title: A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy.
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.
authors: University of Utah, Salt Lake City.
authors: Adam M
authors: AM
authors: Spivak
authors: Adriana
authors: A
authors: Andrade
authors: Evelyn
authors: E
authors: Eisele
authors: Rebecca
authors: R
authors: Hoh
authors: Peter
authors: P
authors: Bacchetti
authors: Namandjé N
authors: NN
authors: Bumpus
authors: Fatemeh
authors: F
authors: Emad
authors: Robert
authors: R
authors: Buckheit
authors: Elinore F
authors: EF
authors: McCance-Katz
authors: Jun
authors: J
authors: Lai
authors: Margene
authors: M
authors: Kennedy
authors: Geetanjali
authors: G
authors: Chander
authors: Robert F
authors: RF
authors: Siliciano
authors: Janet D
authors: JD
authors: Siliciano
authors: Steven G
authors: SG
authors: Deeks
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D004221:Disulfiram / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D014158:Transcription, Genetic / Q000187:drug effects; D019562:Viral Load / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D004221:Disulfiram
keywords: HIV-1 latent reservoir; disulfiram; latency-reversing agents