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

NCT ID: NCT03198559

Last Updated: 2024-02-09

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-08
• Study Completion Date: 2019-04-09

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.

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.

Conditions

HIV Infections

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

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

Intervention Type: 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

Vorinostat, NDC 00006-0568-40

Intervention Type: 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.

Interventions

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

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Zolinza

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

The Alfred

OTHER

Sponsor Role: collaborator

University of Melbourne

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sharon R Lewin, FRACP, PhD

Role: PRINCIPAL_INVESTIGATOR

The Doherty Institute, University of Melbourne

Locations

Department of Infectious Diseases, Alfred Hospital

Melbourne, Victoria, Australia

Countries

Australia

References

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.

Reference Type: RESULT

PMID: 34586085 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

MSD IIS-55750

Identifier Type: -

Identifier Source: org_study_id