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Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART

This study has suspended participant recruitment.
(Review of current adverse events reported by study participants)
Sponsor:
ClinicalTrials.gov Identifier:
NCT03198559
First Posted: June 26, 2017
Last Update Posted: October 9, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Merck Sharp & Dohme Corp.
The Alfred
University of Melbourne
Information provided by (Responsible Party):
The Peter Doherty Institute for Infection and Immunity
  Purpose

Antiretroviral therapy (ART) dramatically reduces Human Immunodeficiency Virus (HIV) replication leading to restoration of immune function and a near normal life expectancy, but treatment is lifelong and there is no cure. The major barrier to a cure is the persistence of long lived cluster of differentiation 4 (CD4+) T-cells that contain a "silenced" form of HIV, called HIV latency.

The purpose of this research is to investigate whether it may be possible to reduce the amount of dormant HIV infection in immune cells, by "turning on" or activating the virus and hence force it out of the latently infected memory T cells. This leads to production of HIV by the cell, which will either die or will be recognized and eliminated by the immune system. As very few T cells are latently infected with HIV, the death of these cells is not expected to affect the function of the immune system and further infection of new cells is expected to be prevented by ART.


Condition Intervention Phase
HIV Infections Drug: Disulfiram, (National Drug Code) NDC 0378-4141-01 Drug: Vorinostat, NDC 00006-0568-40 Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Intervention Model Description:
Single arm, single site,
Masking: None (Open Label)
Masking Description:
Open Label
Primary Purpose: Treatment
Official Title: Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART (DIVA): A Single Arm Clinical Trial

Resource links provided by NLM:


Further study details as provided by The Peter Doherty Institute for Infection and Immunity:

Primary Outcome Measures:
  • Day 11 plasma HIV RNA relative to baseline [ Time Frame: 11 days ]
    To determine the change from baseline to day 11 of plasma HIV RNA levels after 11 continuous days of disulfiram with administration of vorinostat on days 8, 9 and 10 in HIV infected individuals on suppressive ART.


Secondary Outcome Measures:
  • Incidence of Treatment-Emergent Adverse Events [ Time Frame: Days 8, 11, 22, 25, 28, 56 and 196 ]
    To determine the Incidence of treatment-emergent adverse events [Safety and Tolerability] during a 28 day course of continuous disulfiram with intermittent administration of 3 days of vorinostat on two occasions in HIV infected individuals on suppressive ART.

  • Plasma HIV RNA relative to baseline at additional time points [ Time Frame: Days 8, 22, 25, 28, 56 and 196 ]
    To determine the effect of 28 days of disulfiram with intermittent administration of 3 days of vorinostat on two occasions on the frequency of latently infected CD4+ T cells in HIV infected individuals on suppressive ART.


Other Outcome Measures:
  • HIV RNA transcription relative to baseline at additional time points [ Time Frame: Days 8, 11, 22, 25, 28, 56 and 196 ]
    HIV transcription measured by cell-associated unspliced HIV RNA (CA-US HIV RNA) in peripheral blood CD4+ T cells relative to baseline

  • Total amount of HIV DNA relative to baseline at additional points [ Time Frame: Days 56 and 196 ]
    Cell-associated total and integrated HIV DNA in peripheral blood CD4+ T cells relative to baseline

  • HIV levels relative to baseline [ Time Frame: Day 56 ]
    The frequency of inducible virus as measured by Tat/rev limiting dilution assay (TILDA) in peripheral blood CD4+ T cells relative to baseline

  • Blood drug levels [ Time Frame: Days 8, 11, 22, 25, 28, 56 and 196 ]
    Concentrations of vorinostat and disulfiram (including its metabolites) in plasma

  • Diagnosis of HIV levels relative to baseline [ Time Frame: Days 8, 11, 22, 25, 28, 56 and 196 ]
    p24 expression in CD4+ T-cells relative to baseline


Estimated Enrollment: 15
Actual Study Start Date: August 8, 2017
Estimated Study Completion Date: July 2027
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Experimental

Participants current ART regimen:

2 grams disulfiram by mouth per day for a total of 28 days

400mg vorinostat by mouth per day on days 8, 9,10 and days 22, 23, 24

Drug: Disulfiram, (National Drug Code) NDC 0378-4141-01
This study will provide open label disulfiram. Participants will take 2 grams (4x500mg tablets) of disulfiram per day for a total of 28 days
Drug: Vorinostat, NDC 00006-0568-40
This study will provide open label vorinostat. Participants will take 400mg (4x100mg capsules) of vorinostat per day on days 8, 9, 10 and days 22, 23, 24.
Other Name: Zolinza

Detailed Description:
One strategy aimed at reducing the frequency of latently infected cells in HIV-infected individuals on antiretroviral therapy (ART) is the use of pharmacological agents to reverse HIV latency, thereby initiating virus-mediated cell lysis or immune-mediated killing. Recent clinical trials of latency reversing agents (LRAs) in HIV infected subjects on ART, including histone deacetylase inhibitors (HDACi) and the anti-alcoholism drug disulfiram, have shown that inducing an increase in Cell Associated Unspliced (CA-US) HIV RNA or plasma HIV RNA is possible. Yet, these interventions did not have a demonstrable effect on the frequency of latently infected cells or time to viral rebound after cessation of ART, potentially because latency reversal alone didn't trigger an adequate immune response or cell death or that the potency of latency reversal with a single-agent intervention over a very short period of time, lacked sufficient potency, as suggested by recent in vitro studies. It is highly likely that long-term remission off ART will require interventions that lead to both a reduction in latently infected cells and an increase in HIV-specific immunity, therefore identifying a strategy to increase viral antigens on the surface of latently infected cells will be a key component of this strategy.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18-65 years with documented HIV-1 infection (antibody positive or detectable plasma HIV-1 RNA)
  • Receiving combination ART with plasma HIV RNA <50 copies/mL for >3 years
  • CD4+ T cell count >350 microliter at screening
  • Able to provide informed consent
  • Willing to abstain from alcohol consumption from one day before to 14 days after completing 28 days of disulfiram
  • One month post influenza vaccine (from screening visit)
  • Women of non-child-bearing potential defined as > 12 months of spontaneous amenorrhea and ≥ 45 years of age, or documented medical history of one of the following: hysterectomy, bilateral oophorectomy or tubal ligation.
  • Women of Child Bearing Potential (WOCBP) with a negative pregnancy test at Screening and agrees to use one of the study protocol specified methods of contraception to avoid pregnancy

Exclusion Criteria:

  • Current alcohol use disorder or hazardous alcohol use (>7 drinks per week for women or > 14 drinks per week for men) as determined by clinical evaluation
  • Current or recent (in the last 4 days) use of metronidazole or 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, and alcohol-containing preparations such as cough syrups, tonics etc.
  • 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
  • Individuals who intend to modify antiretroviral therapy during the study period for any reason
  • Significant myocardial disease (current myocarditis or reduced left ventricular ejection fraction below the lower limit of normal) or diagnosed coronary artery disease
  • Significant renal disease (eGFR <50 milliliter/minute)
  • History of psychosis, seizure disorder, abnormal electroencephalogram or brain damage with significant persisting neurological deficit
  • Prior malignancy active within the previous 3 years except for local curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix or breast.
  • Known hypersensitivity to disulfiram or vorinostat or contraindications to treatment with these agents
  • Participation in another latency reversal study or receipt of vorinostat or disulfiram in the previous 12 months before starting the investigational treatment
  • Any significant acute medical illness requiring hospitalization within preceding 8 weeks
  • Hepatitis B (HBV) or hepatitis C (HCV) co-infection as determined by detection of HBsAg or HCV RNA (Individuals with prior hepatitis infection that is now cleared are eligible for enrolment)
  • Receipt of immunomodulating agents (excluding immunization) or systemic chemotherapeutic agents within 28 days prior to study entry
  • Current or recent gastrointestinal disease or surgery that may impact the absorption of the investigational drug
  • Active substance use that in the opinion of the investigator will prevent adequate compliance with study procedures
  • Women who are currently pregnant or breastfeeding
  • Women of Child Bearing Potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy
  • Unable or unwilling to adhere to protocol procedures
  • The following laboratory values within 6 weeks before starting the investigational drug (lab tests may be repeated to obtain acceptable values before failure at screening is concluded)

    • Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN)
    • Serum total bilirubin ≥1.5 x ULN
    • eGFR <50 milliliter/min
    • Hemoglobin <11.0 g/deciliter
    • Platelet count ≤100 x10^9/L (liter)
    • Absolute neutrophil count ≤1.5x10^9/L
    • Serum potassium, magnesium, phosphorus outside normal limits
    • Total calcium (corrected for serum albumin) or ionized calcium ≤ lower normal limits
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03198559


Locations
Australia, Victoria
Department of Infectious Diseases, Alfred Hospital
Melbourne, Victoria, Australia, 3004
Sponsors and Collaborators
The Peter Doherty Institute for Infection and Immunity
Merck Sharp & Dohme Corp.
The Alfred
University of Melbourne
Investigators
Principal Investigator: Sharon R Lewin, FRACP, PhD The Doherty Institute, University of Melbourne
  More Information

Responsible Party: The Peter Doherty Institute for Infection and Immunity
ClinicalTrials.gov Identifier: NCT03198559     History of Changes
Other Study ID Numbers: MSD IIS-55750
First Submitted: June 14, 2017
First Posted: June 26, 2017
Last Update Posted: October 9, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No plan to share individual participant data

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by The Peter Doherty Institute for Infection and Immunity:
HIV latency
Disulfiram
Vorinostat
Latency Reversing Agents
Histone Deacetylase Inhibitors (HDACi)

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Vorinostat
Histone Deacetylase Inhibitors
Disulfiram
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Alcohol Deterrents
Acetaldehyde Dehydrogenase Inhibitors