Chidamide reactivates and diminishes latent HIV-1 DNA in patients on suppressive antiretroviral therapy
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.
Y. Sun1, J. Li1, J. Ma2, C. Wang1, F. Bai1,3, K. Zhao1,4, Z. Yu1,5, W. Kang6, Y. Zhuang1, N. Yao1, Q. Liu1, B. Dang1, B. Wang1, Q. Wei1, Z. Liu1, L. Wang1, W. Kang1, L. Wang1, J. Xia1, T. Wang7, T. Zhu8
1Fourth Military Medical University, Xi'an, China, 2Xi'an Jiaotong University, Xi'an, China, 3323th Hospital of PLA, Xi'an, China, 4Xi'an Communication Institute, Xi'an, China, 5Political Work Department of People's Republic of China Central Military Commission, Beijing, China, 6Fourth Military Medical University, Department of Infectious Diseases, Tangdu Hospital, Xi'an, China, 7Jinan University, Institute of Life and Health Engineering, College of Life Science and Technology, Guangzhou, China, 8University of Washington, Department of Laboratory Medicine, Seattle, United States