Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART
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.
|HIV Infections||Drug: Disulfiram, (National Drug Code) NDC 0378-4141-01 Drug: Vorinostat, NDC 00006-0568-40||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Intervention Model Description:
Single arm, single site,Masking: No masking
Open LabelPrimary 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|
- 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.
- 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.
- 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
|Anticipated Study Start Date:||July 2017|
|Estimated Study Completion Date:||July 2027|
|Estimated Primary Completion Date:||December 2018 (Final data collection date for primary outcome measure)|
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 daysDrug: 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT03198559
|Contact: Barbara Scher, BSc(Hons)MSc||+61 3 8344 firstname.lastname@example.org|
|Contact: Vanessa Evans, BSc, PhD||+ 61 3 8344 email@example.com|
|Department of Infectious Diseases, Alfred Hospital||Not yet recruiting|
|Melbourne, Victoria, Australia, 3004|
|Contact: Clinical Research Coordinator +61 3 9076 6908 firstname.lastname@example.org|
|Principal Investigator: James McMahon, FRACP|
|Principal Investigator:||Sharon R Lewin, FRACP, PhD||The Doherty Institute, University of Melbourne|