Phase II study to evaluate the efficacy and safety of baricitinib for reduction of HIV in the central nervous system

II 期研究评估 baricitinib 减少中枢神经系统 HIV 的有效性和安全性

• 批准号: 10681470
• 负责人: Christina Gavegnano
• 金额: $ 63.84万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681470
• 关键词: AIDS clinical trial group; Antibodies; Authorization documentation; Behavioral; Biological Assay; Biological Availability; Blood; Brain; COVID-19; CXCL10 gene; Cells; Central Nervous System; Cerebrospinal Fluid; Clinic; Clinical; DNA; Data; Dose; Drug Kinetics; Emergency Situation; Encephalitis; FDA approved; Future; Genetic; Goals; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; IL7 gene; Immunologic Markers; In Vitro; Individual; Infection; Interleukin-15; Intervention; Janus kinase; Light; Link; Longevity; Macaca mulatta; Magnetic Resonance Imaging; Mental Depression; Microtubule-Associated Protein 2; Modeling; Morbidity - disease rate; Myelofibrosis; Neopterin; Neurocognitive Deficit; Neurons; Neuropsychology; Opportunistic Infections; Oral; Participant; Performance; Peripheral; Persons; Pharmaceutical Preparations; Phase; Placebos; Polycythemia Vera; Property; Publishing; RNA; Randomized; Regimen; Renal clearance function; Reporting; Research; Retroviridae Infections; Rheumatoid Arthritis; Risk; Safety; Site; Source; Spectrum Analysis; Testing; Therapeutic; Virus; Virus Diseases; Work; antiretroviral therapy; authority; brain parenchyma; brain tissue; cytokine; depressive symptoms; efficacy evaluation; immune activation; improved; in vivo; inflammatory marker; inhibitor; inhibitor therapy; innovation; member; mortality; mouse model; neurofilament; neuroprotection; novel; phase 2 study; phase 3 study; phenotypic biomarker; pre-clinical; preference; randomized placebo controlled study; side effect; social stigma; symposium

Project Summary/Abstract Although HIV infection is controllable with antiretroviral therapy (ART), HIV cure continues to be extremely elusive. Cure of HIV is desperately needed for many reasons. People with HIV (PWH) have persistent increases in morbidity and mortality despite ART, and while newer ART agents have become better tolerated, they are still associated with multiple side effects. Having to attend HIV clinics and take ART over the long term still carries significant stigma for PWH. Additionally, many PWH have a preference for cure rather than a lifetime of ART, and some would take significant risks to achieve a cure. For all of these reasons, finding a cure for HIV is one of the ultimate goals of the field. There is a large and growing body of evidence that the central nervous system (CNS) is an HIV reservoir site that represents another barrier to HIV eradication. HIV DNA is commonly found in brain tissue from PWH on suppressive ART, and there are multiple published reports of CNS virologic escape. Multiple studies, including from our group, have demonstrated that HIV RNA can be detected at very low levels in CSF during suppressive ART and that anti-HIV antibodies are also present in the CSF among individuals on ART. New members of our group recently presented findings with an innovative assay (Double-R) to reliably quantitate HIV RNA and DNA from CSF. Our group has performed extensive pre-clinical and clinical work on the Janus Kinase (Jak 1/2) inhibitor drug class to target HIV. This includes work on baricitinib, an FDA approved orally bioavailable Jak 1/2 inhibitor for rheumatoid arthritis. We have demonstrated that baricitinb blocks HIV replication, HIV-induced activation and infection in key CNS cells, and reservoir reseeding. In vivo, we have shown in our murine model that baricitinib decreases CNS HIV and reverses behavioral abnormalities conferred by HIV. We have also demonstrated that baricitinib achieves therapeutic CNS concentrations in the rhesus macaque model. We now propose to study baricitinib as a therapy to decrease the HIV CNS reservoir in a study of PWH with durable virologic suppression on ART. This will be a phase IIa randomized placebo controlled study. Our primary hypothesis is that individuals randomized to baricitinib will be more likely to achieve a decrease in CSF cell associated HIV RNA and DNA by Double-R assay. We also hypothesize that baricitinib treatment will be associated with a significant decrease in other markers of HIV CNS persistence, including HIV-specific CSF antibodies, CSF cell associated DNA including by Integrated Proviral DNA (IPDA), CSF RNA by single copy assay, CSF HIV Tat levels, and markers of inflammation that have been linked to CNS HIV persistence, as well as magnetic resonance imaging and spectroscopy markers. Additionally, we hypothesize that baricitinib treatment will be safe for the CNS as defined by neuropsychological performance, depression symptoms, and neuronal damage. We are confident that this study will provide a strong basis for baricitinib to be included in regimens that target eradication of HIV.

项目摘要/摘要 尽管艾滋病毒感染可通过抗逆转录病毒疗法(ART)控制，但艾滋病毒的治愈仍在继续 非常难以捉摸。出于许多原因，迫切需要治愈艾滋病毒。艾滋病毒携带者(PWH)有持续性 尽管抗逆转录病毒治疗的发病率和死亡率有所增加，但新的抗逆转录病毒药物已经变得更好地耐受， 它们仍然与多种副作用有关。必须长期去艾滋病毒诊所和参加抗逆转录病毒药物治疗 对威斯康星医院来说，这仍然是一种严重的耻辱。此外，许多PWH倾向于治愈而不是终生 一些人会冒着巨大的风险来实现治愈。出于所有这些原因，找到一种治疗艾滋病毒的方法 是该领域的终极目标之一。 越来越多的证据表明，中枢神经系统(CNS)是艾滋病毒的宿主 这是根除艾滋病毒的又一个障碍。人类免疫缺陷病毒脱氧核糖核酸通常在先天疱疹后的脑组织中发现。 抑制性艺术，并且有多个发表的关于中枢神经系统病毒学逃逸的报道。多项研究，包括 已经证明，在抑制期间，可以在脑脊液中检测到非常低水平的艾滋病毒RNA ART和抗HIV抗体也存在于接受ART治疗的个体的脑脊液中。我们的新成员 该小组最近公布了一种创新的方法(Double-R)，以可靠地量化HIV RNA和DNA 从脑脊液。 我们小组对Janus Kinase(JAK1/2)抑制剂进行了广泛的临床前和临床工作 针对HIV病毒的药物类。这包括FDA批准的口服生物可用JAK1/2抑制剂巴利替尼的研究。 治疗类风湿性关节炎。我们已经证明，巴利西丁可以阻止HIV复制、HIV诱导的激活和 关键中枢神经系统细胞的感染，以及水库的重新播种。在体内，我们已经在我们的小鼠模型中证明了巴利替尼 降低中枢神经系统HIV，逆转由HIV引起的行为异常。我们也证明了 巴利替尼在恒河猴模型中达到治疗中枢神经系统浓度。我们现在建议研究 巴利替尼作为一种治疗方法减少HIV CNS储存库，在持续病毒学抑制的PWH研究中 关于艺术。这将是一项IIa期随机安慰剂对照研究。我们的主要假设是，个人 随机服用巴利替尼将更有可能通过以下方式减少脑脊液细胞相关的艾滋病毒RNA和DNA 双R试验。我们还假设，巴利西尼治疗将与显著减少 HIV CNS持久性的其他标志，包括HIV特异性脑脊液抗体、脑脊液细胞相关DNA 包括通过整合前病毒DNA(IPDA)、通过单拷贝分析的脑脊液RNA、脑脊液HIV TAT水平和标志物 与中枢神经系统艾滋病毒持久性有关的炎症，以及磁共振成像和 光谱学标记。此外，我们假设巴利替尼治疗对中枢神经系统是安全的。 通过神经心理表现、抑郁症状和神经元损伤。我们相信，这一点 这项研究将为将巴利替尼纳入旨在根除艾滋病毒的方案提供强有力的基础。