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

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ClinicalTrials.gov Identifier: NCT01944371
Recruitment Status : Completed
First Posted : September 17, 2013
Results First Posted : May 5, 2020
Last Update Posted : May 5, 2020
Sponsor:
Collaborators:
Monash University
amfAR, The Foundation for AIDS Research
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
Steven Deeks, University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE September 12, 2013
First Posted Date  ICMJE September 17, 2013
Results First Submitted Date  ICMJE December 8, 2018
Results First Posted Date  ICMJE May 5, 2020
Last Update Posted Date May 5, 2020
Study Start Date  ICMJE September 2013
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 23, 2020)
Cell-associated HIV RNA [ Time Frame: Baseline and 3 days ]
Fold change cell-associated HIV RNA in Total CD4 T-Cells.
Original Primary Outcome Measures  ICMJE
 (submitted: September 16, 2013)
Cell-associated HIV RNA [ Time Frame: 30 days ]
Cell-associated HIV RNA in total and resting CD4 T-cells
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2020)
  • Plasma HIV RNA [ Time Frame: Baseline and 3 days ]
    Fold change in plasma HIV RNA levels from baseline through day 3
  • Proviral HIV DNA [ Time Frame: Baseline and 30 days ]
    Fold change in HIV DNA levels between Baseline and Day 30
Original Secondary Outcome Measures  ICMJE
 (submitted: September 16, 2013)
  • Plasma HIV RNA [ Time Frame: 30 days ]
    Ultrasensitive plasma HIV RNA
  • Proviral HIV DNA [ Time Frame: 30 days ]
Current Other Pre-specified Outcome Measures
 (submitted: April 23, 2020)
Disufiram Pharmacokinetics [ Time Frame: 31 days ]
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.
Original Other Pre-specified Outcome Measures
 (submitted: September 16, 2013)
  • liquid chromatography tandem mass spectrometry [ Time Frame: 30 days ]
    Measurement of plasma levels of disulfiram, carbamathione, and other metabolites.
  • mRNA expression [ Time Frame: 30 days ]
 
Descriptive Information
Brief Title  ICMJE Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study
Official Title  ICMJE Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study
Brief Summary 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).
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • HIV
  • Human Immunodeficiency Virus
Intervention  ICMJE Drug: Disulfiram
This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.
Other Name: Antabuse,NDC 0093-5036-01
Study Arms  ICMJE
  • Experimental: disulfiram 500mg
    500mg disulfiram by mouth per day for 3 days
    Intervention: Drug: Disulfiram
  • Experimental: disulfiram 1000mg
    1000mg disulfiram by mouth per day for 3 days
    Intervention: Drug: Disulfiram
  • Experimental: disulfiram 2000mg
    2000mg disulfiram per mouth per day for 3 days
    Intervention: Drug: Disulfiram
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 16, 2013)
30
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2014
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01944371
Other Study ID Numbers  ICMJE 13-10948
DAIDS-ES ID 11864 ( Other Grant/Funding Number: NIAID )
K24AI069994 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Steven Deeks, University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE
  • Monash University
  • amfAR, The Foundation for AIDS Research
  • National Institute of Allergy and Infectious Diseases (NIAID)
Investigators  ICMJE
Principal Investigator: Steven Deeks, MD University of Californa, San Francisco
Principal Investigator: Julian Elliott, MD Monash University
PRS Account University of California, San Francisco
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP