Clinical Pharmacology Approaches towards Accelerating HIV Cure Initiatives

加速艾滋病毒治疗计划的临床药理学方法

• 批准号: 10475670
• 负责人: Amelia N Deitchman
• 金额: $ 20.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-27 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475670
• 关键词: Address; Adverse event; Age; Agonist; Amelia; Anti-Retroviral Agents; Antiviral Response; Award; CD4 Positive T Lymphocytes; Cell Cycle; Cells; Characteristics; Chickenpox; Chronic; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Complex; DNA; DNA Vaccines; Data; Development; Disease; Disease remission; Doctor of Philosophy; Dose; Down-Regulation; Drug Exposure; Drug Interactions; Drug Kinetics; Exposure to; FRAP1 gene; Fostering; Funding; Future; Genetic; Grant; HIV; HIV Infections; Hematology; Herpesvirus Type 3; Heterogeneity; Immune; Immune System Diseases; Immune Targeting; Immune response; Immunity; Immunologic Markers; Immunologics; Immunology; Immunosuppressive Agents; Immunotherapeutic agent; Individual; Inflammation; Inflammatory; Interruption; Investigation; K-Series Research Career Programs; Knowledge; Mentors; Mentorship; Metabolic Marker; Modality; Outcome; Participant; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacists; Pharmacodynamics; Pharmacology; Pharmacology Study; Phenotype; RNA; Race; Recombinants; Regimen; Research; Research Personnel; SDZ RAD; Safety; Sampling; Sirolimus; T-Cell Activation; T-Lymphocyte; Therapeutic; Time; Training; Transplant Recipients; Up-Regulation; VZV vaccine; Vaccines; Viral; Viral Markers; Weight; Writing; Zoster Vaccine; antiretroviral therapy; career; chronic infection; clinical translation; drug development; immune activation; immune function; immunomodulatory therapies; immunoregulation; improved; inflammatory marker; inhibitor; neutralizing antibody; novel; novel therapeutic intervention; novel therapeutics; personalized care; pharmacodynamic model; pharmacokinetics and pharmacodynamics; predicting response; preservation; programs; response; sex; trait; treatment risk; trial design; vaccine response; viral rebound; virology

Project Summary/Abstract For the nearly 37 million people living with HIV (PLWH), functional cure, or antiretroviral (ART)-free remission, is rapidly becoming an attainable target. While extensive research on the mechanisms underlying immune dysfunction and viral persistence present promising opportunities for novel therapeutic modalities, a modest understanding of how pharmacology (pharmacokinetics, PK, and pharmacodynamics, PD) contributes to clinical variability in reservoir reduction and immune modulation has frequently resulted in marginal clinical trial outcomes. This career development award will provide Dr. Amelia Deitchman, a pharmacist-researcher with a PhD in PK/PD, with the essential mentorship and training to develop her independent research program to bridge this gap in translational HIV cure research by harnessing heterogeneity in drug response and mismatched clinical translation to further the HIV cure agenda and develop robust and targeted treatments for all patients. Numerous novel therapeutic approaches are being investigated as components of durable HIV cure, including immunosuppressants targeting chronic immune dysfunction and inflammation associated with HIV persistence, as well as broadly neutralizing antibodies (bNAbs) that clear virus and HIV-infected cells. This research investigates the use of sirolimus alone and with Shingrix (recombinant varicella zoster virus, rVZV vaccine) in two clinical trials, and two bNAbs in a combination clinical trial. Using data and samples from these trials in PLWH on virally suppressive ART, and state-of-the-art viral, immune, and pharmacological approaches, the candidate will 1) establish exposure-response of sirolimus and rVZV vaccine on HIV reservoirs, immune function and safety, 2) define predictors of sirolimus and rVZV vaccine response variability attributable to PK and PD heterogeneity, and 3) determine if systemic bNAb levels can predict time to viral rebound after ART interruption in the context of other curative strategies. We hypothesize that changes in outcomes (reservoir size, immune phenotype, inflammatory markers, and for bNAbs, reservoir size and time to viral rebound post ART interruption) are directly related to drug exposure. For sirolimus, these PK/PD relationships may be entirely distinct from those used for other therapeutic indications. Furthermore, we hypothesize that drug-drug interactions, and differences in immune genetics, and patient demographic, clinical, and disease-related traits account for observed variability in clinical drug exposure and response. Ultimately, this award will be the cornerstone for a career in HIV cure clinical pharmacology research through hands-on and didactic training in HIV pharmacology, immunology and virology, clinical trials, and grant writing by an expert team of mentors. These mentors will foster the candidate's development of an independent academic research career answering clinical pharmacology questions in the setting of HIV cure. The research performed as part of this award will support a future R01 submission investigating PK/PD relationships to accelerate drug development, identify novel therapeutic approaches, and deliver precision care to patients.

项目摘要/摘要 对于近3700万艾滋病毒（PLWH），功能治愈或抗逆转录病毒（ART）的缓解的人来说， 正在迅速成为可实现的目标。同时对免疫的基础机制进行了广泛的研究 功能障碍和病毒持续性为新颖的治疗方式带来了有希望的机会，这是一种谦虚 了解药理学（药代动力学，PK和药效学，PD）如何有助于临床 储层减少和免疫调节的可变性经常导致边际临床试验 结果。该职业发展奖将为药剂师研究者Amelia Deitchman博士提供 PK/PD中的博士学位，并进行了必不可少的指导和培训，以制定她的独立研究计划以桥接 通过利用药物反应和临床不匹配的异质性，转化艾滋病毒治疗研究的差距 翻译以进一步艾滋病毒治愈议程，并为所有患者开发可靠和有针对性的治疗方法。 正在研究许多新型的治疗方法作为耐用的HIV治疗的组成部分， 包括针对慢性免疫功能障碍和与HIV相关的炎症的免疫抑制剂 持久性，以及清除感染病毒和HIV感染细胞的广泛中和抗体（BNAB）。这 研究研究了单独使用西罗莫司和Shingrix（重组素水甲藻带状疱疹病毒，RVZV）的使用 疫苗）在两项临床试验中，在一项组合临床试验中进行了两个BNAB。使用这些数据和样本 在病毒抑制艺术以及最先进的病毒，免疫和药理方法的PLWH试验中， 候选人将1）在HIV水库上建立对Sirolimus和RVZV疫苗的暴露反应，免疫 功能和安全性，2）定义源自PK和RVZV疫苗反应变异性的预测因子 PD异质性，3）确定全身性BNAB水平是否可以预测ART后病毒反弹的时间 在其他治愈策略的背景下中断。我们假设结果的变化（储层大小， 免疫表型，炎症标志物以及用于BNAB，储层的大小和病毒反弹后的时间 中断）与药物暴露直接相关。对于Sirolimus，这些PK/PD关系可能完全是 不同于用于其他治疗适应症的那些。此外，我们假设该药物毒品 相互作用以及免疫遗传学以及患者人口，临床和疾病相关的差异 考虑到临床药物暴露和反应的观察到可变性。 最终，该奖项将成为HIV治疗临床药理学研究职业的基石 通过HIV药理学，免疫学和病毒学，临床试验和授予的动手和教学培训 由专业的导师团队写作。这些导师将促进候选人的发展 学术研究职业在艾滋病毒治疗中回答临床药理学问题。研究 作为该奖项的一部分，执行将支持未来的R01提交调查PK/PD关系 加速药物开发，确定新颖的治疗方法，并为患者提供精确护理。