Safety and Effect on HIV Transcription of Vorinostat in Patients Receiving Suppressive Combination Anti-retroviral Therapy
The objective of the study is to assess the safety and ability of vorinostat, a drug currently licensed for the treatment of a type of lymphoma, to 'turn on' dormant HIV infected CD4 T-cells.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Pilot Study to Assess the Safety and Effect on HIV Transcription of Vorinostat in Patients Receiving Suppressive Combination Anti-retroviral Therapy|
- To evaluate the effect of vorinostat on HIV transcription in CD4 T-cells. [ Time Frame: Day 1 (before drug, 2 and 8 hours after first dose), Day 2, 7, 14, 21 and 28 ] [ Designated as safety issue: Yes ]The primary (efficacy) endpoint of this study is to evaluate the effect of vorinostat on HIV transcription from latently infected CD4+ T-cells as measured by HIV unspliced RNA in CD4+ T-cells.
- 1. To evaluate the safety and tolerability of vorinostat in patients receiving effective combination antiretroviral therapy (cART [ Time Frame: Screening, Day 1, 7, 14,21, and 28 ] [ Designated as safety issue: Yes ]
- Plasma HIV RNA (standard assay)
- Adverse events and dose-limiting toxicity
- CD4 T-cell count
- Antiretroviral plasma trough concentrations will be measured before and after 14 days of treatment with vorinostat.
|Study Start Date:||May 2011|
|Estimated Study Completion Date:||February 2013|
|Primary Completion Date:||December 2011 (Final data collection date for primary outcome measure)|
Vorinostat 400mg ( 4 X 100mg ) orally daily for 14 days
Vorinostat 400mg (4 x 100mg) orally daily for 14 days
Treatment of HIV infection with combination antiretroviral therapy (cART) has led to significant improvements in the life expectancy and quality of life of people living with HIV. Nevertheless, life expectancy is significantly lower than uninfected individuals and cART leads to several long term side effects. cART alone is not able to cure HIV infection due to persistence of HIV infection in dormant cells. One potential strategy to eradicate HIV infection is to 'wake up' these dormant infected cells by 'turning on' the cell. The small number of cells that are dormant and infected would start to produce virus and die, but infection of other cells would be prevented by cART. Ultimately this could lead to eradication of dormant infected cells and a potential cure for HIV.
This study is a pilot study in 20 individuals recruited at the Alfred Hospital only.
The hypotheses is that vorinostat will induce HIV transcription in CD4 T-cells with latent HIV infection, it is safe and well tolerated in patients receiving effective cART and will induce histone acetylation in vivo in patients with HIV infection.
The study will run over 12 weeks, involving 9 study visits for the participant. Eligible patients must be between 18 to 60 years of age with confirmed HIV infection, and receiving successful cART as indicated by 'suppressed' HIV virus in blood (plasma HIV RNA <50 copies/ml) for at least 3 years and a strong immune system (two CD4 counts greater than 500 cell/µl in the last 6 months).
Patients will be reviewed at screening and days 1 (three time points), 2, 7, 14, 21, 28 and 84 (week 12). They will have blood tests for HIV viral load assessment, CD4 cell counts, biochemistry, hematology and storage samples. An electrocardiogram of the heart (ECG) will be taken at screening, day 7 and 14.
As part of this study levels of HIV in blood and in white blood cells and the degree to which cells are 'turned on' (histone (H3) acetylation) will be measured at 3 time points on day 1, then once on days 2, 7, 14, 21 and 28. The level of one component of cART will be measured at day 1 and 14. At baseline and day 14 a sigmoidoscopy if performed for the collection of rectal biopsies.
The safety and how well vorinostat is tolerated will be determined based on physical exams, laboratory tests and questions about any problems patients may have experienced during the study. This study has an Independent Safety Monitoring Committee who in addition to evaluating the overall safety of patients will be responsible for assessing safety of the first patient enrolled prior to any recommendation to continue the study.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01365065
|The Alfred Hospital - Infectious Diseases Unit|
|Melbourne, Victoria, Australia, 3004|