HIV-1 Infection
Conditions
Keywords
HIV, HAART suppressed, Disulfiram, Antabuse, Latent reservoir, Eradication, Cure
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).
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.
Interventions
DRUGDisulfiram
Open label 500mg disulfiram per day by mouth for 14 days
Sponsors
Johns Hopkins University
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention Arm Disulfiram: Open label 500mg disulfiram per day by mouth for 14 days | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Intervention Arm |
|---|---|
| Age, Continuous | 47.5 years |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
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.
Time frame: 12 weeks
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Intervention Arm | 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 | 1.16 Fold change in IUPM |
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.
Time frame: Two weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Arm | Number of Participants With Adverse Events | 0 Participants |
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.
Time frame: Two weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Arm | Number of Participants With Detectable Plasma HIV RNA | 1 Participants |
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.
Time frame: Baseline to Day 18
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intervention Arm | The Fold Change in Mean Levels of Viremia During and After Disulfiram Dosing as Compared to Baseline Levels | 1.5 Fold change |