title: Maraviroc Intensification of cART in Patients with Suboptimal Immunological Recovery: A 48-Week, Placebo-Controlled Randomized Trial.
abstract: OBJECTIVE
  The immunomodulatory effects of the CCR5-antagonist maraviroc might be beneficial in patients with a suboptimal immunological response, but results of different cART (combination antiretroviral therapy) intensification studies are conflicting. Therefore, we performed a 48-week placebo-controlled trial to determine the effect of maraviroc intensification on CD4+ T-cell counts and immune activation in these patients.
  
  
  METHODS
  Double-blind, placebo-controlled, randomized trial.
  
  
  METHODS
  Major inclusion criteria were 1. CD4+ T-cell count <350 cells/μL while at least two years on cART or CD4+ T-cell count <200 cells/μL while at least one year on cART, and 2. viral suppression for at least the previous 6 months. HIV-infected patients were randomized to add maraviroc (41 patients) or placebo (44 patients) to their cART regimen for 48 weeks. Changes in CD4+ T-cell counts (primary endpoint) and other immunological parameters were modeled using linear mixed effects models.
  
  
  RESULTS
  No significant differences for the modelled increase in CD4+ T-cell count (placebo 15.3 CD4+ T cells/μL (95% confidence interval (CI) [1.0, 29.5] versus maraviroc arm 22.9 CD4+ T cells/μL (95% CI [7.4, 38.5] p = 0.51) or alterations in the expression of markers for T-cell activation, proliferation and microbial translocation were found between the arms. However, maraviroc intensification did increase the percentage of CCR5 expressing CD4+ and CD8+ T-cells, and the plasma levels of the CCR5 ligand MIP-1β. In contrast, the percentage of ex-vivo apoptotic CD8+ and CD4+ T-cells decreased in the maraviroc arm.
  
  
  CONCLUSIONS
  Maraviroc intensification of cART did not increase CD4+ T-cell restoration or decrease immune activation as compared to placebo. However, ex-vivo T-cell apoptosis was decreased in the maraviroc arm.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00875368.
authors.affiliation: Department of Internal Medicine & Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Internal Medicine & Gastroenterology, Spaarne Gasthuis, Haarlem, The Netherlands.
authors.forename: Steven F L
authors.initials: SF
authors.lastname: van Lelyveld
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Julia
authors.initials: J
authors.lastname: Drylewicz
authors.affiliation: Department of Internal Medicine & Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Krikke
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Veel
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Sigrid A
authors.initials: SA
authors.lastname: Otto
authors.affiliation: Department of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: Clemens
authors.initials: C
authors.lastname: Richter
authors.affiliation: Department of Internal Medicine & Gastroenterology, Spaarne Gasthuis, Haarlem, The Netherlands.
authors.forename: Robin
authors.initials: R
authors.lastname: Soetekouw
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Prins
authors.affiliation: Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Brinkman
authors.affiliation: Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Mulder
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Kroon
authors.affiliation: Department of Internal Medicine & Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ananja
authors.initials: A
authors.lastname: Middel
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jori
authors.initials: J
authors.lastname: Symons
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Annemarie M J
authors.initials: AM
authors.lastname: Wensing
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: José A M
authors.initials: JA
authors.lastname: Borghans
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kiki
authors.initials: K
authors.lastname: Tesselaar
authors.affiliation: Department of Internal Medicine & Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Andy I M
authors.initials: AI
authors.lastname: Hoepelman
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D065100:CCR5 Receptor Antagonists / Q000627:therapeutic use; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003510:Cyclohexanes / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D023581:HIV Fusion Inhibitors / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D019713:Receptors, CCR5 / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc