HIV Infections
Conditions
Keywords
HIV, HIV-1, Pegasys, Peg-IFN-Alpha-2A, Viral Suppression, ART cessation, Immune function, Innate Immunity, Toxicity, Immune-based therapy, Treatment interruption
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: 1. 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). 2. 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) 3. 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).
Interventions
DRUGPegylated 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
DRUGPegylated 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
Sponsors
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Hoffmann-La Roche
The Wistar Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HIV Viral Load < 400 Copies/ml | 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%) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HIV Viral Load < 48 Copies/ml | 12 weeks | % of individuals maintaining VL \< 48 copies/ml while on pegylated interferon alpha-2a treatment without ART |
| HIV Viral Load < 400 Copies/ml | 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%) |
Countries
United States
Participant flow
Recruitment details
locations: medical clinics (Hospital of the University of Pennsylvania, Jonathan Lax clinic, Drexel University Hospital) Recruitment period: may 8, 2008 to May 27, 2010
Pre-assignment details
subjects were randomized to the pegasys dose of 180 or 90 mcg/week four weeks after enrollment (week 0: eligibility determination; week 4: enrollment; week 8: randomization and treatment initiation; week 13: ART interruption; week 25: primary endpoint; week 37: secondary endpoints)
Participants by arm
| Arm | Count |
|---|---|
| Pegasys 180 mcg/Week ART replacement treatment with Pegylated Interferon-alpha 2a, 180 mcg/week sc
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 | 12 |
| Pegasys 90 mcg/Week ART replacement treatment with Pegylated Interferon-alpha 2a, 90 mcg/week sc
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 | 11 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Pegasys 90 mcg/Week | Pegasys 180 mcg/Week | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 12 Participants | 23 Participants |
| Age, Continuous Age | 44 years | 45.5 years | 45 years |
| Region of Enrollment United States | 11 participants | 12 participants | 23 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 11 |
| serious Total, serious adverse events | 2 / 12 | 3 / 11 |
Outcome results
Primary
HIV Viral Load < 400 Copies/ml
% 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%)
Time frame: 12 weeks
Population: excluded 2 withdrawal of consent and 1 lost to follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegasys 180 mcg/Week | HIV Viral Load < 400 Copies/ml | 40 percentage of participants |
| Pegasys 90 mcg/Week | HIV Viral Load < 400 Copies/ml | 50 percentage of participants |
Secondary
HIV Viral Load < 400 Copies/ml
% 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%)
Time frame: 24 weeks
Population: percent of consenting eligible participants (n=8) with VL \< 400 at week 24 of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegasys 180 mcg/Week | HIV Viral Load < 400 Copies/ml | 67 percentage of eligible participants |
| Pegasys 90 mcg/Week | HIV Viral Load < 400 Copies/ml | 80 percentage of eligible participants |
Secondary
HIV Viral Load < 48 Copies/ml
% of individuals maintaining VL \< 48 copies/ml while on pegylated interferon alpha-2a treatment without ART
Time frame: 12 weeks
Population: % of subjects maintaining VL \< 48 copies/ml after 12 weeks of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegasys 180 mcg/Week | HIV Viral Load < 48 Copies/ml | 10 percentage of participants |
| Pegasys 90 mcg/Week | HIV Viral Load < 48 Copies/ml | 30 percentage of participants |