Pegylated Interferon Alfa-2a Maintenance Therapy and Liver Disease Progression in People Infected With Both HIV and Hepatitis C Virus (HCV)
- Conditions
- Liver DiseaseHIV InfectionsHepatitis C
- Interventions
- Registration Number
- NCT00078403
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 333
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm C: OL (PEG-IFN, RBV) then OL (PEG-IFN, RBV) Ribavirin 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. Arm A: Open Label (OL) (PEG-IFN, RBV); OL Randomized (PEG-IFN) Peginterferon alfa-2a 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. Arm A: Open Label (OL) (PEG-IFN, RBV); OL Randomized (PEG-IFN) Ribavirin 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. Arm B: OL (PEG-IFN, RBV) then OL Randomized (Observation) Peginterferon alfa-2a 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). Arm B: OL (PEG-IFN, RBV) then OL Randomized (Observation) Ribavirin 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). Arm C: OL (PEG-IFN, RBV) then OL (PEG-IFN, RBV) Peginterferon alfa-2a 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.
- Primary Outcome Measures
Name Time Method Time-scaled Change in Metavir Liver Fibrosis Score (SCMFS) Baseline and at week 72 or premature discontinuation 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
Name Time Method Number of Participants With Anemia Up to 96 weeks 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.
HCV-specific Immune Response in Intrahepatic Lymphocytes Entry and week 72 (Arms A and B only). Due to premature closure of Arms A and B with insufficient number of participants for analysis, this outcome measure was not pursued.
Number of Participants With Dose Modifications, Temporary Stops, and Premature Treatment Discontinuations Up to 96 Weeks 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.
Sustained Virologic Response 24 weeks after end of treatment Sustained Virologic Response (SVR) was defined as undetectable HCV viral load (\<60 IU/ml) 24 weeks after treatment discontinuation.
Number of Participants With Detectable HCV Viral Load (>= 60 IU/mL) Arms A and B: Weeks 0, 12, 24, 48 and 72; Arm C: Weeks 0, 12, 24, 36, 60, 72, 84 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.
Time-scaled Change in Ishak Liver Inflammation Score (SCIIS) Baseline and at week 72 or premature discontinuation 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 Depression and/or Other Psychological Events Up to 96 weeks 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.
Number of Participants With High-grade Signs and Symptoms or Laboratory Values Up to 96 Weeks 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.
Number of Participants Adherent to Study Medications Arm A: at weeks 12, 24, 48 and 72. Arm C: at entry and weeks 12, 24, 48, 60. 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 Entry and week 72 (Arms A and B only). Due to premature closure of Arms A and B with insufficient number of participants for analysis, this outcome measure was not pursued.
Number of Participants With Undetectable HIV Viral Load (<50 Copies/mL) Arms A and B: Weeks 0, 24, 48 and 72; Arm C: Weeks 0, 12, 24, 36, 48, 60, 72, 84 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.
Number of Participants Who Used Antianorexia Agents, Such as Megestrol and Dronabinol Up to 96 weeks Use of antianorexia agents, such as megestrol and dronabinol at any time after pre-assignment.
Number of Participants With Prescription as Needed of Erythropoietin (EPO), Granulocyte Colony-stimulating Factor (GCSF), and Granulocyte-monocyte Colony-stimulating Factor (GM-CSF) At any time after pre-assignment 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
Number of Participants With Neutropenia Up to 96 weeks 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.
Number of Participants With Thrombocytopenia Up to 96 weeks 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.
Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) 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. 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.
Weight 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. Participant weight in kilograms.
Trial Locations
- Locations (37)
Johns Hopkins University CRS
🇺🇸Baltimore, Maryland, United States
University of Pittsburgh CRS
🇺🇸Pittsburgh, Pennsylvania, United States
Massachusetts General Hospital CRS (MGH CRS)
🇺🇸Boston, Massachusetts, United States
Vanderbilt Therapeutics (VT) CRS
🇺🇸Nashville, Tennessee, United States
Puerto Rico AIDS Clinical Trials Unit CRS
🇵🇷San Juan, Puerto Rico
Weill Cornell Uptown CRS
🇺🇸New York, New York, United States
Cincinnati CRS
🇺🇸Cincinnati, Ohio, United States
Beth Israel Med. Ctr., ACTU
🇺🇸New York, New York, United States
Univ. of Texas Medical Branch, ACTU
🇺🇸Galveston, Texas, United States
Univ. of Rochester ACTG CRS
🇺🇸Rochester, New York, United States
Northwestern University CRS
🇺🇸Chicago, Illinois, United States
Chapel Hill CRS
🇺🇸Chapel Hill, North Carolina, United States
NY Univ. HIV/AIDS CRS
🇺🇸New York, New York, United States
Beth Israel Deaconess Med. Ctr., ACTG CRS
🇺🇸Boston, Massachusetts, United States
Weill Cornell Chelsea CRS
🇺🇸New York, New York, United States
Univ. of Hawaii at Manoa, Leahi Hosp.
🇺🇸Honolulu, Hawaii, United States
Columbia P&S CRS
🇺🇸New York, New York, United States
Brigham and Women's Hosp. ACTG CRS
🇺🇸Boston, Massachusetts, United States
Santa Clara Valley Med. Ctr.
🇺🇸San Jose, California, United States
Indiana Univ. School of Medicine, Infectious Disease Research Clinic
🇺🇸Indianapolis, Indiana, United States
Indiana Univ. School of Medicine, Wishard Memorial
🇺🇸Indianapolis, Indiana, United States
University of Colorado Hospital CRS
🇺🇸Aurora, Colorado, United States
Alabama Therapeutics CRS
🇺🇸Birmingham, Alabama, United States
University of Southern California CRS
🇺🇸Los Angeles, California, United States
UCLA CARE Center CRS
🇺🇸Los Angeles, California, United States
Stanford AIDS Clinical Trials Unit CRS
🇺🇸Palo Alto, California, United States
UCSD Antiviral Research Center CRS
🇺🇸San Diego, California, United States
Ucsf Hiv/Aids Crs
🇺🇸San Francisco, California, United States
Georgetown University CRS (GU CRS)
🇺🇸Washington, District of Columbia, United States
Washington University Therapeutics (WT) CRS
🇺🇸Saint Louis, Missouri, United States
Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
🇺🇸Omaha, Nebraska, United States
Trillium Health ACTG CRS
🇺🇸Rochester, New York, United States
McCree McCuller Wellness Ctr. at the Connection, Infectious Disease Unit
🇺🇸Rochester, New York, United States
MetroHealth CRS
🇺🇸Cleveland, Ohio, United States
Univ. of Pennsylvania Health System, Presbyterian Med. Ctr.
🇺🇸Philadelphia, Pennsylvania, United States
Univ. of Texas Southwestern Med. Ctr., Amelia Court Continuity Clinic
🇺🇸Dallas, Texas, United States
The Miriam Hospital Clinical Research Site (TMH CRS) CRS
🇺🇸Providence, Rhode Island, United States