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

HIV-1 Infection Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01286259
• Other study ID #: IRB 10-02648
• Status: Completed
• Phase: N/A
• Start date: January 2011
• Est. completion date: May 2014

Study information

• Verified date: June 2020
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: May 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

Drug:
• Disulfiram
Open label 500mg disulfiram per day by mouth for 14 days

Locations

Country	Name	City	State
United States	Johns Hopkins University	Baltimore	Maryland
United States	San Francisco General Hospital	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Francisco	Johns Hopkins University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	12 weeks
Primary	Number of Participants With Adverse Events	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.	Two weeks
Primary	The Fold Change in Mean Levels of Viremia During and After Disulfiram Dosing as Compared to Baseline Levels	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.	Baseline to Day 18
Primary	Number of Participants With Detectable Plasma HIV RNA	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.	Two weeks