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

NCT03198559 | Terminated Phase 1 Results

• 1 other identifier: MSD IIS-55750
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

HIV Infections

Keywords

HIV latency; Disulfiram; Vorinostat; Latency Reversing Agents; Histone Deacetylase Inhibitors (HDACi)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Incidence of Treatment-Emergent Adverse Events

  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

  Baseline to Days 8, 15, 21, 38, 59, 196, 197. Data is reported for days where samples were collected for each participant.

Other Outcomes (7)

• HIV RNA Transcription Relative to Baseline at Additional Time Points

  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

  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

  Baseline to Days 38, 59, 197, 196. Data is reported for days where samples were collected for each participant.

Study Arms (1)

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; Drug: Vorinostat, NDC 00006-0568-40

Interventions

Disulfiram, (National Drug Code) NDC 0378-4141-01 DRUG

This study will provide open label disulfiram. Participants will take 2 grams (4x500mg tablets) of disulfiram per day for a total of 28 days

Experimental

Vorinostat, NDC 00006-0568-40 DRUG

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.

Also known as: Zolinza

Experimental

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Melbourne: lead
• Merck Sharp & Dohme LLC: collaborator
• The Alfred: collaborator

Study Sites (1)

Department of Infectious Diseases, Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

Related Publications (1)

• 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.

  PMID: 34586085 RESULT

MeSH Terms

Conditions

HIV Infections

Interventions

Disulfiram; Vorinostat

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Ditiocarb; Thiocarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Disulfides; Sulfides; Sulfur Compounds; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids

Limitations and Caveats

Early termination of the study lead to a small numbers of participants analyzed. Therefore there was insufficient power to measure the effect of the intervention. Other key limitations to this study include: * only 2 participants received study drug; * participants did not complete the full course of treatment as outlined in the study design; * 1 participant missed Day 10 study medication, stopped study treatment on Day 17; * 1 participant ceased study medication on Day 11;

Results Point of Contact

• Title: Professor Sharon Lewin
• Organization: University of Melbourne

sharon.lewin@unimelb.edu.au

+61 (0)3 8344 3309

Study Officials

• Sharon R Lewin, FRACP, PhD

  The Doherty Institute, University of Melbourne

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: Open Label
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single arm, single site,

Study Record Dates

• First Submitted: June 14, 2017
• First Posted: June 26, 2017
• Study Start: August 8, 2017
• Primary Completion: April 9, 2019
• Study Completion: April 9, 2019
• Last Updated: February 9, 2024
• Results First Posted: February 9, 2024

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)