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

• 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).
  
  

• 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
  
  

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.