This study will examine the effectiveness of low-dose peginterferon and ribavirin therapy
for certain patients with chronic hepatitis C-a liver disease that, in some patients, can
progress to cirrhosis of the liver, liver cancer, and liver failure. This disease is caused
by the hepatitis C virus (HCV). There are six major strains, or genotypes, of HCV.
Patients infected with genotypes 2 and 3 respond better and more quickly to the standard
treatment for this disease-high-dose peginterferon and ribavirin for 24 to 48 weeks-than do
patients with other genotypes. Although the side effects of these medications are more
severe at higher doses, patients with all genotypes, including genotypes 2 and 3, currently
receive the same standard treatment. This study will examine whether patients infected with
HCV genotypes 2 and 3 will respond equally well, and with fewer side effects, to lower doses
of peginterferon and ribavirin given for a shorter period of time.
Patients 18 years of age and older with chronic hepatitis C genotype 2 or 3 may be eligible
for this study. Each candidate will be screened with a medical history, physical
examination, blood tests, and liver ultrasound. Patients who have not had a chest x-ray or
electrocardiogram within a year of entering the study will have those tests as well.
Additional tests, such as eye examination, hearing test, stress test, or others, will be
done if deemed necessary because of the individual's particular medical condition or risk
factors for side effects of therapy.
Participants will be admitted to the NIH Clinical Center for 1 day for supervised
administration of the first doses of peginterferon and ribavirin and 24-hour observation.
The treatment regimen consists of two capsules of ribavirin twice a day every day and an
injection of peginterferon under the skin once a week. Patients will return to the clinic
at 2, 4, 8, 12, 16, 20 and 24 weeks after the first dose of therapy for a brief medical
history and physical examination, blood test, and check on hepatitis symptoms and treatment
side effects. Women capable of becoming pregnant will also have a pregnancy test at each
Patients will be tested for HCV levels after 12 weeks of therapy. Those who are negative
for the virus at that time will continue therapy for another 12 weeks to insure that the
response lasts. They will be monitored during that time and re-tested for the virus at the
end of that period. Patients who do not respond to treatment after 12 weeks will stop
low-dose therapy and be offered the higher-dose standard treatment for 48 weeks. Patients
who responded after 12 weeks and completed 24 weeks of therapy but subsequently became
positive after stopping treatment will also be offered standard high-dose treatment for the
full 48-week regimen. Patients on high-dose therapy will return to the clinic every 4 weeks
during the 48-week course for evaluation and blood tests. Patients who remain positive for
HCV after 24 weeks of high-dose therapy will stop treatment, as a response is unlikely to
occur beyond that time.
After treatment, patients will return to the clinic at 4- to 8-week intervals for
evaluations until 6 months. At 6 months, they will have a series of blood and urine tests
and ultrasound of the liver.
Sixty patients with chronic hepatitis C infected with HCV genotype 2 or 3 will be treated
using the combination of either low- or standard dose peginterferon and ribavirin for 24
weeks, with re-treatment using the standard doses and a longer duration (48 weeks) for those
who do not respond to or relapse after initial low dose therapy.
Adult patients with chronic hepatitis C who have HCV genotype 2 or 3 and previously have not
received anti-viral treatment will be given peginterferon alfa-2a (90 or 180 micrograms
weekly by injection) and ribavirin (800 mg daily by mouth). Patients will be monitored at
2- to 4-week intervals for side effects, compliance, complete blood counts, liver
biochemical tests and HCV RNA. Patients becoming HCV RNA negative by week 12 will be
considered on-treatment responders, continue therapy to week 24, and be monitored thereafter
for another 24 weeks. Patients who do not become HCV RNA negative by week 12 as well as
patients who relapse after therapy will be retreated with 180 micrograms of peginterferon
weekly and 800 mg of ribavirin for another 48 weeks.
The primary outcome will be sustained loss of HCV RNA at 24 weeks after low- or
standard-dose combination therapy. Secondary outcomes include viral kinetics and side
effects. Because of preliminary results in the initial 31 patients enrolled in this study,
the dose of peginterferon was changed from 90 to 180 micrograms weekly for the remaining 29
patients to be enrolled, allowing for a direct comparison of efficacy, viral kinetics and
side effects of standard- vs low-dose peginterferon therapy.
This study will evaluate the relative efficacy and safety of the standard versus lower doses
of peginterferon with ribavirin in patients with chronic hepatitis C and HCV genotype 2 or
- INCLUSION CRITERIA:
Age above 18 years, male or female.
Presence of anti-HCV in serum.
Positive HCV RNA determination in serum.
HCV genotype 2 or 3 as determined by Inno LiPa assay or by direct sequencing. Patients
with mixed genotypes will not be eligible if they have genotypes other than 2 or 3.
Written informed consent.
Previous treatment with interferon alpha or peginterferon.
Decompensated liver disease, as marked by bilirubin greater than 4 mg/dL, albumin less
than 3.0 g/dL, prothrombin time greater than 2 sec prolonged, or history of bleeding
esophageal varices, ascites or hepatic encephalopathy.
Patients with ALT levels greater than 1000 U/L (greater than 25 times ULN) will not be
enrolled but may be followed until three determinations are below this level.
Pregnancy or, in women of child-bearing potential or in spouses of such women, inability
to practice adequate contraception, defined as vasectomy in men, tubal ligation in women,
or use of condoms and spermicidal, or birth control pills, or an intrauterine device.
Significant systemic or major illnesses other than liver disease, including congestive
heart failure, renal failure (creatinine clearance less than 50 ml/min), organ
transplantation, serious psychiatric disease not controlled by psychotropic agents, and
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.
Pre-existing, severe bone marrow compromise; anemia (hematocrit less than 30%),
neutropenia (less than 1000 neutrophils/microliter) or thrombocytopenia (less than 70,000
History of hemolytic anemia.
Evidence of another form of liver disease in addition to hepatitis C (for example
hepatitis B, autoimmune liver disease, Wilson's disease, alcoholic liver disease).
Active substance abuse, such as alcohol, inhaled or injection drugs within the previous
Evidence of hepatocellular carcinoma: either alfa-fetoprotein (AFP) levels greater than 50
ng/ml (normal less than 9 ng/ml) and/or ultrasound (or other imaging study) demonstrating
a mass suggestive of liver cancer.
Quiescent or active, serious autoimmune disease such as lupus erythematosus, ulcerative
colitis, Crohn's disease or rheumatoid arthritis that in the opinion of the investigators
might be exacerbated by therapy with alfa interferon.
The use of immunosuppressive medications, including corticosteroids in doses of 10 mg of
prednisone or its equivalent and higher.