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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by University of California, San Francisco
Sponsor:
Collaborators:
Monash University
amfAR, The Foundation for AIDS Research
Information provided by (Responsible Party):
Steven Deeks, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01944371
First received: September 12, 2013
Last updated: September 24, 2013
Last verified: September 2013
  Purpose

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).


Condition Intervention Phase
HIV
Human Immunodeficiency Virus
Drug: Disulfiram
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Cell associated HIV RNA [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Cell-associated HIV RNA in total and resting CD4 T-cells


Secondary Outcome Measures:
  • Plasma HIV RNA [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    Ultrasensitive plasma HIV RNA

  • Proviral HIV DNA [ Time Frame: 30 days ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • liquid chromatography tandem mass spectrometry [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Measurement of plasma levels of disulfiram, carbamathione, and other metabolites.

  • mRNA expression [ Time Frame: 30 days ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: August 2013
Estimated Study Completion Date: August 2014
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: Antabuse,NDC 0093-5036-01

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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01944371

Contacts
Contact: Marian Kerbleski, R.N. 415-476-4082 ext 144 kerbleskim@php.ucsf.edu
Contact: Rebecca Hoh, M.S., R.D. 415-476-4082 ext 139 rhoh@php.ucsf.edu

Locations
United States, California
San Francisco General Hospital Recruiting
San Francisco, California, United States, 94110
Contact: Marian Kerbleski, RN    415-476-4082 ext 144    kerbleskim@php.ucsf.edu   
Contact: Rebecca Hoh, MS, RD    415-476-4082 ext 139    rhoh@php.ucsf.edu   
Principal Investigator: Steven Deeks, MD         
Australia
Alfred Hospital Recruiting
Melbourne, Australia, 3004
Contact: Michelle Hagenauer    61 3 9076 6908    clinresearch@alfred.org.au   
Contact: Janine Roney    61 3 9076 2296    j.roney@alfred.org.au   
Principal Investigator: Julian Elliott, MD         
Sponsors and Collaborators
University of California, San Francisco
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, Melbourne Australia
  More Information

No publications provided

Responsible Party: Steven Deeks, Professor of Medicine, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01944371     History of Changes
Other Study ID Numbers: 13-10948, DAIDS-ES ID 11864
Study First Received: September 12, 2013
Last Updated: September 24, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, San Francisco:
Latent reservoir

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Disulfiram
Alcohol Deterrents
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 16, 2014