Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Cell-associated HIV RNA
研究概览
简要总结
The purpose of this study is to determine the safety, pharmacology and bioactivity of disulfiram in antiretroviral treated HIV-infected adults. The investigators primary hypothesis is that 3 days of disulfiram will result in an increase in HIV transcription in CD4+ T-cells in patients on suppressive antiretroviral therapy (ART).
详细描述
Combination antiretroviral therapy for HIV-1 infection can suppress viremia to below the detection limit in the vast majority of motivated individuals with access to these drugs. However, HIV-1 persists in a small pool of latently infected resting memory CD4+ T cells carrying integrated viral genomes. Although other reservoirs for HIV-1 exist, the general consensus among experts is that latent virus (HIV DNA in resting memory CD4+ T cells) is the primary barrier to HIV-1 eradication. A widely discussed approach for eliminating this viral reservoir requires reactivation of latent HIV-1. Disulfiram, an FDA-approved drug used to treat alcoholism was shown to activate HIV-1 gene expression in vitro, suggesting that activation of latently infected cells in vivo may occur. Our primary hypothesis is that the addition of disulfiram to a stable effective antiretroviral drug regimen will result in a dose dependent increase in HIV transcription in CD4+ T-cells in HIV-1 in patients on highly active antiretroviral therapy (HAART).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HIV-1 infection
- •Age 18 or older
- •HIV plasma viral load <50 copies/ml for at least 3 years with at least one measurement per year and most recent viral load within 3 months of screening.
- •Receiving combination antiretroviral therapy (at least 3 agents); subjects must be on a efavirenz-based or a ritonavir-based regimen
- •Two CD4+ T cell counts greater than 350 cell/µl in the six months prior to screening
- •Willing to abstain from any alcohol one day before, during the three day period in which disulfiram will be administered and the two week period immediately after disulfiram administration
排除标准
- •Current alcohol use disorder or hazardous alcohol use
- •Current use of 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.
- •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
- •Patients who are intending to modify antiretroviral therapy in the next 2 weeks for any reason.
- •Serious illness requiring hospitalization or parental antibiotics within preceding 3 months
- •A screening hemoglobin below 12.5 g/dL
- •A screening TSH consistent with Hypothyroidism
- •Significant renal disease or acute nephritis
- •Significant myocardial disease or diagnosed coronary artery disease
- •Significant respiratory disease
- •History of psychosis, seizure disorder, abnormal electroencephalogram or brain damage with significant persisting neurological deficit.
- •Clinically active hepatitis as evidenced by clinical jaundice or Grade 2 or higher liver function test abnormalities.
- •Hepatic cirrhosis or decompensated chronic liver disease.
- •Diabetes or current hypothyroidism.
- •Concurrent treatment with immunomodulatory drugs, or exposure to any immunomodulatory drug in past 16 weeks.
- •Recent exposure (within the preceding 8 weeks) to any vaccine.
- •Pregnant or breastfeeding women. Women of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.
- •Significant substance use, which in the opinion of the investigator, is likely to interfere with the conduct of the study.
- •Prior or current use of disulfiram, vorinostat or other experimental agent used with the intent to perturb the HIV-1 viral reservoir
- •Current use of an antiretroviral regimen which does not include either efavirenz or a protease inhibitor
研究组 & 干预措施
disulfiram 500mg
500mg disulfiram by mouth per day for 3 days
干预措施: Disulfiram (Drug)
disulfiram 1000mg
1000mg disulfiram by mouth per day for 3 days
干预措施: Disulfiram (Drug)
disulfiram 2000mg
2000mg disulfiram per mouth per day for 3 days
干预措施: Disulfiram (Drug)
结局指标
主要结局
Cell-associated HIV RNA
时间窗: Baseline and 3 days
Fold change cell-associated HIV RNA in Total CD4 T-Cells.
次要结局
- Proviral HIV DNA(Baseline and 30 days)
- Plasma HIV RNA(Baseline and 3 days)
研究者
Steven Deeks
Professor of Medicine
University of California, San Francisco