title: Metabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: implications for cardiovascular risk.
abstract: BACKGROUND
  Concern about costs and antiretroviral therapy (ART)-associated toxicities led to the consideration of CD4 driven strategies for the management of HIV. That approach was evaluated in the SMART trial that reported an unexpected increase of cardiovascular events after treatment interruption (TI). Our goal was to evaluate fasting metabolic changes associated with interruption of antiretroviral therapy and relate them to changes of immune activation markers and cardiovascular risk.
  
  
  METHODS
  ACTG 5102 enrolled 47 HIV-1-infected subjects on stable ART, with <200 HIV RNA copies/mL and CD4 cell count >or=500 cells/microL. Subjects were randomly assigned to continue ART for 18 weeks with or without 3 cycles of interleukin-2 (IL-2) (cycle = 4.5 million IU sc BID x 5 days every 8 weeks). After 18 weeks ART was discontinued in all subjects until the CD4 cell count dropped below 350 cells/microL. Glucose and lipid parameters were evaluated every 8 weeks initially and at weeks 2, 4, 8 and every 8 weeks after TI. Immune activation was evaluated by flow-cytometry and soluble TNFR2 levels.
  
  
  RESULTS
  By week 8 of TI, levels of total cholesterol (TC) (median (Q1, Q3) (-0.73 (-1.19, -0.18) mmol/L, p<0.0001), LDL, HDL cholesterol (-0.36(-0.73,-0.03)mmol/L, p = 0.0007 and -0.05(-0.26,0.03), p = 0.0033, respectively) and triglycerides decreased (-0.40 (-0.84, 0.07) mmol/L, p = 0.005). However the TC/HDL ratio remained unchanged (-0.09 (-1.2, 0.5), p = 0.2). Glucose and insulin levels did not change (p = 0.6 and 0.8, respectively). After TI there was marked increase in immune activation (CD8+/HLA-DR+/CD38+ cells, 34% (13, 43), p<0.0001) and soluble TNFR2 (1089 ng/L (-189, 1655), p = 0.0008) coinciding with the rebound of HIV viremia.
  
  
  CONCLUSIONS
  Our data suggests that interrupting antiretroviral therapy does not reduce cardiovascular disease (CVD) risk, as the improvements in lipid parameters are modest and overshadowed by the decreased HDL levels. Increased immune cell activation and systemic inflammatory responses associated with recrudescent HIV viremia may provide a more cogent explanation for the increased cardiovascular risk associated with treatment interruption and HIV infection.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00015704.
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. pablo.tebas@uphs.upenn.edu
authors.forename: Pablo
authors.initials: P
authors.lastname: Tebas
authors.forename: William Keith
authors.initials: WK
authors.lastname: Henry
authors.forename: Roy
authors.initials: R
authors.lastname: Matining
authors.forename: Deborah
authors.initials: D
authors.lastname: Weng-Cherng
authors.forename: John
authors.initials: J
authors.lastname: Schmitz
authors.forename: Hernan
authors.initials: H
authors.lastname: Valdez
authors.forename: Nasreen
authors.initials: N
authors.lastname: Jahed
authors.forename: Laurie
authors.initials: L
authors.lastname: Myers
authors.forename: William G
authors.initials: WG
authors.lastname: Powderly
authors.forename: David
authors.initials: D
authors.lastname: Katzenstein
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D002318:Cardiovascular Diseases / Q000150:complications*; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D002908:Chronic Disease; D005947:Glucose / Q000378:metabolism; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use; D050356:Lipid Metabolism; D012307:Risk Factors
chemical_list: D008076:Cholesterol, HDL; D007376:Interleukin-2; D002784:Cholesterol; D005947:Glucose