Long-Term Therapy With Ribavirin for Chronic Hepatitis C

Up to 50 patients with chronic hepatitis C will be treated for up to eight years with
ribavirin, an orally administered antiviral agent. Patients will be chosen who have moderate
to severe chronic hepatitis C who previously failed to have a sustained virological response
to the combination of alpha interferon and ribavirin or who were intolerant to interferon
therapy or who have significant contraindications to the use of interferon.

After medical evaluation and liver biopsy, patients will begin receiving ribavirin in a dose
of 1000 mg (body weight less than 75 K) or 1200 mg daily (two or three capsules of 200 mg
twice daily by mouth). Patients will be followed on therapy with visits to the outpatient
clinic for medical interview, physical examinations and blood tests at 2 to 8 week
intervals. After six months, the dose of ribavirin will be stopped or adjusted based upon
changes in alanine aminotransferase (ALT) levels comparing the average of the three values
from month 2, 4, and 6 to the baseline levels. A decrease by 50% or more will be considered
a partial biomedical response and a decrease to within the normal range will be considered a
complete biochemical response. In patients who do not respond by six months, therapy will be
stopped, whereas, in patients who respond, therapy will be continued decreasing the dose in
increments of 200 mg per day every 6 months as long as a biochemical response is maintained.
The minimal dose will be 400 mg per day. In patients with a response, therapy will be
continued for up to 8 years with repeat liver biopsies and evaluations at 2, 4 and 8 years.

The primary criterion for success of therapy will be the degree of histologic improvement on
liver biopsy at 2, 4 and 8 years; supportive, secondary criteria will be improvements in ALT
levels and in symptoms done at the same time points. This open-label pilot study will allow
for therapy of patients with resistant forms of chronic hepatitis C and will address whether
long-term therapy with this agent is safe, as well as whether prolonged monotherapy with
ribavirin leads to sustained improvements in serum ALT levels, whether these can be
maintained using lower doses of ribavirin, and whether the improvements reflect amelioration
of the underlying liver disease as judged histologically.

- INCLUSION CRITERIA:

Age above 18 years, male or female.

Elevated alanine (ALT) or asparate (AST) aminotransferase activities averaging at least
twice the upper limit of normal on three determinations taken at least one month apart
during the previous 6 months. The mean of these three determinations will be defined as
"baseline" ALT and AST levels.

Presence of anti-HCV and HCV RNA in serum tested at least once during the previous six
months.

Evidence of chronic hepatitis on liver biopsy done within the previous 12 months with a
histology activity index of at least 6 (out of a maximum of 22).

Contraindications to the use of alpha interferon, either in the form of specific
contraindications to its use (depression, psychiatric illness, neurological impairment,
severe thrombocytopenia, autoimmune disease), or the history of severe side effects or
intolerance during a previous course of alpha interferon, or lack of a sustained
virological (sustained lost of HCV RNA from serum for more than six months after stopping
treatment) response to an adequate course (6 months) of the combination of alpha
interferon and ribavirin or (after September 1, 2003) the combination of peginterferon and
ribavirin.

Written informed consent.

INCLUSION CRITERIA FOR PATIENTS IN 98-DK-0003:

An important group of patients who were enrolled in the current study, were patients who
participated in the Clinical Research Protocol 98-DK-0003 (Combination of alpha interferon
with long-term ribavirin for patients with chronic hepatitis C) and who did not have a
sustained virological response to this treatment. These patients were eligible to enroll
into the current study once they had finished the therapy and follow up period in that
trial. These patients fit the inclusion criteria listed above with one exception: some
patients were receiving ribavirin monotherapy as a part of their participation in
98-DK-0003. These patients were eligible to be immediately enrolled into this study
without a medication-free period in between.

EXCLUSION CRITERIA:

Pregancy or, in women of childbearing potential, inability to practice adequate
contraception. Men with spouses or sexual partners of childbearing potential also be
excluded if they are unable to practice adequate contraception.

Significant systemic illnesses other than liver disease, including a history of congestive
heart failure, cerebral vascular disease, renal failure (creatinine clearance less than 50
ml/min), and angina pectoris.

Patients with an abnormal stress test or carotid untrasound will not be enrolled into this
study.

Pre-existing anemia (hematocrit less than 32%) or known history of hemolytic anemia.

Interferon or immunosuppressive therapy within the last 6 months.

Evidence of another form of liver disease in addition to viral hepatitis, such as
autoimmune or alcoholic liver disease.

Active or recent (within one year) alcohol or drug abuse or psychiatric illness that is
likely to interfere with compliance and requirements for safety monitoring during this
study.