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

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00078403
• Other study ID #: A5178
• Secondary ID: 10008
• Status: Completed
• Phase: Phase 2
• Start date: July 2004
• Est. completion date: February 2009

Study information

• Verified date: November 2016
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 333
• Est. completion date: February 2009
• Est. primary completion date: May 2007
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• HIV Infections
• Liver Disease
• Liver Diseases

Intervention

Drug:
• Peginterferon alfa-2a
180 mcg PEG-IFN subcutaneously
• Ribavirin
One tablet or capsule containing ribavirin 200 mg

Locations

Country	Name	City	State
Puerto Rico	Puerto Rico AIDS Clinical Trials Unit CRS	San Juan
United States	University of Colorado Hospital CRS	Aurora	Colorado
United States	Johns Hopkins University CRS	Baltimore	Maryland
United States	Alabama Therapeutics CRS	Birmingham	Alabama
United States	Beth Israel Deaconess Med. Ctr., ACTG CRS	Boston	Massachusetts
United States	Brigham and Women's Hosp. ACTG CRS	Boston	Massachusetts
United States	Massachusetts General Hospital CRS (MGH CRS)	Boston	Massachusetts
United States	Chapel Hill CRS	Chapel Hill	North Carolina
United States	Northwestern University CRS	Chicago	Illinois
United States	Cincinnati CRS	Cincinnati	Ohio
United States	MetroHealth CRS	Cleveland	Ohio
United States	Univ. of Texas Southwestern Med. Ctr., Amelia Court Continuity Clinic	Dallas	Texas
United States	Univ. of Texas Medical Branch, ACTU	Galveston	Texas
United States	Univ. of Hawaii at Manoa, Leahi Hosp.	Honolulu	Hawaii
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	UCLA CARE Center CRS	Los Angeles	California
United States	University of Southern California CRS	Los Angeles	California
United States	Vanderbilt Therapeutics (VT) CRS	Nashville	Tennessee
United States	Beth Israel Med. Ctr., ACTU	New York	New York
United States	Columbia P&S CRS	New York	New York
United States	NY Univ. HIV/AIDS CRS	New York	New York
United States	Weill Cornell Chelsea CRS	New York	New York
United States	Weill Cornell Uptown CRS	New York	New York
United States	Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.	Omaha	Nebraska
United States	Stanford AIDS Clinical Trials Unit CRS	Palo Alto	California
United States	Univ. of Pennsylvania Health System, Presbyterian Med. Ctr.	Philadelphia	Pennsylvania
United States	University of Pittsburgh CRS	Pittsburgh	Pennsylvania
United States	The Miriam Hospital Clinical Research Site (TMH CRS) CRS	Providence	Rhode Island
United States	McCree McCuller Wellness Ctr. at the Connection, Infectious Disease Unit	Rochester	New York
United States	Trillium Health ACTG CRS	Rochester	New York
United States	Univ. of Rochester ACTG CRS	Rochester	New York
United States	Washington University Therapeutics (WT) CRS	Saint Louis	Missouri
United States	UCSD Antiviral Research Center CRS	San Diego	California
United States	Ucsf Hiv/Aids Crs	San Francisco	California
United States	Santa Clara Valley Med. Ctr.	San Jose	California
United States	Georgetown University CRS (GU CRS)	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (12)

Borgia G, Reynaud L, Gentile I, Piazza M. HIV and hepatitis C virus: facts and controversies. Infection. 2003 Aug;31(4):232-40. Review. — View Citation

Bräu N. Treatment of chronic hepatitis C in human immunodeficiency virus/hepatitis C virus-coinfected patients in the era of pegylated interferon and ribavirin. Semin Liver Dis. 2005 Feb;25(1):33-51. Review. — View Citation

Butt AA, Umbleja T, Andersen JW, Chung RT, Sherman KE; ACTG A5178 Study Team. The incidence, predictors and management of anaemia and its association with virological response in HCV / HIV coinfected persons treated with long-term pegylated interferon alf — View Citation

Butt AA, Umbleja T, Andersen JW, Sherman KE, Chung RT; ACTG A5178 Study Team. Impact of peginterferon alpha and ribavirin treatment on lipid profiles and insulin resistance in Hepatitis C virus/HIV-coinfected persons: the AIDS Clinical Trials Group A5178 — View Citation

Chung RT, Umbleja T, Chen JY, Andersen JW, Butt AA, Sherman KE; Actg A5178 Study Team. Extended therapy with pegylated interferon and weight-based ribavirin for HCV-HIV coinfected patients. HIV Clin Trials. 2012 Mar-Apr;13(2):70-82. doi: 10.1310/hct1302-7 — View Citation

Khalili M, Bernstein D, Lentz E, Barylski C, Hoffman-Terry M. Pegylated interferon alpha-2a with or without ribavirin in HCV/HIV coinfection: partially blinded, randomized multicenter trial. Dig Dis Sci. 2005 Jun;50(6):1148-55. — View Citation

Manual for Expedited Reporting of Adverse Events to Division of AIDS (DAIDS EAE Manual), May 2004.

Neau D, Trimoulet P, Winnock M, Rullier A, Le Bail B, Lacoste D, Ragnaud JM, Bioulac-Sage P, Lafon ME, Chêne G, Dupon M; ROCO Study Group. Comparison of 2 regimens that include interferon-alpha-2a plus ribavirin for treatment of chronic hepatitis C in human immunodeficiency virus-coinfected patients. Clin Infect Dis. 2003 Jun 15;36(12):1564-71. Epub 2003 Jun 3. — View Citation

Sherman KE, Andersen JW, Butt AA, Umbleja T, Alston B, Koziel MJ, Peters MG, Sulkowski M, Goodman ZD, Chung RT; AIDS Clinical Trials Group A5178 Study Team. Sustained long-term antiviral maintenance therapy in HCV/HIV-coinfected patients (SLAM-C). J Acqui — View Citation

The Division of AIDS Table for Grading the Severity of Adult Adverse Events (DAIDS AE Grading Table), August 1992.

Torriani FJ, Ribeiro RM, Gilbert TL, Schrenk UM, Clauson M, Pacheco DM, Perelson AS. Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) dynamics during HCV treatment in HCV/HIV coinfection. J Infect Dis. 2003 Nov 15;188(10):1498-507. Epub 2003 Nov 13. — View Citation

Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-García J, Lazzarin A, Carosi G, Sasadeusz J, Katlama C, Montaner J, Sette H Jr, Passe S, De Pamphilis J, Duff F, Schrenk UM, Dieterich DT; APRICOT Study Group. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004 Jul 29;351(5):438-50. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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).
Secondary	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).
Secondary	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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.

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