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

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).

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