Hepatitis C, HIV Infections
Conditions
Keywords
Liver Disease, Virologic Response, Immune Mechanisms, Cirrhosis, Eradication, HIV, Hepatitis C
Brief summary
This study will evaluate the safety and effectiveness of combination therapy with peginterferon alfa-2b and ribavirin for treating hepatitis C virus (HCV) infection in HIV-infected patients. In studies of patients with hepatitis C alone, interferon alfa-2b plus ribavirin treatment eradicated the HCV in almost half the patients. Peginterferon alfa-2b is a compound that results from attaching a polyethylene glycol molecule to interferon alfa-2b. This compound stays in the blood longer than unmodified interferon alfa-2b, causing a higher blood concentration and thus maintaining activity against the hepatitis C virus. HIV-infected patients 21 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 will be screened with blood and urine tests and possibly a liver biopsy, if a recent one is not available. The liver biopsy is done to determine the severity of liver disease. For this test, patients are admitted to the NIH Clinical Center for 1 to 2 days. A sedative is injected into an arm vein, 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. A chest X-ray, electrocardiogram (EKG) and liver ultrasound are also done. Within 4 weeks of the screening tests, candidates who appear eligible for the study will have a physical examination, medical history and repeat blood tests. Women who can become pregnant will have serial pregnancy tests throughout the study. Patients who meet the study criteria and decide to participate will begin treatment with weekly injections under the skin of peginterferon alfa-2b and take ribavirin pills twice a day by mouth. In addition, patients will continue to take all other medications prescribed by their doctor. Clinic visits will be scheduled as follows: * Days 1, 3, 5, 7, 10 and 21 - Blood will be drawn for safety tests and to measure blood levels of HIV and HCV. * 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 treatment and its effect on the HCV infection. * Week 48 or end of treatment - Treatment will stop after 48 weeks. At this time, or earlier for those who do not complete the 48 weeks, patients will return to the clinic for a routine test.
Detailed description
Hepatitis C infection occurs in one-third of all HIV-infected individuals. Liver disease has become more clinically significant among patients coinfected with HIV and HCV. Several studies have shown that coinfected individuals develop earlier and severe liver disease. Interferon with ribavirin has become the therapy of choice among people with non-genotype 1a. This is a pilot study to address the relationship of clinical response to combination therapy to the virologic and immunologic parameters. The study will also address the safety and efficacy of the peginterferon alfa-2b among HIV- infected individuals. The predictive ability of baseline HCV viral load, rate of decline of HCV viral load, HIV viral load and CD4 counts to the clinical response of chronic hepatitis to peginterferon and ribavirin will also be studied. Approximately sixty patients who are infected with both HIV and HCV and also have evidence of fibrosis will receive peginterferon alfa-2b and ribavirin for 48 weeks. In order to enroll sixty patients for this study, we will be screening a total of 180 patients. During the 72 weeks study these patients will be monitored for HCV viral load, and other HIV viral load and CD4 counts. Viral kinetics will also be monitored closely and the slope of second, slower phase decline of HCV viral load, which corresponds to the rate of infected cell death presumably may lead to sustained hepatitis C virologic response. The results of the study will enable us to better delineate the possible predictors of sustained response to peginterferon and ribavirin. The safety and tolerability of a combination therapy with peginterferon and ribavirin among HIV-infected individuals on antiretroviral therapy will further define the standard therapy of chronic hepatitis C in HIV-infected individuals.
Interventions
DRUGPeginterferon alfa-2b
Weekly injections for 48 weeks of a dose of 1.5mcg/Kg per week subcutaneously
DRUGRibavirin
Weight based Ribavirin dosing 1-1.2grams/day in divided (twice daily) doses for a total duration of 48 weeks.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Age greater than or equal to 18 years. Documentation of HIV-1 infection by any licensed ELISA test and confirmed by a Western Blot. Documentation of Hepatitis C infection by demonstration of a positive test for hepatitis C antibody. HCV RNA level greater than 2000 IU/ml by bDNA. Infected with HCV genotype 1. Histopathologic features consistent with chronic hepatitis C on liver biopsy at the time of enrollment. Patients with CD4 greater than 300 cells/mm(3). Ability to sign informed consent and willingness to comply with the study requirements and clinic policies. Serum creatinine less than 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 times the NIH upper limit of normal. Serum lipase less than 1.5 times 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 capable of pregnancy: use of effective contraception during study: effective contraception 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 OP8 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. Ability to learn how to safely inject medication subcutaneously.
Exclusion criteria
PT-INR (in the absence of anti-cardiolipin antibody) prolonged by greater than 2 seconds. Organ transplant recipient. Elevated alpha-fetoprotein level (greater than 100 ng/mL). Coexisting neoplastic disease requiring cytotoxic therapy. Child Pugh's class B. Severe cardiac or pulmonary decompensation. Severe liver decompensation or advanced cirrhosis patients. 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. Severe retinopathy. Hemoglobinopathy Direct bilirubin more than or equal to 2 times ULN. No patients 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 160) except history of drug-associated hepatitis with discontinuation of the causative agent. Hepatic mass suggestive of hepatocellular carcinoma. Current alcohol or substance abuse that potentially could interfere with patient compliance. Significant heart failure. Evidence 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. Currently taking didanosine (ddl or Videx-EC or Videx) as part of antiretroviral regimen.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Viral Decline at Day 3 & 28 With Predictors of Post Treatment Response | Day 3 and Day 28 | HCV viral kinetics were used to predict rates of sustained virology response (SVR) in HIV/HCV connected subjects. Measure was determined by analyzing the population of participants with virologic decline of more than 1.0 log at day 3 combined with viral load of less than 5.0 log IU/ml at day 28 to predict sustained virology response |
Countries
United States
Participant flow
Recruitment details
Patients were all recruited from other NIAID HIV clinical trials and from the nearby Maryland, Virginia and the District of Columbia HIV clinics
Pre-assignment details
Open label study. The participants were only excluded if they did not meet eligibility criteria, such as pregnancy, availability to make frequent clinic visits and able to meet laboratory safety criteria as described in the clinical protocol.
Participants by arm
| Arm | Count |
|---|---|
| Peg-interefron Alfa 2b, Ribavirin Weekly Injection
Peginterferon alpha-2b : Weekly injections for 48 weeks of a dose of 1.5mcg/Kg per week subcutaneously
Oral Pills
Ribavirin : Weight based Ribavirin dosing 1-1.2grams/day in divided (twice daily) doses for a total duration of 48 weeks. | 36 |
| Total | 36 |
Baseline characteristics
| Characteristic | Peg-interefron Alfa 2b, Ribavirin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants |
| Region of Enrollment United States | 36 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 36 |
| serious Total, serious adverse events | 3 / 36 |
Outcome results
Primary
Participants With Viral Decline at Day 3 & 28 With Predictors of Post Treatment Response
HCV viral kinetics were used to predict rates of sustained virology response (SVR) in HIV/HCV connected subjects. Measure was determined by analyzing the population of participants with virologic decline of more than 1.0 log at day 3 combined with viral load of less than 5.0 log IU/ml at day 28 to predict sustained virology response
Time frame: Day 3 and Day 28
Population: Participants with Virologic decline at both Day 3 and absolute HCV VL at Week 28 were analyzed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon Alfa-2b, Ribavirin | Participants With Viral Decline at Day 3 & 28 With Predictors of Post Treatment Response | 8 participants with post treatment svr |