Preliminary assessment of the neurocognitive effects of vorinostat administration in HIV eradication
Background: While effective therapy allows most to live long, productive lives, HIV remains incurable due to virus dormant in long-lived cells, established within days of infection and capable of reigniting infection. One method of eliminating latent virus is to awaken dormant HIV, then target the infected cells: the kick and kill strategy. The CNS compartment is an important reservoir in HIV, yet sensitive to the neurotoxic effects of both HIV and antiretroviral treatment. The class I histone deacetylase inhibitor (HDACi), vorinostat (VOR) disrupts latency and upregulates HIV RNA expression, which could be a first step towards practical HIV eradication therapies. However the effect of this intervention within the CNS is unknown, and de novo virion expression of viral protein production could have an adverse effect on neurocognitive function. Here we present the first data on neurocognitive functioning in patients receiving VOR during a clinical trial, demonstrating no change in function with repeated administration.
Methods: Five consenting patients received VOR 400 mg daily M-W for 4 weekly cycles, followed after a 5-6 week rest period by another 4 weekly cycles. Neurocognitive performance was assessed at baseline and study end in the domains of Language (WRAT-4 Reading), Motor (Grooved Pegboard), Learning (HVLT-R), Memory (HVLT-R delayed recall), Speed of Processing (Stroop, Trailmaking A, Digit Symbol), Attention/Working Memory (Symbol Search), and Executive functioning (Stroop interference, Verbal fluency, Trailmaking B) .
Results: VOR was well tolerated, and HIV RNA induction (>1.5-fold) was only seen in three patients in 4 of 6 assays. No significant change in average total z score was found (black dotted line, Fig. 1), the mean baseline total z was -.29 (SD=.21) and the follow-up score showed expected slight improvement at -.12 (SD=.45).
Conclusions: In VOR use for HIV eradication of latent virus with over 22 doses across 4 months, no significant change in neurocognitive performance was found, indicating initial safety for the CNS. However, using this dosing schema, repeated and potent induction of viral expression was not seen, limiting the relevance of this neurocognitive evaluation. Neurocognitive assessments may assist in the evaluation of host effects as improved strategies to disrupt latent HIV infection evolve.
K. Robertson1, J. Kuruc2, C. Gay2, N. Archin2, J. Eron2, D. Margolis2
1University of North Carolina at Chapel Hill, Neurology, Chapel Hill, United States, 2University of North Carolina at Chapel Hill, Infectious Disease, Chapel Hill, United States