AIDS (London, England) · 2015
The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients.
Клиническое исследование I фазыКлиническое исследование II фазыСтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Høgh Kølbæk Kjær Anne Sofie, Brinkmann Christel Rothe, Dinarello Charles A, Olesen Rikke, Østergaard Lars, Søgaard Ole Schmeltz, Tolstrup Martin, Rasmussen Thomas Aagaard
Аннотация
OBJECTIVE: To investigate the effect of the histone deacetylase inhibitor panobinostat on HIV-associated inflammation.
DESIGN: 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.
CONCLUSION: Collectively, these data indicate that panobinostat may have therapeutic potential to target excess inflammation in HIV patients with high cardiovascular risk.
DESIGN: 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.
CONCLUSION: Collectively, these data indicate that panobinostat may have therapeutic potential to target excess inflammation in HIV patients with high cardiovascular risk.