Biomarkers of Replication and Injury in HBV/HIV

摘要 乙肝病毒(HBV)是一个严重的全球健康问题。在那些感染艾滋病毒的人中，它与 急性感染后慢性风险增加，与肝脏相关的发病率增加 死亡率。乙肝病毒治疗领域正在发生变化，焦点从HBVDNA转移到 抑制乙肝病毒的功能和完全治愈。提供明确指导的生物标志物 关于预测，治疗结果和关于肝损伤的准确信息是 有限的。虽然研究中使用了包括pgRNA在内的较新的乙肝生物标志物，但定量表面 抗原和乙肝核心相关抗原在过去一年中加速增长，现有的数据非常有限 关于它们在艾滋病毒携带者中的使用和效用。在这个探索性的 R21的应用我们建议评估几个生物标记物的潜在作用 以前在那些乙肝病毒/艾滋病毒混合感染的人中具有特征。乙肝病毒pgRNA代表一种 CcCDNA微染色体的转录本，该转录本对红斑狼疮的发育和永生化起关键作用 乙肝病毒慢性化。使用PLWH的3个互补队列，我们将评估 这些生物标志物与CD4计数、HIV病毒载量和其他人口学和血清学乙肝病毒 按乙肝病毒疾病复制阶段的自然病史分类的标志物。在一个艾滋病人中 临床试验组(ACTG)队列，我们将检查这些生物标记物的纵向变化 与核苷治疗的启动有关。我们的实验室最近实现了对 一种新的基于血液的cccDNA检测方法，它将与pgRNA检测结合使用 确定基因沉默的频率和比例。使用新型肝源性外切体 我们将探索基因沉默是否与较低水平的 肝损伤比更传统的反应指标，如血清丙氨酸氨基转移酶。 这一特征将提供可能为未来的乙肝治疗策略提供信息的关键信息， 在PLWH，正在ACTG和其他地方进行研究。

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.