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

慢性乙肝病毒感染(CHB)困扰着150-200万美国人，全球约有3亿人 每年导致约100万人过早死亡。在“BeNEG-Do”基金中，我们正在研究一种 干预旨在安全地刺激慢性乙肝患者的免疫介导的临床治疗。而当 类似抗病毒治疗(AVT)中的抑制性标准核(T)很少治愈CHB，通常是 无限期服用，我们正在调查是否可以安全地停止AVT至少192周(3.7年) 在以下情况下，当复制重新激活时，激发对乙肝病毒(乙肝)的成功免疫反应 AVT已停止。临床治愈慢性乙型病毒性肝炎发生时，诊断病毒蛋白，即“表面抗原” (乙肝表面抗原)，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的灵感来自于一个开创性的证据 在雅典大学进行的一项概念研究，该研究停止了患有共同e抗原的患者的AVT “阴性”型(HBeAg-CHB)。雅典的研究首次表明，成功的乙肝免疫 在≥3.7年后停止aVT的患者中，有相当数量的人可以产生临床治愈 并在没有安全问题的情况下实现了病毒抑制。在目前资助的BeNEG-DO赠款中，我们 建议在一个更大的旧金山人口中测试这项希腊研究的结果，自然 为构成世界上最大的乙肝病毒宿主的亚洲人提供了丰富的营养。同时，我们提出了细胞和 应用基础肝活检和系列血液样本进行分子研究以剖析免疫机制 血液中乙肝表面抗原清除量与持久性的对比。翻译科学的部分内容是 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 寻找标志性基因表达模式的证据，这两种模式都可以预测结果 并可能指向意想不到的免疫机制。这些研究的一个关键目标是区分 最有可能或最不可能从停药干预中受益的患者。两个中心 全部纳入BeNEG-DO研究；76例停止AVT，30例对照组仍在接受治疗。所有案例 已经停止治疗至少2.5年了，直到10/25/20。我们已经确认了这种停药 AVT可导致前所未有的临床治愈率，并在以前未知的风险下识别出组 在停止AVT之后。具体地说，11名患者已经失去了乙肝表面抗原，另有24名患者正在逐渐下降 水平；11个具有最新的乙肝表面抗原水平&lt；5个单位/毫升(范围0.05-3.7)。其余参与者的轨迹 仍未定义。此续期申请申请资金，以继续实现 原创研究，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并受益，哪些患者可能在 最大的风险。这项研究可能会对治疗、管理和财务保健产生重大影响。

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.