The Histone Deacetylase Inhibitor Chidamide Induces Intermittent Viraemia in HIV-Infected Patients on Suppressive Antiretroviral Therapy

JH Li; J Ma; W Kang; CF Wang; F Bai; K Zhao; N Yao; Q Liu; BL Dang; BW Wang; QQ Wei; WZ Kang; YT Sun

Disclosures

HIV Medicine. 2020;21(11):747-757. 

In This Article

Abstract and Introduction

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.

Introduction

The advent and subsequent implementation of combination antiretroviral therapy (cART) has transformed HIV-1 infection from a fatal disease to a treatable chronic inflammatory illness.[1] However, in most cases, HIV-1 replication will resume several weeks after the cessation of cART despite years of treatment.[2] This viral rebound primarily originates from long-lived latently infected resting CD4 T cells and, to an unknown extent, other cell populations, in which the genome incorporates transcriptionally silent, non-productive but replication-competent HIV-1 proviruses.[3] These cells comprise the latent reservoir and are unrecognizable to the immune system and unresponsive to cART, representing a major barrier to cure.[4]

A proposed strategy to purge the latent reservoir is to reactivate provirus expression with latency-reversing agents (LRAs), inducing viral antigen expression and allowing for the elimination of virus-producing cells via viral cytopathic effects and immune-mediated mechanisms in the presence of cART to prevent new infections.[5] Many efforts have been made to identify effective LRAs or their combinations that can induce robust latency reversal without significant toxicities.[6] Early clinical trials have demonstrated that three histone deacetylase (HDAC) inhibitors, namely, vorinostat, panobinostat and romidepsin, can disrupt HIV-1 latency in vivo.[7–9] However, only modest perturbation of the latency has been observed to date.

Chidamide is a low nanomolar HDAC inhibitor of the benzamide class,[10] which was approved in 2014 by the China Food and Drug Administration for use in relapsed or refractory peripheral T-cell lymphoma. Chidamide was demonstrated to reactivate latent HIV-1 in cell line models and in primary CD4 T cells from HIV-1-infected individuals.[11,12] Here, we conducted a phase 1b/2a clinical trial to evaluate the safety and efficacy of chidamide to reverse HIV-1 latency in cART-suppressed patients. Further, we compared the in vitro effects of the four HDAC inhibitors on cellular factors vital for HIV-1 gene expression at clinically relevant concentrations.

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