This study will evaluate the effectiveness of an experimental treatment regimen for
hepatitis C. Standard treatment consists of combination therapy with ribavirin, taken by
mouth twice a day, and Peginterferon, injected under the skin once a week. Hepatitis C
genotypes 2 and 3 have a high success rate with this regimen, while genotype 1 is more
difficult to treat. This study will determine if patients with genotype 1 respond better to
treatment that uses a higher dose of ribavirin than the standard approved dose of 1,000 to
1,200 mg daily.
Patients 18 years of age and older with chronic hepatitis C genotype 1 who have not been
successfully treated with a standard course of Peginterferon and ribavirin may be eligible
for this study. Participants are randomly assigned to receive either standard treatment with
Peginterferon and ribavirin or to receive Peginterferon plus twice the dose of ribavirin
(2,000 to 2,400 mg daily) for 48 weeks. In addition to treatment, all patients receive
undergo the following:
- Medical history and physical examination, symptom questionnaires, blood tests, urine
collection, chest x-ray, electrocardiogram, liver ultrasound, Fibroscan (ultrasound to
measure stiffness of the liver) and pregnancy test for women who are able to have
- Patients with other medical conditions or special risk factors may have further
evaluations before starting treatment. These may include, for example, eye evaluation
for patients with diabetes, exercise stress test for people over age 40 or who have
risk factors for heart disease and psychiatric evaluation for people who have
depression or anxiety disorder.
- Periodic blood tests to monitor blood counts and viral levels.
- Outpatient clinic visits every 4 weeks for the duration of the study for laboratory
tests and review of symptoms and treatment side effects. Physical examinations and
urine tests are done every 12 weeks.
Following Completion of Treatment
About 1 1/2 years after starting treatment, subjects are re-evaluated as they were at the
start of treatment.
Up to 60 patients with chronic hepatitis C genotype 1 infection who were previously treated
with standard doses of peginterferon and ribavirin (1000 to 1200 mg daily) but who did not
have a virological response (non-responders: n=35) or who relapsed after therapy (relapsers:
n = 25) will be re-treated using peginterferon and higher doses of ribavirin (2000 to 2400
mg daily). After medical evaluation, documentation of eligibility and written informed
consent, patients will be started on therapy with standard doses of peginterferon alfa-2a
(180 micro g per week) and twice the standard dose of ribavirin (2000 mg daily for patients
less than 75 kg; 2400 mg daily for patients greater than or equal to 75 kg). Viral
kinetics will be evaluated on the basis of changes in HCV RNA levels during the first 24
weeks of therapy with blood sampling done on days 0, 1, and 2 and weeks 1, 2, 3, 4, 8, 12,
16, 20 and 24. Patients who fail to decrease levels of HCV RNA by more than 2 log(10) IU/ml
by week 12 will be considered non-responders and therapy will stop. Similarly, patients who
do not become HCV RNA negative (less than 10 IU) by week 24 will also be considered
non-responders and therapy will be discontinued. Patients who do become HCV RNA negative
during the first 24 weeks of therapy will continue for 48 weeks and be followed for at least
24 weeks thereafter. The primary end-point of this study will be a sustained virological
response (SVR), which is defined by the absence of detectable HCV RNA in serum on treatment
and for at least 24 weeks after stopping therapy. The SVR rate for re-treatment using
conventional doses of peginterferon and ribavirin is expected to be less than 5 percent.
The estimated rate of SVR using peginterferon with high doses of ribavirin is 50 percent for
patients with a previous relapse and 25 percent for those with a previous non-response. A
sample size of 35 patients would be needed to achieve statistical significance based upon
these estimates of response rates for non-responders and 25 patients for relapsers. If none
of the first ten non-responder patients treated in this protocol achieve an SVR, no more
non-responder patients will be enrolled and this part of the study will be terminated early.
Patients also will be monitored closely for side effects of therapy, the major one for
ribavirin being anemia. Patients who develop anemia will be treated with darbepoietin to
maintain a hemoglobin level above 10 gm percent. This pilot study is expected to
demonstrate whether use of high doses of ribavirin is an option for patients who fail to
have an adequate response to conventional doses of peginterferon and ribavirin for chronic
- INCLUSION CRITERIA:
Age 18 years or above, male or female
Documented relapse or non-response to a prior adequate course of peginterferon and
Genotype 1 HCV as determined by probe specific hybridization (Inno-Lipa assay).
Written informed consent.
Age greater than 65 years
If cirrhosis is present, decompensated liver disease, as marked by serum bilirubin greater
than 4 mg percent, albumin less than 3.0 gm percent, prothrombin time greater than 2 sec
prolonged, or history of bleeding esophageal varices, ascites or hepatic encephalopathy.
Serum ALT or AST levels greater than 1000 U/L (greater than 25 times the ULN). Such
patients will not be enrolled but may be followed until three determinations are below
Pregnancy or, in women of child bearing potential or in spouses of pregnant women,
inability to practice adequate contraception, defined as vasectomy in men, tubal ligation
in women, or use of condoms and spermacide, or birth control pills, or an intrauterine
Significant systemic or major illnesses including congestive heart failure, organ
transplantation, serious psychiatric disease or depression, human immunodeficiency virus
(HIV) infection, and angina pectoris.
Previous intolerance of weight based ribavirin dose (1,000-1,200 mg daily) including need
for dose reduction, use of erythropoietin or serious adverse event attributable to
Renal insufficiency (creatinine clearance less than 60 ml/min) or renal failure
Pre existing anemia (hematocrit less than 34 percent) or known history of hemolytic
Uncontrolled hypertension or diabetes mellitus
Other antiviral therapy within the last 6 months.
Immunosuppressive therapy with either corticosteroids (more than 5 mg of prednisone daily)
or major immunosuppressive agents (such as azathioprine or 6-mercaptopurine).
Evidence of another form of liver disease in addition to viral hepatitis (for example
autoimmune liver disease, Wilson disease, alcoholic liver disease, hemochromatosis, alpha
1 antitrypsin deficiency).
Evidence of coronary artery disease or cerebral vascular disease, including abnormalities
on exercise stress testing in patients with defined risk factors who will be screened for
evidence of underlying coronary artery disease.
Active substance abuse, such as alcohol, inhaled or injection drugs within the previous
Evidence of hepatocellular carcinoma; either alpha-fetoprotein (AFP) levels greater than
200 ng/ml (normal less than 9 ng/ml) and/or ultrasound (or other imaging study)
demonstrating a mass suggestive of liver cancer.
Active, serious autoimmune disease, such as lupus erythematosis, ulcerative colitis, Crohn
s disease or rheumatoid arthritis that in the opinion of the investigators might be
exacerbated by therapy with peginterferon.
Uncontrolled thyroid disease
Evidence if severe retinopathy or clinically relevant ophthalmological disorder (only
patients with pre-existing hypertension or diabetes will undergo an ophthalmological