Mechanism of Action: Immune modulator. Aldesleukin (recombinant IL-2; rIL-2) is a non-glycosylated interleukin-2 (IL-2) product. It is made via recombinant DNA technology that uses an E. coli strain containing an analog of the human IL-2 gene. The biological activity of aldesleukin is similar to that of endogenous IL-2. Aldesleukin is currently FDA-approved for treating metastatic renal cell carcinoma and melanoma.3 In HIV-related clinical trials, aldesleukin is the most commonly studied IL-2 product.6
IL-2 is a type I cytokine belonging to a subfamily of cytokines that uses the common γ-chain receptor. Physiologically, IL-2 is produced in secondary lymphoid organs, primarily by CD4 cells, following activation by antigen. Once bound to the IL-2 receptor, IL-2 can activate multiple signaling pathways, including the JAK-STAT, PI3K–AKT, and MAPK pathways.2,7-9
IL-2 is a T cell growth factor that promotes T cell proliferation and survival. It stimulates the cytotoxic activity of CD8 and natural killer (NK) cells and modulates the differentiation of T cells in response to antigen. In addition, IL-2 induces the production and proliferation of antibodies by B cells, stimulates the development of regulatory T cells (Treg), and is essential for activation-induced cell death. During HIV infection, the progressive loss of CD4 cells leads to reduced IL-2 levels in the body, which is an early indicator of T cell exhaustion.2,9-11
In clinical trials, aldesleukin has been extensively studied for its potential to aid in immune restoration by increasing CD4 counts in different populations of individuals with HIV infection.12-15 In two Phase III trials, intermittent aldesleukin plus ART was shown to increase CD4 counts in individuals with HIV; however, the aldesleukin-mediated increases in CD4 counts ultimately did not translate into any clinical benefits in either study.4,5,12 Aldesleukin has also been explored for its ability to boost HIV-1 specific immune responses and as part of a strategy to reduce the latent HIV reservoir. Additionally, aldesleukin has been studied as an adjuvant to therapeutic HIV vaccination and CD4-zeta gene-modified T cell therapy.16-22
Half-life (T½): The elimination half-life of aldesleukin, as derived from studies in individuals with cancer who received a 5-minute intravenous (IV) infusion, was 85 minutes.3
The pharmacokinetic properties of aldesleukin have also been assessed in individuals with HIV. In a dose-escalating study of aldesleukin (12, 15, or 18 million IU per day) administered by subcutaneous (SC) injection once or twice daily for 5 consecutive days every 2 months, the elimination half-life of aldesleukin was 3.3 +/- 0.9 hours.23
Metabolism/Elimination: Following IV infusion, aldesleukin is eliminated by metabolism in the kidneys, with the majority metabolized to amino acids in cells lining the proximal convoluted tubules.3
Select Clinical Trials
Study Identifier: NCT03308786
Case Western Reserve University
This study is not yet open for participant recruitment.
The purpose of this open-label pilot study is to evaluate whether aldesleukin can decrease the number of latently infected CD4 cells and reduce the size of the latent HIV reservoir in individuals with HIV.
- Participants are adults with HIV who have had undetectable viral load levels while on ART for at least 1 year.
- Participants are receiving a stable ART regimen and are willing to continue on their current regimen for the entire study.
- Participants have HIV RNA <50 copies/mL measured within 60 days prior to study entry and have CD4 counts ≥350 cells/mm3.24
: ANRS118; ILIADE; NCT00071890
: National Institute of Allergy and Infectious Diseases (NIAID)
: This study has been completed.
: The purpose of this open-label study was to examine whether aldesleukin, administered prior to a treatment interruption (TI) of ART, could extend the duration of the TI and help preserve CD4 counts above 350 cells/mm3
Selected Study Results:
- Participants were treatment-experienced adults with HIV who were asymptomatic and receiving ART for at least 12 months.
- Participants had HIV RNA <50 copies/mL and CD4 counts ≥500 cells/mm3 for the 3 months before screening. Nadir CD4 counts since diagnosis of HIV infection were ≥200 cells/mm3.25
Study Identifiers: (1) ESPRIT; NCT00004978 and (2) SILCAAT; NCT00013611
Sponsor: (1) National Institute of Allergy and Infectious Diseases (NIAID) and (2) University of Minnesota - Clinical and Translational Science Institute
Status: Both studies have been completed.
Study Purpose: The purpose of these open-label studies was to evaluate whether intermittent aldesleukin plus ART could lower the risk of opportunistic infection and death in individuals with HIV.
Selected Study Results:
- ESPRIT: Participants were adults with HIV who had CD4 counts ≥300 cells/mm3 within 45 days of study entry. Participants were receiving ART or were beginning ART at the time of study entry.
- SILCAAT: Participants were adults with HIV who had HIV RNA <10,000 copies/mL and CD4 counts between 50 and 299 cells/mm3. Participants were receiving ART for at least 4 months prior to study entry.4,5,12
Numerous other HIV-related studies involving aldesleukin are in progress or have been completed. These include (1) the STALWART study (NCT00110812), which evaluated the effects of aldesleukin with/without ART on CD4 counts in participants who were either ART-naive or off ART, (2) ANRS 119 (NCT00120185), which evaluated whether aldesleukin without ART could increase CD4 counts and defer initiation of ART in participants who were either ART-naive or off ART, and (3) the COSMIC trial, which assessed the effects of aldesleukin with/without ART on latent HIV.13,14,17,26,27 A Phase I/II study (NCT01013415) evaluating ART plus autologous CD4-zeta gene-modified T cells with/without aldesleukin is ongoing.21 Similarly, a Phase II study (NCT03346499) is evaluating the safety and tolerability of IL-2 as an adjuvant to activate NK cells, and its ability to boost the activity of the transferred NK cells.28
ANRS 118 (NCT00071890):
In this Phase II/III study, 148 total participants were randomized to either aldesleukin plus ART (n = 81) or ART alone (n = 67). During the first 24 weeks of the trial, numerous aldesleukin-related adverse events (AEs) occurred; however, most were Grade 1 to 2 in severity. The most common AEs, which accounted for 50% of all AEs, were constitutional symptoms, such as asthenia, fever, and nausea. Eleven of 17 participants who discontinued aldesleukin reported aldesleukin-related AEs as the main reason for discontinuing treatment. Severe AEs occurred in seven participants in the aldesleukin group and in three participants in the ART-alone group. Grade 3 or 4 laboratory abnormalities occurred in 11 (14%) aldesleukin participants and 16 (24%) ART-alone participants. One participant in the aldesleukin group and three participants in the ART-alone group experienced an AIDS-defining event. Six cardiovascular events occurred in four participants after Week 24, one of which occurred in the aldesleukin group.25,28
In this Phase III trial, 4,111 total participants were enrolled to receive either aldesleukin plus ART (n = 2,071) or ART alone (n = 2,040). Grade 4 events occurred in 466 participants receiving aldesleukin and in 383 participants receiving ART alone. Among the 466 participants in the aldesleukin group who experienced a Grade 4 event, a total of 711 Grade 4 events occurred (with 82.4% occurring more than 60 days after the last aldesleukin dose). Vascular disorders and AEs within the category of “general disorders and administration site conditions” were more common in the aldesleukin group than in the ART-alone group. The most frequent type of vascular event was deep-vein thrombosis, which was experienced by 10 participants in the aldesleukin group and by two participants in the ART-alone group.4,12
In this Phase III trial, 1,695 total participants were enrolled to receive either aldesleukin plus ART (n = 849) or ART alone (n = 846). A Grade 4 event occurred in 203 participants receiving aldesleukin and in 186 participants receiving ART alone. Among the 203 participants in the aldesleukin group who experienced a Grade 4 event, a total of 342 Grade 4 events occurred (with 78.4% occurring more than 60 days after the last aldesleukin dose). Gastrointestinal and psychiatric disorders were more common in the aldesleukin group than in the ART-alone group.5,12
Additional AEs known to be associated with aldesleukin are described in the FDA-approved Full Prescribing Information for Proleukin
A pharmacokinetic interaction study between indinavir (800 mg every 8 hours) and a 5-day continuous infusion of aldesleukin was conducted in individuals with HIV infection. Between Days 1 and 5 of the aldesleukin infusion, the indinavir area under the curve (AUC) increased by a mean of 88% in eight out of nine participants. Indinavir clearance significantly decreased, while indinavir trough concentrations significantly increased. Changes in indinavir drug concentrations during aldesleukin infusions were possibly related to induction of IL-6.29
Additional known interactions between aldesleukin and coadministered drugs are described in the FDA-approved Full Prescribing Information for Proleukin.
- United States National Library of Medicine. ChemIDplus advanced: Aldesleukin. https://chem.nlm.nih.gov/chemidplus/rn/110942-02-4. Accessed December 31, 2018
- Gougeon M, Chiodi F. Impact of γ-chain cytokines on T cell homeostasis in HIV-1 infection: therapeutic implications. J Intern Med. 2010;(267):502-514.
- Prometheus Laboratories Inc. Proleukin: full prescribing information. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4e2b687e-47f2-4f3c-80ab-e3224befffca. Published December 31, 2014. Accessed December 31, 2018
- National Institute of Allergy and Infectious Diseases (NIAID). 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. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 10, 2000. NLM Identifier: NCT00004978. https://clinicaltrials.gov/ct2/show/NCT00004978. Accessed December 31, 2018
- University of Minnesota - Clinical and Translational Science Institute. A Phase III multicenter randomized study of the biological and clinical efficacy of subcutaneous recombinant, human interleukin-2 in HIV-infected patients with low CD4+ counts under active antiretroviral therapy (SILCAAT Amendment 4). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 24, 2001. NLM Identifier: NCT00013611. https://clinicaltrials.gov/ct2/show/NCT00013611. Accessed December 31, 2018
- Paredes R, López Benaldo de Quirós J, Fernández-Cruz E, Clotet B, Lane H. The potential role of interleukin-2 in patients with HIV infection. AIDS Rev. 2002;4(1):36-40.
- Yamane H, Paul WE. Cytokines of the γc family control CD4+ T cell differentiation and function. Nat Immunol. 2012;13(11):1037-1044.
- Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180-190.
- Liao W, Lin J-X, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38(1):13-25.
- Zhang Y, Yin Y, Zhang S, Luo H, Zhang H. HIV-1 infection-induced suppression of the let-7i/IL-2 axis contributes to CD4(+) T cell death. Sci Rep. 2016;6:25341.
- Kedzierska K, Crowe SM. Cytokines and HIV-1: interactions and clinical implications. Antivir Chem Chemother. 2001;12(3):133-150.
- Abrams D, Lévy Y, Losso M, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361(16):1548-1559.
- Tavel JA. Effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy in early HIV infection: The STALWART study. PLoS ONE. 2010;5(2):e9334.
- Molina J-M, Levy Y, Fournier I, et al. Interleukin-2 before antiretroviral therapy in patients with HIV infection: a randomized trial (ANRS 119). J Infect Dis. 2009;200(2):206–215.
- Viard J-P, Fagard C, Chaix M-L, et al. Immunological success is predicted by enfuvirtide but not interleukin-2 therapy in immunodepressed patients. AIDS. 2009;23(11):1383-1388.
- Sued O, Ambrosioni J, Nicolás D, et al. Structured treatment interruptions and low doses of IL-2 in patients with primary HIV infection. inflammatory, virological and immunological outcomes. PLoS ONE. 2015;10(7):e0131651.
- Stellbrink H-J, van Lunzen J, Westby M, et al. Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). AIDS. 2002;16(11):1479-1487.
- Chun TW, Engel D, Mizell SB, et al. 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;5(6):651-655.
- Kilby JM, Bucy RP, Mildvan D, et al. A randomized, partially blinded Phase 2 trial of antiretroviral therapy, HIV-specific immunizations, and interleukin-2 cycles to promote efficient control of viral replication (ACTG A5024). J Infect Dis. 2006;194(12):1672-1676.
- Mitsuyasu RT, Anton PA, Deeks SG, et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood. 2000;96(3):785-793.
- University of Pennsylvania. A Phase I/II study of the safety, survival, and trafficking of autologous CD4-ZETA gene-modified T cells with and without extension interleukin-2 in HIV infected patients. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 5, 2009. NLM Identifier: NCT01013415. https://clinicaltrials.gov/ct2/show/NCT01013415. Accessed December 31, 2018
- University of Minnesota - Clinical and Translational Science Institute. Adoptive transfer of haploidentical natural killer cells and IL-2 in human immunodeficiency virus (HIV). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 24, 2017. NLM Identifier: NCT03346499. https://www.clinicaltrials.gov/ct2/show/record/NCT03346499. Accessed December 31, 2018
- Piscitelli SC, Wells MJ, Metcalf JA, Baseler M, Stevens R, Davey RT. Pharmacokinetics and pharmacodynamics of subcutaneous interleukin-2 in HIV-infected patients. Pharmacotherapy. 1996;16(5):754-759.
- Case Western Reserve University. HIV reservoir reduction with interleukin-2. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 29, 2017. NLM Identifier: NCT03308786. https://clinicaltrials.gov/ct2/show/NCT03308786. Accessed December 31, 2018
- National Institute of Allergy and Infectious Diseases (NIAID). Phase II/III study evaluating the effect of IL-2 on preservation of the CD4 T-lymphocytes after interruption of anti-retroviral tx in HIV infected patients with CD4 T-lymphocyte count greater than 500 cells/mm(3) who have received anti-retroviral tx. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 3, 2003. NLM Identifier: NCT00071890. https://clinicaltrials.gov/ct2/show/NCT00071890. Accessed December 31, 2018
- National Institute of Allergy and Infectious Diseases (NIAID). STALWART: a randomized, open-label, international study of subcutaneous recombinant interleukin-2 with and without concomitant antiretroviral therapy in patients with HIV-1 infection and CD4+ cell counts of 300 cells/mm3 or more. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 13, 2005. NLM Identifier: NCT00110812. https://clinicaltrials.gov/ct2/show/NCT00110812. Accessed December 31, 2018
- French National Agency for Research on AIDS and Viral Hepatitis. Study of the immunological efficacy of using subcutaneous interleukin-2 (IL-2) in antiretroviral naive HIV-1-infected subjects with a CD4 cell count above 300/mm3. ANRS 119 Trial INTERSTART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 8, 2005. NLM Identifier: NCT00120185. https://clinicaltrials.gov/ct2/show/NCT00120185. Accessed December 31, 2018
- Lévy Y, Thiébaut R, Gougeon M-L, et al. Effect of intermittent interleukin-2 therapy on CD4+ T-cell counts following antiretroviral cessation in patients with HIV. AIDS. 2012;26(6):711.
- Piscitelli SC, Vogel S, Figg WD, et al. Alteration in indinavir clearance during interleukin-2 infusions in patients infected with the human immunodeficiency virus. Pharmacotherapy. 1998;18(6):1212-1216.
Last Reviewed: December 31, 2018