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

Primary Purpose

HIV, Human Immunodeficiency Virus

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Disulfiram
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for HIV focused on measuring Latent reservoir

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • San Francisco General Hospital
  • Alfred Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

disulfiram 500mg

disulfiram 1000mg

disulfiram 2000mg

Arm Description

500mg disulfiram by mouth per day for 3 days

1000mg disulfiram by mouth per day for 3 days

2000mg disulfiram per mouth per day for 3 days

Outcomes

Primary Outcome Measures

Cell-associated HIV RNA
Fold change cell-associated HIV RNA in Total CD4 T-Cells.

Secondary Outcome Measures

Plasma HIV RNA
Fold change in plasma HIV RNA levels from baseline through day 3
Proviral HIV DNA
Fold change in HIV DNA levels between Baseline and Day 30

Full Information

First Posted
September 12, 2013
Last Updated
April 23, 2020
Sponsor
University of California, San Francisco
Collaborators
Monash University, amfAR, The Foundation for AIDS Research, National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT01944371
Brief Title
Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study
Official Title
Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study
Study Type
Interventional

2. Study Status

Record Verification Date
December 2018
Overall Recruitment Status
Completed
Study Start Date
September 2013 (undefined)
Primary Completion Date
May 2014 (Actual)
Study Completion Date
May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, San Francisco
Collaborators
Monash University, amfAR, The Foundation for AIDS Research, National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV, Human Immunodeficiency Virus
Keywords
Latent reservoir

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
disulfiram 500mg
Arm Type
Experimental
Arm Description
500mg disulfiram by mouth per day for 3 days
Arm Title
disulfiram 1000mg
Arm Type
Experimental
Arm Description
1000mg disulfiram by mouth per day for 3 days
Arm Title
disulfiram 2000mg
Arm Type
Experimental
Arm Description
2000mg disulfiram per mouth per day for 3 days
Intervention Type
Drug
Intervention Name(s)
Disulfiram
Other Intervention Name(s)
Antabuse,NDC 0093-5036-01
Intervention Description
This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.
Primary Outcome Measure Information:
Title
Cell-associated HIV RNA
Description
Fold change cell-associated HIV RNA in Total CD4 T-Cells.
Time Frame
Baseline and 3 days
Secondary Outcome Measure Information:
Title
Plasma HIV RNA
Description
Fold change in plasma HIV RNA levels from baseline through day 3
Time Frame
Baseline and 3 days
Title
Proviral HIV DNA
Description
Fold change in HIV DNA levels between Baseline and Day 30
Time Frame
Baseline and 30 days
Other Pre-specified Outcome Measures:
Title
Disufiram Pharmacokinetics
Description
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.
Time Frame
31 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steven Deeks, MD
Organizational Affiliation
University of Californa, San Francisco
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Julian Elliott, MD
Organizational Affiliation
Monash University
Official's Role
Principal Investigator
Facility Information:
Facility Name
San Francisco General Hospital
City
San Francisco
State/Province
California
ZIP/Postal Code
94110
Country
United States
Facility Name
Alfred Hospital
City
Melbourne
ZIP/Postal Code
3004
Country
Australia

12. IPD Sharing Statement

Citations:
PubMed Identifier
26614966
Citation
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.
Results Reference
derived

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

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