Clinical & Immunological Study of Treatment Withdrawal in E-Ag Negative Hepatitis B

慢性乙型肝炎病毒感染 (CHB) 困扰着 15-200 万美国人，全球约 3 亿人 每年导致约 100 万人过早死亡。在“BeNEG-DO”赠款中，我们正在研究 旨在安全刺激慢性乙型肝炎患者免疫介导的临床治愈的干预措施。同时 抑制性标准护理核苷（酸）类似物抗病毒治疗 (AVT) 很少能治愈慢性乙型肝炎，通常只能治愈 无限期地服用，我们正在调查是否可以安全地停止服用 AVT 至少 192 周（3.7 年） 当复制重新激活后，刺激对乙型肝炎病毒（HBV）的成功免疫反应 AVT 已停止。当诊断性病毒蛋白（“表面抗原”）出现时，CHB 就会出现临床治愈 （HBsAg），在血液中检测不到，这是我们正在评估的主要结果 治疗干预，同时密切监测安全性。 BeNEG-DO 的灵感来自于一项开创性的证明 雅典大学进行的概念研究，对患有常见“e 抗原”的患者停止 AVT 阴性”形式的 CHB (HBeAg-CHB)。雅典的研究首次表明成功的乙肝免疫 大量停止 AVT ≥3.7 年的患者可以实现临床治愈 病毒抑制，并且在没有安全问题的情况下实现。在目前资助的 BeNEG-DO 赠款中，我们 建议在更大的旧金山人口中测试这项希腊研究的结果，这自然是 亚洲人是世界上最大的乙肝病毒携带者。与此同时，我们提出了蜂窝和 使用基线肝活检和连续血液样本的分子研究来剖析免疫机制 HBsAg 从血液中的清除率与持续性的比较。转化科学部分部分是 由基于我们的小鼠模型和人类数据的假设驱动；并且它还含有宿主基因 寻找可预测结果的特征基因表达模式证据的勘探部门 并可能指出未知的免疫机制。研究的一个关键目标是区分 最有可能或最不可能从治疗戒断干预中受益的患者。 2中心 BeNEG-DO 研究已全部入组； 76 例患者停止了 AVT，30 例对照者仍在接受治疗。所有案例 截至 2020 年 10 月 25 日，已停止治疗至少 2.5 年。我们已经验证了提款 AVT 可以带来前所未有的临床治愈率，并确定处于先前未知风险的群体 停止 AVT 后。具体而言，11 名患者 HBsAg 已消失，另有 24 名患者的 HBsAg 逐渐下降 级别； 11 最新 HBsAg 水平 <5 IU/mL（范围 0.05-3.7）。其余参与者的轨迹 仍然是未定义的。本续签申请要求提供资金以继续实现 原创研究并利用最新的集成基因组和蛋白质组分析方法 确定哪些 HBeAg-CHB 患者可以安全地停止 AVT 并受益，以及哪些患者可能处于 最大的风险。这项研究可能对治疗、管理和财务医疗保健产生重大影响。

Chronic hepatitis B virus infection (CHB) afflicts 1.5-2 million Americans, about 300 million people globally and causes early death in about 1 million people annually. In the “BeNEG-DO” grant we are studying an intervention aimed at safely stimulating immune-mediated clinical cures in patients with CHB. While suppressive standard-of-care nucleos(t)ide analog antiviral therapy (AVT) rarely cures CHB and is usually taken indefinitely, we are investigating if stopping AVT taken for at least 192 weeks (3.7 yrs), can safely stimulate a successful immune response to the hepatitis B virus (HBV) when replication reactivates after AVT is stopped. Clinical cure of CHB occurs when the diagnostic viral protein, the “surface antigen” (HBsAg), becomes undetectable in blood, which is the principal outcome we are evaluating with the stop- treatment intervention, while closely monitoring safety. BeNEG-DO was inspired by a seminal proof of concept study conducted at the University of Athens which stopped AVT in patients with the common “e-antigen negative” form of CHB (HBeAg-CHB). The Athens study was the first to show that successful HBV immunity and clinical cures can be generated in substantial numbers of people who stopped AVT after ≥3.7 years of viral suppression and was achieved without safety concerns. In the currently funded BeNEG-DO grant, we proposed testing the findings of this Greek study in a much larger San Francisco population that is naturally enriched for Asians who comprise the world's greatest HBV reservoir. In parallel, we proposed cellular and molecular studies using baseline liver biopsy and serial blood samples to dissect immunological mechanisms of HBsAg clearance from blood versus persistence. The translational scientific component was in part driven by hypotheses based on our mouse model and human data; and it also contained a host genetic prospecting arm that sought evidence for signature gene expression patterns that both predict outcome and could point to unsuspected mechanisms of immunity. A key objective of the studies was to distinguish patients who are most or least likely to benefit from the treatment withdrawal intervention. The 2-center BeNEG-DO study was fully enrolled; 76 cases stopped AVT, and 30 controls remained on therapy. All cases have been off therapy for at least 2.5 years through 10/25/20. Already, we have validated that withdrawal from AVT can lead to unprecedented clinical cure rates and identified groups at previously unknown risk after stopping AVT. Specifically, 11 patients have already lost HBsAg, 24 more have progressively falling levels; 11 with latest HBsAg levels <5 IU/mL (range 0.05-3.7). The trajectory of the remaining participants is still undefined. This renewal application requests funding to continue the objectives outlined in the original study and to take advantage of latest integrated genomic and proteomic analytical approaches to determine which HBeAg-CHB patients can safely stop AVT and benefit, and which patients may be at greatest risk. This study could have major therapeutic, management and financial health care implications.