An International Study to Evaluate Recombinant Interleukin-2 in HIV Positive Patients Taking Anti-retroviral Therapy

Study Overview
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Brief Summary
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The purpose of this study is to see if it is effective to give HIV positive patients recombinant interleukin-2 (rIL-2) in addition to anti-HIV therapy. Patients will be followed over a minimum of 4 years to study the long-term effects of rIL-2 on their HIV disease progression. Anti-HIV therapy has been very successful in treating HIV positive patients and in keeping viral load (level of HIV in the blood) low. However, anti-HIV drugs cannot completely rid the body of the virus, and the immune system is never completely restored in HIV positive patients. Doctors hope that giving patients recombinant interleukin-2 (rIL-2) in addition to their anti-HIV therapy will help improve their immune systems and keep them healthier over a longer period of time. rIL-2 is a hormone naturally produced by the body during an immune response to a microbial infection.

Detailed Description
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Much progress has been made in implementing potent antiretroviral therapy that is able to maximally suppress viral replication. However, these drug combinations do not result in viral eradication and, for many patients, virologic and immunologic control cannot be maintained. Even among patients with apparent virologic control, a ceiling effect seems to exist with failure of CD4 cell counts to rise on average more than 100 to 150 cells/mm^3, at least during the first 2 years of therapy. The incomplete recovery of immune function after initiation of therapy remains an obstacle in the management of HIV. Preservation of immune function by direct expansion of CD4 lymphocytes with rIL-2 could represent a significant additional treatment strategy. It also has been speculated recently that rIL-2 in combination with potent antiretroviral therapy may be a useful approach for purging HIV from the latently infected CD4 cells. It is hoped that intervention with rIL-2 therapy in combination with antiretroviral therapy at an early stage of HIV infection can prevent CD4 T-cell depletion and result in fewer AIDS-defining illnesses than with antiretroviral therapy alone. Patients are randomized to receive subcutaneous (SC) rIL-2 therapy or no rIL-2 therapy. All patients must be taking a regimen of combination antiretroviral treatment, with the choice of therapy at the discretion of the treating clinician. Antiretroviral medications are not provided by this study. Recombinant IL-2 is given SC for 5 consecutive days every 8 weeks for at least 3 cycles unless toxicities or other contraindications develop. After the first three cycles, additional cycles are given at the discretion of each patient's physician, with a general goal of maintaining the patient's CD4 cell count at twice the baseline level or at 1,000 cells/mm^3 or above for as long as possible. Patients in the no rIL-2 group receive no injections. Patients in both treatment groups are seen every 4 months for follow-up data collection to monitor viral load and CD4 cell counts. All patients are followed for a minimum of 4 years. During the trial, patients in the no SC rIL-2 group are not given rIL-2 at any point. However, at the end of the study, if rIL-2 is found to be effective in reducing the rate of disease progression [AS PER AMENDMENT 12/15/00: (new and recurrent events)], including death, all patients are offered rIL-2.

Official Title
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A Randomized, Open-Label, Phase III, International Study of Subcutaneous Recombinant IL-2 in Patients With HIV-1 Infection and CD4+ Cell Counts 300/mm^3 or Greater: Evaluation of Subcutaneous Proleukin in a Randomized International Trial

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Recombinant interleukin-2 (rIL-2)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV positive Have a CD4 cell count of 300 cells/mm3 or more within 45 days of study entry Are on combination anti-HIV therapy or are beginning anti-HIV therapy at the time of study entry Are at least 18 years old Exclusion Criteria: Have received IL-2 before Have cancer requiring chemotherapy Have evidence of active clinical disease within the past year for any AIDS-defining illness or certain other conditions such as herpes zoster or Chagas disease. (This study has been changed. Previously, patients were ineligible if they had a history of any AIDS-defining illness or certain other conditions.) Have used certain medications, such as corticosteroids or drugs affecting the immune system, in the 45 days before study entry Have a nervous system disorder requiring antiseizure medication Have an autoimmune or inflammatory disease such as inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), psoriasis, optic neuritis, or any autoimmune/inflammatory diseases with potentially life-threatening complications Are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rIL-2<br>Recombinant interleukin-2 (rIL-2) therapy used with combination anti-HIV medication of choice. | Drug: Recombinant interleukin-2 (rIL-2)<br>* Recombinant interleukin-2 at a dose of 7.5 MIU given twice daily subcutaneously for 5 consecutive days every 8 weeks for at least 3 cycles.<br>* Other names: Aldesleukin;|
| No Intervention: No rIL-2<br>Control arm uses anti-HIV medication of choice without rIL-2. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New or Recurrent HIV Disease Progression Event Including Death | Participants who die or experience at least one: any CDC Category C 1993 AIDS-defining events or one of the following: invasive aspergillosis, bartonellosis, Chagas disease, Herpes zoster, visceral Leishmaniasis, Hodgkin's lymphoma, non-Hodgkin's lymphoma (all cell types), microsporidiosis, nocardiosis, disseminated Penicillium marneffii, extrapulmonary Pneumocystis carinii, and Rhodococcus equi disease | from randomization through study end - median of 7.6 years follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New or Recurrent Serious HIV Disease Progression Event Including Death | Patients with at least one: progressive multifocal leukoencephalopathy, lymphoma, visceral Kaposi's sarcoma, AIDS dementia complex, toxoplasmosis, histoplasmosis, cryptococcosis, Mycobacterium avium complex, wasting syndrome, and cytomegalovirus disease. | from randomization through study end - median of 7.6 years follow-up | 
| Number of Participants Who Died From Any Cause |  | from randomization through study end - median of 7.6 years follow-up | 
| Participants With a New Disease Progression Event or Death | Includes first new episode of: CDC Category C 1993 AIDS-defining events plus invasive aspergillosis, bartonellosis, Chagas disease, Herpes zoster, visceral Leishmaniasis, Hodgkin's lymphoma, non-Hodgkin's lymphoma (all cell types), microsporidiosis, nocardiosis, disseminated Penicillium marneffii, extrapulmonary Pneumocystis carinii, and Rhodococcus equi disease | from randomization through 15 November 2008 - median of 7.6 years follow-up | 
| Absolute CD4 Cell Counts Averaged Throughout Followup | Average of all available CD4+ cell counts measured at follow-up visits | from randomization through study end - median of 7.6 years follow-up | 
| Plasma HIV RNA Levels | log10 HIV-RNA averaged throughout follow-up | From randomization through study end - median of 7.6 years follow-up | 
| Number of Participants With Changes in Anti-retroviral Treatment (ART) | Number of participants who changed ART at least once during the study period. | From randomization through study end - median of 7.6 years follow-up | 
| Grade 4 Signs and Symptoms | Participants with at least one grade 4 sign or symptom (except those limited to a laboratory measurement), other than AIDS-defining conditions. Events were graded according to a standardized toxicity table. Events not specifically contained in the toxicity table were considered Grade 4 if they resulted in extreme limitation in activity or required significant medical intervention/therapy, hospitalization or hospice care. Grade 4 events by type are given under the adverse events section. | From randomization through study end - median of 7.6 years follow-up | 
| Pattern of Use of Prophylaxis for Opportunistic Infections | Number of participants using pneumocystis pneumonia (PCP) prophylaxis at the last attended followup visit. | last followup visit - median of 7.6 years follow-up | 
| Hepatic, Metabolic, and Cardiac Conditions | Number of participants experiencing a serious non-AIDS event defined as first serious cardiovascular, renal, or hepatic event, or non-AIDS malignancy. | From randomization through study end - median of 7.6 years follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recombinant Proteins, Injections, Subcutaneous, HIV-1, Interleukin-2, Drug Therapy, Combination, CD4 Lymphocyte Count, Disease Progression, Follow-Up Studies, Anti-HIV Agents