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NEUROTOXICITY WITH HIGH-DOSE DISULFIRAM AND VORINOSTAT USED FOR LATENCY REVERSAL
James McMahon1, Vanessa Evns2, Jillian S. Lau1, Ajantha Solomon2, Surekha Tennakoon2, Ashanti Dantanarayana2, Michelle Hagenauer1, Sulggi Lee3, Sarah Palmer4, Katie Fisher4, Namandje Bumpus5, David M. Burger6, Bonnie J. Howell7, Thomas A. Rasmussen2, Sharon R. Lewin2
1Alfred Hospital, Melbourne, VIC, Australia,2Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia,3University of California San Francisco, San Francisco, CA, USA,4The Westmead Institute for Medical Research, Westmead, NSW, Australia,5Johns Hopkins University School of Medicine, Baltimore, MD,6Radboud University Medical Center, Nijmegen, Netherlands,7Merck & Co, Inc, Kenilworth, NJ, USA
The histone deacetylase inhibitor, vorinostat (VOR), and disulfiram (DSF), a drug used to treat alcohol dependence, reverse HIV latency in vivo by different pathways and have been safely administered to people with HIV. Three days of 2000mg DSF has been safely given as a latency reversal agent. This study aimed to determine if these two agents (i) reverse HIV latency more potently than a single agent and (ii) are safe and tolerable.
HIV-infected adults on suppressive antiretroviral therapy (ART) were enrolled in a prospective single arm study of DSF 2000mg daily for 28 days and VOR 400mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline. We quantified cell associated (CA) unspliced (US) and multiply spliced (MS) RNA and HIV DNA in CD4+ T-cells from blood; HIV RNA in plasma using a single copy assay; and p24 expression by SiMoA and histone acetylation by flow cytometry from PBMCs. Plasma concentrations of ART, VOR and DSF were quantified.
The first two participants (P1 and P2) experienced grade 3 neurotoxicity (altered mental status possibly and probably related to DSF respectively), which led to trial suspension. P1 was a 67 year-old male on ABC/3TC/DTG with a CD4 count of 762 cells/L and VL <50 copies/mL for 16.7 years. On study day 24 (having missed DSF and VOR on day 10 and stopped DSF and all ART from day 17-24) he presented with confusion, lethargy, and ataxia. Neuroimaging revealed sagittal sinus thrombosis and chronic vertebral artery occlusion. He was admitted to hospital, anticoagulated and symptoms resolved by day 29. P2 was a 61 year-old male on TAF/FTC + RAL with a CD4 of 1085 cells/L and VL <50 copies/mL for 4.8 years. On day 11 he presented with paranoid ideation, emotional lability, lethargy and ataxia. He was admitted to hospital; brain CT scan was normal and his symptoms resolved by day 23. Both participants had increased CA-US RNA following study drugs, which persisted for weeks after drug cessation (Figure). P2 also had increased plasma viremia from day 8-37 (peak 81 copies/mL on day 21) with therapeutic ART drug levels. Low but detectable levels of VOR and histone acetylation were seen in both participants.
The study drug combination was not safe with significant but reversible neurotoxicity, which we suspect was related to prolonged high dose DSF. There was evidence of latency reversal in both participants. Prolonged high dose DSF, with or without VOR, should not be further pursued.