This study will evaluate how controlling HIV infection with HAART (highly active
antiretroviral therapy) affects the response to hepatitis C treatment with peginterferon
alpha-2b and ribavirin in HIV-infected patients with chronic hepatitis C. HIV worsens liver
disease caused by hepatitis C. Since treatment of HIV infection with HAART improves immune
function, it may be beneficial to start HAART before treating HCV.
HIV-infected patients 18 years of age and older with chronic hepatitis C infection may be
eligible for this study. Patients must have an HCV viral load greater than 2000 copies/mL
and a CD4 count that is either more than 500 cells/mm3, or more than 350 cells/mm3 with an
HIV viral load no greater than 40,000 particles/mL. Candidates will be screened for current
or previous diseases, conditions or treatments that may exclude them from this study.
Screening includes a medical history and physical examination, eye examination, blood and
urine tests, chest X-ray, electrocardiogram (EKG), liver ultrasound, and, possibly, a liver
biopsy, if a recent one is not available. The liver biopsy is optional and is done to
determine the severity of liver disease. Patients will be sedated for this test. 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. Patients remain in the
hospital overnight for monitoring. Women of childbearing age will have a pregnancy test.
Patients enrolled in the study will be randomly assigned to one of the following treatment
groups: 1) pegylated interferon and ribavirin for 48 weeks (control group); or 2) HAART for
6 months, followed by 48 weeks of pegylated interferon and ribavirin.
HAART group - Patients taking HAART will be followed in the clinic every 2 weeks for the
first month and then monthly for the next 5 months. After 6 months of HAART they will begin
taking pegylated interferon and ribavirin and will follow the dosing and follow-up schedule
outlined below for patients in the control group.
Control group - Patients will have weekly injections under the skin of peginterferon
alpha-2b and ribavirin pills daily by mouth. Clinic visits will be scheduled as follows:
- Days 1, 3, 7, and 21 - Blood will be drawn for safety tests and to measure blood levels
of HIV and HCV. HCV medications will be injected on days 7 and 21.
- Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 52, 56, and 64 - Blood and urine
tests will be done to determine the side effects of pegylated interferon and ribavirin
treatment and its effect on the HCV infection. Eye examinations will be done every 3
- Week 48 or end of treatment - Treatment with pegylated interferon and ribavirin will
stop after 48 weeks. At this time (or earlier for those who do not complete the 48
weeks of treatment), patients will return to the clinic for a routine visit, blood
tests (including a test for hepatitis B) and abdominal ultrasound. Patients may also be
hospitalized for 2 days for a repeat optional liver biopsy.
- Week 72 and extended follow-up visits - At week 72, patients will return for blood
tests and a routine clinic visit. HCV viral load will be measured. Follow-up visits
every 3 months for an additional year will include a blood test to measure HCV viral
load and a complete physical examination.
Coinfection with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) has
risen dramatically since the explosion of the HIV pandemic twenty years ago, with one third
of all HIV positive persons also infected with HCV. Numerous studies have suggested that
HIV exacerbates several steps in the natural history of hepatitis C, and as survival among
HIV-infected patients increases, hepatitis C-related morbidity and mortality is expected to
follow a similar trend in coinfected patients. Some investigators advocate the initiation
of highly active antiretroviral therapy (HAART) for this population prior to the initiation
of HCV therapy. It is postulated that HAART will improve the host immune function by
increasing the CD4+ cell count and decreasing HIV viral load, thought to be advantageous for
patients starting HCV therapy. Despite its promising hypothesis, whether HAART ultimately
leads to a reduction in HCV load in coinfected persons remains controversial. This is a
non-blinded, randomized controlled trial to evaluate the impact of HAART on the immunologic,
virologic, and clinical responses to HCV treatment with peginterferon and ribavirin in
coinfected individuals with CD4 greater than or equal to 500 cells/mm (3) or greater than or
equal to 350 cells/mm(3) and a viral load less than or equal to 40,000 copies/mL. The study
will also address the safety and efficacy of administering a combination of HAART along with
peginterferon alpha-2b and ribavirin to HIV-infected individuals. 128 patients who are
coinfected with HIV and HCV will be recruited for the study and randomized to receive one of
two treatment regimens: 1) control group: will be treated with peginterferon alpha-2b and
ribavirin for 48 weeks, or 2) experimental group: will be treated with highly active
antiretroviral therapy for six months. At that point, they will begin receiving
peginterferon alpha-2b and ribavirin at the same doses as the control group for 48 weeks.
During the 72-week follow up period, these patients will be monitored for both HCV and HIV
viral loads and CD4+ lymphocyte counts. The results of the study will enable us to better
delineate the relationship between the immune reconstitution effects induced by HAART and
the clinical, immunologic, and virologic responses of coinfected persons treated with
peginterferon and ribavirin. In addition, evaluating the safety of coadministering
peginterferon, ribavirin, and HAART will further refine the best therapeutic regimen for
this patient population.
Age greater than or equal to 18 years
Documentation of HIV-1 infection by a licensed ELISA test and confirmed by a Western Blot
CD4 greater than or equal to 500 cells/mm(3) or CD4 greater than or equal to 350
cells/mm(3) and HIV VL less than or equal to 40,000 copies per milliliter
CD4 nadir not below 200 cells/mm(3)
If not HAART naive, history of HIV VL suppression while on HAART treatment.
Patients who are currently on HAART but do not meet criteria for the initiation of HAART
according to current DHHS guidelines must be willing to come off their regimen 3 months
prior to study initiation.
Documentation of Hepatitis C infection by demonstration of a positive test for hepatitis C
HCV RNA level greater than 2000 copies per milliliter by polymerase chain reaction
Patients naive to HCV treatment at time of enrollment.
Serum creatinine less than or equal to 1.5 mg/dL
Serum phosphorus greater than or equal to 2.2 mg/dL (normal range NIH 2.3-4.3 mg/dL)
Neutrophil count greater than or equal to 1000 cells/mm(3)
Platelets greater than or equal to 75,000/mm(3)
Hemoglobin greater than or equal to 8.0 mg/dL
ALT less than 7 X the NIH upper limit of normal
Not pregnant or breast-feeding. Pregnancy tests must be negative within two weeks prior
to dosing with study medications.
Due to the teratogenic effects of ribavirin, for women of child-bearing age, the use of
effective contraception during the study will be required. These include abstinence,
surgical sterilization of either partner, barrier methods such as a diaphragm, condom, cap
or sponge, or use of hormonal contraception with an anti-HIV regimen that will not alter
the metabolism of hormonal contraception.
Patients must have a primary MD responsible for their HIV infection and liver disease.
Willing to designate a person for durable power of attorney on NIH form for medical
research and medical care purposes at the NIH Clinical Center.
Ability to learn how to safely inject medication subcutaneously or have a family member,
relative or partner who is willing to learn to inject study medication.
Competency to sign informed consent and willingness to comply with study requirements and
Willingness to have blood and tissue specimens stored in NIH facilities.
Child-Pugh score less than 6.
Willingness for female patients to practice at least two reliable forms of effective
contraception during treatment with ribavirin. Effective means of contraception include
barrier and hormonal methods.
Willingness for male patients to practice effective contraception during treatment with
ribavirin, including barrier methods.
PT-INR (in the absence of anti-cardiolipin Ab) by greater than or equal to 2.
Organ transplant recipient
Recent HIV seroconverters (must be 6 months or more with documented HIV diagnosis).
Patients who are medically indicated to begin HAART therapy
Elevated alpha-fetoprotein level (greater than or equal to 100 ng/mL).
Coexisting neoplastic disease requiring cytotoxic therapy.
Have had cancer other than Kaposi's sarcoma of the skin, other skin cancers treated by
resection, Bowen's disease, or localized cervical or anal cancer in the 5 years prior to
Have had significant renal dysfunction within the previous 12 months or evidence of
significant protein wasting
Severe cardiac or pulmonary decompensation as assessed by the PI.
Severe liver decompensation or advanced cirrhosis patients
Severe psychiatric disorder that would interfere with the adherence to protocol
Autoimmune disorders including inflammatory bowel diseases, and optic neuritis as assessed
by the PI.
Uncontrolled seizure disorder
Direct bilirubin more than or equal to 2 times ULN.
No patients using long-term systemic corticosteroids, immunosuppressives, IL-2, or
cytotoxic agents within 60 days of enrollment.
Active systemic infections (other than hepatitis C and HIV).
Liver disease caused by reasons other than hepatitis C like HBV, HDV, Wilson's
hemochromatosis, or autoimmune hepatitis (ANA greater than or equal to 3.0) except history
of drug-associated hepatitis with discontinuation of the causative agent.
Hepatic mass suggestive of hepatocellular carcinoma.
Current alcohol or substance use.
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, chronic nausea, or vomiting
Any pre-existing hemoglobinopathy.
Patients taking any of the following medications: rifampin/rifampicin, rifabutin,
pyrazinamide, isoniazid, ganciclovir, thalidomide, oxymetholone, immunomodulatory
treatments (including supraphysiologic doses of steroids and radiation, and antineoplastic
Patients taking any investigational drugs and herbal remedies, and other
complementary/alternative medications for possible or perceived effects against HCV.
Patients cannot be receiving IL-2 during participation in this study.
Ribavirin is contraindicated in male partners of women who are pregnant. Therefore,
potential male patients with pregnant female partners will be excluded.