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

• New or Recurrent Serious HIV Disease Progression Event Including Death [ Time Frame: from randomization through study end - median of 7.6 years follow-up ] [ Designated as safety issue: Yes ]
  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.
• Number of Participants Who Died From Any Cause [ Time Frame: from randomization through study end - median of 7.6 years follow-up ] [ Designated as safety issue: Yes ]
• Participants With a New Disease Progression Event or Death [ Time Frame: from randomization through 15 November 2008 - median of 7.6 years follow-up ] [ Designated as safety issue: Yes ]
  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
• Absolute CD4 Cell Counts Averaged Throughout Followup [ Time Frame: from randomization through study end - median of 7.6 years follow-up ] [ Designated as safety issue: Yes ]
  Average of all available CD4+ cell counts measured at follow-up visits
• Plasma HIV RNA Levels [ Time Frame: From randomization through study end - median of 7.6 years follow-up ] [ Designated as safety issue: No ]
  log10 HIV-RNA averaged throughout follow-up
• Number of Participants With Changes in Anti-retroviral Treatment (ART) [ Time Frame: From randomization through study end - median of 7.6 years follow-up ] [ Designated as safety issue: No ]
  Number of participants who changed ART at least once during the study period.
• Grade 4 Signs and Symptoms [ Time Frame: From randomization through study end - median of 7.6 years follow-up ] [ Designated as safety issue: Yes ]
  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.
• Pattern of Use of Prophylaxis for Opportunistic Infections [ Time Frame: last followup visit - median of 7.6 years follow-up ] [ Designated as safety issue: No ]
  Number of participants using pneumocystis pneumonia (PCP) prophylaxis at the last attended followup visit.
• Hepatic, Metabolic, and Cardiac Conditions [ Time Frame: From randomization through study end - median of 7.6 years follow-up ] [ Designated as safety issue: Yes ]
  Number of participants experiencing a "serious non-AIDS" event defined as first serious cardiovascular, renal, or hepatic event, or non-AIDS malignancy.

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.

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.

• Experimental: rIL-2
  Recombinant interleukin-2 (rIL-2) therapy used with combination anti-HIV medication of choice.
  Intervention: Drug: Recombinant interleukin-2 (rIL-2)
• No Intervention: No rIL-2
  Control arm uses anti-HIV medication of choice without rIL-2.

• Arduino RC, Nannini EC, Rodriguez-Barradas M, Schrader S, Losso M, Ruxrungtham K, Allende MC, Emery S, Fosdick L, Neaton J, Tavel JA, Davey RT, Lane HC; Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) Vanguard Group; ESPRIT Executive Committee. CD4 cell response to 3 doses of subcutaneous interleukin 2: meta-analysis of 3 Vanguard studies. Clin Infect Dis. 2004 Jul 1;39(1):115-22. Epub 2004 Jun 14.
• INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee; Abrams D, Lévy Y, Losso MH, Babiker A, Collins G, Cooper DA, Darbyshire J, Emery S, Fox L, Gordin F, Lane HC, Lundgren JD, Mitsuyasu R, Neaton JD, Phillips A, Routy JP, Tambussi G, Wentworth D. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009 Oct 15;361(16):1548-59.
• Chun TW, Engel D, Mizell SB, Hallahan CW, Fischette M, Park S, Davey RT Jr, Dybul M, Kovacs JA, Metcalf JA, Mican JM, Berrey MM, Corey L, Lane HC, Fauci AS. Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nat Med. 1999 Jun;5(6):651-5.
• Connors M, Kovacs JA, Krevat S, Gea-Banacloche JC, Sneller MC, Flanigan M, Metcalf JA, Walker RE, Falloon J, Baseler M, Feuerstein I, Masur H, Lane HC. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med. 1997 May;3(5):533-40.
• Emery S, Abrams DI, Cooper DA, Darbyshire JH, Lane HC, Lundgren JD, Neaton JD; ESPRIT Study Group. The evaluation of subcutaneous proleukin (interleukin-2) in a randomized international trial: rationale, design, and methods of ESPRIT. Control Clin Trials. 2002 Apr;23(2):198-220.
• Mocroft A, Neuhaus J, Peters L, Ryom L, Bickel M, Grint D, Koirala J, Szymczak A, Lundgren J, Ross MJ, Wyatt CM; INSIGHT SMART Study Group; ESPRIT Study Group. Hepatitis B and C co-infection are independent predictors of progressive kidney disease in HIV-positive, antiretroviral-treated adults. PLoS One. 2012;7(7):e40245. Epub 2012 Jul 20.
• Pett SL, Carey C, Lin E, Wentworth D, Lazovski J, Miró JM, Gordin F, Angus B, Rodriguez-Barradas M, Rubio R, Tambussi G, Cooper DA, Emery S; INSIGHT-ESPRIT Study Group. Predictors of bacterial pneumonia in Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT). HIV Med. 2011 Apr;12(4):219-27. Epub 2010 Aug 31.

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