This study will evaluate the safety and effectiveness of combination therapy with
peginterferon alpha-2a and ribavirin for treating hepatitis C virus (HCV) infection in
HIV-infected patients. Peginterferon alpha with ribavirin is the therapy of choice for
people with HCV alone. Peginterferon alpha-2a is a compound that results from attaching a
polyethylene glycol molecule to interferon alpha-2a. This compound stays in the blood longer
than unmodified interferon alpha-2a, causing a higher blood concentration and thus
maintaining greater activity against the hepatitis C virus.
HIV-infected patients 18 years of age and older with chronic hepatitis C infection and a
viral load greater than 2000 copies/mL may be eligible for this 2-1/2 year study. Candidates
are screened with a medical history and physical examination, blood and urine tests, eye
examination, chest x-ray, electrocardiogram (EKG), liver ultrasound, and pregnancy test in
women who are able to become pregnant. If a recent liver biopsy is not available, this test
is done to determine the type and severity of liver disease. The patient is given a sedative
before the procedure. Then, the skin in the area over the biopsy site is numbed with a local
anesthetic and a needle is inserted rapidly into and out of the liver to obtain a small
tissue sample. The patient remains in the hospital overnight for monitoring.
Participants begin treatment with injections under the skin of peginterferon alpha-2a and
ribavirin pills by mouth on study day 0. Peginterferon is given either once or twice a week
for 4 weeks and then once a week for 44 weeks. Ribavirin is given daily. In addition,
patients continue to take all other medications prescribed by their doctor. Clinic visits
are scheduled for the following procedures:
- Days 1, 3, 4, 7, 10 and weeks 2, 3, and 4 - Blood tests for safety measures and to
measure blood levels of HIV and HCV.
- Weeks 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 - Blood and urine tests to determine the
side effects of treatment and its effect on the HCV infection. In addition, eye
examinations are done every 3 months, and pregnancy and thyroid function tests are done
several times during the treatment period.
- Week 48 or end of treatment - Treatment stops after 48 weeks. At this time, or earlier
for those who do not complete the 48 weeks, patients return to the clinic for a chest
x-ray, EKG, blood tests, and abdominal ultrasound. Patients are hospitalized for a
repeat liver biopsy.
- Weeks 52, 56, 64 and 72 - Blood and urine tests to determine the side effects of
treatment and its effect on the HCV infection, and a urine pregnancy test in women.
Hepatitis C infection occurs in one-third of all HIV-infected individuals. Liver disease has
become more significant among patients coinfected with HIV and HCV. Several studies have
shown that coinfected individuals develop earlier and more severe liver disease. Pegylated
interferon alpha with ribavirin has become the therapy of choice among people with HCV
alone. This is a randomized controlled study to address the safety and efficacy of a 4 week
induction therapy consisting of twice-weekly pegylated interferon alpha-2a and daily
ribavirin on HIV-1 and hepatitis C coinfected individuals. Twenty-two patients who are
infected with both HIV and HCV and who also have evidence of chronic hepatitis will be
randomized to receive peginterferon alpha-2a either twice weekly or once weekly for four
weeks. They will then continue with standard weekly peginterferon for 44 more weeks. The
patients will receive standard daily dose of ribavirin during the entire 48 weeks. These
patients will be monitored for peginterferon level, HCV viral load, HIV viral load and CD4
counts and undergo a baseline liver biopsy and another at the end of 72 weeks. The results
of the study will enable us to better delineate the efficacy of twice weekly peginterferon
induction therapy in suppressing the hepatitis C virus in the first 4 weeks of the therapy.
Since viral suppression for hepatitis C in the early phase of the combination treatment has
predictive values for long term eradication of the virus, a therapy that improves early
viral suppression may improve the long term cure rate. This will be especially important
given the current low cure rate of HCV among HIV coinfected individuals.
- INCLUSION CRITERIA
Age greater than or equal to18 years.
Documentation of HIV-1 infection by licensed ELISA test and confirmed by a Western Blot.
Documentation of Hepatitis C infection by demonstration of a positive test for hepatitis C
antibody and on HCV RNA level of 2000 or greater.
Histopathologic features consistent with chronic hepatitis C on liver biopsy at the time
of enrollment. A liver biopsy done for a subject within a year prior to his or her
participation may be used as the baseline biopsy.
Patients with CD4+ cell count greater than 200 cells/mm3 or CD4+ cell percentage greater
Ability to sign informed consent and willingness to comply with the study requirements and
Serum phosphorus greater than or equal to 2.2 mg/dL and less than or equal to 4.4 (normal
range NIH 2.3-4.3 mg/dL).
Neutrophil count greater than or equal to 1000 cells/mm3.
Platelets greater than or equal to 50,000/ mm3.
Hemoglobin greater than or equal to 10.5 mg/dL.
ALT less than 7 X the NIH upper limit of normal.
Serum lipase less than 1.5 X the NIH upper limit of normal.
Not pregnant or breast-feeding. Pregnancy test must be negative within two weeks prior to
dosing with study medications.
If the patient is able to become pregnant then she must use two effective methods of
contraception during the study. Effective contraceptive methods include abstinence,
surgical sterilization of either partner, barrier methods such as diaphragm, condom, cap
or sponge, or use of hormonal contraception with an anti-HIV regimen that will not alter
metabolism of hormonal contraception. This is advised on the basis of using ribavirin,
which may have a potential teratogenic effect in pregnant women.
Need to have a primary doctor outside of OP8 or as part of the OP8 training clinic who
will be taking care of the patients for their HIV infection and liver disease.
Willing to designate a person for durable power of attorney on the NIH form for medical
research and medical care purposes at the NIH Clinical Center.
Able to learn to safely inject medication subcutaneously or be able to find another person
or a clinic to inject for him/her.
Patient should not be on other experimental therapies during their participation in this
Patients should not have used interferon or peginterferon previously for the treatment of
Liver histology which, in the opinion of Clinical center pathologist, is consistent with
any other co-existent cause of chronic liver disease as defined as chronic hepatitis B
with positive HBSag, autoimmune hepatitis with a positive ANA greater than 1 unit or
positive anti mitochondrial antibody greater than 1 unit, cholestatic disease with
persistent elevation of Alkaline phosphatase, primary biliary cirrhosis or sclerosing
cholangitis, Wilson's disease, alpha-1-antitrypsin deficiency, steatohepatitis (alcohol or
non alcoholic) with marked steatosis, many Mallory bodies, or extensive zone 3 periportal
Hemochromatosis or secondary iron overload as defined by (1) an elevated serum ferritin or
an iron saturation (serum iron/IBC X 100%) of greater than 50% and (2) presence of 3+ or
more stainable Iron on liver biopsy according to the study pathologist or a history of
previous phlebotomy for Iron overload will undergo HFE genetic counseling and those with a
positive HFE genetic test demonstrating homozygosity for C282Y and H63D are not eligible.
Those who have compound heterozygosity to C282Y and H63D are also not eligible.
Child Turcotte Pugh score greater than 7.
PT-INR greater than 2 or history of hemophilia.
Organ transplant recipient.
Creatinine clearance less than 50 mL/min.
Elevated alpha-fetoprotein level (greater than 100 ng/mL).
Coexisting neoplastic disease except for Kaposi's Sarcoma, any non-metastatic skin cancer
that has been resected, non-metastatic cervical or anal cancer that has been resected.
Severe cardiac or pulmonary decompensation.
Severe psychiatric disorder that would interfere with the adherence to protocol
Preexisting autoimmune disorders including inflammatory bowel diseases, psoriasis, and
Preexisting uncontrolled seizure disorder.
Severe retinopathy as determined by the ophthalmologist.
Currently taking didanosine as part of antiretroviral regimen.
Direct bilirubin greater than 0.6 mg/dL.
Using long-term systemic corticosteroids, immunosuppressives, or cytotoxic agents within
60 days of enrollment into the trial.
Chronic viral hepatitis of any other etiology other than hepatitis C.
Active systemic infections other than hepatitis C and HIV.
Liver disease caused by reasons other than hepatitis C like HBV, HDV, Wilson's,
hemochromatosis, autoimmune hepatitis (ANA greater than 1 unit) except history of
drug-associated hepatitis with discontinuation of the causative agent.
Hepatic mass suggestive of hepatocellular carcinoma as detected by ultrasound scan.
Alcohol or substance abuse that potentially could interfere with patient compliance.
History of esophageal varices.
Any systemic illness that will make it unlikely that the subject will be able to return to
NIH for the required study visits.
Evidence of gastrointestinal malabsorption or chronic nausea or vomiting.
Male partners of pregnant women.