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Lancet HIV. 2015 Dec;2(12):e520-9. doi: 10.1016/S2352-3018(15)00226-X. Epub 2015 Nov 17.

Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study.

Author information

1
Department of Infectious Diseases, Monash University and Alfred Hospital, Melbourne, VIC, Australia.
2
Department of Infectious Diseases, Monash University and Alfred Hospital, Melbourne, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
3
University of California San Francisco, San Francisco, CA, USA.
4
Johns Hopkins University, Baltimore, MD, USA.
5
The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
6
AIDS and Cancer Virus Program, Leidos Biomedical Research Inc, Frederick National Laboratory, Frederick, MD, USA.
7
Department of Infectious Diseases, Monash University and Alfred Hospital, Melbourne, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. Electronic address: sharon.lewin@unimelb.edu.au.

Abstract

BACKGROUND:

In vitro, disulfiram activated HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate drug exposure. We assessed the effect of disulfiram on HIV transcription in a dose-escalation study.

METHODS:

In this prospective dose-escalation study, to optimise disulfiram exposure we included adults with HIV on suppressive antiretroviral therapy, with plasma HIV RNA of less than 50 copies per mL and a CD4 cell count greater than 350 cells per μL. Participants were allocated sequentially to one of three dosing groups (500 mg, 1000 mg, and 2000 mg) and received disulfiram daily for 3 days. Only the staff who did laboratory assays were masked to group assignment. The primary endpoint was change in cell-associated unspliced HIV RNA in CD4 cells. The primary analysis method was a negative binomial regression, with the number of copies as the outcome variable and the input total RNA or plasma volume as an exposure variable, which is equivalent to modelling copies or input. We used these models to estimate changes from before disulfiram to timepoints during and after disulfiram administration. This study is registered with ClinicalTrials.gov, number NCT01944371.

FINDINGS:

Of 34 participants screened for eligibility at The Alfred Hospital (Melbourne, VIC, Australia), and San Francisco General Hospital (San Francisco, CA, USA), 30 people were enrolled between Sept 24, 2013, and March 31, 2014. The estimated fold increases in cell-associated unspliced HIV RNA from baseline were 1·7 (95% CI 1·3-2·2; p<0·0001) to the timepoint during disulfiram treatment and 2·1 (1·5-2·9; p<0·0001) to the timepoint after disulfiram in the 500 mg group; 1·9 (1·6-2·4; p<0·0001) and 2·5 (1·9-3·3; p<0·0001) in the 1000 mg group; and 1·6 (1·2-2·1; p=0·0026) and 2·1 (1·5-3·1; p=0·0001) in the 2000 mg group. No deaths occurred, and no serious adverse events were noted. Disulfiram was well tolerated at all doses.

INTERPRETATION:

Short-term administration of disulfiram resulted in increases in cell-associated unspliced HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV.

FUNDING:

The Foundation for AIDS Research (amfAR); National Institute of Allergy and Infectious Diseases, National Institutes of Health; Australian National Health and Medical Research Council.

PMID:
26614966
PMCID:
PMC5108570
DOI:
10.1016/S2352-3018(15)00226-X
[Indexed for MEDLINE]
Free PMC Article

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