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

NCT ID: NCT01944371

Last Updated: 2020-05-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-30
• Study Completion Date: 2014-05-31

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).

Conditions

HIV; Human Immunodeficiency Virus

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

disulfiram 500mg

500mg disulfiram by mouth per day for 3 days

Group Type: EXPERIMENTAL

Disulfiram

Intervention Type: DRUG

This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.

disulfiram 1000mg

1000mg disulfiram by mouth per day for 3 days

Group Type: EXPERIMENTAL

Disulfiram

Intervention Type: DRUG

This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.

disulfiram 2000mg

2000mg disulfiram per mouth per day for 3 days

Group Type: EXPERIMENTAL

Disulfiram

Intervention Type: DRUG

This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.

Interventions

Disulfiram

This study will provide open label disulfiram. Subjects will take 1 dose of disulfiram per day for 3 days.

Intervention Type: DRUG

Other Intervention Names

Antabuse,NDC 0093-5036-01

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Monash University

OTHER

Sponsor Role: collaborator

amfAR, The Foundation for AIDS Research

OTHER

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Steven Deeks

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Steven Deeks, MD

Role: PRINCIPAL_INVESTIGATOR

University of Californa, San Francisco

Julian Elliott, MD

Role: PRINCIPAL_INVESTIGATOR

Monash University

Locations

San Francisco General Hospital

San Francisco, California, United States

Alfred Hospital

Melbourne, , Australia

Countries

United States; Australia

References

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.

Reference Type: DERIVED

PMID: 26614966 (View on PubMed)

Other Identifiers

DAIDS-ES ID 11864

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

K24AI069994

Identifier Type: NIH

Identifier Source: secondary_id

View Link

13-10948

Identifier Type: -

Identifier Source: org_study_id