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

Study Overview
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Brief Summary
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Infection with both HIV and hepatitis C virus (HCV) may result in serious and sometimes fatal liver disease. The purpose of this study was 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.

Detailed Description
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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 tested the effectiveness of using PEG-IFN in reducing the rate of liver fibrosis progression in participants coinfected with HIV and HCV who could not lower their HCV viral load to undetectable or who could not maintain their HCV viral load at undetectable on PEG-IFN and ribavirin treatment. Participants entered Step 1 (initial run-in period) to receive 12 weeks of 180 mcg PEG-IFN subcutaneously once weekly plus 1 to 1.2 g/day ribavirin based on body weight. At week 12, HCV RNA testing was performed. Participants with early virologic response (EVR), defined as >=2 log10 drop in HCV RNA from baseline or undetectable HCV RNA (<600 IU/ml with quantitative assay used in Step 1) at Week 12, who had tolerated Step 1 treatment, entered into Step 3 to continue receiving the Step 1 treatment for a total of 72 weeks (Arm C). Participants who did not meet the criteria for entry into Step 3 were discontinued from the study. In Step 3, participants were followed for an additional 24 weeks after treatment discontinuation to determine sustained virologic response (SVR). Initially, Step 3 participants who had a detectable HCV viral load (>=60 IU/ml with the qualitative assay used in Step 3) at Week 36 were eligible to enroll in Step 2. After early closure of Step 2, such participants remained in Step 3 until study completion. Participants with <2 log10 drop in HCV RNA from baseline and detectable HCV RNA at Week 12 (non-EVR) discontinued Step 1 treatment. Non-EVRs who met the Step 2 eligibility criteria, were enrolled in Step 2 and randomized to receive 180 mcg PEG-IFN subcutaneously weekly for 72 weeks (Arm A) or observation for 72 weeks (Arm B). Participants who did not meet the criteria for entry into Step 2 were discontinued from the study. Step 2 of the study was closed prematurely in May 2007 due to lower than expected progression rates among the participants in the observation arm such that the primary objective could not be reached. There were no safety concerns. Liver biopsies were conducted at study screening, and at Step 2 entry and exit until the early closure of Step 2. Medical history assessment, physical exams, and blood collection were conducted every 4-12 weeks for participants in Steps 1, 2, and 3. Participants were followed for up to 18 weeks in Step 1, followed by a total of 72 in Step 2 or by up to a total of 84 weeks in Step 3.

Official Title
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Suppressive Long-Term Antiviral Management of Hepatitis C Virus (HCV) and HIV-1 Coinfected Subjects (SLAM-C)

Conditions
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HIV Infections, Hepatitis C, Liver Disease

Intervention / Treatment
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* Drug: Peginterferon alfa-2a
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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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/mm^3 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 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 2: Currently enrolled in Step 1 or received 12 weeks of PEG-IFN plus ribavirin outside this study Detectable HCV viral load and <2 log10 decrease from baseline in plasma/serum HCV viral load at Week 12. On Step 1 study treatment for no longer than 18 weeks 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 no 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, if non-EVRs, were considered for direct entry into Step 2, without the run-in period in Step 1. Could not tolerate 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 have prevented participant's completion of the study Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Open Label (OL) (PEG-IFN, RBV); OL Randomized (PEG-IFN)<br>At week 12 (end of the initial run-in period - Step 1) participants were found to have detectable HCV RNA (HCV RNA >=600 IU/mL) and had less than a 2 log10 decrease in HCV RNA from baseline. For Step 2, participants were randomized to receive the pegylated interferon (PEG-IFN) 180 mcg weekly for 72 weeks. | Drug: Peginterferon alfa-2a<br>* 180 mcg PEG-IFN subcutaneously<br>Drug: Ribavirin<br>* One tablet or capsule containing ribavirin 200 mg<br>|
| Experimental: Arm B: OL (PEG-IFN, RBV) then OL Randomized (Observation)<br>At week 12 (end of the initial run-in period - Step 1) participants were found to have detectable HCV RNA (HCV RNA >=600 IU/mL) and had less than a 2 log10 decrease in HCV RNA from baseline. For Step 2, participants were randomized to 72 weeks of observation (no treatment). | Drug: Peginterferon alfa-2a<br>* 180 mcg PEG-IFN subcutaneously<br>Drug: Ribavirin<br>* One tablet or capsule containing ribavirin 200 mg<br>|
| Experimental: Arm C: OL (PEG-IFN, RBV) then OL (PEG-IFN, RBV)<br>At week 12 (end of initial run-in period, Step 1) participants were found to have undetectable HCV RNA (HCV RNA <600 IU/mL) or at least a 2 log10 decrease in HCV RNA from baseline. Participants entered Step 3 and were assigned to continue the run-in treatment (PEG-IFN 180 mcg weekly & RBV1-1.2 g/day based on weight) for a total of 72 weeks. At week 36, participants who had detectable HCV RNA (HCV RNA >=60 IU/mL using a qualitative assay) could enter Step 2 and be randomized to OL PEG-IFN or Observation. | Drug: Peginterferon alfa-2a<br>* 180 mcg PEG-IFN subcutaneously<br>Drug: Ribavirin<br>* One tablet or capsule containing ribavirin 200 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-scaled Change in Metavir Liver Fibrosis Score (SCMFS) | 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). | Baseline and at week 72 or premature discontinuation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Detectable HCV Viral Load (>= 60 IU/mL) | Qualitative plasma HCV viral load was categorized as less than 60 IU/mL vs greater than or equal to 60 IU/mL where 60 IU/mL is the lower limit of qualitative assay used in Steps 2 and 3. | Arms A and B: Weeks 0, 12, 24, 48 and 72; Arm C: Weeks 0, 12, 24, 36, 60, 72, 84 | 
| Time-scaled Change in Ishak Liver Inflammation Score (SCIIS) | 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. | Baseline and at week 72 or premature discontinuation | 
| Number of Participants With Anemia | 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. | Up to 96 weeks | 
| Number of Participants With Neutropenia | Number of participants with neutropenia by grade (defined by absolute neutrophil count [ANC] per cubic millimeter; mm^3). DAIDS Toxicity Grading Table (1992) was used for grading where Grade 1 = ANC of 1000 to 1500 /mm^3; Grade 2 = 750 to 999 /mm^3; Grade 3 = 500 to 749 /mm^3; Grade 4 = below 500 /mm^3. | Up to 96 weeks | 
| Number of Participants With Thrombocytopenia | Number of participants with thrombocytopenia by grade (defined by platelet count per cubic millimeter; mm^3). DAIDS Toxicity Grading Table (1992) was used for grading where Grade 1 = platelets of 75,000 to 99,000 /mm^3; Grade 2 = 50,000 to 74,999 /mm^3; Grade 3 = 20,000 to 49,999 /mm^3; Grade 4 = below 20,000 /mm^3. | Up to 96 weeks | 
| Number of Participants With Depression and/or Other Psychological Events | 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. | Up to 96 weeks | 
| Number of Participants With High-grade Signs and Symptoms or Laboratory Values | Number of participants with high-grade (Grade 3 or higher) signs and symptoms or 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. | Up to 96 Weeks | 
| Number of Participants With Dose Modifications, Temporary Stops, and Premature Treatment Discontinuations | 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. | Up to 96 Weeks | 
| Number of Participants Adherent to Study Medications | 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. | Arm A: at weeks 12, 24, 48 and 72. Arm C: at entry and weeks 12, 24, 48, 60. | 
| HCV Polymorphisms | Due to premature closure of Arms A and B with insufficient number of participants for analysis, this outcome measure was not pursued. | Entry and week 72 (Arms A and B only). | 
| HCV-specific Immune Response in Intrahepatic Lymphocytes | Due to premature closure of Arms A and B with insufficient number of participants for analysis, this outcome measure was not pursued. | Entry and week 72 (Arms A and B only). | 
| Number of Participants With Undetectable HIV Viral Load (<50 Copies/mL) | 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. | Arms A and B: Weeks 0, 24, 48 and 72; Arm C: Weeks 0, 12, 24, 36, 48, 60, 72, 84 | 
| Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | Insulin resistance was evaluated by HOMA-IR, calculated as [fasting glucose (mg/dL) x fasting insulin (uIU/mL)]/405. Study protocol required fasting for at least 8 hours (nothing by mouth except medications and water) prior to specimen collection for fasting insulin and fasting glucose testing. | Arms A and B: at entry and weeks 24, 48 and 72; Arm C: at entry and at weeks 12, 24, 36, 48, 72, 84 and 96. | 
| Sustained Virologic Response | Sustained Virologic Response (SVR) was defined as undetectable HCV viral load (<60 IU/ml) 24 weeks after treatment discontinuation. | 24 weeks after end of treatment | 
| Number of Participants Who Used Antianorexia Agents, Such as Megestrol and Dronabinol | Use of antianorexia agents, such as megestrol and dronabinol at any time after pre-assignment. | Up to 96 weeks | 
| Number of Participants With Prescription as Needed of Erythropoietin (EPO), Granulocyte Colony-stimulating Factor (GCSF), and Granulocyte-monocyte Colony-stimulating Factor (GM-CSF) | 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 | At any time after pre-assignment | 
| Weight | Participant weight in kilograms. | Arms A and B: at entry and weeks 4, 8, 12, 16, 24, 32, 40, 48, 56, 64 and 72; Arm C: at entry and weeks 4, 8, 12, 16, 24, 36, 48, 72, 84 and 96. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Experienced