The histone deacetylase inhibitor chidamide induces intermittent viraemia in HIV‐infected patients on suppressive antiretroviral therapy

Abstract

Objectives To evaluate the safety and efficacy of chidamide to reverse HIV‐1 latency in vivo and to compare the effects of four clinically tested histone deacetylase (HDAC) inhibitors on non‐histone proteins in vitro. Methods Participants received chidamide orally at 10 mg twice weekly for 4 weeks while maintaining baseline antiretroviral therapy. The primary outcome was plasma viral rebound during chidamide dosing and the secondary outcomes were safety, pharmacokinetic and pharmacodynamic profiles, changes in cell‐associated HIV‐1 RNA and HIV‐1 DNA, and immune parameters. Western blotting was used to compare the in vitro effects of the four HDAC inhibitors on HSP90, NF‐κB and AP‐1. Results Seven aviraemic participants completed eight oral doses of chidamide, and only grade 1 adverse events were observed. Cyclic increases in histone acetylation were also detected. All participants showed robust and repeated plasma viral rebound (peak viraemia 147–3850 copies/mL), as well as increased cell‐associated HIV‐1 RNA, during chidamide treatment. Furthermore, we identified an enhanced HIV‐1‐specific cellular immune response and a modest 37.7% (95% CI: 12.7–62.8%, P = 0.028) reduction in cell‐associated HIV‐1 DNA. Compared with the other three HDAC inhibitors, chidamide had minimal cytotoxicity in vitro at clinically relevant concentrations and showed mechanistically superior effects on non‐histone proteins, including HSP90, NF‐κB and AP‐1. Conclusions Chidamide safely and vigorously disrupts HIV‐1 latency in vivo, which makes it a promising latency‐reversing agent.

Latency Reversing Agents: Kick and Kill of HTLV-1?

“…In the context of HIV-1 infection, chidamide can reactivate the latent viral reservoir through NF-κB signaling. It is a safe treatment option and can induce intermittent viremia in HIV-1 positive patients and, beyond that, a modest decrease in viral DNA [ 114 , 115 ]. Based on chidamide’s and entinostat’s ability to reactivate HIV-1 from latency, these agents should be further evaluated in the context of HTLV-1 latency reversal.…”

Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment

“…Tucidinostat, a novel and orally active benzamide class of HDAC inhibitor, exhibited high potency for the treatment of cancer and non-cancer diseases, such as the common autoimmune bleeding disorder ITP and AIDS as an antiretroviral therapy (Schmiegelow, 2019;Zhao et al, 2019;Li et al, 2020). In the cancer field, tucidinostat is currently being evaluated in many clinical trials with the most advanced research progress being in the field of hematological malignancies.…”

The Current Status of Latency Reversing Agents for HIV-1 Remission

“…In addition, this class of LRAs has demonstrated an acceptable tolerability in cART-treated individuals infected with HIV-1. However, to date, even if some HDACis could increase HIV production in vivo, clinical trials using HDACis alone have shown no or only a modest decrease in viral reservoir size (35)(36)(37)(38), presumably because the degree of latency reversal was limited and/or the immune system was not primed to clear antigen-expressing cells (27). These results underline the importance of testing combination LRA treatments in order to address the multifactorial and heterogeneous nature of HIV-1 latency (as discussed in the section titled Latency Reversing Agent Combination Therapy) (23).…”