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

Condition(s) targeted: HIV Infections; Hepatitis C; Liver Disease

Intervention: Peginterferon alfa-2a (Drug); Ribavirin (Drug)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Kenneth E. Sherman, MD, PhD, Study Chair, Affiliation: University of Cincinnati
Raymond Chung, MD, Study Chair, Affiliation: Harvard/Massachusetts General Hospital

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.

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

Study design: Treatment, Randomized, Open Label, Active Control, Crossover Assignment, Efficacy Study

Primary outcome: Liver fibrosis (Metavir) score

Secondary outcome:

HCV viral loads

Liver inflammation (Metavir) score

Safety, defined as rates and grades of anemia, neutropenia, thrombocytopenia, depression, and other psychological events, and all other high-grade signs and symptoms and laboratory values

Regimen tolerability, defined as dose modification and temporary and permanent drug discontinuation, increased symptom distress, or decreased quality of life

Adherence to study medication

HCV polymorphisms

HCV-specific immune response in intrahepatic lymphocytes

Noninvasive measures of liver fibrosis, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, albumin, and protein measurements

HIV viral load

Weight

Insulin resistance, defined as fasting glucose

Step 3 end of treatment virologic response and sustained virologic response

Use of antianorexia agents, such as megestrol and dronabinol

Use of hematologic adjuvant therapies, such as erythropoietin, granulocyte colony-stimulating factor, and granulocyte-monocyte colony-stimulating factor

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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, CPT score of 5 or less and no more than Child-Pugh Class A

- Liver enzyme (ALT, 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 CT scan or 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 TSH and 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

University of Puerto Rico, San Juan 00936-5067, Puerto Rico

University of Alabama at Birmingham, Birmingham, Alabama 35924-2050, United States

Stanford University, Stanford, California 94305-5107, United States

Santa Clara Valley Medical Center, Stanford, California 94305-5107, United States

UCLA School of Medicine, Los Angeles, California 90095-1793, United States

San Francisco General Hospital, San Francisco, California 94110, United States

University of Southern California, Los Angeles, California 90033-1079, United States

Univ. of Colorado Health Sciences Center, Denver, Denver, Colorado 80262-3706, United States

Georgetown University Medical Center, Washington, District of Columbia 20007, United States

University of Miami, Miami, Florida 33136-1013, United States

Emory University, Atlanta, Georgia 30308, United States

University of Hawaii, Honolulu, Hawaii 96816-2396, United States

Cook County Hospital Core Center, Chicago, Illinois 60612, United States

Northwestern University, Chicago, Illinois 60611-3015, United States

Indiana University Hospital, Indianapolis, Indiana 46202-5250, United States

Methodist Hospital of Indiana, Indianapolis, Indiana 46202-5250, United States

Wishard Hospital, Indianapolis, Indiana 46202, United States

Johns Hopkins University, Baltimore, Maryland 21287-8106, United States

4651 University of Maryland, Institute of Human Virology, Baltimore, Maryland 21201, United States

Harvard (Massachusetts General Hospital), Boston, Massachusetts 02114, United States

Boston Medical Center (Harvard), Boston, Massachusetts 02118, United States

Brigham and Womens Hospital, Boston, Massachusetts 02115, United States

Beth Israel Deaconess - West Campus, Boston, Massachusetts 02215, United States

Washington University (St. Louis), St. Louis, Missouri 63108-2138, United States

Nebraska Health System, Omaha, Nebraska 68198-5130, United States

Chelsea Clinic, New York, New York 10011, United States

The Cornell Clinic, New York, New York 10021, United States

New York University/Bellevue, New York, New York 10016-6481, United States

University of Rochester Medical Center, Rochester, New York 14642-0001, United States

Community Health Network, Inc., Rochester, New York 14642-0001, United States

Beth Israel Medical Center, New York, New York 10003, United States

McCree McCuller Wellness Center at the Connection, Rochester, New York 14642-0001, United States

Columbia University, New York, New York 10032-3784, United States

SUNY - Buffalo (Rochester), Buffalo, New York 14215, United States

University of North Carolina, Chapel Hill, North Carolina 27514, United States

University of Cincinnati, Cincinnati, Ohio 45267-0405, United States

MetroHealth Medical Center, Cleveland, Ohio 44109-1998, United States

University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2582, United States

University of Pennsylvania, Philadelphia, Philadelphia, Pennsylvania 19104, United States

Presbyterian Medical Center - Univ. of PA, Philadelphia, Pennsylvania 19104, United States

The Miriam Hospital, Providence, Rhode Island 02906, United States

Rhode Island Hospital, Providence, Rhode Island 02906, United States

Stanley Street Treatment and Resource, Providence, Rhode Island 02906, United States

Comprehensive Care Clinic, Nashville, Tennessee 37203, United States

University of Texas. Galveston, Galveston, Texas 77555-0435, United States

University of Texas, Southwestern Medical Center, Dallas, Texas 75235-9173, United States

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Related publications:

Brau 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.

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

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.

Neau D, Trimoulet P, Winnock M, Rullier A, Le Bail B, Lacoste D, Ragnaud JM, Bioulac-Sage P, Lafon ME, Chene 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 03.

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.

Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia 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.

Last updated: August 16, 2007