Pilot Comparison of Standard Antiviral Therapy With and Without 12 Weeks of Betaine in Genotype 1 Naive Patients

Although pegylated alpha interferon and ribavirin will likely be part of the core therapy for
chronic HCV for the next several years, there are a number of complimentary antiviral agents
in development including protease or polymerase inhibitors, RNA vaccines and immunomodulators
(5). However, it would be unlikely to have FDA approval for any of these newer agents before
the next 3 - 5 years, i.e. 2010-2012.

Betaine, a naturally occurring anti-oxidant metabolite of choline and an amino acid analog
(tri-methyl-glycine), serves as a methylation agent to re-methylate damaged cell proteins or
enzymes (6). By virtue of its metabolic role in decreasing toxic metabolites, betaine also
protects against alcohol-induced fatty liver and apoptosis. Recently, pilot studies performed
both at the Mayo Clinic and here at UNMC showed its applicability as a treatment of
non-alcoholic fatty liver in human subjects (7, 8).

Betaine has also recently been found to promote interferon function by overcoming HCV -
induced inhibition of interferon signaling (9). Naturally-occurring HCV proteins during human
infection can hypo-methylate proteins integral to the Jak - STAT (signal transducers and
activators of transcription) pathway, thereby inhibiting the antiviral activity of
interferon. In cultured cells betaine administration, in a physiologically attainable
concentration, restored STAT methylation and improved interferon signaling (9).

Inclusion Criteria:

- Subject must be willing to give informed consent and be able to adhere to dose and
visit schedules.

- History of chronic hepatitis C as documented by either anti-HCV or HCV RNA positivity.

- Adult subjects 19-70 years of age, of either gender

- Liver biopsy within 3 years prior to the screening 1 visit.

- Compensated liver disease with the following maximum hematologic, biochemical and
serologic criteria at the Screening visit (WNL=within normal limits) Hemoglobin > 12
g/dl for females and >13 g/dl for males, WBC > 3000/mm3, Platelets > 80,000/mm3,
Direct Bilirubin - WNL. Indirect bilirubin - WNL, Albumin - WNL, Serum Creatinine -
WNL.

- Fasting glucose should be 70 -140 mg/dl, results between 116-140 require a HbA1c <
8.5%

- TSH - WNL

- Subjects with a history of mild depression may be considered for entry in to this
study provided that a pretreatment assessment of the subject's affective status
supports that the subject is clinically stable.

- Subjects with a history of substance abuse must have abstained from using the
substance for at least one year prior to the Screening visit.

- Antinuclear antibodies (ANA) < 1:320

- No radiologic evidence of a focal mass suggestive of hepatoma and/or ascites.

Exclusion Criteria:

- Pregnant or nursing subjects. Subjects who intend to become pregnant during the study
period. Subjects with partners who intend to become pregnant during the study period.

- History of new hepatitis C exposure within the last 6 months

- Prior treatment for chronic hepatitis C.

- Current or intended use of G-CSF and/or GM-CSF during the stud period is prohibited.
Current use of erythropoietin (EPO) is prohibited.

- Suspected hypersensitivity to any interferon product or ribavirin

- Participation in any other clinical trial within 30 days of Screening visit

- Treatment with any investigational drug within 30 days of Screening visit 1.

- Any other cause for liver disease other than CHC.

- Coagulopathies including hemophilia

- Hemoglobinopathies

- G6PD deficiency

- Coinfection with HIV and/or HBV

- Evidence of active or suspected malignancy or a history of malignancy within the last
five years (with the exception of adequately treated basal cell carcinoma of the
skin).

- Evidence of decompensated liver disease such as history or presence of ascites,
bleeding varices or hepatic encephalopathy

- Subjects with organ transplants other than cornea or hair transplant

- Any Known preexisting medical condition, that could interfere with the subject's
participation in and completion of the study.