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

慢性B型肝炎病毒感染（CH B）困扰着150 - 200万美国人，全球约3亿人 每年导致大约一百万人过早死亡。在“BeNEG-DO”赠款中，我们正在研究一种 旨在安全刺激免疫介导的CHB患者临床治愈的干预。而 抑制性标准治疗核苷（酸）类似物抗病毒治疗（AVT）很少治愈CHB， 无限期服用，我们正在研究是否停止服用AVT至少192周（3.7年）， 当复制重新激活后，刺激对B肝炎病毒（HBV）的成功免疫应答 AVT停止。慢性乙型肝炎的临床治愈发生在诊断病毒蛋白，“表面抗原”， （HBsAg），在血液中检测不到，这是我们正在评估的主要结果与停止- 治疗干预，同时密切监测安全性。BeNEG-DO的灵感来自于一个开创性的证据， 在雅典大学进行的一项概念研究，该研究在具有常见“e-抗原”的患者中停止AVT 慢性乙型肝炎（HBeAg-CHB）。雅典的研究首次表明成功的HBV免疫 并且在≥3.7年的AVT治疗后停止AVT的大量患者中可以获得临床治愈。 病毒抑制，并且在没有安全性问题的情况下实现。在目前资助的BeNEG-DO赠款中，我们 我建议在一个更大的旧金山弗朗西斯科人口中测试这项希腊研究的结果， 亚洲人是世界上最大的HBV储存库。同时，我们提出了蜂窝和 使用基线肝活检和系列血液样本进行分子研究，以剖析免疫机制 HBsAg从血液中清除与持久性。翻译科学部分是 由基于我们的小鼠模型和人类数据的假设驱动;它还包含一个宿主基因， 一个寻找证据的勘探手臂，寻找标志性基因表达模式，既预测结果 并可能指向未知的免疫机制。研究的一个关键目标是区分 最有可能或最不可能从治疗退出干预中获益的患者。2中心 BeNEG-DO研究完全入组; 76例停止AVT，30例对照继续治疗。所有情况 截至2020年10月25日，已停止治疗至少2.5年。我们已经确认了撤军 从AVT可以导致前所未有的临床治愈率和确定的群体在以前未知的风险 停止AVT后。具体来说，11名患者已经失去了HBsAg，24名患者的HBsAg水平逐渐下降， 水平; 11例最新HBsAg水平<5 IU/mL（范围0.05-3.7）。其余参与者的轨迹 还没有定义。这一更新申请要求提供资金，以继续实现 原始研究，并利用最新的整合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并获益，以及哪些患者可能在 最大的风险这项研究可能有重大的治疗，管理和财政保健的影响。

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.