Anti-alcoholism drug reactivates latent HIV-1 infection

Short-term administration of the anti-alcoholism drug disulfiram appeared to reactivate latent HIV-1 infection in vivo, indicating its potential to eliminate viral reservoir, according to the results of a phase 2 study.

“Combination [ART] has profound health benefits for people with HIV but is not able to cure the infection,” Julian H. Elliot, MBBS, of the department of infectious diseases at Monash University, Melbourne, Australia, and colleagues wrote. “This inability to cure is primarily because HIV establishes latent infection, particularly in long-lived memory CD2 T-cells. A major strategy under investigation is the elimination of latently infected cells by inducing production of virus from these cells and thus making the cell susceptible to virus-induced cytolysis or killing by HIV-specific T-cells (shock and kill).”

Disulfiram, an FDA-approved drug used to treat alcoholism, recently demonstrated its ability to activate HIV transcription in latent CD4 cells, according to researchers. In an earlier study published in Clinical Infectious Diseases, 500 mg disulfiram was administered daily for 2 weeks in patients with HIV-1 infection receiving ART. There was no significant change in the size of the viral reservoir after 10 weeks of treatment; however, a post-hoc analysis showed residual viremia rapidly and transiently increased 2.96-fold (95% CI, 1.29-6.81) in patients with an immediate post-dose sampling. No serious adverse events were reported. The researchers concluded that future studies should evaluate the drug in higher doses to determine whether there is a dose-dependent effect.

“The apparent exposure-response effect observed in this study highlights significant inter-subject variability in disulfiram pharmacokinetics and suggest that higher doses of disulfiram might be more effective,” they wrote.

In the current analysis, Elliot and colleagues assessed several doses of disulfiram in HIV-infected patients receiving stable ART who had less than 50 copies per mL of plasma HIV RNA and a CD4 count greater than 350 cells per µL.

A 3-day regimen of disulfiram was administered to 30 patients (90% men; median age 54.3 years) at The Alfred Hospital in Melbourne, Australia, and San Francisco General Hospital between Sept. 24, 2013 and March 31, 2014. Ten patients received 500 mg disulfiram, 10 patients received 1,000 mg, and 10 patients received 2,000 mg.

The only significant increase in mean plasma HIV RNA before, during and after disulfiram administration was observed in patients who received 2,000 mg disulfiram, according to researchers. A 1.7-fold (95% CI, 1.14-2.7) increase was observed on day 7 and a twofold increase (95% CI, 1.3-3.1) was observed on day 30.

From baseline, the researchers estimated that cell-associated unspliced HIV RNA increased:

1.7-fold (95% CI, 1.3-2.2) during 500 mg treatment and 2.1-fold (95% CI, 1.5-2.9) posttreatment;
1.9-fold (95% CI, 1.6-2.4) during 1,000 mg treatment and 2.5-fold (95% CI, 1.9-3.3) posttreatment; and
1.6-fold (95% CI, 1.2-2.1) during 2,000 mg treatment and 2.1-fold (95% CI, 1.5-3.1) posttreatment.

Cell-associated unspliced HIV RNA concentrations were highest at day 30, when the last samples were collected.

“In vitro, an increase in HIV transcription in latently infected cells lines with disulfiram was mediated by depletion of the phosphatase and tensin homologue protein and activation of protein kinase B, but whether this is the main mechanism in vivo is unknown.”

Although disulfiram was administered up to four times the current licensed dose of 6 g, the drug was safe and well-tolerated, the researchers wrote. Minor adverse events occurred more frequently in higher-dosing cohorts, with no events in the 500-mg group, 10 events in the 1,000-mg group and 14 events in the 2,000-mg group.

“In view of the good safety profile, disulfiram might be suited for future studies of combination therapy to activate latent HIV,” the researchers concluded. – by Stephanie Viguers

References:

Elliott JH, et al. Lancet HIV. 2015;doi:10.1016/S2352-3018(15)00226-X.

Spivak AM, et al. Clin Infect Dis. 2013;doi:10.1093/cid/cit813.

Disclosure: Elliott reports that his institution received funding from Gilead Sciences, Merck and ViiV Healthcare for investigator-initiated research and for chairing and speaking at educational activities. Please see the full studies for a list of all other authors’ relevant financial disclosures.