HIV Infections
Conditions
Keywords
Treatment Naive, IL-2, rIL-2
Brief summary
The purpose of this study is to determine the effect of short cycles of recombinant interleukin-2 (also known as rIL-2 or aldesleukin) given with or without anti-HIV drugs in HIV infected patients. The effects will be compared with a study group that receives no IL-2 or antiretroviral therapy. Study hypothesis: Intermittent aldesleukin, when given without antiretroviral therapy to patients with early HIV infection, will produce no change in HIV viral load and increases in CD4+ T lymphocyte counts comparable to aldesleukin administered with antiretrovirals.
Detailed description
Highly active antiretroviral therapy (HAART) has dramatically improved prognosis and lowered morbidity and mortality rates for HIV infected patients. However, significant drug toxicities, difficulties with patient compliance to HAART regimens, and development of drug resistance highlight the need for less toxic, immune-based strategies. Aldesleukin is a synthetic protein that can increase CD4 counts; it is currently approved by the Food and Drug Administration (FDA) for use in patients with metastatic melanoma and renal cell carcinoma. Previous studies of aldesleukin in HIV infected patients indicated that increased CD4 counts can persist for years after aldesleukin administration, and aldesleukin given with HAART may also lead to significant lowering of viral load. This study will examine the immunologic effects of intermittent cycles of aldesleukin administered with and without HAART as compared to no therapy in HIV infected patients. This study will last approximately 31 months. Participants will be randomly assigned to one of three groups at study entry. Group A will receive no aldesleukin or HAART. Group B will receive aldesleukin under the skin twice daily for 5 consecutive days every 8 weeks for 3 cycles, then as needed to maintain CD4 counts at or above a goal level. Group C will receive aldesleukin under the skin twice daily for 5 consecutive days every 8 weeks for 3 cycles, then as needed to maintain CD4 counts at or above a goal level; Group C participants will also take HAART for 3 days prior to the start of each aldesleukin cycle, throughout the 5-day aldesleukin cycle, and for 2 days after the end of each aldesleukin cycle (for a maximum of 10 days with each aldesleukin cycle). HAART will not be provided by the study. Some Group B and C participants may take part in additional cycles of aldesleukin if they meet certain study criteria. All participants in this study will have at least 8 study visits; these visits will occur at study entry and Weeks 4, 8, 12, 16, 20, 24, and 32. Blood collection will occur at all visits and will include tests for CD4 count and viral load. Groups B and C will have additional blood collection within 4 days prior to the start of each aldesleukin cycle. On the last day of each aldesleukin cycle, Groups B and C will be assessed for toxicities, adverse events, and adherence to the aldesleukin daily injections; they will also have another blood collection. Group C participants will have an additional blood collection for HIV genotyping after they have completed their third aldesleukin cycle. Extended follow-up visits will occur approximately every 4 months for an additional two years. Blood collection will occur at these visits and will include tests for CD4 count, viral load, and other laboratory tests.
Interventions
DRUGIL-2
7.5 MIU injected intramuscularly; one arm uses Proleukin together with HAART of choice (protease inhibitor and at least 2 nucleoside/nucleotide reverse transcriptase inhibitors)
Sponsors
Chiron Corporation
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV infected * CD4 count of 300 cells/mm3 or more * Access to a HAART regimen consisting of 1 or more protease inhibitors (PIs) and 2 or more nucleoside or nucleotide reverse transcriptase inhibitors
Exclusion criteria
* Prior use of aldesleukin * Approved or experimental antiretroviral drug (including hydroxyurea) within 1 year prior to study entry * Evidence of virologic failure on a PI- or nonnucleoside-based HAART regimen * Any current indication for continuous HAART, in the opinion of the investigator * Any contraindication to HAART, in the opinion of the investigator * Systemic corticosteroids, chemotherapy, or experimental cytotoxic drugs within 45 days of randomization * Approved or experimental agents with clinically significant immunomodulatory effects within 8 weeks prior to randomization * History of any AIDS-defining illness or certain other diseases. More information on this criterion can be found in the protocol. * Concurrent cancer requiring cytotoxic therapy * Any central nervous system (CNS) abnormality requiring ongoing treatment with antiseizure medication * Current or prior autoimmune or inflammatory diseases, including inflammatory bowel disease, psoriasis, optic neuritis, or any other autoimmune or inflammatory diseases with potentially life-threatening complications * Significant heart, lung, kidney, liver, gastrointestinal, CNS, or psychiatric disease OR illicit substance use or abuse that, in the opinion of the investigator, would interfere with the study * Pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in CD4+ T Lymphocyte Count | Week 32 | Change in CD4 count from baseline to week 32. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma HIV RNA | At Week 32 | change from baseline in HIV-RNA copies/ml (log10) |
| Change in CD4 T Lymphocyte Count | At Month 12 | change from baseline to month 12 in CD4 T lymphocyte count |
| HIV-1 Genotype Changes | after 3rd cycle of IL-2 | Patients who developed mutations associated with antiretroviral drugs. |
| Fasting Lipid Profile | week 32 | total fasting cholesterol |
| Discontinuation of IL-2 | week 32 | Patients receiving fewer than 3 cycles of IL-2 by week 32 |
| Initiation of Continuous ART | from randomization through February 28, 2009 | While patients were not taking ART at baseline or while undergoing IL-2 cycles (other than use of pericycle ART in one of the three groups), some chose to start an ART regimen during the study. |
| Change in HIV-RNA Copies/ml (log10) From Baseline to Month 12 | month 12 | — |
| Thyroid Stimulating Hormone | week 32 | Number of participants with thyroid stimulating hormone greater than the upper limit of normal |
| SGOT | week 32 | Number of participants with aspartate aminotransferase (SGOT) greater than 5 times the upper limit of normal |
| Disease Progression or Death | throughout study, through Feb 28 2009 (median followup of 19 months) | occurrence of an opportunistic event (AIDS-defining infection or malignancy) or death |
Countries
Argentina, Australia, Chile, Italy, Morocco, Poland, Portugal, Spain, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled by HIV care providers between December 2005 and June 2008. When the main study ended in February 2009, patients who consented to a study extension were followed another 2 years, during which study drug was not given.
Participants by arm
| Arm | Count |
|---|---|
| No IL-2 Participants will receive no aldesleukin or HAART | 91 |
| IL-2 Without ART Participants will receive aldesleukin under the skin twice daily for 5 consecutive days every 8 weeks for 3 cycles, then as needed to maintain CD4 counts at or above a goal level. | 89 |
| IL-2 With Pericycle HAART Participants will receive aldesleukin under the skin twice daily for 5 consecutive days every 8 weeks for 3 cycles, then as needed to maintain CD4 counts at or above a goal level; in addition, this group will also take HAART for 3 days prior to the start of each aldesleukin cycle, throughout the 5-day aldesleukin cycle, and for 2 days after the end of each aldesleukin cycle (for a maximum of 10 days with each aldesleukin cycle). | 87 |
| Total | 267 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extended Follow-up | Death | 1 | 0 | 3 |
| Extended Follow-up | Lost to Follow-up | 1 | 3 | 1 |
| Extended Follow-up | Withdrawal by Subject | 0 | 1 | 0 |
| Main Study | Death | 0 | 0 | 2 |
| Main Study | Lost to Follow-up | 8 | 11 | 10 |
| Main Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | No IL-2 | IL-2 Without ART | IL-2 With Pericycle HAART | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 91 Participants | 89 Participants | 85 Participants | 265 Participants |
| Age, Continuous | 37.1 years STANDARD_DEVIATION 7.7 | 37.3 years STANDARD_DEVIATION 9.6 | 37.8 years STANDARD_DEVIATION 11 | 37.4 years STANDARD_DEVIATION 9.5 |
| CD4 cell count | 432 cells/mm^3 | 398 cells/mm^3 | 425 cells/mm^3 | 418 cells/mm^3 |
| Region of Enrollment Argentina | 25 participants | 24 participants | 21 participants | 70 participants |
| Region of Enrollment Australia | 10 participants | 8 participants | 8 participants | 26 participants |
| Region of Enrollment Chile | 2 participants | 5 participants | 4 participants | 11 participants |
| Region of Enrollment Italy | 9 participants | 7 participants | 5 participants | 21 participants |
| Region of Enrollment Morocco | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Poland | 3 participants | 2 participants | 3 participants | 8 participants |
| Region of Enrollment Portugal | 3 participants | 3 participants | 4 participants | 10 participants |
| Region of Enrollment Spain | 1 participants | 1 participants | 1 participants | 3 participants |
| Region of Enrollment Thailand | 21 participants | 21 participants | 22 participants | 64 participants |
| Region of Enrollment United Kingdom | 8 participants | 9 participants | 10 participants | 27 participants |
| Region of Enrollment United States | 8 participants | 9 participants | 9 participants | 26 participants |
| Sex: Female, Male Female | 16 Participants | 17 Participants | 13 Participants | 46 Participants |
| Sex: Female, Male Male | 75 Participants | 72 Participants | 74 Participants | 221 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 87 | 3 / 89 | 3 / 91 |
| serious Total, serious adverse events | 6 / 87 | 6 / 89 | 3 / 91 |
Outcome results
Primary
Mean Change in CD4+ T Lymphocyte Count
Change in CD4 count from baseline to week 32.
Time frame: Week 32
Population: patients for whom the week-32 CD4+ cell count was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| No IL-2 | Mean Change in CD4+ T Lymphocyte Count | -21.8 cell/mm^3 | Standard Deviation 93.1 |
| IL-2 Without ART | Mean Change in CD4+ T Lymphocyte Count | 113.7 cell/mm^3 | Standard Deviation 216.8 |
| IL-2 With Pericycle HAART | Mean Change in CD4+ T Lymphocyte Count | 110.4 cell/mm^3 | Standard Deviation 174.7 |
p-value: <0.00195% CI: [70, 198]ANOVA
p-value: <0.00195% CI: [68, 199]ANOVA
Secondary
Change in CD4 T Lymphocyte Count
change from baseline to month 12 in CD4 T lymphocyte count
Time frame: At Month 12
Population: patients for whom the month 12 CD4 count was available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| No IL-2 | Change in CD4 T Lymphocyte Count | -8.4 cell/mm^3 | Standard Deviation 129.1 |
| IL-2 Without ART | Change in CD4 T Lymphocyte Count | 59.0 cell/mm^3 | Standard Deviation 176 |
| IL-2 With Pericycle HAART | Change in CD4 T Lymphocyte Count | 49.8 cell/mm^3 | Standard Deviation 155.6 |
p-value: 0.009ANOVA
p-value: 0.02ANOVA
Secondary
Change in HIV-RNA Copies/ml (log10) From Baseline to Month 12
Time frame: month 12
Population: patients for whom HIV-RNA measurement was available at baseline and month 12.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| No IL-2 | Change in HIV-RNA Copies/ml (log10) From Baseline to Month 12 | -0.64 copies/ml (log 10) | Standard Deviation 1.24 |
| IL-2 Without ART | Change in HIV-RNA Copies/ml (log10) From Baseline to Month 12 | -0.28 copies/ml (log 10) | Standard Deviation 0.95 |
| IL-2 With Pericycle HAART | Change in HIV-RNA Copies/ml (log10) From Baseline to Month 12 | -0.09 copies/ml (log 10) | Standard Deviation 0.84 |
p-value: 0.0395% CI: [0.03, 0.64]ANOVA
p-value: <0.00195% CI: [0.24, 0.85]ANOVA
Secondary
Discontinuation of IL-2
Patients receiving fewer than 3 cycles of IL-2 by week 32
Time frame: week 32
Population: all patients randomized to a study arm containing IL-2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No IL-2 | Discontinuation of IL-2 | 12 participants |
| IL-2 Without ART | Discontinuation of IL-2 | 32 participants |
Secondary
Disease Progression or Death
occurrence of an opportunistic event (AIDS-defining infection or malignancy) or death
Time frame: throughout study, through Feb 28 2009 (median followup of 19 months)
Population: all randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No IL-2 | Disease Progression or Death | 1 participants |
| IL-2 Without ART | Disease Progression or Death | 5 participants |
| IL-2 With Pericycle HAART | Disease Progression or Death | 7 participants |
p-value: 0.1495% CI: [0.59, 43.6]Regression, Cox
p-value: 0.0895% CI: [0.8, 53.6]Regression, Cox
Secondary
Fasting Lipid Profile
total fasting cholesterol
Time frame: week 32
Population: all patients with laboratory data at week 32 who reported fasting
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| No IL-2 | Fasting Lipid Profile | 173.4 mg/dl | Standard Deviation 33.7 |
| IL-2 Without ART | Fasting Lipid Profile | 167.0 mg/dl | Standard Deviation 32.7 |
| IL-2 With Pericycle HAART | Fasting Lipid Profile | 164.6 mg/dl | Standard Deviation 40.8 |
Secondary
HIV-1 Genotype Changes
Patients who developed mutations associated with antiretroviral drugs.
Time frame: after 3rd cycle of IL-2
Population: Per protocol, the analysis of genotypic changes associated with antiretroviral resistance was restricted patients in one arm, namely, patients assigned to take pericycle HAART who completed 3 cycles of IL-2 and who had successful genotypes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No IL-2 | HIV-1 Genotype Changes | 2 participants |
Secondary
Initiation of Continuous ART
While patients were not taking ART at baseline or while undergoing IL-2 cycles (other than use of pericycle ART in one of the three groups), some chose to start an ART regimen during the study.
Time frame: from randomization through February 28, 2009
Population: all patients randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No IL-2 | Initiation of Continuous ART | 34 participants |
| IL-2 Without ART | Initiation of Continuous ART | 23 participants |
| IL-2 With Pericycle HAART | Initiation of Continuous ART | 14 participants |
p-value: 0.04895% CI: [0.34, 0.99]Regression, Cox
p-value: <0.00195% CI: [0.17, 0.62]Regression, Cox
Secondary
Plasma HIV RNA
change from baseline in HIV-RNA copies/ml (log10)
Time frame: At Week 32
Population: Patients for whom HIV-RNA was available at week 32
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| No IL-2 | Plasma HIV RNA | -.39 copies/ml (log 10) | Standard Deviation 1.03 |
| IL-2 Without ART | Plasma HIV RNA | -.07 copies/ml (log 10) | Standard Deviation 0.8 |
| IL-2 With Pericycle HAART | Plasma HIV RNA | -.01 copies/ml (log 10) | Standard Deviation 0.4 |
p-value: 0.0195% CI: [0.08, 0.54]ANOVA
p-value: 0.00395% CI: [0.12, 0.6]ANOVA
Secondary
SGOT
Number of participants with aspartate aminotransferase (SGOT) greater than 5 times the upper limit of normal
Time frame: week 32
Population: all patients with SGOT measured at week 32
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No IL-2 | SGOT | 1 participants |
| IL-2 Without ART | SGOT | 0 participants |
| IL-2 With Pericycle HAART | SGOT | 0 participants |
Secondary
Thyroid Stimulating Hormone
Number of participants with thyroid stimulating hormone greater than the upper limit of normal
Time frame: week 32
Population: all patients with TSH measured at 32 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No IL-2 | Thyroid Stimulating Hormone | 3 participants |
| IL-2 Without ART | Thyroid Stimulating Hormone | 2 participants |
| IL-2 With Pericycle HAART | Thyroid Stimulating Hormone | 7 participants |
Post Hoc
CD4+ Cell Count 2 Years Post-study
Time frame: two years following close of main study
Population: All patients for whom a CD4 count measurement was available during the extension phase. Because the focus of the extension was on the safety of patients exposed to IL-2, the outcomes were summarized for the two groups exposed to IL-2 vs. the group that did not take IL-2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| No IL-2 | CD4+ Cell Count 2 Years Post-study | 499.9 cell/mm^3 | Standard Deviation 191.4 |
| IL-2 Without ART | CD4+ Cell Count 2 Years Post-study | 557.2 cell/mm^3 | Standard Deviation 225.5 |
p-value: 0.05ANOVA
Post Hoc
Commencement of Continuous Antiretroviral Treatment
Number of patients commencing continuous antiretroviral treatment.
Time frame: from randomization through February 28, 2011, the end of the extension phase
Population: All randomized patients are counted. Patients who did not consent to the extension phase are censored at the end of the main study (Feb 28, 2009). Because the focus of the extension was on the safety of patients exposed to IL-2, the outcomes were summarized for the two groups exposed to IL-2 vs. the group that did not take IL-2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No IL-2 | Commencement of Continuous Antiretroviral Treatment | 108 participants |
| IL-2 Without ART | Commencement of Continuous Antiretroviral Treatment | 66 participants |
p-value: 0.0395% CI: [0.52, 0.97]Regression, Cox
Post Hoc
Opportunistic Disease or Death During the Trial Extension Phase
Incidence of an opportunistic event (AIDS-defining infection or malignancy) or death between February 28, 2009, when the main study ended, and February 28, 2011, when the extended phase was completed.
Time frame: two years following close of main study
Population: All patients who were alive at the end of the main study and who consented to be followed for an additional 2 years in the extension phase. Because the focus of the extension was on the safety of patients exposed to IL-2, the outcomes were summarized for the two groups exposed to IL-2 vs. the group that did not take IL-2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No IL-2 | Opportunistic Disease or Death During the Trial Extension Phase | 8 participants |
| IL-2 Without ART | Opportunistic Disease or Death During the Trial Extension Phase | 3 participants |
p-value: 0.5995% CI: [0.38, 5.45]Regression, Cox
Post Hoc
Undetectable HIV-RNA
Patients with undetectable HIV-RNA levels measured at 24 months after the close of the main study, at the end of the extension phase.
Time frame: 24 months post-trial
Population: All patients for whom an HIV-RNA measurement was available during the extension phase. Because the focus of the extension was on the safety of patients exposed to IL-2, the outcomes were summarized for the two groups exposed to IL-2 vs. the group that did not take IL-2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No IL-2 | Undetectable HIV-RNA | 97 participants |
| IL-2 Without ART | Undetectable HIV-RNA | 60 participants |