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 (Responsible Party):	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:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Suppressive Long-Term Antiviral Management of Hepatitis C Virus (HCV) and HIV-1 Coinfected Subjects (SLAM-C)

Resource links provided by NLM:

Genetics Home Reference related topics: complement factor I deficiency

MedlinePlus related topics: HIV/AIDS Hepatitis Hepatitis A Hepatitis C Liver Diseases

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

U.S. FDA Resources

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

Primary Outcome Measures:

Time-scaled Change in Metavir Liver Fibrosis Score (SCMFS) [ Time Frame: Baseline and at week 72 or premature discontinuation ] [ Designated as safety issue: No ]
SCMFS is the difference between the Metavir fibrosis scores of the study exit and study entry liver biopsies where the difference is scaled to one year. The SCMFS assesses the annualized change in the severity of liver fibrosis on a continuous scale from -4.0 Metavir units per year (reduced fibrosis over time, a positive study outcome) to +4.0 Metavir units per year (increased fibrosis over time).

Secondary Outcome Measures:

Number of Participants With Detectable HCV RNA Viral Load (>= 60 IU/mL) [ Time Frame: Arms A and B: Weeks 0, 12, 24, 48 and 72; Arm C: Weeks 0, 12, 24, 36, 60, 72, 84 ] [ Designated as safety issue: No ]
Qualitative plasma HCV viral load was categorized as less than 60 IU/mL vs greater than 60 IU/mL whereas 60 IU/mL is the lower limit of qualitative assay
Time-scaled Change in Ishak Liver Inflammation Score (SCIIS) [ Time Frame: Baseline and at week 72 or premature discontinuation ] [ Designated as safety issue: No ]
Liver biopsies were performed within 42 days prior to randomization between Arms A and B while the participant remained on PEG-IFN plus RBV (=entry biopsy) and again at week 72 or premature study discontinuation (=exit biopsy). SCIIS was defined as the difference between the Ishak inflammation score of the exit biopsy and the Ishak inflammation score of the entry biopsy, where the difference is scaled to one year.
Number of Participants With Anemia [ Time Frame: Up to 96 weeks ] [ Designated as safety issue: Yes ]
Number of participants with anemia by grade (defined by hemoglobin level in grams per deciliter; g/dL). DAIDS Toxicity Grading Table (1992) was used for grading where Grade 1 = hemoglobin of 8 to 9.4 g/dl; Grade 2 = 7 to 7.9 g/dl; Grade 3 = 6.5 to 6.9 g/dl; Grade 4 = below 6.5 g/dl.
Number of Participants With Neutropenia [ Time Frame: Up to 96 weeks ] [ Designated as safety issue: Yes ]
Number of participants with neutropenia by grade (defined by absolute neutrophil count [ANC] per cubic millimeter; mm3). DAIDS Toxicity Grading Table (1992) was used for grading where Grade 1 = ANC of 1000 to 1500 /mm3; Grade 2 = 750 to 999 /mm3; Grade 3 = 500 to 749 /mm3; Grade 4 = below 500 /mm3.
Number of Participants With Thrombocytopenia [ Time Frame: Up to 96 weeks ] [ Designated as safety issue: Yes ]
Number of participants with thrombocytopenia by grade (defined by platelet count per cubic millimeter; mm3). DAIDS Toxicity Grading Table (1992) was used for grading where Grade 1 = platelets of 75,000 to 99,000 /mm3; Grade 2 = 50,000 to 74,999 /mm3; Grade 3 = 20,000 to 49,999 /mm3; Grade 4 = below 20,000 /mm3.
Number of Participants With Depression and/or Other Psychological Events [ Time Frame: Up to 96 weeks ] [ Designated as safety issue: Yes ]
Depression and other psychological events. DAIDS Toxicity Grading Table (1992) was used for grading. The protocol required reporting of depression and other psychological events of Grade 3 or higher or if led to a change in treatment, regardless of grade.
Other High-grade Signs and Symptoms and Laboratory Values [ Time Frame: Up to 96 Weeks ] [ Designated as safety issue: Yes ]
Number of participants with "Other high-grade signs and symptoms and laboratory values. DAIDS Toxicity Grading Table (1992) was used for grading where Grade 1 = transient/mild discomfort, no limitation in activity, no medical intervention; Grade 2 = mild/moderate limitation in activity, some assistance, no/minimal medical intervention; Grade 3 = marked limitation in activity, some assistance, medical intervention required); Grade 4 = extreme limitation in activity, significant medical intervention, assistance, hospitalization.
Number of Participants With Dose Modifications, Temporary Stops, and Premature Treatment Discontinuations [ Time Frame: Up to 96 Weeks ] [ Designated as safety issue: No ]
3-level categorical of the worst of 1) premature treatment discontinuation, 2) temporary stop or 3) dose reduction. For Arm C, the worst for either PEG-IFN or RBV is summarized.
Symptom Distress [ Time Frame: Arms A and B: at entry and weeks 12, 24, 48 and 72. Arm C: at entry and weeks 12, 24, 48, 60, 84. ] [ Designated as safety issue: No ]
Will never be posted. Additional endpoint for supportive/exploratory analyses that may be defined in more detail in separate analysis plans.
Quality of Life [ Time Frame: Arms A and B: at entry and weeks 12, 24, 48 and 72. Arm C: at entry and weeks 12, 24, 48, 60, 84. ] [ Designated as safety issue: No ]
Will never be posted. Additional endpoint for supportive/exploratory analyses that may be defined in more detail in separate analysis plans.
Number of Participants Adherent to Study Medications [ Time Frame: Arm A: at weeks 12, 24, 48 and 72. Arm C: at entry and weeks 12, 24, 48, 60. ] [ Designated as safety issue: No ]
A categorical variable with levels adherent and non-adherent based on participants' self report. For Arm A, adherence was defined as not missing PEG within 2 weeks of visit. For Arm C, adherence was defined as not missing any PEG within 2 weeks of visit and not missing RBV within 4 days of visit.
HCV Polymorphisms [ Time Frame: Entry and week 72 ] [ Designated as safety issue: No ]
Will never be posted due to premature closure of Arms A and B with insufficient subjects for analysis.
HCV-specific Immune Response in Intrahepatic Lymphocytes [ Time Frame: Entry and week 72 ] [ Designated as safety issue: No ]
Will never be posted due to premature closure of Arms A and B with insufficient subjects for analysis.
Noninvasive Measures of Liver Fibrosis, Including Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Bilirubin, Albumin, and Protein Measurements [ Time Frame: Entry and week 72 ] [ Designated as safety issue: No ]
Will never be posted due to premature closure of Arms A and B with insufficient subjects for analysis.
Number of Participants With Undetectable HIV Viral Load (<50 Copies/mL) [ Time Frame: Arms A and B: Weeks 0, 24, 48 and 72; Arm C: Weeks 0, 12, 24, 36, 48, 60, 72, 84 ] [ Designated as safety issue: No ]
A blood sample was drawn to determine the HIV-1 viral load. HIV-1 viral load was categorized as <50 copies/mL (undetectable) or >=50 copies/mL (detectable). 50 is the lower limit of detection of the assay.
Metabolic Parameters Including Insulin Resistance, Defined as Fasting Glucose, and Weight. [ Time Frame: Weight: throughout study. Metabolic parameters: Arms A and B: entry and weeks 24, 48 and 72; Arm C: at entry and at weeks 12, 24, 36, 48, 60, 72 and 84. ] [ Designated as safety issue: No ]
Will never be posted. Additional endpoint for supportive/exploratory analyses that may be defined in more detail in separate analysis plans.
Sustained Virologic Response [ Time Frame: 24 weeks after end of treatment ] [ Designated as safety issue: No ]
Sustained Virologic Response (SVR) was defined as undetectable HCV viral load (<60 IU/ml) 24 weeks after treatment discontinuation.
Use of Antianorexia Agents, Such as Megestrol and Dronabinol [ Time Frame: Up to 96 weeks ] [ Designated as safety issue: No ]
Use of antianorexia agents, such as megestrol and dronabinol at any time after pre-assignment.
Prescription as Needed of Erythropoietin (EPO), Granulocyte Colony-stimulating Factor (GCSF), and Granulocyte-monocyte Colony-stimulating Factor (GM-CSF) [ Time Frame: At any time after pre-assignment ] [ Designated as safety issue: No ]
Prescription as needed of hematologic adjuvant therapies: erythropoietin (EPO), granulocyte colony-stimulating factor (GCSF), and granulocyte-monocyte colony-stimulating factor (GM-CSF) any time after pre-assignment

Enrollment:	255
Study Start Date:	July 2004
Study Completion Date:	February 2009
Primary Completion Date:	September 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: A: Open Label (OL) (PEG-IFN, RBV); OL Randomized (PEG-IFN) At week 12 (end of the initial run-in period - Step 1) participants were found to be HCV RNA positive (HCV RNA > 60 IU/mL) and had less than a 2 log decrease in HCV RNA from Baseline. For Step 2, participants were assigned to the Randomized Open Label (OL) part of the study to receive the pegylated interferon (PEG-IFN) 180 mcg weekly Arm.	Drug: Peginterferon alfa-2a 180 mcg PEG-IFN subcutaneously Drug: Ribavirin One tablet or capsule containing ribavirin 200 mg
Experimental: B: OL (PEG-IFN, RBV) then OL Randomized (Observation) At week 12 (end of the initial run-in period - Step 1) participants were found to be HCV RNA positive (HCV RNA > 60 IU/mL) and had less than a 2 log decrease in HCV RNA from Baseline. For Step 2, participants were assigned to the Randomized Open Label (OL) part of the study to be followed on the Observation (no treatment) Arm.	Drug: Peginterferon alfa-2a 180 mcg PEG-IFN subcutaneously Drug: Ribavirin One tablet or capsule containing ribavirin 200 mg
Experimental: C: OL (PEG-IFN, RBV) then OL (PEG-IFN, RBV) At week 12 (end of initial run-in period, Step 1) participants were found to be HCV RNA negative (HCV RNA < 60 IU/mL) or had more than a 2 log decrease in HCV RNA from Baseline. Participants were assigned to remain in the Open Label (OL) part of the study continuing the run-in treatment (PEG-IFN 180 mcg weekly & RBV1-1.2 g/day based on weight). At the beginning of week 36, participants were retested and, if found to be HCV RNA positive (HCV RNA > 60 IU/mL), participants could be randomized to OL PEG-IFN or Observation.	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, Child-Pugh-Turcotte (CPT) score of 5 or less and no more than Child-Pugh Class A
Liver enzyme (alanine aminotransferase [ALT], aspartate aminotransferase [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 computed tomography [CT] scan or magnetic resonance imaging [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 thyroid-stimulating hormone (TSH) and free thyroxine index (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:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00078403 History of Changes
Other Study ID Numbers:	ACTG A5178, SLAM-C, 10008
Study First Received:	February 24, 2004
Results First Received:	November 5, 2010
Last Updated:	September 8, 2011
Health Authority:	United States: Food and Drug Administration