Clinical trial NCT00078403: Pegylated Interferon Alfa-2a Maintenance Therapy and Liver Disease Progression in People Infected With Both HIV and Hepatitis C Virus (HCV)
Official title: Suppressive Long-Term Antiviral Management of Hepatitis C Virus (HCV) and HIV-1 Coinfected Subjects (SLAM-C)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Hepatitis C
Liver Disease
Keywords: Treatment Experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2004-02-25
Enrollment: 333
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Time-scaled Change in Metavir Liver Fibrosis Score (SCMFS)
timeFrame: Baseline and at week 72 or premature discontinuation
Secondary outcomes:
measure: Number of Participants With Detectable HCV Viral Load (>= 60 IU/mL)
timeFrame: Arms A and B: Weeks 0, 12, 24, 48 and 72; Arm C: Weeks 0, 12, 24, 36, 60, 72, 84
measure: Time-scaled Change in Ishak Liver Inflammation Score (SCIIS)
timeFrame: Baseline and at week 72 or premature discontinuation
measure: Number of Participants With Anemia
timeFrame: Up to 96 weeks
measure: Number of Participants With Neutropenia
timeFrame: Up to 96 weeks
measure: Number of Participants With Thrombocytopenia
timeFrame: Up to 96 weeks
measure: Number of Participants With Depression and/or Other Psychological Events
timeFrame: Up to 96 weeks
measure: Number of Participants With High-grade Signs and Symptoms or Laboratory Values
timeFrame: Up to 96 Weeks
measure: Number of Participants With Dose Modifications, Temporary Stops, and Premature Treatment Discontinuations
timeFrame: Up to 96 Weeks
measure: Number of Participants Adherent to Study Medications
timeFrame: Arm A: at weeks 12, 24, 48 and 72. Arm C: at entry and weeks 12, 24, 48, 60.
measure: HCV Polymorphisms
timeFrame: Entry and week 72 (Arms A and B only).
measure: HCV-specific Immune Response in Intrahepatic Lymphocytes
timeFrame: Entry and week 72 (Arms A and B only).
measure: Number of Participants With Undetectable HIV Viral Load (<50 Copies/mL)
timeFrame: Arms A and B: Weeks 0, 24, 48 and 72; Arm C: Weeks 0, 12, 24, 36, 48, 60, 72, 84
measure: Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
timeFrame: 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.
measure: Sustained Virologic Response
timeFrame: 24 weeks after end of treatment
measure: Number of Participants Who Used Antianorexia Agents, Such as Megestrol and Dronabinol
timeFrame: Up to 96 weeks
measure: Number of Participants With Prescription as Needed of Erythropoietin (EPO), Granulocyte Colony-stimulating Factor (GCSF), and Granulocyte-monocyte Colony-stimulating Factor (GM-CSF)
timeFrame: At any time after pre-assignment
measure: Weight
timeFrame: 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.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Los Angeles
country: United States
facility: University of Southern California CRS
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Palo Alto
country: United States
facility: Stanford AIDS Clinical Trials Unit CRS
state: California
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Hiv/Aids Crs
state: California
city: San Jose
country: United States
facility: Santa Clara Valley Med. Ctr.
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Washington
country: United States
facility: Georgetown University CRS (GU CRS)
state: District of Columbia
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Infectious Disease Research Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Wishard Memorial
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital CRS (MGH CRS)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS
state: Missouri
city: Omaha
country: United States
facility: Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
state: Nebraska
city: New York
country: United States
facility: Beth Israel Med. Ctr., ACTU
state: New York
city: New York
country: United States
facility: Weill Cornell Chelsea CRS
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: New York
country: United States
facility: Weill Cornell Uptown CRS
state: New York
city: New York
country: United States
facility: Columbia P&S CRS
state: New York
city: Rochester
country: United States
facility: Trillium Health ACTG CRS
state: New York
city: Rochester
country: United States
facility: McCree McCuller Wellness Ctr. at the Connection, Infectious Disease Unit
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Philadelphia
country: United States
facility: Univ. of Pennsylvania Health System, Presbyterian Med. Ctr.
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital Clinical Research Site (TMH CRS) CRS
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics (VT) CRS
state: Tennessee
city: Dallas
country: United States
facility: Univ. of Texas Southwestern Med. Ctr., Amelia Court Continuity Clinic
state: Texas
city: Galveston
country: United States
facility: Univ. of Texas Medical Branch, ACTU
state: Texas
city: San Juan
country: Puerto Rico
facility: Puerto Rico AIDS Clinical Trials Unit CRS
Study officials:
affiliation: University of Cincinnati
name: Kenneth E. Sherman, MD, PhD
role: STUDY_CHAIR
affiliation: Harvard/Massachusetts General Hospital
name: Raymond Chung, MD
role: STUDY_CHAIR
References:
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citation: 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. doi: 10.1086/379255. Epub 2003 Nov 13.
citation: 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. doi: 10.1056/NEJMoa040842.
citation: The Division of AIDS Table for Grading the Severity of Adult Adverse Events (DAIDS AE Grading Table), August 1992.
citation: Manual for Expedited Reporting of Adverse Events to Division of AIDS (DAIDS EAE Manual), May 2004.
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 alfa 2a and ribavirin. Aliment Pharmacol Ther. 2011 Jun;33(11):1234-44. doi: 10.1111/j.1365-2036.2011.04648.x. Epub 2011 Mar 29.
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 Acquir Immune Defic Syndr. 2010 Dec 15;55(5):597-605. doi: 10.1097/QAI.0b013e3181f6d916.
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/hct1302-70.
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 Study. Clin Infect Dis. 2012 Sep;55(5):631-8. doi: 10.1093/cid/cis463. Epub 2012 May 4.
citation: Branch AD, Kang M, Hollabaugh K, Wyatt CM, Chung RT, Glesby MJ. In HIV/hepatitis C virus co-infected patients, higher 25-hydroxyvitamin D concentrations were not related to hepatitis C virus treatment responses but were associated with ritonavir use. Am J Clin Nutr. 2013 Aug;98(2):423-9. doi: 10.3945/ajcn.112.048785. Epub 2013 Jun 5.
citation: Shire NJ, Rao MB, Succop P, Buncher CR, Andersen JA, Butt AA, Chung RT, Sherman KE; AIDS Clinical Trials Group 5178 Study Group. Improving noninvasive methods of assessing liver fibrosis in patients with hepatitis C virus/human immunodeficiency virus co-infection. Clin Gastroenterol Hepatol. 2009 Apr;7(4):471-80, 480.e1-2. doi: 10.1016/j.cgh.2008.12.016. Epub 2008 Dec 25.