Long-term treatment with valproic acid does not alleviate the condition of HAM/TSP

Long-Term Treatment with Valproic Acid Does Not Alleviate the Condition of HAM/TSP
Olindo, S.,1 Belrose, G.,2 Lezin, A.,2 Gillet, N.,3 Defoiche, J.,4 Rodriguez, S.,4 Signaté, A.,1 Verlaeten, O.,4 Smadja, D.,1 Césaire, R.,2 Willems, L.4
1Service de Neurologie and JE 2503, Centre Hospitalier Universitaire de Fort-de-France, 97200 Fort-de-France, Martinique, France;
2Laboratoire de Virologie-Immunologie and JE 2503, Centre Hospitalier Universitaire de Fort-de-France, 97200 Fort-de-France, Martinique, France;
3Department of Immunology, Imperial College, London, UK;
4Molecular and Cellular Biology, University Academia ‘‘Wallonie-Europe’’, 5030 Gembloux, Belgium.
LW is Research Director of the FNRS.

We previously proposed to interfere with proviral loads in HAM/TSP patients by modulating lysine deacetylase activity using valproic acid (VPA). The strategy aims at activating viral gene expression in order to expose virus-positive cells to the host immune response.
We conducted a single-center, two-year open-label trial, with 19 HAM/TSP volunteers treated with oral doses of VPA (20mg/Kg/day). Objectives were to assess biological response and clinical safety to VPA treatment in HAM/TSP patients.
By microarray analysis, we show that VPA treatment moderately stimulated expression of cyclinD2 and Rho GTPase activating protein 18 in CD4-T cells. CD8-mediated lysis efficiency of Tax-expressing cells was unaltered by VPA treatment. The CD4-T cell turnover rate was calculated by GC/MS analysis from quantitative incorporation of deuterium into DNA. Transient increase in proviral loads correlated with accelerated proliferation.
After 2 years, the proviral loads reached levels similar to those before treatment. The main clinical side effects were drowsiness (52%), tremor (47%), digestive symptoms (37%), vertigo (26%), and alopecia (10%). The frequency of side symptoms tended to decrease over the trial course. The neurological status over the study constituted the primary clinical safety measures. Disability Status Scale, muscle testing score, Ashworth score, and urinary dysfunction score showed no significant changes. Walking Time Test (WTT) slightly varied over the study except in 3 patients in whom the WTT variation rates were>20%. These 3 patients experienced drowsiness and tremor and improved rapidly after treatment discontinuation.
Together, these observations indicated that long term treatment with VPA is safe but does not alleviate the condition of HAM/TSP.