HIV Infection
Conditions
Keywords
HIV, Proleukin, IL-2, Adult, HAART, Treatment Experienced
Brief summary
This study will examine whether interleukin-2 (IL-2) plus antiretroviral therapy (ART) slows HIV disease progression in patients with low CD4+ T cell counts compared with patients taking ART alone. CD4+ T cells are a subset of lymphocytes-white blood cells that are part of the body's immune system. IL-2 is a protein that is naturally produced by lymphocytes. Given in intermittent cycles, IL-2 can raise CD4+ T cell counts in some HIV-infected patients taking antiretroviral drugs. This study will examine whether the increase in CD4+ T cells lowers the risk of AIDS-related illnesses and death. HIV-infected patients 18 years of age and older with a viral load under 10,000 copies per milliliter and a CD4+ T cell count between 50 and 299 cells per cubic millimeter who are taking antiretroviral therapy and who have not previously received IL-2 therapy may be eligible for this study. Candidates will be screened with a medical history, physical examination, and blood and urine tests. Participation in the study will be from 4.5 to 6 years, depending on what point in the duration of the study the individual patient is enrolled. Patients will be randomly assigned to receive IL-2 plus ART or ART alone. All participants will be advised individually about the best ART regimen for them. Patients in the IL-2 treatment group will be taught how to self-inject IL-2 under the skin (similar to insulin injections). They will inject IL-2 twice a day for 5 days every 8 weeks for the first year (until week 49 of the study). From week 49 on they may receive 5-day cycles of IL-2 every 4 months when needed to maintain CD4+ T cell count elevations. An extra cycle may be given 2 months after the week 49 follow-up visit (see follow-up schedule below), depending on their CD4+ T cell count. Patients whose cell counts have not increased after 12 to 16 months of IL-2 treatment will discuss with the doctor the possibility of stopping IL-2. Those who do stop IL-2 treatment will be asked to remain in the study for follow-up evaluations. All patients will be followed in the clinic every 2 months for the first year of the study (weeks 1, 9, 17, 25, 33, 41 and 49) and every 4 months during years 2-6 for a brief history and physical exam, urine and blood tests, return of diary cards (record of drug side effects) and medication review. During the visits from the second year on, patients will also be asked about their ability to do certain ordinary tasks, such as taking care of themselves; ...
Detailed description
The purpose of this study is to compare the clinical results of individuals living with advanced HIV infection who are treated with interleukin-2 (IL-2) plus active antiretroviral therapy (ART) to a control group of individuals treated with stable ART alone. The primary objective of the study is to determine if intermittent cycles of IL-2 delay the occurrence of opportunistic infections and the progression of advanced HIV disease compared to ART alone. Patients will be assigned randomly to 1 of 2 groups. Patients in Group 1 will receive subcutaneous IL-2 twice a day for 5 days, every 8 weeks, in addition to ART. Patients in Group 2 will receive ART only. In both groups, CD4+ T cell counts and viral load are monitored.
Interventions
DRUGProleukin
Recombinant IL-2 was given at a dose of 4.5 MIU twice daily subcutaneously for 5 consecutive days every 8 weeks, in addition to antiretroviral therapy, for 6 cycles. After the first 6 cycles, additional cycles were given to either achieve or maintain the patient's CD4+ cell count goal.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
University of Minnesota
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
* INCLUSION CRITERIA: Subjects are eligible for this study if they have been on greater than or equal to 2 ART for greater than or equal to 4 months prior to randomization, with no change in the type of ART received during this 4-month period of time. For subjects who receive only 2 ART, at least one of these two medications should be a protease inhibitor (PI). Subjects are not eligible if ART is discontinued for a cumulative period of 7 or more days during the 4 months prior to randomization. Subjects with documented HIV-1 infection. Acceptable documentation consists of either of the following: Positive HIV-1 ELISA test and Western Blot; Detectable plasma viral load measurement (greater than 500 RNA copies/mL using an ultrasensitive bDNA or PCR test or greater than 1500 RNA copies/mL using a non-ultrasensitive bDNA or PCR test). CD4+ T cell counts: mean of 2 points obtained within 4 calendar months of randomization greater than or equal to 50 and less than 300 cells/mm(3). The first CD4+ count should be the most recent documented historical value and should be greater than or equal to 50 and less than 300 cells/mm(3); the second point should be pre-study visit 1. Viral load less than 10,000 copies/mL, at 2 time points within 4 calendar months of randomization. The first viral load should be the most recent documented historical value and should be less than 10,000 copies/mL; the second time point should be pre-study visit 1. Karnofsky performance status greater than or equal to 80%. Age greater than or equal to 18 years old. Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to randomization. They must also understand that if they are randomized to the IL-2 group, they must practice effective contraception during their first 2 years of study participation. Pregnancy is discouraged among IL-2 recipients, but if an IL-2 recipient wishes to become pregnant after two years of trial participation she must alert the investigator prior to interruption of contraception. The potential for risk to the fetus must be carefully discussed with the subject before contraception is interrupted. Effective contraception will be continued for at least 24 hours following the interruption of IL-2 therapy. IL-2 will be held throughout the period of time during which the subject is not practicing effective birth control, throughout the pregnancy, and throughout any period of breast feeding. If oral contraceptive therapy is resumed after a period of interruption, IL-2 dosing will be delayed for 1 month following the reinstatement of oral contraceptive therapy. The subject must have a negative pregnancy test result prior to dosing with IL-2 after a lapse in effective contraception. The following laboratory criteria must be fulfilled within 28 days of enrollment in the study: Serum AST of less than or equal to 5 times upper limit of normal range (ULN); Serum bilirubin less than or equal 2 times ULN (patients with Gilbert's syndrome or protease inhibitor-induced hyperbilirubinemia must have a serum bilirubin less than or equal to five times ULN); Amylase less than 2.0 times ULN (hyperamylasemia that is determined to be non-pancreatic in origin does not necessarily constitute an exclusion to enrollment); Less than 2 + proteinuria; Serum creatinine less than or equal to 1.5 times ULN; Absolute neutrophil count greater than or equal to 1000 cells/mm(3); Hemoglobin of greater than or equal to 9.5 g/dL; Platelet count of greater than or equal to 75,000/mm(3); Negative HTLV-1 result. Agree to participate in the study for 4.5 to 7.5 years. Written informed consent.
Exclusion criteria
Certain AIDS-defining illnesses. These conditions include: Patients with no prior history of AIDS-defining events are eligible for SILCAAT; Patients with a prior medical history of one or more of the following AIDS-defining events are eligible only under the condition specified below: Lymphoma (other than lymphoma of the brain): Patients with a history of successfully treated lymphoma are eligible, provided full remission was obtained at least 5 years prior to randomization. Full remission (or complete response) is defined as the absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, and bone marrow examination. Patients with bone marrow positive lymphoma prior to chemotherapy must have had two repeat bone marrow examinations negative for lymphoma after chemotherapy at least 12 months prior to randomization. Esophageal candidiasis; Patients with a prior history of successfully treated esophageal candidiasis are eligible if they have been free of clinical symptoms in the absence of antifungal suppressive therapy for at least 12 months prior to randomization. Documentation of a negative endoscopy should ideally be on record. Invasive cervical cancer: Patients with a prior history of invasive cervical cancer are eligible if complete local cure of the cancer has been documented at least 5 years prior to randomization and there has been no evidence of metastatic disease at any time. Kaposi's sarcoma: Patients are eligible if mucocutaneous lesions have been resolved or clinically stable for at least 12 months prior to randomization. Subjects with a history of visceral KS are excluded. Mycobacterium tuberculosis or M. kansasii: Patients are eligible if clinical resolution of disease occurred at least 12 months prior to randomization and previously abnormal imaging studies have been normal, or stable after improvement, for at least 12 months prior to randomization. Documentation of microbiologic cure should ideally be on record. Therapy for tuberculosis or M. kansasii must have been completed at least 12 months prior to randomization. Pneumocystis carinii pneumonia (PCP): Patients are eligible if clinical resolution of the disease occurred at least 12 months prior to randomization and previously abnormal imaging studies have been normal, or stable after improvement, for at least 12 months prior to randomization. Recurrent pneumonia: Patients are eligible if there has been no evidence of pneumonia within 12 months prior to randomization. Recurrent Salmonella septicemia: Patients are eligible if there has been no evidence of Salmonella septicemia within 12 months prior to randomization. Wasting syndrome due to HIV: Patients are eligible for enrollment in SILCAAT if they have had a stable or increasing weight for at least 12 months prior to randomization. Toxoplasmosis of the brain: Patients are eligible if their disease has been clinically resolved for at least 12 months prior to randomization. In addition, these patients must have a MRI or contrast CT scan of the brain performed within 1 month prior to randomization showing no sign of active disease. Chronic intestinal cryptosporidiosis and chronic intestinal isosporiasis (greater than 1 month duration): Patients are eligible if their disease has been clinically resolved and they have been off specific therapy for at least 12 months prior to randomization. In addition, these patients must have at least one stool specimen documenting clearance of parasitic infection obtained within 1 month prior to randomization. Patients with a history of any other AIDS-defining conditions as listed in the CDC 1993 Case Definition are not eligible for SILCAAT. Subjects must not have clinically significant cardiac, pulmonary, thyroid, kidney or neurologic impairment, hemostasis disorder, or significant medical condition that would, in the opinion of the principal investigator, affect patient safety and/or compliance. In addition, subjects with the following conditions are specifically excluded: autoimmune disease, inflammatory bowel disease, psoriasis, optic neuritis, congestive heart failure, active ischemic heart disease, uncontrolled diabetes mellitus, moderate or severe hemophilia ( less than or equal to 5% of normal factor VIII levels), seizure disorder, uncontrolled hypothyroidism, cirrhosis and a prior medical history of transplantation. If an investigator has any reservations about the safety of enrolling a particular subject, he/she should consult with the medical monitor prior to screening the subject. Psychiatric or cognitive disturbance or illness, or recreational drug/alcohol use that, in the opinion of the principal investigator, would affect patient safety and/or compliance. Malignancy requiring systemic chemotherapy within 12 months prior to randomization. Current use or use within 4 weeks prior to randomization of systemic corticosteroid therapy or any agent, licensed or experimental, with known immunomodulatory effects (use of erythropoietin and anabolic steroids is allowed). Current use, or use within 4 weeks of randomization of cytotoxic agents or antimetabolites; current use or use within 4 months of randomization of hydroxyurea or intravenous immunoglobulin. Pregnant or lactating subjects. Prior therapy with IL-2. Prior participation in an ongoing IL-2 trial, eg, the ESPRIT trial. Protocol non-compliance in a previous IL-2 trial. Subjects with evidence of active acute infection within 2 weeks of randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| New or Recurrent Disease Progression Events, as Defined, or Death. | From randomization to date last known to be alive or November 15, 2008, whichever is earlier | Number of participants with fatal or non-fatal AIDS-related opportunistic disease or death from any cause. AIDS-related opportunistic disease includes CDC Category C 1993 definition plus the following diseases: Aspergillosis, invasive; Bartonellosis; Chagas disease of the CNS; Herpes zoster, multidermal; Leishmaniasis, visceral; Lymphoma, Hodgkin's; Microsporidiosis (\> 1 month's duration); Nocardiosis; Penicillium marneffti, disseminated; Pneumocystis carinii, extrapulmonary; Rhodococcus equi disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality | From randomization to date last known to be alive or November 15, 2008, whichever is earlier | Number of participants who died. |
| New or Recurrent Disease Progression Events | From randomization to date last known to be alive or November 15, 2008, whichever is earlier | Number of participants with fatal or non-fatal AIDS-related opportunistic disease. AIDS-related opportunistic disease includes CDC Category C 1993 definition plus the following diseases: Aspergillosis, invasive; Bartonellosis; Chagas disease of the CNS; Herpes zoster, multidermal; Leishmaniasis, visceral; Lymphoma, Hodgkin's; Microsporidiosis (\> 1 month's duration); Nocardiosis; Penicillium marneffti, disseminated; Pneumocystis carinii, extrapulmonary; Rhodococcus equi disease. |
| Grade 4 Clinical Events | From randomization to date last known to be alive or November 15, 2008, whichever is earlier | Grade 4 clinical events were defined as potentially life-threatening events (excluding opportunistic disease) requiring medical intervention. |
| CD4+ Cell Count | Every 4 months from randomization through date last known to be alive or November 15, 2008, whichever was earliest . | Mean CD4+ cell count (cells per cubic mm) averaged over follow-up |
| New or Recurrent Serious Disease Progression Events or Death | From randomization to date last known to be alive or November 15, 2008, whichever is earlier | Number of participants with fatal or non-fatal serious AIDS-related opportunistic disease. A serious disease progression event is one of the following: progressive multifocal leukoencephalopathy (PML), lymphoma, Kaposi's sarcoma (visceral), AIDS dementia complex (ADC) stage II or higher, toxoplasmosis, histoplasmosis (systemic), cryptococcosis (systemic), disseminated Mycobacterium avium complex (MAC) disease, wasting syndrome, and cytomegalovirus (CMV) disease. |
Countries
United States
Participant flow
Recruitment details
1971 participants were randomized at 139 sites in 11 countries. The first randomization was on 30 April 1999 and the last randomization was on 28 September 2002. Sites who re-consented 2/3 or more of their participants to Version 3 of the protocol were included in the analysis cohort. There are 1695 participants in the analysis cohort.
Participants by arm
| Arm | Count |
|---|---|
| Proleukin Plus Antiretroviral Therapy | 849 |
| Antiretroviral Therapy Only | 846 |
| Total | 1,695 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 91 | 100 |
Baseline characteristics
| Characteristic | Proleukin Plus Antiretroviral Therapy | Antiretroviral Therapy Only | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 8 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 841 Participants | 838 Participants | 1679 Participants |
| Age Continuous | 41.8 years STANDARD_DEVIATION 8.7 | 42.0 years STANDARD_DEVIATION 8.8 | 41.9 years STANDARD_DEVIATION 8.7 |
| Region of Enrollment Argentina | 85 participants | 85 participants | 170 participants |
| Region of Enrollment Australia | 62 participants | 64 participants | 126 participants |
| Region of Enrollment Belgium | 16 participants | 13 participants | 29 participants |
| Region of Enrollment Brazil | 37 participants | 38 participants | 75 participants |
| Region of Enrollment Canada | 68 participants | 62 participants | 130 participants |
| Region of Enrollment France | 47 participants | 50 participants | 97 participants |
| Region of Enrollment Germany | 50 participants | 46 participants | 96 participants |
| Region of Enrollment Italy | 131 participants | 142 participants | 273 participants |
| Region of Enrollment Netherlands | 11 participants | 12 participants | 23 participants |
| Region of Enrollment Spain | 139 participants | 131 participants | 270 participants |
| Region of Enrollment United States | 203 participants | 203 participants | 406 participants |
| Sex: Female, Male Female | 137 Participants | 143 Participants | 280 Participants |
| Sex: Female, Male Male | 712 Participants | 703 Participants | 1415 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 203 / 849 | 186 / 846 |
Outcome results
Primary
New or Recurrent Disease Progression Events, as Defined, or Death.
Number of participants with fatal or non-fatal AIDS-related opportunistic disease or death from any cause. AIDS-related opportunistic disease includes CDC Category C 1993 definition plus the following diseases: Aspergillosis, invasive; Bartonellosis; Chagas disease of the CNS; Herpes zoster, multidermal; Leishmaniasis, visceral; Lymphoma, Hodgkin's; Microsporidiosis (\> 1 month's duration); Nocardiosis; Penicillium marneffti, disseminated; Pneumocystis carinii, extrapulmonary; Rhodococcus equi disease.
Time frame: From randomization to date last known to be alive or November 15, 2008, whichever is earlier
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Proleukin Plus Antiretroviral Therapy | New or Recurrent Disease Progression Events, as Defined, or Death. | 110 Participants |
| Antiretroviral Therapy Only | New or Recurrent Disease Progression Events, as Defined, or Death. | 119 Participants |
Comparison: Null hypothesis was that event rates in two groups are equal. Study was designed with 80%, two-sided alpha=.05, assuming a 28% reduction in the hazard of opportunistic disease or death.p-value: 0.4795% CI: [0.7, 1.18]Regression, Cox
Secondary
All-cause Mortality
Number of participants who died.
Time frame: From randomization to date last known to be alive or November 15, 2008, whichever is earlier
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Proleukin Plus Antiretroviral Therapy | All-cause Mortality | 81 Participants |
| Antiretroviral Therapy Only | All-cause Mortality | 77 Participants |
p-value: 0.7395% CI: [0.77, 1.44]Regression, Cox
Secondary
CD4+ Cell Count
Mean CD4+ cell count (cells per cubic mm) averaged over follow-up
Time frame: Every 4 months from randomization through date last known to be alive or November 15, 2008, whichever was earliest .
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Proleukin Plus Antiretroviral Therapy | CD4+ Cell Count | 345.1 cells per cubic mm | Standard Error 5.1 |
| Antiretroviral Therapy Only | CD4+ Cell Count | 292.1 cells per cubic mm | Standard Error 4.1 |
p-value: <0.00195% CI: [40.3, 65.7]Mixed Models Analysis
Secondary
Grade 4 Clinical Events
Grade 4 clinical events were defined as potentially life-threatening events (excluding opportunistic disease) requiring medical intervention.
Time frame: From randomization to date last known to be alive or November 15, 2008, whichever is earlier
Population: The outcome is the number of participants experiencing at least one grade 4 event.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Proleukin Plus Antiretroviral Therapy | Grade 4 Clinical Events | 203 Participants |
| Antiretroviral Therapy Only | Grade 4 Clinical Events | 186 Participants |
p-value: 0.3595% CI: [0.9, 1.34]Regression, Cox
Secondary
New or Recurrent Disease Progression Events
Number of participants with fatal or non-fatal AIDS-related opportunistic disease. AIDS-related opportunistic disease includes CDC Category C 1993 definition plus the following diseases: Aspergillosis, invasive; Bartonellosis; Chagas disease of the CNS; Herpes zoster, multidermal; Leishmaniasis, visceral; Lymphoma, Hodgkin's; Microsporidiosis (\> 1 month's duration); Nocardiosis; Penicillium marneffti, disseminated; Pneumocystis carinii, extrapulmonary; Rhodococcus equi disease.
Time frame: From randomization to date last known to be alive or November 15, 2008, whichever is earlier
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Proleukin Plus Antiretroviral Therapy | New or Recurrent Disease Progression Events | 49 Participants |
| Antiretroviral Therapy Only | New or Recurrent Disease Progression Events | 66 Participants |
p-value: 0.195% CI: [0.51, 1.06]Regression, Cox
Secondary
New or Recurrent Serious Disease Progression Events or Death
Number of participants with fatal or non-fatal serious AIDS-related opportunistic disease. A serious disease progression event is one of the following: progressive multifocal leukoencephalopathy (PML), lymphoma, Kaposi's sarcoma (visceral), AIDS dementia complex (ADC) stage II or higher, toxoplasmosis, histoplasmosis (systemic), cryptococcosis (systemic), disseminated Mycobacterium avium complex (MAC) disease, wasting syndrome, and cytomegalovirus (CMV) disease.
Time frame: From randomization to date last known to be alive or November 15, 2008, whichever is earlier
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Proleukin Plus Antiretroviral Therapy | New or Recurrent Serious Disease Progression Events or Death | 19 Participants |
| Antiretroviral Therapy Only | New or Recurrent Serious Disease Progression Events or Death | 28 Participants |