Peginterferon Alpha-2a and Ribavirin to Treat Hepatitis C in HIV-infected Patients
Condition: Hepatitis C; HIV Infections
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis
Intervention: Double dose pegylated interferon with weight based Ribavirin; standard dose pegylated interferon alfa -2a and ribavirin
Intervention description: pegylated interferon alfa -2a 180ug/twice weekly and weight based ribavirin for 4 weeks then pegylated interferon alfa -2a 180ug/ weekly for the remainder of the treatment; pegylated interferon alfa -2a 180ug weekly and weight based ribavirin for duration of the treatment
Intervention MeSH terms: Interferons; Ribavirin; Interferon-alpha; Peginterferon alfa-2a
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 29.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pegasys; Ribavirin; Early Virological Response; Hepatitis C; HIV

Summary:

      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.
    

Eligibility criteria:

        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 than 14%.

          -  Ability to sign informed consent and willingness to comply with the study requirements
             and clinic policies.

          -  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.

        EXCLUSION CRITERIA

          -  Patient should not be on other experimental therapies during their participation in
             this protocol.

          -  Patients should not have used interferon or peginterferon previously for the treatment
             of hepatitis C

          -  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 fibrosis.

          -  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
             requirements.

          -  Preexisting autoimmune disorders including inflammatory bowel diseases, psoriasis, and
             optic neuritis.

          -  Preexisting uncontrolled seizure disorder.

          -  Preexisting pancreatitis.

          -  Severe retinopathy as determined by the ophthalmologist.

          -  Hemoglobinopathy.

          -  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.

          -  Pregnant women.

          -  Breastfeeding women.