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Drugs

, Volume 70, Issue 9, pp 1115–1130 | Cite as

Role of Interleukin-2 in Patients with HIV Infection

  • Sarah L. PettEmail author
  • Anthony D. Kelleher
  • Sean Emery
Review Article

Abstract

Control of viral replication to below the level of quantification using combination antiretroviral therapy (ART) [cART] has led to a dramatic fall in mortality and morbidity from AIDS. However, despite the success of cART, it has become apparent that many patients do not achieve normalized CD4+ T-cell counts despite virological suppression to below the level of quantification (<50 copies/mL). Increasing data from cohort studies and limited data from clinical trials, such as the SMART study, have shown that higher CD4+ T-cell counts are associated with reductions in morbidity and mortality from both AIDS and serious non-AIDS (SNA) conditions, including cardiovascular disease. Enhancement of immune restoration over and above that achievable with ART alone, using a number of strategies including cytokine therapy, has been of interest for many years. The most studied cytokine in this setting is recombinant interleukin (IL)-2 (rIL-2).

The purpose of this review is to describe the current status of rIL-2 as a therapeutic agent in the treatment of HIV-1 infection. The review focuses on the rationale underpinning the exploration of rIL-2 in HIV infection, summarizing the phase II and III findings of rIL-2 as an adjunctive therapy to ART and the phase II studies of rIL-2 as an antiretroviral-sparing agent.

The phase II studies demonstrated the potential utility of continuous intravenous IL-2 and subsequently intermittent dosing with subcutaneous rIL-2 as a cytokine that could expand the CD4+ T-cell pool in HIV-1-infected patients without any significant detrimental effect on HIV viral load and with an acceptable adverse-effect profile. These data were utilized in designing the phase II studies of rIL-2 as an ART-sparing agent and, more importantly, the large phase III clinical endpoint studies of rIL-2 in HIV-1-infected adults, ESPRIT and SILCAAT. In the latter, subcutaneous rIL-2 was given intermittently (5 days of twice-daily dosing at 4.5–7.5 million international units per dose every 8 weeks) to HIV-1-infected adults receiving cART using an induction/maintenance strategy. Both studies explored the clinical benefit of intermittent subcutaneous rIL-2 with cART versus cART in HIV-infected adults with CD4+ T-cell counts ≥300 cells/mL (ESPRIT study) and 50–299 cells/mL (SILCAAT study). Both studies showed that receipt of rIL-2 conferred no clinical benefit despite a significantly higher CD4+ T-cell count in the rIL-2 arms of both studies. Moreover, there was an excess of grade 4 clinical events in ESPRIT rIL-2 recipients.

The results of the phase III clinical endpoint studies showed that rIL-2 has no place as a therapeutic agent in the treatment of HIV infection.

Keywords

Therapeutic Vaccination Viral Rebound Opportunistic Disease Dose Cycle Clinical Endpoint Study 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors thank Professor David A. Cooper for his continued advice, support and mentorship.

This study was funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government. The National Centre in HIV Epidemiology and Clinical Research is affiliated with the Faculty of Medicine, University of New South Wales. None of the authors have any conflict of interest or financial interest in recombinant interleukin-2 preparations.

References

  1. 1.
    Sodora DL, Silvestri G. Immune activation and AIDS pathogenesis. AIDS 2008; 22: 439–46PubMedCrossRefGoogle Scholar
  2. 2.
    Pett SL, Kelleher AD. Cytokine therapies in HIV-1 infection: present and future. Expert Rev Anti Infect Ther 2003; 1(1): 83–96PubMedCrossRefGoogle Scholar
  3. 3.
    Pallela Jr FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–60CrossRefGoogle Scholar
  4. 4.
    Palella Jr FJ, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43: 27–34PubMedCrossRefGoogle Scholar
  5. 5.
    The Antiretroviral (ART) Collaboration. HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Lancet 2006; 368: 451–8CrossRefGoogle Scholar
  6. 6.
    Smit C, Geskus R, Walker S, et al. Effective therapy has altered the spectrum of cause-specific mortality following HIV seroconversion. AIDS 2006; 20: 741–9PubMedCrossRefGoogle Scholar
  7. 7.
    Moore DM, Hogg RS, Chan K, et al. Disease progression in patients with virological suppression in response to HAART is associated with the degree of immunological response. AIDS 2006; 20: 371–7PubMedCrossRefGoogle Scholar
  8. 8.
    The UK Collaborative HIV Cohort (CHIC) Study Steering Committee. HIV diagnosis at CD4 count above 500/uL and progression to below 350/uL without antiretroviral therapy. J Acquir Immune Defic Syndr 2007; 46: 275–8CrossRefGoogle Scholar
  9. 9.
    Mocroft A, Phillips A, Gatell J, et al. Normalization of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet 2007; 370: 407–13PubMedCrossRefGoogle Scholar
  10. 10.
    Gras L, Kesselring AM, Griffin JT, et al. CD4 cell counts of 800cells/uL or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350cells/uL or greater. J Acquir Immune Defic Syndr 2007; 45: 183–92PubMedCrossRefGoogle Scholar
  11. 11.
    ART Collaboration Cohort. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008; 372: 293–9CrossRefGoogle Scholar
  12. 12.
    Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/uL on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007 Sep 1; 46(1): 72–7PubMedGoogle Scholar
  13. 13.
    Kitahata MM, Gange SJ, Abraham AG, et al., NAACCORD Investigators. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009 Apr 30; 360(18): 1815–26PubMedCrossRefGoogle Scholar
  14. 14.
    Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. December 1, 2009 [online]. Available from URL: http://AIDSinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf [Accessed 2010 Apr 20]
  15. 15.
    The D:A:D Study Group. Class of antiretroviral drugs and risk of myocardial infarction. N Engl J Med 2007; 356: 1723–35CrossRefGoogle Scholar
  16. 16.
    D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008; 371: 1417–26CrossRefGoogle Scholar
  17. 17.
    The SMART/INSIGHT and D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 2008; 22: F17–24CrossRefGoogle Scholar
  18. 18.
    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: 1295–300PubMedCrossRefGoogle Scholar
  19. 19.
    Wong JK, Hezareh M, Gunthard HF, et al. Recovery of replication competent HIV despite prolonged suppression of plasma viraemia. Science 1997; 278: 1291–5PubMedCrossRefGoogle Scholar
  20. 20.
    Ho DD. Toward HIV eradication or remission: the tasks ahead. Science 1998; 280(5371): 1866–7PubMedCrossRefGoogle Scholar
  21. 21.
    Ho DD, Zhang L. HIV-1 rebound after anti-retroviral therapy. Nat Med 2000; 6(7): 736–7PubMedCrossRefGoogle Scholar
  22. 22.
    Mohri H, Perelson AS, Tung K, et al. Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy. J Exp Med 2001; 194(9): 1277–87PubMedCrossRefGoogle Scholar
  23. 23.
    Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12: 1365–71PubMedCrossRefGoogle Scholar
  24. 24.
    Brenchley JM, Paiardini M, Knox KS, et al. Differential Th17 CD4 T-cell depletion in pathogenic and non pathogenic lentiviral infections. Blood 2008; 112: 2826–35PubMedCrossRefGoogle Scholar
  25. 25.
    Pakker NG, Kroon ED, Roos MT, et al. Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. AIDS 1999; 13(2): 203–12PubMedCrossRefGoogle Scholar
  26. 26.
    Smith CJ, Sabin CA, Lampe FC, et al. The potential for CD4 cell increases in HIV-positive individuals who control viraemia with highly active antiretroviral therapy. AIDS 2003; 17: 963–9PubMedCrossRefGoogle Scholar
  27. 27.
    Rajesh G, Spritzler J, Chan E, et al. Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1 positive subjects: results from ACTG 384. J Acquir Immune Defic Syndr 2006; 42: 426–34CrossRefGoogle Scholar
  28. 28.
    Battegay M, Nüesch R, Hirschel B, et al. Immunological recovery and antiretroviral therapy in HIV-1 infection. Lancet Infect Dis 2006; 6: 280–7PubMedCrossRefGoogle Scholar
  29. 29.
    Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis 2007; 44: 441–6PubMedCrossRefGoogle Scholar
  30. 30.
    The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355: 2283–96CrossRefGoogle Scholar
  31. 31.
    Watson JD, Mochizuki DY, Gillis S. Molecular characterisation of interleukin-2. Fed Proc 1983; 42: 2747–52PubMedGoogle Scholar
  32. 32.
    Rook AH, Hooks JJ, Quinnan GV, et al. Interleukin-2 enhances the natural killer cell activity of acquired immunodeficiency syndrome patients through a gamma-interferon-independent mechanism. J Immunol 1985; 134: 1503–7PubMedGoogle Scholar
  33. 33.
    Smith KA. Interleukin-2: inception, impact and implications. Science 1988; 240: 1169–77PubMedCrossRefGoogle Scholar
  34. 34.
    Connors M, Kovacs JA, Krevat S, et al. 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; 3: 533–40PubMedCrossRefGoogle Scholar
  35. 35.
    Shearer GM, Bernstein DC, Tung KS, et al. A model for the selective loss of major histocompatibility complex self-restricted T cell immune responses during the development of acquired immunodeficiency (AIDS). J Immunol 1986; 137: 2514–21PubMedGoogle Scholar
  36. 36.
    Liegler TJ, Stites DP. HIV-1 gp120 and anti-gp120 induce reversible unresponsiveness in peripheral CD4 T-lymphocytes. J Acquir Immune Defic Syndr 1994; 7: 340–8PubMedGoogle Scholar
  37. 37.
    Osborn L, Kunkel S, Nabel GJ. Tumor necrosis factor and interleukin-1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor B. Proc Natl Acad Sci U S A 1989; 86: 2336–40PubMedCrossRefGoogle Scholar
  38. 38.
    Kovacs JA, Vogel S, Albert JM, et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med 1996; 335: 1350–6PubMedCrossRefGoogle Scholar
  39. 39.
    de Boer AW, Markowitz N, Lane HC, et al. A randomized controlled trial evaluating the efficacy and safety of intermittent 3-, 4-, and 5-day cycles of intravenous recombinant human interleukin-2 combined with antiretroviral therapy (ART) versus ART alone in HIV-seropositive patients with 100–300 CD4+ T cells. Clin Immunol 2003; 106: 188–96PubMedCrossRefGoogle Scholar
  40. 40.
    Carr A, Emery S, Lloyd A, et al. Outpatient continuous intravenous interleukin-2 or subcutaneous, polyethylene glycol modified interleukin-2 in human immunodeficiency virus-infected patients: a randomized, controlled, multicenter study. J Infect Dis 1998; 178: 992–9PubMedCrossRefGoogle Scholar
  41. 41.
    Levy Y, Capitant C, Houhou S, et al. Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group. Lancet 1999; 353: 1923–9Google Scholar
  42. 42.
    Davey RT, Chaitt DG, Albert JM, et al. A randomised trial of high-versus low-dose subcutaneous interleukin-2 outpatient therapy for early human immunodeficiency virus type 1 infection. J Infect Dis 1999; 179: 849–58PubMedCrossRefGoogle Scholar
  43. 43.
    Davey RT, Murphy RL, Graziano FM, et al. Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy. JAMA 2000; 284: 183–9PubMedCrossRefGoogle Scholar
  44. 44.
    Ruxrungtham K, Suwanagool S, Tavel JA, et al., Vanguard Study Group. A randomized, controlled 24-week study of intermittent subcutaneous interleukin-2 in HIV-1 infected patients in Thailand. AIDS 2000 Nov 10; 14(16): 2509–13PubMedCrossRefGoogle Scholar
  45. 45.
    Abrams DI, Bebchuk JD, Denning ET, et al. Randomized, open-label study of the impact of two doses of subcutaneous recombinant interleukin-2 on viral burden in patients with HIV-1 infection and CD4 cells counts of > or=300/mm3: CPCRA 059. J Acquir Immune Defic Syndr 2002; 29: 221–31PubMedGoogle Scholar
  46. 46.
    Davey RT, Chaitt RT, Piscitelli SC, et al. Subcutaneous administration of interleukin-2 in human immunodeficiency virus type-1 infected persons. J Infect Dis 1997; 175: 781–9PubMedCrossRefGoogle Scholar
  47. 47.
    Emery S, Capra WB, Cooper DA, et al. Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease. J Infect Dis 2000; 182: 428–34PubMedCrossRefGoogle Scholar
  48. 48.
    Losso MH, Belloso WH, Emery S, et al. A randomized, controlled, phase II trial comparing escalating doses of subcutaneous interleukin-2 plus antiretrovirals versus antiretrovirals alone in human immunodeficiency virus-infected patients with CD4+ cell counts >/=350/mm3. J Infect Dis 2000 May; 181(5): 1614–21PubMedCrossRefGoogle Scholar
  49. 49.
    Gougeon ML, Rouzioux C, Liberman I, et al., ANRS 048 Study Group. Immunological and virological effects of long term IL-2 therapy in HIV-1-infected patients. AIDS 2001 Sep 7; 15(13): 1729–31PubMedCrossRefGoogle Scholar
  50. 50.
    Tambussi G, Ghezzi S, Nozza S, et al. Efficacy of low-dose intermittent subcutaneous interleukin (IL)-2 in antiviral drug-experienced human immunodeficiency virus-infected persons with detectable virus load: a controlled study of 3 IL-2 regimens with antiviral drug therapy. J Infect Dis 2001; 183: 1476–84PubMedCrossRefGoogle Scholar
  51. 51.
    Miller KD, Spooner K, Herpin BR, et al. Immunotherapy of HIV-infected patients with intermittent interleukin-2: effects of cycle frequency and cycle duration on degree of CD4+ T-lymphocyte expansion. Clin Immunol 2001; 99(1): 30–42PubMedCrossRefGoogle Scholar
  52. 52.
    Tavel JA, Fosdick L. Closeout of four phase II Vanguard trials and patient rollover into a large international phase III HIV clinical endpoint trial. Control Clin Trials 2001; 22: 42–8PubMedCrossRefGoogle Scholar
  53. 53.
    Levy Y, Durier C, Krzysiek R, et al., ANRS 079 Study Group. Effects of interleukin-2 therapy combined with highly active antiretroviral therapy on immune restoration in HIV-1 infection: a randomized controlled trial. AIDS 2003 Feb 14; 17(3): 343–51PubMedCrossRefGoogle Scholar
  54. 54.
    Farel CE, Chaitt DG, Hahn BK, et al. Induction and maintenance therapy with intermittent interleukin-2 in HIV-1 infection. Blood 2004; 103: 3282–6PubMedCrossRefGoogle Scholar
  55. 55.
    Arduino RC, Nannini EC, Rodriguez-Barradas M, et al. CD4 cell response to 3 doses of subcutaneous interleukin 2: meta-analysis of 3 Vanguard studies. Clin Infect Dis 2004; 39: 115–22PubMedCrossRefGoogle Scholar
  56. 56.
    Durier C, Capitant C, Lascaux A-S, et al. Long-term effects of intermittent interleukin-2 therapy in chronic HIV-infected patients (ANRS 048-079 Trials). AIDS 2007; 21: 1887–97PubMedCrossRefGoogle Scholar
  57. 57.
    Kovacs JA, Lempicki RA, Sidorov IA, et al. Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients. J Clin Invest 2005; 115(8): 2139–48PubMedCrossRefGoogle Scholar
  58. 58.
    Read SW, Lempicki RA, Di Mascio M, et al. CD4+ T cell survival after intermittent interleukin-2 therapy is predictive of an increase in the CD4 T cell count of HIV-infected patients. J Infect Dis 2008; 198: 843–50PubMedCrossRefGoogle Scholar
  59. 59.
    Sereti I, Sklar P, Ramchandani MS, et al. CD4+ T cell response to interleukin-2 administration in HIV-infected patients are directly related to the baseline level of immune activation. J Infect Dis 2007; 196: 677–83PubMedCrossRefGoogle Scholar
  60. 60.
    Sereti I, Martinez-Wilson H, Metcalf JA, et al. Long-term effects of intermittent interleukin 2 therapy in patients with HIV infection: characterization of a novel subset of CD4(+)/CD25(+) T cells. Blood 2002; 100(6): 2159–67PubMedGoogle Scholar
  61. 61.
    Natarajan V, Lempicki RA, Sereti I, et al. Increased peripheral expansion of naive CD4+ T cells in vivo after IL-2 treatment of patients with HIV infection. Proc Natl Acad Sci U S A 2002; 99(16): 10712–7PubMedCrossRefGoogle Scholar
  62. 62.
    Sereti I, Anthony KB, Martinez-Wilson H, et al. IL-2-induced CD4 T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation. Blood 2004; 104: 775–80PubMedCrossRefGoogle Scholar
  63. 63.
    Levy Y, Gahéry-Ségard H, Durier C, et al., ANRS 093 Study Group. Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patients. AIDS 2005 Feb 18; 19(3): 279–86PubMedGoogle Scholar
  64. 64.
    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): 651–5PubMedCrossRefGoogle Scholar
  65. 65.
    Sereti I, Sklar P, Ramchandani MS, et al. CD4+ T cell responses to interleukin-2 administration in HIV-Infected patients are directly related to the baseline levels of immune activation. J Infect Dis 2007; 196: 667–83CrossRefGoogle Scholar
  66. 66.
    Proleukin®/Aldesleukin. Recombinant human interleukin-2/PRL002A for use in oncologic diseases. Investigator’s brochure. Novartis edition number 1. Emeryville (CA): Novartis Vaccines and Diagnostics, Inc., 2007 Apr 30Google Scholar
  67. 67.
    Tavel JA, Sereti I, Walker RE, et al. A randomized, double-blinded, placebo-controlled trial of intermittent administration of interleukin-2 and prednisone in subjects infected with human immunodeficiency virus. J Infect Dis 2003 Aug 15; 188(4): 531–6PubMedCrossRefGoogle Scholar
  68. 68.
    Auphan N, DiDanato JA, Rosette C, et al. Immunosuppression by glucocorticoids: inhibition of NFkB activity through induction of IkB synthesis. Science 1995; 270: 286–90PubMedCrossRefGoogle Scholar
  69. 69.
    Mitsuyasu R, Gelman R, Cherng DW, et al., for the AIDS Clinical Trials Group 328 Study Team. The virologic, immunologic, and clinical effects of interleukin 2 with potent antiretroviral therapy in patients with moderately advanced human immunodeficiency virus infection: a randomized controlled clinical trial. AIDS Clinical Trials Group 328. Arch Intern Med 2007; 167(6): 57–605Google Scholar
  70. 70.
    Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996 Oct 1; 125(7): 605–13PubMedGoogle Scholar
  71. 71.
    Hughes MD, Daniels MJ, Fischl MA, et al. CD4 cell count as a surrogate endpoint in HIV clinical trials: a meta-analysis of studies of the AIDS Clinical Trials Group. AIDS 1998; 12: 1823–32PubMedCrossRefGoogle Scholar
  72. 72.
    Delta Coordinating Committee and Virology Group. An evaluation of HIV RNA and CD4 cell count as surrogates for clinical outcome. AIDS 1999; 13: 565–73CrossRefGoogle Scholar
  73. 73.
    Abrams D, Lévy Y, Losso MH, et al., INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee. Interleukin-2 therapy in patients with HIV infection. N Engl J Med 2009 Oct 15; 361(16): 1548–59PubMedCrossRefGoogle Scholar
  74. 74.
    Katlama C, Carcelain G, Duvivier C, et al. Interleukin-2 accelerates CD4 cell reconstitution in HIV-infected patients with severe immunosuppression despite highly active antiretroviral therapy: the ILSTIM study — ANRS 082. AIDS 2002; 16(15): 2027–34PubMedCrossRefGoogle Scholar
  75. 75.
    Table for grading the severity of adult and pediatric adverse events. Version 1.0, December 2004 [online]. Available from URL: http://rcc.tech-res.com/safetyandpharmacovigilance/ [Accessed 2010 Apr 01]
  76. 76.
    Centers for Disease Control. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992; 41: 1–19Google Scholar
  77. 77.
    Emery S, Abrams DI, Cooper DA, et al. The evaluation of subcutaneous proleukin® (interleukin-2) in a randomized international trial: rationale, design, and methods of ESPRIT. Control Clin Trials 2002; 23: 198–220PubMedCrossRefGoogle Scholar
  78. 78.
    Losso M, Abrams D, for the INSIGHT-ESPRIT Study Group. Effect of interleukin-2 on clinical outcomes in patients with a CD4+ cell count of 300/mm3: primary results of the ESPRIT study [abstract no. 90aLB]. 16th Conference on Retroviruses and Opportunistic Infections (CROI); 2009 Feb 8–11; Montreal (QC)Google Scholar
  79. 79.
    Porter BO, Shen J, Kovacs JA, et al. Interleukin-2 cycling causes transient increases in high-sensitivity C-reactive protein and D-dimer that are not associated with plasma HIV-RNA levels. AIDS 2009 Sep 24; 23(15): 2015–9PubMedCrossRefGoogle Scholar
  80. 80.
    Babiker AG, for the INSIGHT ESPRIT Study Group and the SILCAAT Scientific Committee. An analysis of pooled data from the ESPRIT and SILCAAT studies: findings by latest CD4+ count [abstract no. TUAB101]. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; 2009 Jul 19–22; Cape TownGoogle Scholar
  81. 81.
    Kuller LH, Tracy R, Belloso W, et al., for the INSIGHT SMART Study Group. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008 Oct 21; 5(10): e203PubMedCrossRefGoogle Scholar
  82. 82.
    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: 1479–87PubMedCrossRefGoogle Scholar
  83. 83.
    Kulkosky J, Nunnari G, Otero M, et al. Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. J Infect Dis 2002; 186: 1403–11PubMedCrossRefGoogle Scholar
  84. 84.
    Youle M, Emery S, Fisher M, et al. A randomised trial of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients: the UK-Vanguard Study [published erratum appears in PLoS Clin Trials 2007; 2 (5): e23]. PLoS Clin Trials 2006 May; 1(1): e3PubMedCrossRefGoogle Scholar
  85. 85.
    Molina JM, Levy Y, Fournier I, et al., for Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS) 119 Interstart Study Team. Interleukin-2 before antiretroviral therapy in patients with HIV infection: a randomized trial (ANRS 119). J Infect Dis 2009; 200(2): 206–15PubMedCrossRefGoogle Scholar
  86. 86.
    Tavel JA, INSIGHT STALWART Study Group. Effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy in early HIV infection: the STALWART study. PLoS One 2010 Feb 23; 5(2): e9334PubMedCrossRefGoogle Scholar
  87. 87.
    Zoufaly A, Stellbrink HJ, Heiden MA, et al., for ClinSurv Study Group. Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma. J Infect Dis 2009 Jul 1; 200(1): 79–87PubMedCrossRefGoogle Scholar
  88. 88.
    Healey LM, Hahn BK, Rehm CA, et al. The effect of continuous versus pericycle antiretroviral therapy on IL-2 responsiveness. J Interferon Cytokine Res 2008 Jul; 28(7): 455–62PubMedCrossRefGoogle Scholar
  89. 89.
    Keh CE, Shen JM, Hahn B, et al. Interruption of antiretroviral therapy blunts but does not abrogate CD4 T-cell responses to interleukin-2 administration in HIV infected patients. AIDS 2006 Feb 14; 20(3): 361–9PubMedCrossRefGoogle Scholar
  90. 90.
    Angus B, Lampe F, Tambussi G, et al. TILT: a randomized controlled trial of interruption of antiretroviral therapy with or without interleukin-2 in HIV-1 infected individuals. AIDS 2008; 22(6): 737–40PubMedCrossRefGoogle Scholar
  91. 91.
    Porter BO, Anthony KB, Shen J, et al. Inferiority of IL-2 alone versus IL-2 with HAART in maintaining CD4 T cell counts during HAART interruption: a randomized controlled trial. AIDS 2009 Jan 14; 23(2): 203–12PubMedCrossRefGoogle Scholar
  92. 92.
    Davey RT, Pertel PE, Benson A, et al. Safety, tolerability, pharmacokinetics, and efficacy of an interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy. J Interferon Cytokine Res 2008; 28: 89–100PubMedCrossRefGoogle Scholar
  93. 93.
    Autran B, Carcelain G, Combadiere B, et al. Therapeutic vaccines for chronic infections. Science 2004; 305: 205–8PubMedCrossRefGoogle Scholar
  94. 94.
    Leone A, Picker LJ, Sodora DL. IL-2, IL-7 and IL-15 as immuno-modulators during SIV/HIV vaccination and treatment. Curr HIV Res 2009 Jan; 7(1): 83–90PubMedCrossRefGoogle Scholar
  95. 95.
    Levy Y, Durier C, Lascaux AS, et al. Sustained control of viremia following therapeutic immunization in chronically HIV-1-infected individuals. AIDS 2006; 20: 405–13PubMedCrossRefGoogle Scholar
  96. 96.
    Kilby JM, Bucy RP, Mildvan D, et al., Adult AIDS Clinical Trials Group A5024 Protocol Team. 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 Dec 15; 194(12): 1672–6PubMedCrossRefGoogle Scholar
  97. 97.
    Smith KA, Andjelic S, Popmihajlov Z, et al. Immunotherapy with canarypox vaccine and interleukin-2 for HIV-1 infection: termination of a randomized trial. PLoS Clin Trials 2007 Jan 26; 2(1): e5PubMedCrossRefGoogle Scholar
  98. 98.
    Goujard C, Marcellin F, Hendel-Chavez H, et al., for the PRIMOVAC-ANRS 095 Study Group. Interruption of antiretroviral therapy initiated during primary HIV-1 infection: impact of a therapeutic vaccination strategy combined with interleukin (IL)-2 compared with IL-2 alone in the ANRS 095 Randomized Study. AIDS Res Hum Retroviruses 2007 Sep; 23(9): 1105–13PubMedCrossRefGoogle Scholar
  99. 99.
    Johnston MI, Fauci AS. An HIV vaccine: evolving concepts. N Engl J Med 2007 May 17; 356(20): 2073–81PubMedCrossRefGoogle Scholar
  100. 100.
    Cohen J. AIDS research: promising AIDS vaccine’s failure leaves field reeling. Science 2007 Oct 5; 318(5847): 28–9PubMedCrossRefGoogle Scholar
  101. 101.
    Schooley R, Wang H, Spritzler J, et al., for the AIDS Clinical Trials Group. Therapeutic vaccination with a replication defective adenovirus type 5 HIV-1 gag vaccine in a prospective, double-blinded, placebo-controlled trial (ACTG 5197) [abstract no. 87]. 15th Conference on Retroviruses and Opportunistic Infections (CROI); 2008 Feb 3–6; Boston (MA)Google Scholar
  102. 102.
    Sereti I, Dunham RM, Spritzler J, et al. IL-7 administration drives T cell cycle entry and expansion in HIV-1 infection. Blood 2009; 113(25): 6304–14PubMedCrossRefGoogle Scholar
  103. 103.
    Levy Y, Lacabaratz C, Weiss L, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest 2009 Apr; 119(4): 997–1007PubMedGoogle Scholar

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© Adis Data Information BV 2010

Authors and Affiliations

  • Sarah L. Pett
    • 1
    • 2
    Email author
  • Anthony D. Kelleher
    • 1
    • 2
  • Sean Emery
    • 1
  1. 1.National Centre in HIV Epidemiology and Clinical Research, Faculty of MedicineUniversity of New South WalesCoogeeAustralia
  2. 2.Centre for Applied Medical Research (AMR)St Vincent’s HospitalSydneyAustralia

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