title: The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients.
abstract: OBJECTIVE
  To investigate the effect of the histone deacetylase inhibitor panobinostat on HIV-associated inflammation.
  
  
  METHODS
  Sub-study of a single-arm, phase I/II clinical trial.
  
  
  METHODS
  HIV-infected adults on suppressive antiretroviral therapy received oral panobinostat 20 mg three times per week, every other week, for 8 weeks, that is, four cycles of treatment. Plasma levels of high-sensitivity C-reactive protein, matrix metalloproteinase 9, soluble CD40 ligand and interleukin-6 were determined using human ELISA kits. Soluble endothelia selectin (E-selectin) was measured by a multiplex immunoassay. Total monocyte count, phenotype changes on monocytes and monocyte histone acetylation were analyzed using flow cytometry. Whole-genome expression in peripheral blood mononuclear cells was analyzed at baseline and on-panobinostat employing the Affymetrix Human Transcriptome Array 2.0 microarray assay. Changes from baseline were analyzed using Wilcoxon signed-rank test. For the gene-expression analyses, fold-changes, P values and false detection rate were computed using TAC software.
  
  
  RESULTS
  Panobinostat treatment led to significant reductions in multiple established plasma markers of inflammation. Notably, high-sensitivity C-reactive protein decreased by a median of 58% during treatment and this change persisted for 4 weeks after treatment. Plasma levels of interleukin-6, matrix metalloproteinase 9, E-selectin and soluble CD40 ligand also significantly decreased on and/or postpanobinostat. Additionally, we observed a significant reduction in the proportions of intermediate monocytes and tissue factor-positive monocytes. This suppression of cardiovascular risk biomarkers was associated with a prominent reduction in the expression of genes related to inflammation and atherosclerosis.
  
  
  CONCLUSIONS
  Collectively, these data indicate that panobinostat may have therapeutic potential to target excess inflammation in HIV patients with high cardiovascular risk.
authors: aDepartment of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark bDepartment of Medicine, University of Colorado Denver, Aurora, Colorado, USA. *Anne Sofie Høgh Kølbæk Kjær and Christel Rothe Brinkmann contributed equally to the writing of this article.
authors: Anne Sofie
authors: AS
authors: Høgh Kølbæk Kjær
authors: Christel Rothe
authors: CR
authors: Brinkmann
authors: Charles A
authors: CA
authors: Dinarello
authors: Rikke
authors: R
authors: Olesen
authors: Lars
authors: L
authors: Østergaard
authors: Ole Schmeltz
authors: OS
authors: Søgaard
authors: Martin
authors: M
authors: Tolstrup
authors: Thomas Aagaard
authors: TA
authors: Rasmussen
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage; D015415:Biomarkers / Q000097:blood*; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D007249:Inflammation / Q000473:pathology*; D000077767:Panobinostat; D016896:Treatment Outcome
chemical_list: D044966:Anti-Retroviral Agents; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat