Antiviral Activity of Peg-IFN-Alpha-2A in Chronic HIV-1 Infection

Tracking Information
First Submitted Date ICMJE	January 4, 2008
First Posted Date ICMJE	January 16, 2008
Results First Submitted Date	January 24, 2013
Results First Posted Date	February 10, 2015
Last Update Posted Date	February 10, 2015
Study Start Date ICMJE	January 2008
Actual Primary Completion Date	November 2010 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: January 28, 2015)	HIV Viral Load < 400 Copies/ml [ Time Frame: 12 weeks ]; % of individuals maintaining viral suppression (VL < 400 copies/ml) as compared to the anticipated rate of viral suppression in individuals interrupting ART without interferon (9%)
Original Primary Outcome Measures ICMJE; (submitted: January 15, 2008)	HIV viral suppression [ Time Frame: 29 weeks ]
Change History	Complete list of historical versions of study NCT00594880 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: January 28, 2015)	HIV Viral Load < 48 Copies/ml [ Time Frame: 12 weeks ]% of individuals maintaining VL < 48 copies/ml while on pegylated interferon alpha-2a treatment without ART; HIV Viral Load < 400 Copies/ml [ Time Frame: 24 weeks ]% of individuals maintaining viral suppression (VL < 400 copies/ml) as compared to the anticipated rate of viral suppression in individuals interrupting ART without interferon (9%)
Original Secondary Outcome Measures ICMJE; (submitted: January 15, 2008)	Treatment-associated toxicity and tolerance measurement. [ Time Frame: 29 weeks ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Antiviral Activity of Peg-IFN-Alpha-2A in Chronic HIV-1 Infection
Official Title ICMJE	Antiviral Activity of Peg-IFN-Alpha-2A in Chronic HIV-1 Infection
Brief Summary	The objective of the study is to compare two different doses of Peg-INF-α-2A (90 or 180 ug/wk) for their ability to maintain viral control when initiated 5 weeks before ART (antiretroviral therapy) interruption in HIV positive, ART-suppressed subjects (viral load <50 copies/ml) as determined by observing the percentages of viral load measurements <400 copies/ml between the two arms over a 24-week period, corresponding to the Pegasys monotherapy period (exclusive of dual ART/Pegasys 5-week period). Primary analysis will be an "intent to treat" analysis and will address the hypothesis that two different doses of Peg-INF-α-2A (90 and 180 ug/week) will be similarly effective at inhibiting viral replication.
Detailed Description	The high toxicity of current Anti-Retroviral Therapy (ART) regimens has driven a number of studies investigating therapeutic approaches aimed at reducing drug exposure while maintaining the beneficial effects of immune reconstitution. Preliminary observations in HCV/HIV co-infected individuals already support an antiviral effect by Pegylated Interferon-Alpha-2A (Peg-IFN-Alpha-2A:Pegasys®) on HIV-1 replication; however, the ability of Peg-IFN-Alpha-2A (as a single agent) to maintain long-term suppression of HIV-1 replication in patients who interrupt ART after having achieved immune reconstitution remains undetermined. The rationale for addressing two doses of Peg-IFN-Alpha-2A (180 and 90 ug/week) is based on the antiviral activity reported with both doses and the lower incidence of adverse events associated with doses lower than that approved for HCV therapy (90 versus 180ug/week). The long-range goal of this proposal is to determine if Peg-IFN-Alpha-2A monotherapy can sustain HIV-1 suppression in the absence of ART in infected individuals. Our short-range goal is to determine the safety, viral suppressive potential and immune correlates of Peg-IFN-Alpha-2A administered upon the cessation of suppressive ART. Based on the current literature and our preliminary studies, we hypothesize that weekly doses of 90 or 180 ug/wk of Peg-IFN-Alpha-2A administered to pharmacologically-suppressed HIV-infected individuals in the course of antiretroviral therapy (ART) discontinuation will result in equivalent frequency of viral control, with the lower dose resulting in measurably lower rate and intensity of therapy-related adverse events (AE). We propose to compare two different doses of Peg-IFN-Alpha-2A (90 or 180 ug/wk) as a simplification step to ART, for their ability to maintain viral load suppression when initiated 5 weeks before ART interruption in HIV-infected, ART-suppressed patients (VL<50 copies/ml). Briefly, control will be determined by the the percentages of viral load measurements <400 copies/ml between the two arms over a period of 24 weeks, corresponding to the Pegasys monotherapy period (exclusive of dual ART/Pegasys 5-week period). A threshold of 400 is used based on the known potential for blipping on ART between 50 and 400 copies/ml with no clinical consequence to sustained suppression thereafter (JAMA 2005, 293:817-829). Primary analysis will be an "intent to treat" analysis and will address the hypothesis that two different doses of Peg-IFN-Alpha-2A (90 and 180 ug/week) will be similarly effective at inhibiting viral replication. The secondary objectives of the research are: To prospectively evaluate dose-dependent, treatment-associated toxicity, safety and tolerability of 29 weekly doses of Peg-IFN-Alpha-2A at 180 ug or 90 ug/week (in association with ART for the initial 5 weeks, followed by 24 weeks of Peg-IFN-Alpha-2A in the absence of ART).; To determine innate immunity outcomes correlated to Peg-IFN-Alpha-2A dose and antiviral activity by monitoring Natural Killer (NK) and Dendritic cell (DC) subsets changes and the ability to maintain innate immune function (DC secretory responses, NK antiviral cytotoxic responses); To determine adaptive immunity outcomes correlated to Peg-IFN-Alpha-2A dose and antiviral activity by monitoring T-cell subsets changes and the ability to maintain cell-mediated proliferative and cytokine responses against recall antigens (anti-HIV-1 gag p55).
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	HIV Infections
Intervention ICMJE	Drug: Pegylated Interferon-alpha 2a, 180 mcg/week sc Pegylated Interferon-alpha 2a, 90 mcg/week sc for 24 weeks, 5 weeks in combination with ART, then 7 weeks without ART to primary endpoint (VL < 400 c/ml at 12 weeks) and further 12 weeks without ART (24 weeks) to secondary endpoints Other Name: Pegasys; Drug: Pegylated Interferon-alpha 2a, 90 mcg/week sc Pegylated Interferon-alpha 2a, 90 mcg/week sc for 24 weeks, 5 weeks in combination with ART, then 7 weeks without ART to primary endpoint (VL < 400 c/ml at 12 weeks) and further 12 weeks without ART (24 weeks) to secondary endpoints Other Name: Pegasys
Study Arms	Active Comparator: Pegasys 180 mcg/week ART replacement treatment with Pegylated Interferon-alpha 2a, 180 mcg/week sc Intervention: Drug: Pegylated Interferon-alpha 2a, 180 mcg/week sc; Active Comparator: Pegasys 90 mcg/week ART replacement treatment with Pegylated Interferon-alpha 2a, 90 mcg/week sc Intervention: Drug: Pegylated Interferon-alpha 2a, 90 mcg/week sc
Publications *	Azzoni L, Foulkes AS, Papasavvas E, Mexas AM, Lynn KM, Mounzer K, Tebas P, Jacobson JM, Frank I, Busch MP, Deeks SG, Carrington M, O'Doherty U, Kostman J, Montaner LJ. Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J Infect Dis. 2013 Jan 15;207(2):213-22. doi: 10.1093/infdis/jis663. Epub 2012 Oct 26.; Chitre AS, Kattah MG, Rosli YY, Pao M, Deswal M, Deeks SG, Hunt PW, Abdel-Mohsen M, Montaner LJ, Kim CC, Ma A, Somsouk M, McCune JM. A20 upregulation during treated HIV disease is associated with intestinal epithelial cell recovery and function. PLoS Pathog. 2018 Mar 5;14(3):e1006806. doi: 10.1371/journal.ppat.1006806. eCollection 2018 Mar.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: June 13, 2012)	23
Original Estimated Enrollment ICMJE; (submitted: January 15, 2008)	52
Actual Study Completion Date	May 2011
Actual Primary Completion Date	November 2010 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Male or female, age ≥ 18 but <65 years; Able and willing to provide informed consent.; HIV-1 infection documented by any licensed enzyme-linked immunosorbent assay (ELISA) test kit and confirmed by Western Blot at any time prior to or at study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test; HIV RNA < 75 copies/ml on a regimen of a) 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and 1 non-nucleoside RTI (NNRTI) OR b) 2 NRTIs and Protease Inhibitor (PI) for at least 24 weeks OR c) 3 NRTIs; HIV RNA < 75 copies/ml at screening; > 6 months ≥ 400 CD4+ T cells/mm3 (CD4 nadir ≥ 200 cells); Female subjects with childbearing potential: negative pregnancy test (Beta human horionic gonadotropin (HCG)). Must agree to use appropriate contraceptive methods (barrier devices such as diaphragms or condoms + spermicidal or intrauterine device (IUD) or oral contraceptives) while on study.; Karnofsky performance scale score of 80% or better; Willing to adhere to the treatment and schedule approved by the study investigators in conjunction with the patient's primary provider.; Willing to abstain from immunomodulatory drugs during the study period, with the exception of the study drug (Pegasys®).; Patient Health Questionnaire (PHQ)-2 score < 2, OR PHQ-9 score< 10, OR PHQ-9 score 10-14 AND medical provider's favorable opinion. In either case, score for PHQ-9 question # 9 (suicidal ideation) must be 0.; Thyroid stimulating hormone (TSH) within normal range, unless accompanied by thyroid profile consistent with normal thyroid function; A negative cardiac stress test if >45yrs men/>55yrs women years of age or if below these years of age but with two added risk factors for coronary artery disease [smoking, hypertension (BP >140/90 or on antihypertensive medications), low Hight density lipoprotein (HDL)-associated cholesterol (<40 mg/dL), family history of premature Coronary heart disease (CHD) (<55 yrs males/<65 females)] or a Framingham score > 15% (men) or 10% (women)) Exclusion Criteria: Currently pregnant or breast feeding.; CD4 cell count < 400 or recorded CD4 nadir < 200 cells/mm3; History of immunomodulatory therapy for over 2 weeks during the 6 months prior to enrollment, including, but not limited to: IFN-Alpha or Beta (recombinant or pegylated), systemic corticosteroids; systemic cancer chemotherapy/irradiation; cyclosporin; tacrolimus (FK-506); OKT-3; any Interleukin, including IL-2; cyclophosphamide; methotrexate; IVIG (gamma globulin); G/M-CSF; hydroxyurea; thalidomide; pentoxifylline; thymopentin; thymosin; dithiocarbonate; polyribonucleoside.; Significant co-existing medical conditions including: Anemia (Hgb <9.1 men, <8.9 women), Neutropenia (ANC < 1000), Thrombocytopenia (platelet count <50K), Liver disease (AST/ALT > 5x, Total Bilirubin > 1.5x upper limits of normal, or Total Bilirubin >3x upper limit of the norm (ULN) if receiving indinavir), Renal disease (creatinine > 2x upper normal limits), or other conditions, such as active drug/alcohol abuse or dependence which would interfere with study compliance.; Any history of heart attacks, myocardial infarction or coronary arterial disease (MI/CAD). .; Prior history of major depression or other severe psychiatric disorder/condition requiring treatment and/or hospitalization; PHQ-9 score >14, OR PHQ-9 score > 10 - 14 and lack of medical provider's favorable opinion, or score for PHQ-9 answer # 9 (suicidal ideation) > 0.; Evidence of chronic active Hepatitis B infection (Surface Antigen HBsAg) or Hepatitis C plymerase chain reaction (PCR) positivity at screening (cleared of HCV at entry >6 months).; Past evidence of medical conditions associated with chronic liver disease including genetic hemochromatosis, autoimmune hepatitis, alcoholic liver disease, toxin exposures etc.; History of neutropenia or other hematological abnormalities; Type I diabetes mellitus, or type II diabetes mellitus that is not controlled with oral agents and/or insulin.; Ongoing treatment with Isoniazide, Pyrazinamide, Rifabutin, Rifampicin, Diadenosine Ganciclovir, Valganciclovir, Oxymetholone, Thalidomide or Theophylline.; History of autoimmune processes including Crohn's disease, ulcerative colitis, severe psoriasis, rheumatoid arthritis, myositis, hepatitis etc.; History of major organ transplantation with an existing functional graft.; Active coronary artery disease within 24 weeks prior to study; Hemoglobinopathies such as sickle cell anemia or Thalassemia major.; Hypersensitivity to Pegasys®or any of its components.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years to 65 Years (Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00594880
Other Study ID Numbers ICMJE	DAIDS-ES 10401; U01AI065279 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Luis Montaner, The Wistar Institute
Study Sponsor ICMJE	The Wistar Institute
Collaborators ICMJE	National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); Hoffmann-La Roche
Investigators ICMJE	Study Chair: Luis Montaner, DVM, PhD The Wistar Institute Principal Investigator: Jay Kostman, MD Penn-Presbyterian Medical Center Principal Investigator: Pablo Tebas, MD University of Pennsylvania Principal Investigator: Jeffrey Jacobson, MD Drexel University College of Medicine Principal Investigator: Karam Mounzer, MD Jonathan Lax Immune Disorders Clinic- Philadelphia FIGHT
PRS Account	The Wistar Institute
Verification Date	January 2015
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP