Pegylated Interferon Alfa-2a Maintenance Therapy and Liver Disease Progression in People Infected With Both HIV and Hepatitis C Virus (HCV) - Full Text View

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00078403

Purpose

Infection with both HIV and hepatitis C virus (HCV) may result in serious and sometimes fatal liver disease. The purpose of this study is to test the effectiveness of long-term pegylated interferon alfa-2a (PEG-IFN) and ribavirin treatment in slowing liver disease progression in people infected with both HIV and HCV.

Condition	Intervention	Phase
HIV Infections Hepatitis C Liver Disease	Drug: Peginterferon alfa-2a Drug: Ribavirin	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Active Control, Crossover Assignment, Efficacy Study
Official Title:	Suppressive Long-Term Antiviral Management of Hepatitis C Virus (HCV) and HIV-1 Coinfected Subjects (SLAM-C)

Resource links provided by NLM:

MedlinePlus related topics: AIDS Hepatitis Hepatitis C Liver Diseases

Drug Information available for: Ribavirin Interferon alfa-2a Peginterferon Alfa-2a

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Liver fibrosis (Metavir) score [ Time Frame: within 30 days of Step 2 entry and at Week 72 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

HCV viral loads [ Time Frame: Step 1 entry and Week 12; Step 2 entry and Weeks 12, 24, 48, and 72; and Step 3 entry and Weeks 12, 24, 36, 54, 66, 72, 78, and 84 ] [ Designated as safety issue: No ]
Liver inflammation (Metavir) score [ Time Frame: within 42 days of Step 2 entry and Week 72 ] [ Designated as safety issue: No ]
Safety, defined as rates and grades of anemia, neutropenia, thrombocytopenia, depression, and other psychological events, and all other high-grade signs and symptoms and laboratory values [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Regimen tolerability, defined as dose modification and temporary and permanent drug discontinuation, increased symptom distress, or decreased quality of life [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Adherence to study medication [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
HCV polymorphisms [ Time Frame: at Step 2 entry and Weeks 24, 48, and 72 ] [ Designated as safety issue: No ]
HCV-specific immune response in intrahepatic lymphocytes [ Time Frame: at Step 2 entry and Week 72 ] [ Designated as safety issue: No ]
Noninvasive measures of liver fibrosis, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, albumin, and protein measurements [ Time Frame: at Step 2 entry and Week 72 ] [ Designated as safety issue: No ]
HIV viral load [ Time Frame: at Step 2 entry and Weeks 24, 48, and 72; and Step 3 entry and Weeks 12, 24, 36, 54, 60, 66, 72, 78, and 84 ] [ Designated as safety issue: No ]
Weight [ Time Frame: at entry and all study visits ] [ Designated as safety issue: No ]
Insulin resistance, defined as fasting glucose [ Time Frame: at Step 2 entry and Weeks 24, 48, and 72; and Step 3 entry and Weeks 12, 24, 32, 54, 60, 66, 72, 78, and 84 ] [ Designated as safety issue: No ]
Step 3 end of treatment virologic response and sustained virologic response [ Time Frame: 24 weeks after the end of treatment ] [ Designated as safety issue: No ]
Use of antianorexia agents, such as megestrol and dronabinol [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Use of hematologic adjuvant therapies, such as erythropoietin, granulocyte colony-stimulating factor, and granulocyte-monocyte colony-stimulating factor [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Estimated Enrollment:	300
Study Start Date:	July 2004
Study Completion Date:	February 2009
Primary Completion Date:	February 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Arm A participants will receive 180 mcg PEG-IFN once weekly for at least 12 weeks and up to 18 weeks. They will also receive 1 to 1.2 g/day ribavirin based on weight.	Drug: Peginterferon alfa-2a 180 mcg PEG-IFN subcutaneously Drug: Ribavirin One tablet or capsule containing ribavirin 200 mg
2: Experimental Arm B participants will receive pegylated interferon and ribavirin. Arm B is closed as of 05/10/07.	Drug: Peginterferon alfa-2a 180 mcg PEG-IFN subcutaneously Drug: Ribavirin One tablet or capsule containing ribavirin 200 mg
3: Experimental Arm C participants will continue their Step 1 treatment for an additional 60 weeks and will be followed for 24 weeks after stopping treatment. Due to the closure of Step 2, Step 3 patients who have a detectable HCV viral load at Week 36 will now stay on Step 3 until the end of the study.	Drug: Peginterferon alfa-2a 180 mcg PEG-IFN subcutaneously Drug: Ribavirin One tablet or capsule containing ribavirin 200 mg

Detailed Description:

Rapid progression of liver disease to liver failure has been observed in people coinfected with HIV and HCV. This observation appears to be directly related to an increase in the rate of fibrotic progression in the liver compared to people infected with HCV alone. PEG-IFN and ribavirin are used in standard treatment of HCV. This study will test the effectiveness of using PEG-IFN and ribavirin in reducing the rate of liver fibrosis progression in patients coinfected with HIV and HCV who cannot lower their HCV viral load to undetectable or who cannot maintain their HCV viral load at undetectable.

Patients will enter Step 1 (also known as Arm A) and will receive 180 mcg PEG-IFN subcutaneously once weekly for at least 12 weeks and up to 18 weeks. They will also receive 1 to 1.2 g/day ribavirin based on weight. Participants may continue to receive Step 1 treatment to determine if they meet the early viral response criteria based on an evaluation at the Week 12 visit. If a participant has less than a 2-log drop in HCV viral load and detectable HCV viral load in their blood, participants must discontinue study treatment. Those who tolerated Step 1 therapy and have a 2-log or more drop in HCV viral load or have undetectable HCV viral load will enter Step 3. Step 2 is closed as of 05/10/07. If a participant does not meet the criteria for entry into Step 3, the participant must discontinue study treatment and follow procedures for the Step 1 discontinuation. Step 3 patients will continue their Step 1 treatment for an additional 60 weeks and will be followed for 24 weeks after stopping treatment. Due to the closure of Step 2, Step 3 patients who have a detectable HCV viral load at Week 36 will now stay on Step 3 until the end of the study.

Liver biopsies will be conducted at study entry and at the end of Step 3. Medical history assessment, physical exams, and blood collection will be conducted every 4 weeks for patients in Steps 1, 2, and 3. Patients will be followed for 72 to 102 weeks, depending on their treatment arm assignment.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Note: Step 2 of this study is now closed. Liver biopsies in preparation for Step 2 will no longer be performed.

Inclusion Criteria for Step 1:

HIV infected
Stable antiretroviral therapy for at least 8 weeks prior to study entry OR have not received any antiretroviral therapy for at least 4 weeks prior to entry
HIV viral load less than 50,000 copies/ml within 6 weeks prior to study entry
CD4 count greater than 200 cells/mm3 within 6 weeks prior to study entry
Hepatitis C virus (HCV) infected
Either HCV treatment naive OR previously treated with interferon (IFN), PEG-IFN, IFN and ribavirin, or PEG-IFN and ribavirin for at least 12 weeks and are HCV RNA positive following their last course of HCV treatment
Chronic liver disease consistent with chronic viral hepatitis
At least stage I fibrosis on a liver biopsy obtained within 104 weeks of study entry
If at stage VI fibrosis, CPT score of 5 or less and no more than Child-Pugh Class A
Liver enzyme (ALT, AST, and alkaline phosphatase) levels 10 times or less than upper limit of normal
Agree to use acceptable methods of contraception

Inclusion Criteria for Step 3:

Currently enrolled in Step 1
Undetectable HCV RNA or a 2-log or greater decrease in plasma/serum HCV viral load.
On Step 1 study treatment for longer than 18 weeks

Exclusion Criteria for Steps 1 and 3:

Have received HCV treatment within 4 weeks of study entry. Participants currently receiving treatment for HCV may be considered for Step 3 entry.
Discontinuous treatment with PEG-IFN, defined as missing 3 or more consecutive PEG-IFN doses during the first 12 weeks or a total of 5 doses prior to Step 3 entry. Participants who have missed doses of ribavirin will not be excluded from Step 3 entry.
Use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) within 14 days prior to study entry
Alpha feto protein level 400 ng/ml or greater within 24 weeks prior to study entry, or alpha feto protein level greater than 50 ng/ml and less than 400 ng/ml (unless CT scan or MRI shows no evidence of hepatic tumor) within 24 weeks prior to study entry
Decompensated liver disease, including presence or history of ascites, variceal bleeding, and brain or nervous system damage as a result of liver damage
Other causes of significant liver disease, including hepatitis A or B, excess iron deposits in the liver (hemochromatosis), or homozygote alpha-1 antitrypsin deficiency
Use of systemic corticosteroids, interferon gamma, TNF-alpha inhibitors, rifampin, rifabutin, pyrazinamide, isoniazid, ganciclovir, or hydroxyurea within 2 weeks prior to study entry
Known allergy/sensitivity to PEG-IFN alfa-2a or ribavirin or their formulations
History of uncontrolled seizure disorders
Clinically active thyroid disease. Thyroid hormone replacement therapy is permitted, but TSH and FTI must be in normal range.
History of autoimmune processes, including Crohn's disease, ulcerative colitis, severe psoriasis, and rheumatoid arthritis, that may be made worse by interferon use
Any systemic antineoplastic or immunomodulatory treatment or radiation within 24 weeks prior to study entry
Malignancy
Active coronary artery disease within 24 weeks prior to study entry
Acute or active AIDS-defining opportunistic infections within 12 weeks of study entry
Hemoglobin abnormalities (e.g., thalassemia) or any other cause of or tendency to break down red blood cells (hemolysis)
History of major organ transplantation with an existing functional graft
Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with study adherence
Uncontrolled or active depression or other psychiatric disorder, such as untreated Grade 3 psychiatric disorder, medically untreatable Grade 3 disorder, or any hospitalization within 52 weeks of study entry that, in the opinion of the investigator, may interfere with study requirements
Other serious illness or chronic medical condition that, in the opinion of the investigator, may prevent patient's completion of the study
Pregnant or breastfeeding

Study Chair:	Kenneth E. Sherman, MD, PhD	University of Cincinnati
Study Chair:	Raymond Chung, MD	Harvard/Massachusetts General Hospital

Responsible Party:	DAIDS ( Rona Siskind )
Study ID Numbers:	ACTG A5178, SLAM-C, 10008
Study First Received:	February 24, 2004
Last Updated:	November 10, 2009
ClinicalTrials.gov Identifier:	NCT00078403 History of Changes
Health Authority:	United States: Food and Drug Administration