Abstract Body

Background: Histone deacetylase inhibitors (HDACi) are currently being evaluated in experimental clinical trials for their ability to reactivate HIV-1 expression in latently infected cells with the aim of eradicating the latent HIV-1 reservoir. Panobinostat has previously been shown to reactivate HIV-1 expression in latently infected cells in vitro. However, caution has been raised that reactivation of latent HIV-1 could potentially have harmful consequences on the brain. The proposed adverse effects on the central nervous system (CNS) include neuronal injury caused by activated T cells or by early viral proteins induced by HDACi, CNS immune reconstitution inflammatory syndrome and, finally, adverse effects on brain function due to elimination of latently infected microglia and/or astrocytes. Methodology: In a clinical trial among HIV-infected adults on suppressive combination antiretroviral therapy (cART), patients were treated with the potent HDACi panobinostat (20 mg orally 3 times per week every other week over the course of 8 weeks). To address whether viral reactivation induced by panobinostat was associated with adverse effects on CNS, we evaluated biomarkers of neurodegeneration and neuroinflammation in cerebrospinal fluid (CSF) obtained before panobinostat administration and during the final dosing week. Biomarkers of neurodegeneration and neuroinflammation were determined by enzyme-linked immunosorbent assays. C-reactive protein (CRP) was determined by a particle-enhanced immunoturbidimetric assay. Changes from baseline in biomarker levels were tested using Wilcoxon signed rank test. Results: Among study subjects who consented to lumbar punctures (11 of 15 participants) we found no significant change from baseline to the final panobinostat treatment week neither in biomarkers of neurodegeneration (total tau, phosphorylated tau, soluble amyloid-β) nor in biomarkers of neuroinflammation (CRP, soluble CD14, soluble CD163, neopterin, monocyte chemotactic protein-1 (MCP-1), interferon-γ induced protein-10 (IP-10), macrophage inflammatory protein-1β (MIP1-β), matrix metallopeptidase-9 (MMP-9)). Conclusions: Repeated, cyclic treatment with the HDACi panobinostat was not associated with CNS adverse effects as measured by CSF biomarkers of inflammation and neurodegeneration in HIV patients on suppressive cART.