A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy

Adam M. Spivak, Adriana Andrade, Evelyn Eisele, Rebecca Hoh, Peter Bacchetti, Namandjé N. Bumpus, Fatemeh Emad, Robert Buckheit, Elinore F. Ccance-Katz, Jun Lai, Margene Kennedy, Geetanjali Chander, Robert F. Siliciano, Janet D. Siliciano, Steven G. Deeks

Research output: Contribution to journalArticlepeer-review

Abstract

Background. Transcriptionally silent human immunodeficiency virus type 1 (HIV-1) DNA persists in resting memory CD4+ T cells despite antiretroviral therapy. In a primary cell model, the antialcoholism drug disulfiram has been shown to induce HIV-1 transcription in latently infected resting memory CD4+ T cells at concentrations achieved in vivo.Methods. We conducted a single-arm pilot study to evaluate whether 500 mg of disulfiram administered daily for 14 days to HIV-1-infected individuals on stable suppressive antiretroviral therapy would result in reversal of HIV-1 latency with a concomitant transient increase in residual viremia or depletion of the latent reservoir in resting memory CD4+ T cells.Results. Disulfiram was safe and well tolerated. There was a high level of subject-to-subject variability in plasma disulfiram levels. The latent reservoir did not change significantly (1.16-fold change; 95% confidence interval [CI],. 70- to 1.92-fold; P =. 56). During disulfiram administration, residual viremia did not change significantly compared to baseline (1.53-fold; 95% CI,. 88- to 2.69-fold; P =. 13), although residual viremia was estimated to increase by 1.88-fold compared to baseline during the postdosing period (95% CI, 1.03- to 3.43-fold; P =. 04). In a post hoc analysis, a rapid and transient increase in viremia was noted in a subset of individuals (n = 6) with immediate postdose sampling (HIV-1 RNA increase, 2.96-fold; 95% CI, 1.29- to 6.81-fold; P =. 01).Conclusions. Administration of disulfiram to patients on antiretroviral therapy does not reduce the size of the latent reservoir. A possible dose-related effect on residual viremia supports future studies assessing the impact of higher doses on HIV-1 production. Disulfiram affects relevant signaling pathways and can be safely administered, supporting future studies of this drug.

Original languageEnglish (US)
Pages (from-to)883-890
Number of pages8
JournalClinical Infectious Diseases
Volume58
Issue number6
DOIs
StatePublished - Mar 2014

Keywords

  • HIV-1 latent reservoir
  • disulfiram
  • latency-reversing agents

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of 'A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy'. Together they form a unique fingerprint.

Cite this