Short-term Disulfiram Administration to Accelerate the Decay of the HIV Reservoir in Antiretroviral-treated HIV Infected Individuals

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT01286259
• Collaborator: Johns Hopkins University (Other)
• Enrollment: 16
• Locations: 2
• Arm: 1
• Duration (Months): 40
• Patients Per Site: 8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether a two-week course of disulfiram will reduce the HIV-1 latent reservoir in patients on highly active antiretroviral therapy (HAART).

Condition or Disease	Intervention/Treatment	Phase
HIV-1 Infection	Drug: Disulfiram	N/A

Detailed Description

This study is using a new approach to try and force HIV out of its protected cellular reservoirs.

Although current therapies are effective at "killing" new viruses that are produced, they are unable to access the virus in cells which were infected before antiretroviral therapy began. HIV can remain "hidden" in a latent (or resting) form in these cells for many years. Since these infected cells can live for many years, they are thought to be the most important barrier to HIV eradication (or "cure").

Many experts believe that one way to attack latent or "hidden" HIV is to use a drug than can "turn on" the virus and hence force HIV-1 out of resting T cells. In a recent study done in the laboratory, disulfiram proved to be among the most effective drugs currently available that can reactivate latent HIV-1,

Our primary hypothesis is that disulfiram will reduce the latent reservoir of HIV-1 in patients on highly active antiretroviral therapy (HAART). Theoretically, disulfiram will force HIV to replicate (grow) and thus result in the death of the infected cell. Standard antiretroviral drugs should prevent new cells from becoming infected. The end result of this process is that the total amount of HIV in the body will decline over time.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Short-term Disulfiram Administration to Accelerate the Decay of the HIV Reservoir in Antiretroviral-treated HIV Infected Individuals
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intervention Arm	Drug: Disulfiram; Open label 500mg disulfiram per day by mouth for 14 days; Other Names: Antabuse

Outcome Measures

Primary Outcome Measures

1. Impact of Two Weeks of Disulfiram, as Measured by the Fold Change in the Infectious Units Per Million Cells (IUPM) Between Baseline and Week 12 [12 weeks]

   The size of the latent reservoir from each participant was measured by limiting dilution co-culture assay and reported as "infectious units per million cells" (IUPM).This assay measures the frequency of peripheral blood cells from which replication-competent HIV can be grown. The assay was performed at a baseline visit (two weeks before dosing began) and week 12 (10 weeks after the last dose). The primary outcome was the fold-change in IUPM before and after disufiram.

2. Number of Participants With Adverse Events [Two weeks]

   The safety and tolerability of a two-week course of disulfiram was defined using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009). Details are available on the RSC website (http://rsc.tech-res.com/safetyandpharmacovigilance/). The number of adverse events and their grade was determined for each subject.

3. The Fold Change in Mean Levels of Viremia During and After Disulfiram Dosing as Compared to Baseline Levels [Baseline to Day 18]

   Residual viremia was measured using a singe copy assay (SCA) in plasma samples obtained at enrollment, Days -14, -7, 0, 2, 4, 7, 9, 11, 14, 16, and 18, and at weeks 3, 4, 8 and 12. The level of residual viremia measured by SCA prior to disulfiram (Days 14, 17 and 0), during treatment (Days 1 to 14) and after dosing (Days 16 and 18) was modelled using negative binomial regression, and reported as the mean fold-change during and after disulfiram as compared to that during the baseline period.

4. Number of Participants With Detectable Plasma HIV RNA [Two weeks]

   Plasma HIV RNA levels were measured weekly using a commercial assay. The number of participants who had a detectable viral load (> 50 copies RNA/mL) was determined.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Documented continuous HAART for at least 18 months prior to study entry and on a stable regimen for at least 3 months prior to entry.

• Documented undetectable HIV viral loads for at least one year. Intermittent isolated episodes of detectable low-level viremia "blips" (> 50 but < 500 copies RNA/mL) remain eligible.

• Screening plasma HIV-1 RNA levels < 40 copies RNA/mL.

• CD4 T-cell count above 200 cells/uL for 24 weeks prior to screen.

• 90% adherence to therapy within the preceding 30 days.

• Females 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.

• Willing to abstain from any alcohol during the two week period in which disulfiram will be administered and during the two week period immediately after disulfiram administration.

Exclusion Criteria:

• Current alcohol use disorder or hazardous alcohol use as determined by clinical evaluation.

• Current use of any drug formulation that contains alcohol or that might contain alcohol.

• Current use of tipranavir.

• Current use of maraviroc.

• Current use of warfarin.

• Intending to modify antiretroviral therapy in the next 27 weeks for any reason.

• Serious illness requiring hospitalization or parental antibiotics within preceding 3 months.

• Severe myocardial disease or coronary artery disease.

• History of psychosis.

• Clinically active hepatitis determined by the study physician; ALT or AST >3 x the upper limit of normal.

• Concurrent treatment with immunomodulatory drugs, or exposure to any immunomodulatory drug in past 16 weeks.

• Pregnant or breastfeeding women.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	San Francisco General Hospital	San Francisco	California	United States	94110
2	Johns Hopkins University	Baltimore	Maryland	United States	21205

Sponsors and Collaborators

• University of California, San Francisco
• Johns Hopkins University

Investigators

• Principal Investigator: Steven G. Deeks, M.D., University of California, San Francisco
• Principal Investigator: Adriana Andrade, M.D., Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01286259
• Other Study ID Numbers: IRB 10-02648
• First Posted: Jan 31, 2011
• Last Update Posted: Jun 30, 2020
• Last Verified: Jun 1, 2020

• Keywords provided by University of California, San Francisco: HIV; HAART suppressed; Disulfiram; Antabuse; Latent reservoir; Eradication; Cure
• Additional relevant MeSH terms: Disulfiram

Study Results

Participant Flow

Arm/Group Title	Intervention Arm
Arm/Group Description	Disulfiram: Open label 500mg disulfiram per day by mouth for 14 days
Period Title: Overall Study
STARTED	16
COMPLETED	16
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Intervention Arm
Arm/Group Description	Disulfiram: Open label 500mg disulfiram per day by mouth for 14 days
Overall Participants	16
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	47.5
Sex: Female, Male (Count of Participants)
Female	1 6.3%
Male	15 93.8%
Region of Enrollment (participants) [Number]
United States	16 100%

Outcome Measures

1. Primary Outcome

Title	Impact of Two Weeks of Disulfiram, as Measured by the Fold Change in the Infectious Units Per Million Cells (IUPM) Between Baseline and Week 12
Description	The size of the latent reservoir from each participant was measured by limiting dilution co-culture assay and reported as "infectious units per million cells" (IUPM).This assay measures the frequency of peripheral blood cells from which replication-competent HIV can be grown. The assay was performed at a baseline visit (two weeks before dosing began) and week 12 (10 weeks after the last dose). The primary outcome was the fold-change in IUPM before and after disufiram.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

The size of the latent reservoir from each participant was measured by limiting dilution co-culture assay two weeks before and ten weeks after disulfiram administration..

Arm/Group Title	Intervention Arm
Arm/Group Description	Disulfiram: Open label 500mg disulfiram per day by mouth for 14 days
Measure Participants	16
Measure Blood samples	32
Mean (95% Confidence Interval) [Fold change in IUPM]	1.16

2. Primary Outcome

Title	Number of Participants With Adverse Events
Description	The safety and tolerability of a two-week course of disulfiram was defined using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009). Details are available on the RSC website (http://rsc.tech-res.com/safetyandpharmacovigilance/). The number of adverse events and their grade was determined for each subject.
Time Frame	Two weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention Arm
Arm/Group Description	Disulfiram: Open label 500mg disulfiram per day by mouth for 14 days
Measure Participants	16
Count of Participants [Participants]	0 0%

3. Primary Outcome

Title	The Fold Change in Mean Levels of Viremia During and After Disulfiram Dosing as Compared to Baseline Levels
Description	Residual viremia was measured using a singe copy assay (SCA) in plasma samples obtained at enrollment, Days -14, -7, 0, 2, 4, 7, 9, 11, 14, 16, and 18, and at weeks 3, 4, 8 and 12. The level of residual viremia measured by SCA prior to disulfiram (Days 14, 17 and 0), during treatment (Days 1 to 14) and after dosing (Days 16 and 18) was modelled using negative binomial regression, and reported as the mean fold-change during and after disulfiram as compared to that during the baseline period.
Time Frame	Baseline to Day 18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention Arm
Arm/Group Description	Disulfiram: Open label 500mg disulfiram per day by mouth for 14 days
Measure Participants	16
Mean (95% Confidence Interval) [Fold change]	1.5

4. Primary Outcome

Title	Number of Participants With Detectable Plasma HIV RNA
Description	Plasma HIV RNA levels were measured weekly using a commercial assay. The number of participants who had a detectable viral load (> 50 copies RNA/mL) was determined.
Time Frame	Two weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention Arm
Arm/Group Description	Disulfiram: Open label 500mg disulfiram per day by mouth for 14 days
Measure Participants	16
Count of Participants [Participants]	1 6.3%

Adverse Events

Arm/Group Title	Intervention Arm
Arm/Group Description	Disulfiram: Open label 500mg disulfiram per day by mouth for 14 days
All Cause Mortality
	Intervention Arm
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Intervention Arm
	Affected / at Risk (%)	# Events
Total	0/16 (0%)
Other (Not Including Serious) Adverse Events
	Intervention Arm
	Affected / at Risk (%)	# Events
Total	0/16 (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.