title: Daily low-dose subcutaneous interleukin-2 added to single- or dual-nucleoside therapy in HIV infection does not protect against CD4+ T-cell decline or improve other indices of immune function: results of a randomized controlled clinical trial (ACTG 248).
abstract: BACKGROUND
  Approaches to preserve or enhance immune function in HIV-1 infection are needed.
  
  
  OBJECTIVE
  To examine the ability of daily low-dose interleukin-2 (IL-2) in combination with antiretroviral therapy to preserve circulating CD4+ T-cell counts, the clinical safety and tolerability of this treatment, and safety with respect to changes in plasma HIV-1 RNA levels.
  
  
  METHODS
  Twenty-four-week, phase 2, multicenter, randomized, open-label trial conducted at 12 AIDS Clinical Trials Units between September 1995 and May 1997.
  
  
  METHODS
  A total of 115 HIV-infected persons with screening CD4+ T-cell counts between 300 and 700 cells/mm who were on stable single- or dual-nucleoside therapy for at least 2 months, 11% of whom were also on a protease inhibitor at study entry.
  
  
  METHODS
  Patients were randomly assigned to receive IL-2 at a dose of 1 million IU subcutaneously once daily plus continued anti-retroviral therapy (ART + IL-2, n = 57) vs. continued ART alone (ART alone, n = 58). IL-2 dose reductions were made for objective or subjective toxicities. All subjects randomly assigned to the IL-2 arm who interrupted ART were also required to discontinue IL-2 for the same period.
  
  
  METHODS
  The primary endpoint was a decrease in CD4 T-cell count from baseline; the safety analysis was based on change in plasma HIV RNA by bDNA; and clinical safety and tolerability were analyzed by standard clinical criteria.
  
  
  RESULTS
  Of the patients with a baseline CD4 T-cell count recorded, 15 (27%) of 55 patients randomly assigned to ART alone had a drop of > or =25% in their CD4 T-cell count and 23 (41%) of 56 patients randomly assigned to ART + IL-2 had a drop of > or =25% in their CD4 T-cell count at some time over the 24 weeks of the study. This difference was not statistically significant. There was a statistically significant greater variance in CD4 T-cell counts in the IL-2-treated group. More patients in the IL-2 group had at least a 25% increase in CD4 T-cell counts over baseline (34 vs. 13%, P = 0.007). A comparison of grade 3 or worse toxicity showed no differences between the arms, but IL-2 was associated with significantly more grade 2 or worse general body symptoms, primarily discomfort and fatigue. There was no significant difference between the groups with regard to changes in plasma HIV RNA, lymphocyte proliferation, natural killer cell activity, skin test responses to recall antigens, or antibody responses to immunization. Plasma markers of immune activation all increased significantly in IL-2 recipients.
  
  
  CONCLUSIONS
  In patients with baseline CD4 T-cell counts > or =300 cells/mm primarily treated with single- or dual-nucleoside ART, subcutaneously administered IL-2 at a dose of 1 million IU daily for up to 24 weeks had low toxicity but showed no consistent benefit in preventing decline in CD4 T-cell counts and minimal evidence of immunologic improvement vs. continued ART alone.
authors.affiliation: New York University Medical Center, New York, NY 10016, USA. mary.vogler@med.nyu.edu
authors.forename: Mary A
authors.initials: MA
authors.lastname: Vogler
authors.forename: Hedy
authors.initials: H
authors.lastname: Teppler
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gelman
authors.forename: Fred
authors.initials: F
authors.lastname: Valentine
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Pomerantz
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pollard
authors.forename: Deborah Weng
authors.initials: DW
authors.lastname: Cherng
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Gonzalez
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Squires
authors.forename: Ian
authors.initials: I
authors.lastname: Frank
authors.forename: Donna
authors.initials: D
authors.lastname: Mildvan
authors.forename: Laura F
authors.initials: LF
authors.lastname: Mahon
authors.forename: Barbara
authors.initials: B
authors.lastname: Schock
mesh_terms: D016915:AIDS Vaccines; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D018791:CD4 Lymphocyte Count; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load
chemical_list: D016915:AIDS Vaccines; D019380:Anti-HIV Agents; D007376:Interleukin-2; D012367:RNA, Viral