Biomarkers of Replication and Injury in HBV/HIV

HBV/HIV 复制和损伤的生物标志物

• 批准号: 10449351
• 负责人: KENNETH E SHERMAN
• 金额: $ 20.73万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449351
• 关键词: AIDS clinical trial group; Africa South of the Sahara; Antigens; Biological Assay; Biological Markers; Blood; Blood Tests; CD4 Lymphocyte Count; Categories; Chronic; Cirrhosis; Clinical; Cross-Sectional Studies; Data; Detection; Development; Diagnostic; Disease; Enrollment; Europe; Evolution; Frequencies; Future; Gene Silencing; Genetic Transcription; Ghana; Goals; HIV; HIV Infections; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Therapy; Hepatitis B Virus; Hepatitis C Therapy; Individual; Injury; Intervention; Laboratories; Lead; Liver; Liver diseases; Monitor; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Natural History; Nucleosides; Persons; Prognosis; Randomized; Research; Risk; Role; Sampling; Serology; Serum; Staging; Strategic Planning; Surface Antigens; Tenofovir; Testing; Tissues; Transcript; Treatment outcome; United States National Institutes of Health; Universities; Validation; Viral; Viral Load result; Virus Diseases; Virus Replication; acute infection; adefovir; base; biomarker identification; chronic infection; clinical care; co-infection; cohort; end stage liver disease; exosome; global health; innovation; interest; liver injury; mortality; novel; novel marker; nucleoside analog; pgRNA; repository; response; response biomarker; treatment response; trial comparing; two-arm trial; viral DNA; virus core

Abstract Hepatitis B virus (HBV) is a serious global health concern. In those with HIV it is associated with increased risk of chronicity after acute infection, and increased rates of liver-associated mortality. The field of HBV treatment is undergoing evolution, changing focus from HBV DNA suppression to functional and complete HBV cure. Biomarkers that provide clear guidance regarding prediction, treatment outcome and accurate information regarding liver injury are limited. Though research use of newer HBV biomarkers including pgRNA, quantitative surface antigen and HBV core-related antigen has accelerated in the last year, very limited data exists with regard to their use and utility among persons living with HIV (PLWH). In this Exploratory R21 application we propose to evaluate the potential role of several biomarkers that have not been previously characterized in those with HBV/HIV coinfection. HBV pgRNA represents a transcript of the cccDNA minichromosome that is central to development and perpetuation of HBV chronicity. Using 3 complementary cohorts of PLWH, we will evaluate the association of these biomarkers with CD4 count, HIV viral load and other demographic and serologic HBV markers stratified by categorical natural history replicative stages of HBV disease. In one AIDS Clinical Trials Group (ACTG) cohort, we will examine longitudinal changes in these biomarkers associated with initiation of nucleoside therapy. Our laboratory has recently implemented use of a new blood-based cccDNA assay which will be utilized in conjunction with the pgRNA assays to determine the frequency and proportion of gene silencing. Using novel liver-derived exosome markers of liver injury we will explore whether gene silencing is associated with lower levels of liver injury than are identified with more traditional markers of response such as serum ALT. This characterization will provide key information that may inform future cure strategies for HBV, in PLWH which are being studied within the ACTG and elsewhere.

摘要 B型肝炎病毒（HBV）是一种严重的全球性健康问题。在艾滋病毒感染者中， 急性感染后慢性化风险增加，肝脏相关性 mortality. HBV治疗领域正在发生变化，从HBV DNA转移到 抑制到功能性和完全的HBV治愈。提供明确指导的生物标志物 关于肝损伤的预测、治疗结果和准确信息， 有限公司虽然研究使用更新的HBV生物标志物，包括pgRNA，定量表面 抗原和HBV核心相关抗原在过去一年中加速增长，数据非常有限 关于它们在艾滋病毒感染者（PLWH）中的使用和效用。在这次探索中 R21应用，我们建议评估几种生物标志物的潜在作用， 先前在HBV/HIV合并感染者中进行了表征。HBV pgRNA代表 cccDNA微型染色体的转录物，其对细胞的发育和延续至关重要。 HBV慢性化。使用3个互补的PLWH队列，我们将评估 这些生物标志物与CD 4计数、HIV病毒载量和其他人口统计学和血清学HBV 根据HBV疾病的分类自然史复制阶段分层的标志物。在一个艾滋 临床试验组（ACTG）队列，我们将检查这些生物标志物的纵向变化 与开始核苷治疗相关。我们的实验室最近实施了使用 一种新的基于血液的cccDNA检测试剂盒，将与pgRNA检测试剂盒联合使用 以确定基因沉默的频率和比例。使用新的肝源性外泌体 我们将探讨基因沉默是否与肝损伤的低水平相关。 肝损伤比用更传统的反应标志物如血清ALT鉴定的更严重。 这种表征将提供关键信息，可能为未来的HBV治疗策略提供信息， 在艾滋病毒携带者和艾滋病患者中，ACTG和其他地方正在研究这些问题。