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

Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART (DIVA): A Single Arm Clinical Trial

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.

Study Overview

• Status: Terminated
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Disulfiram, (National Drug Code) NDC 0378-4141-01; Drug: Vorinostat, NDC 00006-0568-40

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Department of Infectious Diseases, Alfred Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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 Names: Zolinza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Day 11 Plasma HIV RNA Relative to Baseline	The primary endpoint was 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.	Baseline and 11 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	This secondary outcome was 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. An adverse event is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations as judged by physician. Systematic assessments of adverse events were performed at each visit, including unscheduled visits	Adverse events were collected continuously throughout the study duration from day 1 on treatment until 2 months since last dose of study drug, an average duration of 3 months
Plasma HIV RNA Relative to Baseline at Additional Time Points	This secondary outcome was to determine the fold change in plasma HIV RNA levels at additional time points during and after 11 continuous days of disulfiram with administration of vorinostat on days 8, 9 and 10 in HIV infected individuals on suppressive ART.	Baseline to Days 8, 15, 21, 38, 59, 196, 197. Data is reported for days where samples were collected for each participant.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV RNA Transcription Relative to Baseline at Additional Time Points	This secondary outcome was to measure HIV transcription measured by cell-associated unspliced HIV RNA (CA-US HIV RNA) in peripheral blood CD4+ T cells relative to baseline	Baseline to Days 8, 11, 15, 21, 38, 59, 196, 197. Data is reported for days where samples were collected for each participant.
Cell Associated Total HIV DNA Relative to Baseline at Additional Points	This outcome was to measure Cell-associated total and integrated HIV DNA in peripheral blood CD4+ T cells relative to baseline	Baseline and Days 38, 59, 196 and 197. Data is reported for days where results are available for each participant.
Cell-associated Integrated HIV DNA Relative to Baseline at Additional Points	This outcome was to measure cell-associated integrated HIV DNA in peripheral blood CD4+ T cells relative to baseline	Baseline to Days 38, 59, 197, 196. Data is reported for days where samples were collected for each participant.
HIV Levels Relative to Baseline	This outcome was to measure the frequency of inducible virus as measured by Tat/rev limiting dilution assay (TILDA) in peripheral blood CD4+ T cells relative to baseline. Not conducted as part of the analysis and there are no future plans to assess this outcome, as analysis from 2 participants would not provide any meaningful results, given that the participants did not manage to complete the treatment course.	Day 56
Vorinostat Concentration in Plasma	This outcome was to measure the concentrations of vorinostat (including its metabolites) in plasma.	Baseline and days 8, 11, 15, 21, 37, 58. Data is reported for days where samples were collected for each participant.
Disulfiram Concentration in Plasma	This outcome was to measure the concentrations of disulfiram (including its metabolites) in plasma	Days 8, 11, 22, 25, 28, 56 and 196 Data is reported for days where samples were collected for each participant.
p24 Expression in CD4+ T-cells Relative to Baseline	This outcome was to measure the p24 expression in CD4+ T-cells relative to baseline	Baseline and Days 8, 11, 15, 21, 37, 58, 196 and 197. Data is reported for days where samples were collected for each participant.

Collaborators and Investigators

• Sponsor: University of Melbourne
• Collaborators: Merck Sharp & Dohme LLC; The Alfred
• Investigators: Principal Investigator: Sharon R Lewin, FRACP, PhD, The Doherty Institute, University of Melbourne

Publications and helpful links

General Publications

• McMahon JH, Evans VA, Lau JSY, Symons J, Zerbato JM, Chang J, Solomon A, Tennakoon S, Dantanarayana A, Hagenauer M, Lee S, Palmer S, Fisher K, Bumpus N, Heck CJS, Burger D, Wu G, Zuck P, Howell BJ, Zetterberg HH, Blennow K, Gisslen M, Rasmussen TA, Lewin SR. Neurotoxicity with high-dose disulfiram and vorinostat used for HIV latency reversal. AIDS. 2022 Jan 1;36(1):75-82. doi: 10.1097/QAD.0000000000003091.

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2017
• Primary Completion (Actual): April 9, 2019
• Study Completion (Actual): April 9, 2019

Study Registration Dates

• First Submitted: June 14, 2017
• First Submitted That Met QC Criteria: June 22, 2017
• First Posted (Actual): June 26, 2017

Study Record Updates

• Last Update Posted (Estimated): February 9, 2024
• Last Update Submitted That Met QC Criteria: June 2, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Vorinostat; Disulfiram; Histone Deacetylase Inhibitors (HDACi); HIV latency; Latency Reversing Agents
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Alcohol Deterrents; Histone Deacetylase Inhibitors; Acetaldehyde Dehydrogenase Inhibitors; Vorinostat; Disulfiram
• Other Study ID Numbers: MSD IIS-55750

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No plan to share individual participant data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No