Background: A proposed strategy to purge HIV reservoir is to reactivate provirus transcription with latency-reversing agents (LRAs), inducing viral antigen expression and allowing immune-mediated clearance of reservoir cells in the presence of combination antiretroviral therapy (cART). Here we evaluated the safety and efficacy of chidamide, a benzamide histone deacetylase inhibitor, in patients on suppressive cART.
Methods: Seven aviremic HIV-1-infected patients received eight oral doses of 10 mg chidamide twice a week (Tuesday/Friday) for 4 weeks while maintaining baseline cART. Safety was evaluated at each visit and plasma concentrations of chidamide was measured by liquid chromatography-mass spectrometry. Histone acetylation levels in CD4+ T cells were analyzed by flow cytometry. Plasma HIV RNA was determined using Cobas Taqman HIV-1 Test, v2.0. Cell-associated HIV RNA (CA-HIV RNA) and total HIV DNA (CA-tHIV DNA) were quantified by the SupBio PCR test in PBMCs. Thirteen plasma biomarkers of inflammation were evaluated by luminex multiplex assays and ELISA. Changes from baseline to specific time points were compared using Wilcoxon matched-pairs signed-rank tests, and a two-sided p-value of less than 0.05 was considered significant.
Results: All participants (6 male, 1 female) completed full chidamide dosing, and showed acceptable drug tolerance with only grade 1 adverse events presented. No drug accumulation effects were detected per chidamide dosing. In addition, the cyclic increase of histone acetylation in CD4+ T cells was observed. All participants showed robust and cyclic viremia (peak viremia range 147-3850 copies/mL) as well as increased CA-HIV RNA (median peak increase 9.4-fold vs. baseline, range 2.0-fold to 34.9-fold) during chidamide treatment. At day 56, plasma HIV RNA of all participants recovered to undetectable level. Furthermore, we discerned the significant reduction of CA-tHIV DNA (day 27 vs. baseline, p = 0.018, and day 56 vs. baseline, p = 0.028). Equally important was that chidamide exhibited an anti-inflammatory property as evidenced by inhibition of pro-inflammatory cytokines: MCP-1, MMP-9, IP-10, LBP, P-selectin, and CD40 ligand.
Conclusions: Chidamide can safely disrupt the latency of HIV DNA resulting in the clearance of reactivated reservoirs, which makes it a promising candidate toward the eradication of HIV reservoir.