH Vit D < 25 ng/mL

- Infection with HCV genotype 1 (subjects infected with multiple genotypes are not
eligible).

- Plasma HCV RNA concentration of >100,000 IU/mL.

- HCV-infected subjects naïve to treatment: subjects who either have never been treated
for HCV infection or who previously received HCV treatment ending > 3 months prior to
enrollment (including, any IFN-Alpha with or without ribavirin, or other anti-HCV
antiviral medication).

Exclusion Criteria:

- Women who are pregnant or breastfeeding.

- Patients with Sarcoidosis, Histoplasmosis, Lymphoma, Primary Hyperparathyroidism or
Idiophatic Hypercalcemia.

- Liver Cirrhosis.

- Known active gastrointestinal disease that could interfere with the absorption of the
test article.

- Laboratory determinations at screening as follows:

- Hemoglobin <10 g/dL .

- Serum creatinine that is not within normal limits. However, such subjects may be
enrolled if the Cockroft-Gault glomerular filtration rate (GFR) is > 50 mL/minute.

- Unstable hypertension, cardiac disease or type 2 diabetes requiring changes in
treatment with medications 4 weeks prior to screening or during the screening period.

- Use of an investigational drug within 4 weeks before the screening visit or during
the screening period.

- Use of systemic immunosuppressants (including systemic, oral, or intravenous
corticosteroids) or immunomodulating agents within 4 weeks before the screening visit
or during the screening period.