Clinical trial NCT01944371: Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study
Official title: Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV
Human Immunodeficiency Virus
Keywords: Latent reservoir
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Monash University
name: amfAR, The Foundation for AIDS Research
name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2013-09-17
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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).

Eligibility criteria: 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

Primary outcomes:
measure: Cell-associated HIV RNA
timeFrame: Baseline and 3 days
Secondary outcomes:
measure: Plasma HIV RNA
timeFrame: Baseline and 3 days
measure: Proviral HIV DNA
timeFrame: Baseline and 30 days
Other outcomes:
measure: Disufiram Pharmacokinetics
timeFrame: 31 days
Locations:
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
city: Melbourne
country: Australia
facility: Alfred Hospital
Study officials:
affiliation: University of Californa, San Francisco
name: Steven Deeks, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Monash University
name: Julian Elliott, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Elliott JH, McMahon JH, Chang CC, Lee SA, Hartogensis W, Bumpus N, Savic R, Roney J, Hoh R, Solomon A, Piatak M, Gorelick RJ, Lifson J, Bacchetti P, Deeks SG, Lewin SR. Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study. Lancet HIV. 2015 Dec;2(12):e520-9. doi: 10.1016/S2352-3018(15)00226-X. Epub 2015 Nov 17.