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: 10484645
• 负责人: Albert Anderson
• 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/10484645
• 关键词: AIDS clinical trial group; Antibodies; Behavioral; Biological Assay; Blood; Brain; COVID-19; CXCL10 gene; Cells; 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; Neuraxis; 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; Testing; Therapeutic; Virus; Virus Diseases; Work; antiretroviral therapy; base; brain parenchyma; brain tissue; cytokine; depressive symptoms; efficacy evaluation; immune activation; in vivo; inflammatory marker; inhibitor therapy; innovation; kinase inhibitor; member; mortality; mouse model; neurofilament; novel; phase 2 study; phase 3 study; phenotypic biomarker; pre-clinical; preference; randomized placebo controlled study; side effect; social stigma; spectroscopic imaging; 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HIV感染可通过抗逆转录病毒疗法（ART）控制，但HIV治疗仍为 极其难以捉摸。由于许多原因，迫切需要治愈艾滋病毒。患有艾滋病毒（PWH）的人持久 尽管有艺术，但发病率和死亡率的提高，虽然较新的艺术特工的容忍度变得更好，但 它们仍然与多种副作用有关。不得不参加艾滋病毒诊所并长期服用艺术 仍然对PWH具有明显的污名。此外，许多PWH都偏爱治愈而不是一生 艺术品，有些人会冒着明显的风险来实现治愈。由于所有这些原因，找到治愈艾滋病毒的方法 是该领域的最终目标之一。 有大量越来越多的证据表明中枢神经系统（CNS）是艾滋病毒的水库 代表艾滋病毒的另一个障碍的部位。 HIV DNA通常在脑组织中从PWH上发现 抑制性艺术，以及有关中枢神经系统病毒学逃生的多个已发表报告。多个研究，包括 从我们的小组中证明，在抑制性过程中，CSF中可以在非常低的水平中检测到HIV RNA ART和抗HIV抗体也存在于CSF中的艺术中。我们的新成员 Group最近提出了一种创新测定（Double-R）的发现，以可靠地量化HIV RNA和DNA 来自CSF。 我们的小组在Janus激酶（JAK 1/2）抑制剂上进行了广泛的临床和临床工作 靶向艾滋病毒的药物类别。这包括关于Bariticinib的工作，FDA批准了口服生物可利用JAK 1/2抑制剂 用于类风湿关节炎。我们已经证明了bariticinb阻断了HIV复制，HIV诱导的激活和 关键CNS细胞中的感染，并恢复储层。在体内，我们在鼠模型中显示了bariticinib 减少CNS HIV并逆转艾滋病毒赋予的行为异常。我们还证明了 Baricitinib在恒河猕猴模型中达到了治疗性中枢神经系统浓度。我们现在建议学习 在一项持久的病毒抑制作用的PWH研究中，巴甲替尼作为降低HIV CNS储层的一种疗法 关于艺术。这将是IIA期随机安慰剂对照研究。我们的主要假设是个人 随机分配至baritodinib将更有可能通过CSF细胞相关的HIV RNA和DNA降低 双R分析。我们还假设Bariticinib治疗将与大幅下降有关 HIV CNS持久性的其他标记，包括HIV特异性CSF抗体，CSF细胞相关的DNA 包括综合前病毒DNA（IPDA），单拷贝分析的CSF RNA，CSF HIV TAT水平和标记 与CNS HIV持久性以及磁共振成像和 光谱标记。此外，我们假设Bariticinib治疗对CNS的定义是安全的 通过神经心理学表现，抑郁症状和神经元损害。我们有信心这 研究将为baritodinib纳入靶向艾滋病毒的治疗方案提供强大的基础。