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Short-Term Disulfiram to Reverse Latent HIV Infection: A Dose Escalation Study
Julian H. Elliott1, James H. McMahon1, Wendy Hartogensis2, Namandje Bumpus3, Christina Chang4, Sulggi A. Lee2, Jeff Lifson5, Peter Bacchetti2, Steven Deeks2, Sharon R. Lewin4
1 Department of Infectious Diseases, Monash University/Alfred Hospital, Melbourne, VIC, Australia. 2 University of California San Francisco, San Francisco, CA, United States. 3 Johns Hopkins University, Baltimore, MD, United States. 4 Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. 5 National Cancer Institute, Frederick, MD, United States.
Background: Disulfiram (DSF) is a licensed oral agent, dosed daily and well tolerated in the absence of alcohol. DSF reactivates HIV in a primary T-cell model of HIV latency and had a variable effect on plasma HIV RNA in a pilot clinical study.
Methods: We conducted a prospective dose escalation study. Three cohorts of participants on suppressive antiretroviral therapy (n=10 each) were sequentially enrolled and received DSF daily for three days at doses of 500mg (licensed dose), 1000mg or 2000mg. Baseline samples were obtained at three pre-dosing timepoints (B1-B3); 2, 6 and 24 hours after the first and third doses; and at days 8 and 31. The primary endpoint was cell-associated unspliced HIV RNA (CA-US RNA) in CD4 T-cells. Random intercept negative binomial regression models were used to estimate changes from pre-DSF baseline to timepoints during DSF dosing (days 1-3) and post-DSF. Standard non-compartmental methods were used to estimate pharmacokinetic parameters.
Results: DSF was well-tolerated at all doses. Compared to the mean of three pre-DSF time points, the estimated fold-increases in CA-US RNA during and post-DSF for each cohort were: 500mg: 1.7 (95% confidence interval 1.3 – 2.2) and 2.1 (1.5 – 2.9); 1000mg: 1.9 (1.6 – 2.4) and 2.5 (1.9 – 3.3); and 2000mg: 1.6 (1.2 – 2.1) and 2.1 (1.5 – 3.1) (p<0.01 for all). Of the three baseline samples, the third (B3) was collected earlier in the day, prior to first dose. CA-US RNA (but not DNA or plasma RNA) at this timepoint was substantially higher (p<0.0001). Using B3 only as the baseline, increases in CA-US RNA during and post-DSF were still observed, but were modest (fold change range 1.0 – 1.6). Compared to the pre-DSF time points, no consistent changes in plasma HIV RNA were noted during dosing, but an increase was seen post-dosing in the cohort receiving 2000mg/day (fold change 1.9 [95% CI 1.3 – 2.7], p=0.001). In a post-hoc analysis of the subgroup of participants with high baseline CA-US RNA and high exposure to DSF or its metabolites, there were significant increases in plasma HIV RNA at days 8 and 31 (fold-change ranged from 1.6 – 2.0 ; all p<0.032).
Conclusions: Short-term administration of disulfiram resulted in increased CA-US RNA during dosing and up to 4 weeks after the last dose. Possible diurnal variation in baseline CA-US RNA levels was noted, complicating the analysis. The late post-DSF increases in both CA-US RNA and plasma HIV RNA remain unexplained, but are consistent with trends observed with other latency reversing agents.