Multi Interventional Approaches to Mitigate HIV Reservoirs for the Sustained HIV Remission Without Use of Antiretrovirals
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 70
- 试验地点
- 2
- 主要终点
- Evolution of viral load of HIV RNA over the time frame of study
研究概览
简要总结
A modern and urgent challenge in fighting HIV infection is to achieve sustained HIV remission without the use of antiretrovirals. The investigators' preliminary data indicate that the use of combined strategies to mitigate the HIV proviral reservoir size among individuals with suppressive antiretroviral treatment achieved unprecedented results in the reduction of HIV DNA present in these cells and in the reduction of CD4 + and CD8 + T cell activation. Combined interventions include intensified antiretroviral treatment to mitigate residual HIV replication, use of a histone deacetylase inhibitor to interrupt viral latency, use of an anti-proliferative medication to reduce long-lived T cells that harbor HIV and a personalized dendritic cell therapy vaccine to eliminate cells with latent HIV infection or cells present in viral sanctuaries. Due to the good results obtained in the exploratory stage of the project, the investigators propose to expand it by recruiting a larger number of patients to confirm the previously obtained results and to generate new insights related to the mechanisms involved in viral latency, latency disruption and the effects of analytical treatment interruption of antiretrovirals among patients undergoing all above mentioned interventions.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •- > 18 years old < 65 years old Documented HIV-1 infection. Has voluntarily signed ICF. On HAART ≥ 2 years, without changes in the 24 weeks immediately prior to screening.
- •HIV viral load <50 copies/mL, and never > 50 copies/mL on 2 consecutive occasions in the last 2 years. CD4 count nadir.
- •> 350 cells/ mm3 Current CD4 count > 500 cells/ mm
- •R5 HIV-1 at Screening as defined by proviral DNA genotropism.
排除标准
- •- Any evidence of an active AIDS-defining condition. Any significant acute medical illness in the past 8 weeks. Women who are pregnant or breastfeeding. Use of any of the following within 90 days prior to entry: systemic cytotoxic chemotherapy; investigational agents; immunomodulators (colonystimulating factors, growth factors, systemic corticosteroids, HIV vaccines, immune globulin, interleukins, interferons); coumadin, warfarin, or other coumadin derivative anticoagulants. Use of an agent definitely or possibly associated with effects on QT intervals: amiodarone, arsenic trioxide, astemizole, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, probucol, procainamide, quinidine, sotalol, sparfloxacin, terfenadine, thioridazine.
- •Receipt of compounds with HDAC inhibitor-like activity, such as valproic acid or nicotinamide within the last 30 days. Potential participants may enroll after a 30-day washout period.
- •Known hypersensitivity to the components of gold salt, nicotinamide or its analogs.
- •Hepatitis B (HBsAg +) or Hepatitis C (HCV RNA +) infection. Known renal insufficiency defined as calculated creatinine clearance (Cockcroft Gault formula) <60 mL/min.
- •Subjects with a laboratory abnormality grade 3 or 4 with the following exceptions: pancreatic amylase, cholesterol, triglyceride, gamma glutamyl transpeptidase, bilirubin.
- •Any condition which, in the investigators opinion, could compromise the subject's safety or adherence to the trial protocol.
研究组 & 干预措施
Antiretroviral Treated (ART) Group
Ten patients will receive no further intervention (control group)
ART Intensification Group
Sixty patients will be included in this stage to undergo antiretroviral intensification with dolutegravir, the Sirtuin Histone deacetylase inhibitor nicotinamide for 48 weeks, gold salt (auranofin) for the last 24 weeks and dendritic cell vaccine, with the adjustment to use also maraviroc during the first 48 weeks.
干预措施: Sirtuin Histone deacetylase inhibitor (Drug)
ART Intensification Group
Sixty patients will be included in this stage to undergo antiretroviral intensification with dolutegravir, the Sirtuin Histone deacetylase inhibitor nicotinamide for 48 weeks, gold salt (auranofin) for the last 24 weeks and dendritic cell vaccine, with the adjustment to use also maraviroc during the first 48 weeks.
干预措施: Dendritic Cell Vaccine (Biological)
ART Intensification Group
Sixty patients will be included in this stage to undergo antiretroviral intensification with dolutegravir, the Sirtuin Histone deacetylase inhibitor nicotinamide for 48 weeks, gold salt (auranofin) for the last 24 weeks and dendritic cell vaccine, with the adjustment to use also maraviroc during the first 48 weeks.
干预措施: Dolutegravir (Drug)
ART Intensification Group
Sixty patients will be included in this stage to undergo antiretroviral intensification with dolutegravir, the Sirtuin Histone deacetylase inhibitor nicotinamide for 48 weeks, gold salt (auranofin) for the last 24 weeks and dendritic cell vaccine, with the adjustment to use also maraviroc during the first 48 weeks.
干预措施: Auranofin (Drug)
ART Intensification Group
Sixty patients will be included in this stage to undergo antiretroviral intensification with dolutegravir, the Sirtuin Histone deacetylase inhibitor nicotinamide for 48 weeks, gold salt (auranofin) for the last 24 weeks and dendritic cell vaccine, with the adjustment to use also maraviroc during the first 48 weeks.
干预措施: Maraviroc (Drug)
结局指标
主要结局
Evolution of viral load of HIV RNA over the time frame of study
时间窗: baseline, weeks 12, 24, 36 and 48 and every 3 weeks after the antiretroviral ATI up to 36 months after antiretroviral ATI
Viral load count by qPCR at each time point to measure the viral persistence in each participant
Evolution of total DNA and episomal HIV in PBMCs
时间窗: baseline, weeks 12, 24, 36 and 48 and every 3 weeks after the antiretroviral ATI up to 36 months after antiretroviral ATI
Quantification of total DNA and episomal HIV in a virological assay
Evolution of cell-associated HIV RNA in PBMCs over the study time frame
时间窗: baseline, weeks 12, 24, 36 and 48 and every 3 weeks after the antiretroviral ATI up to 36 months after antiretroviral ATI
Quantification of HIV RNA in PBMCs by qPCR
Evolution of total DNA and episomal HIV DNA in lymphoid tissue (rectal biopsy)
时间窗: baseline, week 48, after resurgence of viremia in the analytical interruption of antiretrovirals, or after 24 and 96 weeks after analytical interruption of antiretrovirals.
Quantification by in-house virological assay
Evolution of the HIV DNA sequence of the V3 region of gp 120, protease, reverse transcriptase and integrase regions of the pol gene, and of the gag gene
时间窗: baseline, week 24, week 48, after resurgence of viremia after ATI and before reintroduction of ART
NGS sequencing of the V3 region of gp120, the protease, reverse transcriptase, and integrase regions of the pol gene, and of the gag gene of HIV DNA
Evolution of the HIV RNA sequence of the V3 region of gp 120, protease, reverse transcriptase and integrase regions of the pol gene, and of the gag gene
时间窗: baseline, week 24, week 48, after resurgence of viremia after ATI and before reintroduction of ART
NGS sequencing of the V3 region of gp120, the protease, reverse transcriptase, and integrase regions of the pol gene, and of the gag gene of HIV RNA
Evolution of CD4 + and CD8 + T lymphocyte count
时间窗: baseline, weeks 12, 24, 36 and 48 and every 3 weeks after the antiretroviral ATI up to a total of 36 months after ATI.
Count by flow cytometry of CD4+ and CD8+ lymphocytes
Evolution of percentages of CD38 and HLA DR in CD4 + and CD8 + T lymphocytes
时间窗: baseline, weeks 12, 24, 36 and 48 and every 3 weeks after the antiretroviral ATI up to 36 months after antiretroviral ATI
Measurement by flow cytometry of cell activation of CD4+ and CD8+ T lymphocytes as a means of assessing immune and inflammatory responses
Evolution of plasma cytokines IL-2, IL-4, IL-6, IL-10, IL-17, TNF and IFN-γ
时间窗: baseline, weeks 12, 24, 36 and 48 and every 3 weeks after the antiretroviral ATI up to 36 months after antiretroviral ATI
Measurement by ELISA Assay of plasma cytokines IL-2, IL-4, IL-6, IL-10, IL-17, TNF and IFN-γ as a means of assessing immune and inflammatory responses
Changes in bacterial translocation levels by quantification of plasma LPS levels
时间窗: baseline, weeks 12, 24, 36 and 48 and every 3 weeks after the antiretroviral ATI up to 36 months after antiretroviral ATI
Assay for determining the proinflammatory level of endotoxin (LPS)
次要结局
未报告次要终点
研究者
Ricardo Sobhie Diaz
Associated Professor
Federal University of São Paulo