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

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT01944371
• Collaborator: Monash University (Other), amfAR, The Foundation for AIDS Research (Other), National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 30
• Locations: 2
• Arms: 3
• Duration (Months): 8
• Patients Per Site: 15
• Patients Per Site Per Month: 1.9

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
HIV; Human Immunodeficiency Virus	Drug: Disulfiram	Phase 1/Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study
• Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Cell-associated HIV RNA [Baseline and 3 days]

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

Secondary Outcome Measures

1. Plasma HIV RNA [Baseline and 3 days]

   Fold change in plasma HIV RNA levels from baseline through day 3

2. Proviral HIV DNA [Baseline and 30 days]

   Fold change in HIV DNA levels between Baseline and Day 30

Other Outcome Measures

1. Disufiram Pharmacokinetics [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	San Francisco General Hospital	San Francisco	California	United States	94110
2	Alfred Hospital	Melbourne		Australia	3004

Sponsors and Collaborators

• University of California, San Francisco
• Monash University
• amfAR, The Foundation for AIDS Research
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Steven Deeks, MD, University of Californa, San Francisco
• Principal Investigator: Julian Elliott, MD, Monash University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Steven Deeks, Professor of Medicine, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01944371
• Other Study ID Numbers: 13-10948; DAIDS-ES ID 11864; K24AI069994
• First Posted: Sep 17, 2013
• Last Update Posted: May 5, 2020
• Last Verified: Dec 1, 2018

• Keywords provided by Steven Deeks, Professor of Medicine, University of California, San Francisco: Latent reservoir
• Additional relevant MeSH terms: HIV Infections; Acquired Immunodeficiency Syndrome; Disulfiram

Study Results

Participant Flow

Recruitment Details	Of 34 participants screened for eligibility, we recruited 30 participants at The Alfred Hospital (Melbourne, VIC, Australia) and the San Francisco General Hospital (San Francisco, CA, USA) between September 24, 2013, and March 31, 2014.

Arm/Group Title	Disulfiram 500mg	Disulfiram 1000mg	Disulfiram 2000mg
Arm/Group Description	500mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	1000mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	2000mg disulfiram per mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.
Period Title: Overall Study
STARTED	10	10	10
COMPLETED	10	10	10
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Disulfiram 500mg	Disulfiram 1000mg	Disulfiram 2000mg	Total
Arm/Group Description	500mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	1000mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	2000mg disulfiram per mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	Total of all reporting groups
Overall Participants	10	10	10	30
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	53	54	51	53
Sex: Female, Male (Count of Participants)
Female	1 10%	0 0%	1 10%	2 6.7%
Male	9 90%	10 100%	9 90%	28 93.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 10%	1 3.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	4 40%	1 10%	1 10%	6 20%
White	6 60%	9 90%	7 70%	22 73.3%
More than one race	0 0%	0 0%	1 10%	1 3.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	4 40%	6 60%	5 50%	15 50%
Australia	6 60%	4 40%	5 50%	15 50%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Disulfiram 500mg	Disulfiram 1000mg	Disulfiram 2000mg
Arm/Group Description	500mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	1000mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	2000mg disulfiram per mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.
Measure Participants	10	10	10
Mean (95% Confidence Interval) [Fold change]	1.7	1.9	1.6

2. Secondary Outcome

Title	Plasma HIV RNA
Description	Fold change in plasma HIV RNA levels from baseline through day 3
Time Frame	Baseline and 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Disulfiram 500mg	Disulfiram 1000mg	Disulfiram 2000mg
Arm/Group Description	500mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	1000mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	2000mg disulfiram per mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.
Measure Participants	10	10	10
Mean (Full Range) [Fold change]	1.50	0.90	1.22

3. Secondary Outcome

Title	Proviral HIV DNA
Description	Fold change in HIV DNA levels between Baseline and Day 30
Time Frame	Baseline and 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Disulfiram 500mg	Disulfiram 1000mg	Disulfiram 2000mg
Arm/Group Description	500mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	1000mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	2000mg disulfiram per mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.
Measure Participants	10	10	10
Mean (95% Confidence Interval) [Fold change]	1.07	0.83	0.91

4. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Disulfiram 500mg	Disulfiram 1000mg	Disulfiram 2000mg
Arm/Group Description	500mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	1000mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.	2000mg disulfiram per mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.
Measure Participants	10	10	10
Mean (97.5% Confidence Interval) [mg-hour/liter]	3,186	8,386	22,331

Adverse Events

Time Frame	Subjects were monitored in an outpatient clinic during the first 6 hours post-dose on days 1 and 3. At each visit, subjects were assessed for any new symptoms and vital signs. A complete blood count and complete metabolic panel were performed during screening, and then at Days 1, 2, 3, 4, 8 and 31. No evaluations were made after Day 31.
Adverse Event Reporting Description	The grading system for drug toxicities is located in the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004 (Clarification, August 2009), which can be found on the DAIDS RSC Web Site (http://rsc.tech-res.com/safetyandpharmacovigilance/.)
Arm/Group Title	Disulfiram 500mg		Disulfiram 1000mg		Disulfiram 2000mg
Arm/Group Description	500mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.		1000mg disulfiram by mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.		2000mg disulfiram per mouth per day for 3 days Disulfiram: This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.
All Cause Mortality
	Disulfiram 500mg		Disulfiram 1000mg		Disulfiram 2000mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)
Serious Adverse Events
	Disulfiram 500mg		Disulfiram 1000mg		Disulfiram 2000mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Disulfiram 500mg		Disulfiram 1000mg		Disulfiram 2000mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/10 (10%)		1/10 (10%)		0/10 (0%)
Hepatobiliary disorders
Increased aspartate aminotransferase	1/10 (10%)	1	1/10 (10%)	1	0/10 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.