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.

项目概要/摘要 尽管艾滋病毒感染可以通过抗逆转录病毒治疗（ART）来控制，但艾滋病毒治愈仍然困难重重。 极其难以捉摸。由于多种原因，迫切需要治愈艾滋病毒。 HIV 感染者 (PWH) 持续存在 尽管接受了抗逆转录病毒治疗，发病率和死亡率仍然增加，而且虽然新的抗逆转录病毒治疗药物的耐受性更好， 它们仍然与多种副作用有关。必须去艾滋病诊所并长期接受抗逆转录病毒治疗 感染者卫生保健人员仍然带有明显的耻辱。此外，许多感染者更愿意治愈而不是终生 ART，有些人会冒很大的风险来实现治愈。出于所有这些原因，寻找艾滋病毒的治疗方法 是该领域的最终目标之一。 越来越多的证据表明中枢神经系统 (CNS) 是 HIV 储存库 是根除艾滋病毒的另一个障碍的地点。 HIV DNA 普遍存在于感染者出生后的脑组织中 抑制性 ART，并且有多篇已发表的中枢神经系统病毒逃逸报告。多项研究，包括 我们小组的研究人员证明，在抑制期间，可以在脑脊液中检测到非常低水平的 HIV RNA ART 和抗 HIV 抗体也存在于接受 ART 的个体的脑脊液中。我们的新成员 该小组最近提出了一种创新测定法 (Double-R) 的研究结果，可可靠地定量 HIV RNA 和 DNA 来自脑脊液。 我们的团队对 Janus 激酶 (Jak 1/2) 抑制剂进行了广泛的临床前和临床工作 针对艾滋病毒的药物类别。其中包括 Baricitinib 的研究，Baricitinib 是 FDA 批准的口服生物可利用的 Jak 1/2 抑制剂 用于类风湿性关节炎。我们已经证明 baricitinb 可以阻断 HIV 复制、HIV 诱导的激活和 关键中枢神经系统细胞的感染和储存库重新播种。在体内，我们在小鼠模型中证明了巴瑞替尼 减少中枢神经系统艾滋病毒并逆转艾滋病毒造成的行为异常。我们还证明了 巴瑞替尼在恒河猴模型中达到治疗中枢神经系统浓度。我们现在建议学习 在一项具有持久病毒学抑制作用的 PWH 研究中，巴瑞克替尼作为一种减少 HIV CNS 储存的疗法 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体 随机接受巴瑞替尼治疗更有可能实现脑脊液细胞相关 HIV RNA 和 DNA 的减少 双 R 测定。我们还假设巴瑞克替尼治疗将与显着降低相关 HIV CNS 持久性的其他标记，包括 HIV 特异性 CSF 抗体、CSF 细胞相关 DNA 包括综合原病毒 DNA (IPDA)、单拷贝检测 CSF RNA、CSF HIV Tat 水平和标记 与 CNS HIV 持续存在相关的炎症，以及磁共振成像和 光谱标记。此外，我们假设巴瑞替尼治疗对于定义的中枢神经系统是安全的 通过神经心理学表现、抑郁症状和神经元损伤。我们有信心这 该研究将为巴瑞克替尼纳入以根除艾滋病毒为目标的治疗方案提供坚实的基础。