Mechanisms of HBV Functional Cure During Tenofovir-based ART in HIV/HBV Coinfection

HIV/HBV 合并感染中基于替诺福韦的 ART 期间 HBV 功能性治愈的机制

基本信息

批准号：
10221470
负责人：
Michael Jeffrey Vinikoor
金额：
$ 63.86万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221470
关键词：
AIDS clinical trial group Adult Affect Antibodies Antigens Antiviral Agents Biological Markers CD4 Lymphocyte Count Cells Chronic Chronic Hepatitis B Circular DNA Clinical Clinical Research Core Biopsy Country DNA DNA Markers Development Epidemiology Fibrosis Fine needle aspiration biopsy Funding Genetic Transcription Genotype Goals HIV HIV Infections HIV therapy Hepatitis B Hepatitis B Surface Antigens Hepatitis B Virus Hepatocyte Immune Immune response Immunity Immunologic Factors Immunologics Immunotherapy Individual Intervention Kidney Kinetics Laboratories Liver Measures Mediating Modeling Natural History Outcome Patients Peripheral Phenotype Population Predictive Factor Prospective cohort RNA Research Risk Sampling Serology Surface Surrogate Markers T-Lymphocyte Tenofovir Testing Therapeutic Toxic effect United States National Institutes of Health Viral Virus Work Zambia acute infection analog antiretroviral therapy base bone cell type clinical predictors co-infection cohort elastography exhaustion experience genetic signature immune reconstitution immunoregulation inhibitor/antagonist intrahepatic liver biopsy novel novel marker novel therapeutics predicting response programmed cell death protein 1 reconstitution response single-cell RNA sequencing viral DNA virology

项目摘要

PROJECT SUMMARY/ABSTRACT Chronic hepatitis B virus (HBV) infection, affecting 240 million worldwide including 5-20% of HIV-infected individuals, results from an inadequate immune response to acute infection and persistence of covalently closed circular DNA (cccDNA) in the host hepatocyte. During nucleos(t)ide analog therapy for chronic HBV, `functional cure', the central therapeutic goal defined by loss of hepatitis B surface antigen (HBsAg) with or without surface antibody development, occurs slowly (~1%/year). There are now a growing number of novel therapies in development to increase HBV functional cure if not achieve virological cure (i.e., elimination of the cccDNA reservoir), including agents to restore HBV-specific immunity. Yet, the immune factors critical to achieving functional cure remain poorly understood because HBsAg loss is usually rare and few studies have assessed intrahepatic immune responses. To guide the use of novel therapies in HIV-HBV coinfection, a better understanding is needed of the impact of HIV and HBV-active antiretroviral therapy (ART) on immune control of HBV. In Zambia, we established a prospective cohort of HIV-HBV coinfected (n=303) and HBV monoinfected (n=63) adults taking tenofovir (TDF)-based therapies. Within this cohort, which has strong local laboratory capacity and access to liver sampling, we documented a strikingly high rate (13.1%) of HBsAg loss among HIV-HBV patients during the first 2 years on TDF-based ART. We now propose to exploit this unique scientific opportunity to investigate HBV functional cure in HIV infection. Our central hypothesis – that in ART- treated HIV-HBV coinfection, robust immune reconstitution unleashes an enhanced HBV functional cure response – will be tested in 3 aims. In Aim 1, using liver fine needle aspirations, we will define the immune milieu in which HIV-HBV patients experience HBsAg loss/reduction during TDF-based therapy. Phenotypic responses and single cell RNA-sequencing signatures of T cells and other immune cell types will be compared by HIV status and CD4 changes during therapy. In Aim 2, we will determine the impact of ART-induced immune reconstitution in HIV-HBV coinfection on the change in peripheral markers of cccDNA transcription including quantitative HBsAg and two novel markers, hepatitis B core-related antigens and HBV RNA. In Aim 3, we will define the clinical predictors of HBV functional cure among HIV-HBV coinfected individuals. This project, which combines translational, clinical, and epidemiological approaches, and leverages an existing NIH- funded cohort, will lead to a better understanding of (a) the impact of HIV on HBV natural history, (b) how immunological therapies might work in HIV-HBV coinfection, and (c) whether novel peripheral cccDNA markers can be used in this population. The proposed research will also advance the broader HBV cure agenda, including the strategy to combine immune modulation with targeted virological interventions to achieve HBV functional cure.

项目概要/摘要慢性乙型肝炎病毒 (HBV) 感染，影响全球 2.4 亿人，其中 5-20% 为 HIV 感染者个体，由于对急性感染的免疫反应不足和共价键的持续存在而导致宿主肝细胞中的闭合环状 DNA (cccDNA) 在核（酸）类似物治疗慢性 HBV 期间， “功能性治愈”，中心治疗目标定义为乙型肝炎表面抗原（HBsAg）丧失或没有表面抗体的发展，发生缓慢（〜1％/年）现在有越来越多的小说。如果没有实现病毒学治愈（即消除 cccDNA 库），包括恢复 HBV 特异性免疫力的药物，然而，免疫因素对乙肝病毒至关重要。实现功能性治愈仍然知之甚少，因为 HBsAg 消失通常很少见，而且很少有研究表明评估肝内免疫反应，以指导 HIV-HBV 合并感染的新疗法的使用，以更好地指导治疗。需要了解 HIV 和 HBV 活性抗逆转录病毒治疗 (ART) 对免疫控制的影响在赞比亚，我们建立了 HIV-HBV 合并感染者 (n=303) 和 HBV 的前瞻性队列。在该队列中，接受基于替诺福韦 (TDF) 的治疗的单一感染 (n=63) 成年人，具有很强的局部作用。实验室能力和肝脏采样的获取，我们记录了 HBsAg 丢失率惊人的高 (13.1%) 在基于 TDF 的 ART 的头 2 年中，我们建议利用这种独特的方法。研究 HIV 感染中的 HBV 功能性治愈的科学机会我们的中心假设 - 在 ART 中 - HIV-HBV 合并感染、强大的免疫重建可增强 HBV 功能性治愈反应 – 将在 3 个目标中进行测试在目标 1 中，我们将使用细肝针穿刺来定义免疫。 HIV-HBV 患者在基于 TDF 的表型治疗期间经历 HBsAg 丢失/减少的环境。将比较 T 细胞和其他免疫细胞类型的反应和单细胞 RNA 测序特征在目标 2 中，我们将通过治疗期间的 HIV 状态和 CD4 变化来确定 ART 引起的影响。 HIV-HBV合并感染中免疫重建对cccDNA转录外周标志物变化的影响包括 HBsAg 和两种定量新型标记物：乙型肝炎核心相关抗原和 HBV RNA。 3，我们将定义 HIV-HBV 合并感染个体中 HBV 功能性治愈的临床预测因子。该项目结合了转化、临床和流行病学方法，并利用现有的 NIH- 资助的队列，将导致更好地了解 (a) HIV 对 HBV 自然史的影响，(b) 如何影响免疫疗法可能对 HIV-HBV 合并感染有效，以及 (c) 新型外周 cccDNA 标记是否有效拟议的研究也将推动更广泛的乙肝治疗议程，包括将免疫调节与有针对性的病毒学干预措施相结合以实现乙型肝炎的策略功能性治愈。