Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study

The purpose of this study is to determine the safety, pharmacology and bioactivity of disulfiram in antiretroviral treated HIV-infected adults. The investigators primary hypothesis is that 3 days of disulfiram will result in an increase in HIV transcription in CD4+ T-cells in patients on suppressive antiretroviral therapy (ART).

Study Overview

• Status: Completed
• Conditions: HIV; Human Immunodeficiency Virus
• Intervention / Treatment: Drug: Disulfiram

Detailed Description

Combination antiretroviral therapy for HIV-1 infection can suppress viremia to below the detection limit in the vast majority of motivated individuals with access to these drugs. However, HIV-1 persists in a small pool of latently infected resting memory CD4+ T cells carrying integrated viral genomes. Although other reservoirs for HIV-1 exist, the general consensus among experts is that latent virus (HIV DNA in resting memory CD4+ T cells) is the primary barrier to HIV-1 eradication. A widely discussed approach for eliminating this viral reservoir requires reactivation of latent HIV-1. Disulfiram, an FDA-approved drug used to treat alcoholism was shown to activate HIV-1 gene expression in vitro, suggesting that activation of latently infected cells in vivo may occur. Our primary hypothesis is that the addition of disulfiram to a stable effective antiretroviral drug regimen will result in a dose dependent increase in HIV transcription in CD4+ T-cells in HIV-1 in patients on highly active antiretroviral therapy (HAART).

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia, 3004
    • Alfred Hospital
• United States
  • California
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 infection
• Age 18 or older
• HIV plasma viral load <50 copies/ml for at least 3 years with at least one measurement per year and most recent viral load within 3 months of screening.
• Receiving combination antiretroviral therapy (at least 3 agents); subjects must be on a efavirenz-based or a ritonavir-based regimen
• Two CD4+ T cell counts greater than 350 cell/µl in the six months prior to screening
• Willing to abstain from any alcohol one day before, during the three day period in which disulfiram will be administered and the two week period immediately after disulfiram administration

Exclusion Criteria:

• Current alcohol use disorder or hazardous alcohol use
• Current use of any drug formulation that contains alcohol or that might contain alcohol, including the gelatin capsule and liquid formulations of ritonavir, ritonavir/lopinavir, amprenavir and fosamprenavir.
• Current use of tipranavir or maraviroc.
• Current use of zidovudine, stavudine or didanosine (as disulfiram potentially has potent irreversible inhibitory effects on mitochondrial metabolism and hence could exacerbate the toxicity of these drugs).
• Concurrent use of rivaroxaban ( a CYP3A metabolized medication) as the cytochrome P450 inhibitory effects of disulfiram on rivaroxaban are unknown.
• Current use of warfarin
• Patients who are intending to modify antiretroviral therapy in the next 2 weeks for any reason.
• Serious illness requiring hospitalization or parental antibiotics within preceding 3 months
• A screening hemoglobin below 12.5 g/dL
• A screening TSH consistent with Hypothyroidism
• Significant renal disease or acute nephritis
• Significant myocardial disease or diagnosed coronary artery disease
• Significant respiratory disease
• History of psychosis, seizure disorder, abnormal electroencephalogram or brain damage with significant persisting neurological deficit.
• Clinically active hepatitis as evidenced by clinical jaundice or Grade 2 or higher liver function test abnormalities.
• Hepatic cirrhosis or decompensated chronic liver disease.
• Diabetes or current hypothyroidism.
• Concurrent treatment with immunomodulatory drugs, or exposure to any immunomodulatory drug in past 16 weeks.
• Recent exposure (within the preceding 8 weeks) to any vaccine.
• Pregnant or breastfeeding women. Women of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.
• Significant substance use, which in the opinion of the investigator, is likely to interfere with the conduct of the study.
• Prior or current use of disulfiram, vorinostat or other experimental agent used with the intent to perturb the HIV-1 viral reservoir
• Current use of an antiretroviral regimen which does not include either efavirenz or a protease inhibitor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: disulfiram 500mg; 500mg disulfiram by mouth per day for 3 days	Drug: Disulfiram; This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.; Other Names: Antabuse,NDC 0093-5036-01
Experimental: disulfiram 1000mg; 1000mg disulfiram by mouth per day for 3 days	Drug: Disulfiram; This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.; Other Names: Antabuse,NDC 0093-5036-01
Experimental: disulfiram 2000mg; 2000mg disulfiram per mouth per day for 3 days	Drug: Disulfiram; This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.; Other Names: Antabuse,NDC 0093-5036-01

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cell-associated HIV RNA	Fold change cell-associated HIV RNA in Total CD4 T-Cells.	Baseline and 3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma HIV RNA	Fold change in plasma HIV RNA levels from baseline through day 3	Baseline and 3 days
Proviral HIV DNA	Fold change in HIV DNA levels between Baseline and Day 30	Baseline and 30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disufiram Pharmacokinetics	Plasma concentrations of disulfiram were measured on dosing day 1 (hours 0, 2, and 6), day 2 (hour 0), and day 3 (hours 0, 2, and 6), as well as on postdosing days 4, 8, and 31. The area under the curve (AUC) levels over 72 hours was estimated.	31 days

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Monash University; amfAR, The Foundation for AIDS Research
• Investigators: Principal Investigator: Steven Deeks, MD, University of Californa, San Francisco; Principal Investigator: Julian Elliott, MD, Monash University

Publications and helpful links

General Publications

• Elliott JH, McMahon JH, Chang CC, Lee SA, Hartogensis W, Bumpus N, Savic R, Roney J, Hoh R, Solomon A, Piatak M, Gorelick RJ, Lifson J, Bacchetti P, Deeks SG, Lewin SR. Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study. Lancet HIV. 2015 Dec;2(12):e520-9. doi: 10.1016/S2352-3018(15)00226-X. Epub 2015 Nov 17.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: September 12, 2013
• First Submitted That Met QC Criteria: September 16, 2013
• First Posted (Estimate): September 17, 2013

Study Record Updates

• Last Update Posted (Actual): May 5, 2020
• Last Update Submitted That Met QC Criteria: April 23, 2020
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Latent reservoir
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Alcohol Deterrents; Acetaldehyde Dehydrogenase Inhibitors; Disulfiram
• Other Study ID Numbers: 13-10948; DAIDS-ES ID 11864 (Other Grant/Funding Number: NIAID); K24AI069994 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No