Journal
CLINICAL INFECTIOUS DISEASES
Volume 58, Issue 6, Pages 883-890Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/cid/cit813
Keywords
HIV-1 latent reservoir; disulfiram; latency-reversing agents
Categories
Funding
- ARCHE Collaborative Research Grant from the Foundation for AIDS Research
- NIH [AI096113, 1U19AI096109, 43222]
- National Institute of Allergy and Infectious Diseases [K24 AI069994]
- UCSF/Gladstone Center for AIDS Research [P30 AI027763]
- UCSF Clinical and Translational Science Institute [UL1 RR024131]
- Johns Hopkins Center for AIDS Research
- Howard Hughes Medical Institute
- Center for AIDS Prevention Studies [P30 MH62246]
- Johns Hopkins ICTR
- NCATS, a component of the NIH [UL1 TR 000424-06]
- NIH Roadmap for Medical Research
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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.
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