title: A pilot study evaluating time to CD4 T-cell count <350 cells/mm(3) after treatment interruption following antiretroviral therapy +/- interleukin 2: results of ACTG A5102.
abstract: BACKGROUND
  Although an intermittent antiviral treatment (ART) strategy may limit long-term toxicity and cost, there is concern about the risk for virologic failure, selection of drug resistance mutations, and disease progression. By boosting CD4 T-cell counts, interleukin 2 (IL-2) could safely prolong the duration of treatment interruption (TI) in a CD4-driven strategy.
  
  
  METHODS
  The AIDS Clinical Trials Group (ACTG) study A5102 evaluated 3 cycles of IL-2 before TI, on clinical and immunologic outcomes, using a CD4 T-cell count of <350 cells/mm as the threshold for restarting ART. Forty-seven HIV-infected subjects on potent ART with CD4 T-cell counts of > or =500 cells/mm or more and HIV RNA levels of less than 200 copies/mL were randomized to arm A (ART + three 5-day cycles of IL-2 at 4.5 million U, Sc, BID every 8 weeks, n = 23) or arm B (ART alone, n = 24) for 18 weeks (step 1). At the end of step 1, subjects with a CD4 T-cell count of > or =500 cells/mm or more stopped ART until a CD4 count of <350 cells/mm (step 2). CD4 T-cell count, time to return of viremia, and the emergence of drug resistance mutations after TI were compared between study arms.
  
  
  RESULTS
  IL-2 recipients maintained higher CD4 counts during TI for 48 weeks with a waning of the CD4 effect by 72 weeks. A sustained CD4 T-cell count of more than 350 cells/mm and more durable TI were associated with a higher nadir CD4 T-cell count before ART and higher naive CD4 T-cell count at entry. After TI, a higher viral set point and drug resistance mutations at virologic rebound were associated with a shorter time to CD4 T-cell count of less than 350 cell/mm. There were no differences in the magnitude of virologic rebound (at week 8 of step 2, median log10 HIV RNA level was 4.23 for arm A and 4.21 for arm B) or the steady-state HIV-1 RNA level after week 8.
  
  
  CONCLUSIONS
  IL-2 before TI did not prolong time to CD4 of less than 350 cells/mm. A TI strategy utilizing a CD4 T-cell threshold of less than 350 cells/mm for restarting ART appears generally safe with most subjects in both arms remaining off ART for more than 1 year. Implications of our results for TI strategies include the potential advantage of starting ART at higher CD4 T-cell levels while avoiding any drug resistance and evaluating immunomodulators or drugs to reduce T-cell activation and HIV-1 RNA rebound during the TI.
authors.affiliation: HIV Program, Hennepin County Medical Center and the University of Minnesota, Minneapolis, MN 55415, USA. keithh6680@aol.com
authors.forename: Keith
authors.initials: K
authors.lastname: Henry
authors.forename: David
authors.initials: D
authors.lastname: Katzenstein
authors.forename: Deborah Weng
authors.initials: DW
authors.lastname: Cherng
authors.forename: Hernan
authors.initials: H
authors.lastname: Valdez
authors.forename: William
authors.initials: W
authors.lastname: Powderly
authors.forename: Michelle Blanchard
authors.initials: MB
authors.lastname: Vargas
authors.forename: Nasreen C
authors.initials: NC
authors.lastname: Jahed
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Jacobson
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Myers
authors.forename: John L
authors.initials: JL
authors.lastname: Schmitz
authors.forename: Mark
authors.initials: M
authors.lastname: Winters
authors.forename: Pablo
authors.initials: P
authors.lastname: Tebas
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D010865:Pilot Projects; D012367:RNA, Viral / Q000097:blood; D013997:Time Factors; D014766:Viremia
chemical_list: D019380:Anti-HIV Agents; D007376:Interleukin-2; D012367:RNA, Viral