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.

项目总结/摘要 虽然艾滋病毒感染是可控的抗逆转录病毒疗法（ART），艾滋病毒的治愈仍然是一个挑战。 非常难以捉摸艾滋病毒的治疗是迫切需要的原因有很多。艾滋病毒感染者（PWH）持续 尽管有ART，发病率和死亡率仍在增加，尽管较新的ART药物已变得更耐受， 它们仍然与多种副作用有关。不得不去艾滋病诊所并长期接受抗逆转录病毒治疗 仍然是威尔斯亲王医院的耻辱。此外，许多PWH更喜欢治愈而不是终身治疗 有些人会冒很大的风险来实现治愈。由于所有这些原因，找到治愈艾滋病的方法 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的储存库 这是艾滋病毒根除的另一个障碍。爱滋病病毒脱氧核糖核酸通常在威尔斯亲王医院的脑组织中发现， 抑制性ART，并且存在CNS病毒逃逸的多个已发表的报告。多项研究，包括 已经证明，在抑制性治疗期间，可以在CSF中检测到非常低水平的HIV RNA。 抗艾滋病毒抗体也存在于接受抗逆转录病毒治疗的个体的脑脊液中。我们的新成员 一个研究小组最近提出了一种创新的检测方法（Double-R），可以可靠地定量HIV RNA和DNA CSF的。 我们的团队已经对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。这包括对baricitinib的研究，baricitinib是FDA批准的口服生物可利用的Jak 1/2抑制剂 治疗类风湿性关节炎我们已经证明，baricitinb阻断HIV复制，HIV诱导的激活， 关键CNS细胞中的感染和储库再接种。在体内，我们已经在我们的鼠模型中表明，baricitinib 降低CNS HIV并逆转HIV引起的行为异常。我们还证明， baricitinib在恒河猴模型中达到治疗性CNS浓度。我们现在建议研究 Baricitinib作为减少HIV CNS储库的治疗在PWH研究中具有持久的病毒学抑制 这将是一项IIa期随机安慰剂对照研究。我们的主要假设是 随机分配至baricitinib组的受试者更有可能通过以下方式实现CSF细胞相关HIV RNA和DNA的降低： 双R测定。我们还假设，baricitinib治疗将与显着降低， HIV CNS持久性的其他标志物，包括HIV特异性CSF抗体、CSF细胞相关DNA 包括整合前病毒DNA（IPDA）、单拷贝测定CSF RNA、CSF HIV达特水平和标志物 炎症与中枢神经系统HIV持续存在有关，以及磁共振成像和 光谱标记物此外，我们假设baricitinib治疗对CNS是安全的， 神经心理学表现、抑郁症状和神经元损伤。我们相信这 研究将为baricitinib纳入以根除HIV为目标方案提供强有力的基础。