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: 10551347
• 负责人: Harel Dahari
• 金额: $ 70.07万
• 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/10551347
• 关键词: Acceleration; 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; Evaluation; Experimental Models; FDA approved; Genome; Genotype; Goals; Half-Life; Hepatitis B Infection; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis D; Hepatitis Delta Virus; Hepatocyte; Human; Individual; Infection; Infectious hepatitides; Interdisciplinary Study; Interferon Type II; Interferons; Kinetics; Knowledge; Life Cycle Stages; Link; Liver diseases; Lonafarnib; Mathematics; Modeling; Molecular; Monitor; Mus; Nucleic Acids; Patients; Pegylated Interferon Alfa; Persons; Pharmaceutical Preparations; Polymers; Prevalence; Recommendation; Relapse; System; Testing; Therapeutic; Time; Viral; Virion; Virus; Virus Assembly; Virus Diseases; Virus Replication; adaptive immune response; analog; chronic infection; circular RNA; clinical efficacy; clinically relevant; co-infection; env Gene Products; experimental study; extracellular; humanized mouse; infancy; inhibitor; insight; intrahepatic; mathematical model; mouse model; novel; permissiveness; 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）是一种可在个体中传播的感染性亚病毒因子 感染B型肝炎病毒（HBV）。它是人类慢性病毒性肝炎中最严重的形式 据估计，全世界约有2000万人被慢性感染。在美国，的 慢性HDV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。目前尚无FDA批准的HDV治疗方法 包括聚乙二醇化干扰素-α，其仅在约25%的患者中实现治愈。有限的 治疗数据可用，了解HDV感染和治疗反应的动态 还处于起步阶段新的异戊二烯化抑制剂洛那法尼是第一个直接作用的抗HDV药物 正在进行临床测试，但聚乙二醇干扰素-λ，核酸聚合物和HDV/HBV 进入抑制剂myrcludex B也正在被研究作为抗HDV疗法， 机会表征HDV治疗动力学和HDV的作用机制 抗病毒药物，并提供了一个窗口，HDV，HBV和主机之间的动态在共同感染。 为了深入了解HDV-HBV-宿主-药物动力学，我们建立了一个跨学科团队 包括进行HDV治疗临床试验的临床医生， 在人源化小鼠模型中的治疗和HDV/HBV共感染研究以及数学模型 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 用于治疗丁型肝炎病毒的抗病毒药物。