Data-Driven Mathematical and Computational Modeling of Hepatitis D Infection and Treatment Response

丁型肝炎感染和治疗反应的数据驱动数学和计算模型

• 批准号: 9973575
• 负责人: Harel Dahari
• 金额: $ 72.51万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973575
• 关键词: American; Antiviral Agents; Antiviral Therapy; Blood; Cells; Chronic; Chronic Hepatitis B; Chronic Hepatitis D; Chronic viral hepatitis; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Collaborations; Computer Models; Data; Development; FDA approved; Genome; Genotype; Goals; Half-Life; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis D; Hepatitis Delta Virus; Hepatocyte; Human; Individual; Infection; Infectious hepatitides; Interdisciplinary Study; Interferon-alpha; Interferons; Kinetics; Knowledge; Life Cycle Stages; Link; Liver diseases; Lonafarnib; Mathematics; Modeling; Molecular; Monitor; Mus; Nucleic Acids; Patients; Persons; Pharmaceutical Preparations; Polymers; Prevalence; Relapse; System; Testing; Therapeutic; Therapy Evaluation; Time; Viral; Virion; Virus Assembly; Virus Diseases; Virus Replication; adaptive immune response; analog; base; chronic infection; circular RNA; clinical efficacy; clinically relevant; co-infection; env Gene Products; experimental study; extracellular; humanized mouse; infancy; inhibitor/antagonist; insight; intrahepatic; mathematical model; mouse model; novel; prenylation; response; screening; treatment optimization; treatment response

Hepatitis delta virus (HDV) is an infectious subviral agent that can propagate in individuals infected with hepatitis B virus (HBV). It is the most severe form of chronic viral hepatitis in humans and ~20 million people worldwide are estimated to be chronically infected. In the U.S., the prevalence of chronic HDV infection is rising with recent data suggesting an urgent need for screening and treatment. There is no FDA approved treatment for HDV with current therapy consisting of pegylated interferon-alpha which only achieves cure in ~25% of patients. With limited treatment data available, understanding the dynamics of HDV infection and treatment response is in its infancy. The new prenylation inhibitor lonafarnib is the first direct acting anti-HDV agent being tested clinically, but pegylated interferon-lambda, Nucleic acid polymers and HDV/HBV entry inhibitor myrcludex B are also being investigated as anti-HDV therapies providing ongoing opportunities characterize HDV treatment dynamics and the mechanism of action of HDV antivirals and provide a window into the dynamics among HDV, HBV and host during co-infection. To gain insights into HDV-HBV-host-drug dynamics we have established an interdisciplinary team that includes clinicians who perform HDV treatment clinical trials, experimentalists to perform treatment and HDV/HBV coinfection studies in humanized mouse models and mathematical modelers to create mathematical/computational models to explain the patient and mouse data. The long-term goal of this proposal is to determine the MOA of anti-HDV drugs and optimal use of antiviral agents for the treatment of HDV.

丁型肝炎病毒 (HDV) 是一种传染性亚病毒，可以在个体中传播 感染乙型肝炎病毒（HBV）。它是人类最严重的慢性病毒性肝炎 据估计，全世界约有 2000 万人受到慢性感染。在美国， 慢性丁型肝炎病毒感染的患病率正在上升，最近的数据表明迫切需要 筛查和治疗。目前的疗法尚无 FDA 批准的 HDV 治疗方法 由聚乙二醇化干扰素-α 组成，只能治愈约 25% 的患者。与有限的 可获得治疗数据，了解丁型肝炎病毒感染的动态和治疗反应 正处于起步阶段。新型异戊二烯化抑制剂 lonafarnib 是第一个直接作用的抗 HDV 药物 正在临床测试中，但聚乙二醇化干扰素-λ、核酸聚合物和 HDV/HBV 进入抑制剂 myrlucex B 也正在作为抗 HDV 疗法进行研究，以提供持续的 丁型肝炎治疗动态的机会特征和丁型肝炎的作用机制 抗病毒药物并为了解 HDV、HBV 和宿主在共同感染期间的动态提供了一个窗口。 为了深入了解 HDV-HBV-宿主-药物动态，我们建立了一个跨学科团队 其中包括进行 HDV 治疗临床试验的临床医生、进行 HDV 治疗临床试验的实验人员 人源化小鼠模型中的治疗和 HDV/HBV 共感染研究和数学 建模者创建数学/计算模型来解释患者和小鼠数据。 该提案的长期目标是确定抗 HDV 药物的 MOA 和最佳使用 用于治疗 HDV 的抗病毒药物。