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A Risk-Benefit Assessment of Interleukin-2 as an Adjunct to Antiviral Therapy in HIV Infection

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Abstract

Immunomodulation has become a major focus of HIV research in an effort to augment, boost or restore the patient’s damaged immune system. Recombinant interleukin-2 is currently being studied in phase II/III trials in HIV-infected patients. Several clinical studies have demonstrated that intermittent regimens are associated with marked rises in CD4+ cell counts without an increase in viral load. Most of these studies employ 5 consecutive days of interleukin-2 therapy by continuous intravenous infusion or subcutaneous injection, repeated every 8 weeks. An alternative strategy is the daily administration of low doses of interleukin-2, but clinical experience with this regimen is limited.

Interleukin-2 administration can adversely affect virtually every organ system, requiring aggressive supportive care. A variety of administration strategies and interventions are being evaluated to minimise toxicity.

Currently, no clinical end-point data are available for interleukin-2 in HIV-infected patients. Until phase III studies are completed, interleukin-2 can be used in the research setting as an immunomodulator and adjunct to antiretroviral therapy. Its potential to activate latently infected cells and promote HIV eradication from reservoir sites is also an important area for further study. If clinical benefit can be demonstrated, interleukin-2 could be useful as an adjunct to antiretroviral therapy if adverse effects can beminimised and therapy can be given infrequently on an outpatient basis.

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References

  1. Palella Jr FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med 1998 Mar 26; 338: 853–60

    Article  PubMed  Google Scholar 

  2. Rook AH, Hooks JJ, Quinnan GV, et al. Interleukin-2 enhances the natural killer cell activity of acquired immunodeficiency syndrome patients through a y-interferon-dependent mechanism. J Immunol 1985; 134: 1503–7

    PubMed  CAS  Google Scholar 

  3. Rook AH, Masur H, Lane HC, et al. Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immunodeficiency syndrome. J Clin Invest 1983; 72: 398–403

    Article  PubMed  CAS  Google Scholar 

  4. Winkelstein A, Kingsley LA, Klein RS, et al. Defective T-cell colony formation and IL-2 receptor expression at all stages of HIV infection. Clin Exp Immunol 1988; 71: 417–22

    PubMed  CAS  Google Scholar 

  5. Smith K. Interleukin-2: inception, impact and implications. Science 1988; 240: 1169–76

    Article  PubMed  CAS  Google Scholar 

  6. Connors M, Kovacs JA, Krevat S, et al. HIV infection induces changes in CD4+ T-cell phenotype within the CD4+ cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med 1997; 3: 533–40

    Article  PubMed  CAS  Google Scholar 

  7. Kovacs JA, Vogel S, Albert JM, et al. Controlled trial of interleukin-2 infusions in patients with the human immunodeficiency virus. N Engl J Med 1996; 335: 1350–6

    Article  PubMed  CAS  Google Scholar 

  8. Saravolatz L, Mitsuyasu R, Sneller M, et al. Duration of proleukin IL-2 therapy is more importantthan total dose in achieving CD4 expansion [abstract I149]. Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1996 Sep 15-18; New Orleans (LA)

    Google Scholar 

  9. Carr A, Emery S, Lloyd A, et al. Outpatient continuous intravenous interleukin-2 or subcutaneous, polyethylene glycolmodified interleukin-2 in human immunodeficiency virus-infected patients: a randomized, controlled, multicenter study. J Infect Dis 1998; 178: 992–9

    Article  PubMed  CAS  Google Scholar 

  10. Davey Jr RT, Chaitt DG, Piscitelli SC, et al. Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons. J Infect Dis 1997; 175: 781–9

    Article  PubMed  CAS  Google Scholar 

  11. Hengge UR, Exner V, Esser S, et al. Randomized controlled phase II trial of subcutaneous interleukin-2 in HIV patients [abstract 612]. Abstracts of the 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1-5; Chicago (IL)

    Google Scholar 

  12. Levy Y, Capitant C, Houhou S, et al. IL-2 in HIV patients: a randomized trial comparing SC, PEG, CIV IL-2 with AZT + ddI. Abstracts of the 12th World AIDS Conference; 1998 Jun 28-Jul 3; Geneva, Switzerland

    Google Scholar 

  13. Arno A, Ruiz L, Juan M, et al. Efficacy of low-dose subcutaneous interleukin-2 to treat advanced human immunodeficiency versus type 1 in persons with >250/ml CD4 T cells and undetectable plasma virus load. J Infect Dis 1999; 180: 56–60

    Article  PubMed  CAS  Google Scholar 

  14. Wood LV, Wiggington JM, Zuckerman J, et al. Pharmacokinetics, tolerance, and immunomodulatory activity of recombinant IL-2 in HIV-infected children and adolescents: results of a pilot study [abstract 222]. Abstracts of the 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1-5; Chicago (IL)

    Google Scholar 

  15. Davey RT, Chaitt DG, Alberet JM, et al. A randomized trial of high-versus low-dose subcutaneous interleukin-2 outpatient therapy for early human immunodeficiency virus type 1 infection. J Infect Dis 1999; 179: 849–58

    Article  PubMed  CAS  Google Scholar 

  16. Davey RT, Murphy R, Graziano F, et al. Arandomized, controlled multicenter trial of subcutaneous interleukin-2 therapy in HIV infected patients with CD4 counts 200-500 cells/μl [abstract 357]. Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31-Feb 4; Chicago (IL)

    Google Scholar 

  17. Losso M, Belloso W, Benetucci J, et al. Evaluation of subcutaneous interleukin-2 plus antiretroviral therapy vs ARV alone in patients with HIV-1 infection and CD4+ cell count > 350/mm3 [abstract 354]. Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31-Feb 4; Chicago (IL)

    Google Scholar 

  18. Tambussi G, Magenta L, Nozza S, et al. Efficacy of a four arms controlled trial of antivirals and interleukin-2 in drug-experienced HIV-1+ individuals with CD4 counts 200-500 cells/mm3 [abstract 355]. Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31-Feb 4; Chicago (IL)

    Google Scholar 

  19. Emery S, Capra W, Vig P, et al. IL-2 therapy for HIV disease: a meta-analysis of three randomized, controlled trials [abstract 608]. Abstracts of the 5th Conference on Retroviruses and Opportunistic Infections. 1998 Feb 1-5; Chicago (IL)

    Google Scholar 

  20. Kovacs JA, Baseler M, Dewar RJ, et al. Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection - a preliminary study. N Engl J Med 1995; 332: 567–75

    Article  PubMed  CAS  Google Scholar 

  21. Piscitelli SC, Wells MJ, Metcalf JA, et al. Pharmacokinetics and pharmacodynamics of subcutaneous interleukin-2 in HIV-infected patients. Pharmacotherapy 1996; 16: 754–9

    PubMed  CAS  Google Scholar 

  22. Smith KA. Rational interleukin-2 therapy. Cancer J Sci Am 1997; 3Suppl. 1: S137–40

    PubMed  Google Scholar 

  23. Mier JW, Vachino G, van der Meer JW, et al. Induction of circulating tumor necrosis factor (TNF alpha) as the mechanism for the febrile response to interleukin-2 (IL-2) in cancer patients. J Clin Immunol 1988 Nov; 8(6): 426–36

    Article  PubMed  CAS  Google Scholar 

  24. Mier JW, Vachino G, Klempner MS, et al. Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2-associated side effects [see comments]. Blood 1990; 76(10): 1933–40

    PubMed  CAS  Google Scholar 

  25. Caligiuri MA. Low-dose recombinant interleukin-2 therapy: rationale and potential clinical applications. Semin Oncol 1993; 20(6 Suppl. 9): 3–10

    PubMed  CAS  Google Scholar 

  26. Smith KA. Lowest dose interleukin-2 immunotherapy [see comments]. Blood 1993; 81(6): 1414–23

    PubMed  CAS  Google Scholar 

  27. Robb RJ, Munck A, Smith KA. T cell growth factor receptor: quantitation, specificity, and biological relevance. J Exp Med 1981; 154(5): 1455–74

    Article  PubMed  CAS  Google Scholar 

  28. Smith KA. The interleukin-2 receptor. Annu Rev Cell Biol 1989; 5: 397–45

    Article  PubMed  CAS  Google Scholar 

  29. Teppler H, Kaplan G, Smith KA, et al. Efficacy of low doses of polyethylene glycol derivative of interleukin-2 in modulating the immune response of patents with human immunodeficiency virus type 1 infection. J Infect Dis 1993; 167: 291–8

    Article  PubMed  CAS  Google Scholar 

  30. Teppler H, Kaplan G, Smith KA, et al. Prolonged immuno-stimulatory effect of low-dose polyethylene glycol interleukin-2 in patients with human immunodeficiency virus type 1 infection. J Exp Med 1993; 177: 483–92

    Article  PubMed  CAS  Google Scholar 

  31. Wood R, Montoya JG, Kundu SK, et al. Safety and efficacy of polyethylene glycol-modified interleukin-2 and zidovudine in human immunodeficiency virus type 1 infection: a phase I/II study. J Infect Dis 1993; 167: 519–25

    Article  PubMed  CAS  Google Scholar 

  32. Jacobson EL, Pilaro F, Smith KA. Rational interleukin-2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity. Proc Natl Acad Sci USA 1996; 93: 10405–10

    Article  PubMed  CAS  Google Scholar 

  33. Bernstein ZP, Porter MM, Gould M, et al. Prolonged administration of low-dose interleukin-2 in human immunodeficiency virus-associated malignancy results in selective expansion of innate immune effectors without significant clinical toxicity. Blood 1995; 86(9): 3287–94

    PubMed  CAS  Google Scholar 

  34. Bernstein ZP, Barresi G, Gould M, et al. A phase II study of daily subcutaneous low dose interleukin-2 in HIV-associated malignancies [abstract]. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14: A40

    Article  Google Scholar 

  35. Welsh RM. Regulation of virus infections by natural killer cells: a review. Nat Immune Cell Growth Regul 1986; 5(4): 169–99

    CAS  Google Scholar 

  36. Caligiuri MA, Murray C, Robertson MJ, et al. Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin-2. J Clin Invest 1993; 91: 123–32

    Article  PubMed  CAS  Google Scholar 

  37. Aukrust P, Liabakk N-B, Muller F, et al. Serum levels of tumor necrosis factor-a and soluble TNF receptors inhuman immunodeficiency virus type 1 infection - correlations to clinical, immunologic, and virologic parameters. J Infect Dis 1994; 169: 420–4

    Article  PubMed  CAS  Google Scholar 

  38. Wong JK, Hezareh M, Gunthard HF, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997; 278(5341): 1291–4

    Article  PubMed  CAS  Google Scholar 

  39. Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997; 278(5341): 1295–300

    Article  PubMed  CAS  Google Scholar 

  40. Chun TW, Stuyver L, Mizell SB, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA 1997; 94(24): 13193–7

    Article  PubMed  CAS  Google Scholar 

  41. Chun TW, Engel D, Berrey MM, et al. Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection. Proc Natl Acad Sci USA 1998; 95(15): 8869–73

    Article  PubMed  CAS  Google Scholar 

  42. Schrager LK, D’Souza MP. Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy. JAMA 1998; 280(1): 67–71

    Article  PubMed  CAS  Google Scholar 

  43. Chun TW, Engel D, Mizell SB, et al. Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J Exp Med 1998; 188: 83–91

    Article  PubMed  CAS  Google Scholar 

  44. Weidmann E, Bergmann L, Stock J, et al. Rapid cytokine release in cancer patients treated with interleukin-2. J Immunother 1992; 12: 123–31

    Article  PubMed  CAS  Google Scholar 

  45. McIntyre CA, Chapman K, Reeder S et al. Treatment of malignant melanoma and renal cell carcinoma with recombinant human interleukin-2: analysis of cytokine levels in sera and culture supernatants. Eur J Cancer 1992; 28: 58–63

    Article  PubMed  CAS  Google Scholar 

  46. Schaafsma MR, Falkenburg JH, Landegent JE et al. In vivo production of interleukin-5, granulocyte-monocyte colony-stimulating factor, monocyte colony-stimulating factor, and interleukin-6 during intravenous administration of high-dose interleukin-2 in cancer patients [see comments]. Blood 1991; 78: 1981–7

    PubMed  CAS  Google Scholar 

  47. Chun TW, Engel D, Mizell S, et al. Effect of interleukin-2 in diminution of a pool of latently infected, resting CD4+ T cells in HIV-1 infected patients receiving highly active antiretroviral therapy [abstract no. 496]. Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31-Feb 4; Chicago (IL)

    Google Scholar 

  48. Natarajan V, Bosche M, Metcalf JA, et al. HIV-1 replication in patients with undetectable plasma virus receiving HAART. Lancet 1999; 353: 119–20

    Article  PubMed  CAS  Google Scholar 

  49. Siegel JP, Puri RK. Interleukin-2 toxicity. J Clin Oncol 1991; 9: 694–704

    PubMed  CAS  Google Scholar 

  50. Witzke O, Winterhagen T, Reinhardt W, et al. Comparison between subcutaneous and intravenous interleukin-2 treatment in HIV disease. J Int Med 1998; 244: 235–40

    Article  CAS  Google Scholar 

  51. Simonelli C, Zannusi S, Sandri S, et al. Concomitant therapy with subcutaneous interleukin-2 and zidovudine plus didanosine in patients with early stage HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20: 20–7

    Article  PubMed  CAS  Google Scholar 

  52. Grady C, Anderson R, Chase GA. Fatigue in HIV-infected men receiving investigational interleukin-2. Nurs Res 1998; 47: 227–34

    Article  PubMed  CAS  Google Scholar 

  53. Sundin DJ, Wolin MJ. Toxicity management in patients receiving low-dose aldesleukin therapy. Ann Pharmacol 1998; 32: 1344–52

    Article  CAS  Google Scholar 

  54. Sumida S, Miller K, Vogel S, et al. Hypothyroidism is associated with IL-2 therapy in a randomized controlled trial (RCT) of IL-2 for the treatment of HIV-infection. Abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; 1988 Nov 12-15; Denver (CO)

    Google Scholar 

  55. Proleukin™ [package insert]. Emeryville, CA: Chiron Therapeutics, 1998

  56. Gabriel CM, Minor JR, Vogel S, et al. Supportive care during aldesleukin therapy for patients infected with human immunodeficiency virus. Am J Health Syst Pharm 1997; 54: 1191–3

    PubMed  CAS  Google Scholar 

  57. Davey RT, Chaitt RG, Kovacs JA, et al. Long-term follow-up of an early HIV-infected cohort receiving intermittent outpatient treatment with subcutaneous interleukin-2. Abstracts of the 12th World AIDS Conference; 1998 Jun 28-Jul 3; Geneva, Switzerland

  58. Walker RE, Hahn B, Kelly GG, et al. Effects of TNF-alpha antagonists thalidomide and monoclonal anti-TNF antibody (cA2) on reducing IL-2-associated toxicities: a randomized, controlled trial [abstract no. 36]. Abstracts of the 4th Conference on Retrovirus and Opportunistic Infections; 1997 Jan 22-26; Washington DC

    Google Scholar 

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Piscitelli, S.C., Bhat, N. & Pau, A. A Risk-Benefit Assessment of Interleukin-2 as an Adjunct to Antiviral Therapy in HIV Infection. Drug-Safety 22, 19–31 (2000). https://doi.org/10.2165/00002018-200022010-00003

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