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.

项目总结/摘要 对于近3700万艾滋病毒感染者（PLWH），功能性治愈或无抗逆转录病毒（ART）缓解， 正在迅速成为一个可以实现的目标。虽然对免疫机制的广泛研究 功能障碍和病毒持续存在为新的治疗方式提供了有希望的机会， 了解药理学（药代动力学、PK和药效学、PD）如何有助于临床 水库减少和免疫调节的可变性经常导致边缘临床试验 结果。这个职业发展奖将为药剂师-研究员Amelia Deitchman博士提供一个 博士在PK/PD，与必要的指导和培训，以发展她的独立研究计划， 通过利用药物反应的异质性和不匹配的临床试验， 翻译，以进一步艾滋病毒治愈议程，并为所有患者开发强大的和有针对性的治疗。 许多新的治疗方法正在研究作为持久的艾滋病毒治愈的组成部分， 包括针对慢性免疫功能障碍和HIV相关炎症的免疫抑制剂 持久性，以及清除病毒和HIV感染细胞的广泛中和抗体（bNAb）。这 一项研究调查了西罗莫司单独使用和与Shingrix（重组水痘带状疱疹病毒，rVZV）联合使用的情况 疫苗），以及两种bNAb组合临床试验。使用这些数据和样本 在PLWH中进行的病毒抑制性ART试验，以及最先进的病毒、免疫和药理学方法， 候选人将1）建立西罗莫司和rVZV疫苗对HIV宿主的免疫应答， 功能和安全性，2）定义可归因于PK的西罗莫司和rVZV疫苗应答变异性的预测因子， PD异质性，和3）确定全身bNAb水平是否可以预测ART后病毒反弹的时间 在其他治疗策略的背景下中断。我们假设，结果的变化（水库大小， 免疫表型、炎症标志物和形成bNAb、储库大小和ART后病毒反弹时间 （三）与药物暴露直接相关。对于西罗莫司，这些PK/PD关系可能完全 与用于其他治疗适应症的那些不同。此外，我们假设药物-药物 相互作用和免疫遗传学差异，以及患者人口统计学，临床和疾病相关特征 解释了临床药物暴露和反应中观察到的变异性。 最终，该奖项将成为艾滋病毒治疗临床药理学研究职业生涯的基石 通过艾滋病毒药理学、免疫学和病毒学、临床试验和赠款方面的实践和教学培训， 由一个专家团队的导师撰写。这些导师将促进候选人的独立发展 学术研究生涯回答艾滋病毒治疗背景下的临床药理学问题。研究 作为该奖项的一部分进行的研究将支持未来研究PK/PD关系的R 01提交， 加速药物开发，确定新的治疗方法，并为患者提供精确的护理。