The addition of vorinostat to current antiretroviral therapy (ART) regimens can potentially help to eradicate hidden pockets of dormant human immunodeficiency virus (HIV), according to study results published in Nature.
Persistent reservoirs of dormant HIV often remain despite years of treatment with ART. Histone deacetylase (HDAC) inhibitors have been shown to disrupt these reservoirs in vitro, but when the HDAC inhibitor valproic acid was given to patients on ART there was no significant reduction in infected cells.
Vorinostat is a more potent HDAC inhibitor that is currently indicated for the treatment of certain types of lymphoma. David Margolis (The University of North Carolina at Chapel Hill, USA) and colleagues hypothesized that vorinostat could reduce latent HIV infection in vivo.
Eight patients were identified who had been on ART for at least 6 months and in whom an induction of HIV RNA expression following in vitro exposure to vorinostat could be measured. The patients were given a single dose of vorinostat 200 mg followed by a single 400 mg dose 2 to 4 weeks later, and a second 400 mg dose 4 to 5 weeks after that. Circulating resting CD4+ T cells were then isolated and assessed.
When the resting CD4+ T cells were exposed to vorinostat, there was a mean 4.8-fold increase in HIV RNA expression. Significant increases compared with levels of RNA expression at baseline were noted in all patients. In two patients who underwent leukapheresis 3 to 4 months after being given vorinostat, there was a significant decline in HIV RNA expression. Vorinostat was well tolerated and only mild adverse events were noted.
The authors comment that "these observations support the conclusion that the increase in HIV RNA expression was causally related to vorinostat exposure," and that "the quiescence of latent, integrated HIV provirus within resting CD4+ T cells, a significant barrier to the eradication of HIV infection, can be disrupted by an achievable and tolerable exposure to an HDAC inhibitor."
They recommend additional studies to determine the exact dosing regimens of vorinostat or other HDAC inhibitors that would be the most effective for sustained disruption of HIV latency, with a further goal of developing treatment options with improved specificity.
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