HIV, Human Immunodeficiency Virus
Conditions
Keywords
Latent reservoir
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).
Interventions
DRUGDisulfiram
This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.
Sponsors
Monash University
amfAR, The Foundation for AIDS Research
National Institute of Allergy and Infectious Diseases (NIAID)
University of California, San Francisco
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cell-associated HIV RNA | Baseline and 3 days | Fold change cell-associated HIV RNA in Total CD4 T-Cells. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma HIV RNA | Baseline and 3 days | Fold change in plasma HIV RNA levels from baseline through day 3 |
| Proviral HIV DNA | Baseline and 30 days | Fold change in HIV DNA levels between Baseline and Day 30 |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Australia, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Disulfiram 500mg 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. | 10 |
| Disulfiram 1000mg 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. | 10 |
| Disulfiram 2000mg 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. | 10 |
| Total | 30 |
Baseline characteristics
| Characteristic | Disulfiram 500mg | Disulfiram 1000mg | Disulfiram 2000mg | Total |
|---|---|---|---|---|
| Age, Continuous | 53 years | 54 years | 51 years | 53 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 9 Participants | 7 Participants | 22 Participants |
| Region of Enrollment Australia | 6 participants | 4 participants | 5 participants | 15 participants |
| Region of Enrollment United States | 4 participants | 6 participants | 5 participants | 15 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 9 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 1 / 10 | 1 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Cell-associated HIV RNA
Fold change cell-associated HIV RNA in Total CD4 T-Cells.
Time frame: Baseline and 3 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Disulfiram 500mg | Cell-associated HIV RNA | 1.7 Fold change |
| Disulfiram 1000mg | Cell-associated HIV RNA | 1.9 Fold change |
| Disulfiram 2000mg | Cell-associated HIV RNA | 1.6 Fold change |
Secondary
Plasma HIV RNA
Fold change in plasma HIV RNA levels from baseline through day 3
Time frame: Baseline and 3 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Disulfiram 500mg | Plasma HIV RNA | 1.50 Fold change |
| Disulfiram 1000mg | Plasma HIV RNA | 0.90 Fold change |
| Disulfiram 2000mg | Plasma HIV RNA | 1.22 Fold change |
Secondary
Proviral HIV DNA
Fold change in HIV DNA levels between Baseline and Day 30
Time frame: Baseline and 30 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Disulfiram 500mg | Proviral HIV DNA | 1.07 Fold change |
| Disulfiram 1000mg | Proviral HIV DNA | 0.83 Fold change |
| Disulfiram 2000mg | Proviral HIV DNA | 0.91 Fold change |
Other Pre-specified
Disufiram Pharmacokinetics
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Disulfiram 500mg | Disufiram Pharmacokinetics | 3,186 mg-hour/liter |
| Disulfiram 1000mg | Disufiram Pharmacokinetics | 8,386 mg-hour/liter |
| Disulfiram 2000mg | Disufiram Pharmacokinetics | 22,331 mg-hour/liter |