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. 2014 Mar;58(6):883-90.
doi: 10.1093/cid/cit813. Epub 2013 Dec 12.

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

Adam M Spivak  1 , Adriana Andrade, Evelyn Eisele, Rebecca Hoh, Peter Bacchetti, Namandjé N Bumpus, Fatemeh Emad, Robert Buckheit 3rd, Elinore F McCance-Katz, Jun Lai, Margene Kennedy, Geetanjali Chander, Robert F Siliciano, Janet D Siliciano, Steven G Deeks
Affiliations

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

Adam M Spivak et al. Clin Infect Dis. 2014 Mar.

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.

Keywords: HIV-1 latent reservoir; disulfiram; latency-reversing agents.

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Figures

Figure 1.
Figure 1.
Timing of trial events. After enrollment, participants underwent several baseline measurements of residual viremia using a highly sensitive quantitative real-time reverse transcriptase polymerase chain reaction assay (the single-copy assay). Five hundred milligrams of disulfiram was administered daily from day 0 to day 13. A 180-mL blood sample was obtained at day –14 and again on day 84 to estimate the frequency of latently infected cells in peripheral blood using a limiting dilution co-culture method. Safety laboratory tests including a complete blood count and metabolic panel were drawn weekly before, during, and 2 weeks after disulfiram administration, and monthly thereafter. Abbreviation: DSF, disulfiram.
Figure 2.
Figure 2.
Effect of disulfiram (DSF) on latent reservoir size. No substantial change in the frequency of latently infected cells was observed 10 weeks after disulfiram administration compared to baseline as measured by limiting dilution co-culture assay (post-DSF fold-effect = 1.16; 95% confidence interval, .70–1.92; P = .56). *Dashed lines/open circles represent 3 co-culture assays in which no infected cells were identified (these co-cultures had 12.5 million to 27.5 million cells assayed). Abbreviation: IUPM, infectious units per million.
Figure 3.
Figure 3.
Individual single-copy assay and disulfiram (DSF) plasma concentration results. The gray bar (between days 0 and 13) represents the period of directly observed DSF administration. Half of Johns Hopkins Hospital participants (numbers 7151–7161) had an increase in viremia within several hours of the first DSF dose, but viremia during DSF administration after that time averaged only slightly higher than baseline and was not statistically significant. Six of 15 participants had detectable DSF plasma concentrations during the dosing interval. The lower limit of detection of DSF plasma concentrations using mass spectrometry was 15 ng/mL.
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