Clinical Pharmacology Approaches towards Accelerating HIV Cure Initiatives

项目摘要/摘要 对于近3700万艾滋病毒携带者(PLWH)、功能性治疗或抗逆转录病毒(ART)免费缓解患者， 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)对临床的贡献 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。这一职业发展奖将为药剂师兼研究员阿米莉亚·迪奇曼博士提供 PK/PD博士，在必要的指导和培训下，开发她的独立研究计划，以建立 通过利用药物反应的异质性和不匹配的临床，翻译HIV治疗研究中的这一差距 以推动艾滋病毒治疗议程，并为所有患者开发强有力和有针对性的治疗方法。 许多新的治疗方法正在被研究，作为持久艾滋病毒治愈的组成部分， 包括针对慢性免疫功能障碍和与艾滋病毒相关的炎症的免疫抑制剂 持久性，以及清除病毒和艾滋病毒感染细胞的广谱中和抗体(BNAbs)。这 研究调查了西罗莫司单独和与Shingrix(重组水痘带状疱疹病毒，rVZV)一起使用的情况 疫苗)在两个临床试验中，以及在联合临床试验中两个bNAbs。使用这些数据和样本 在PLWH上关于病毒抑制技术的试验，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疫苗对艾滋病毒宿主的暴露反应，免疫 功能和安全性，2)定义西罗莫司和rVZV疫苗应答变异性的预测因子，可归因于PK和 PD异质性，以及3)确定系统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(储集层大小， 免疫表型、炎性标记物和bNAbs、库大小和ART后病毒反弹的时间 中断)与药物暴露直接相关。对于西罗莫司，这些PK/PD关系可能完全是 有别于用于其他治疗适应症的药物。此外，我们假设毒品--药物 免疫遗传学与患者人口学、临床和疾病相关特征的相互作用和差异 解释临床药物暴露和反应中观察到的可变性。 最终，这一奖项将成为艾滋病毒治疗临床药理学研究事业的基石。 通过艾滋病毒药理学、免疫学和病毒学、临床试验和赠款的实践和授课培训 由导师组成的专家团队撰写。这些导师将帮助候选人发展成为一个独立的 在HIV治疗的背景下回答临床药理学问题的学术研究生涯。这项研究 作为本奖项的一部分执行，将支持未来的R01提交，调查PK/PD与 加快药物开发，确定新的治疗方法，为患者提供精准护理。

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.