Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.
Clin Gastroenterol Hepatol. 2023 Jul;21(8):2040-2050. doi: 10.1016/j.cgh.2023.02.032. Epub 2023 Apr 18.
A functional cure of chronic hepatitis B defined as sustained hepatitis B surface antigen loss after finite course of therapy is rarely achieved with current therapy but is the goal of novel treatments. Understanding the virological and immunological mechanisms of hepatitis B virus persistence has enabled the identification of novel treatment targets, drug discovery, and the evaluation of novel agents in clinical trials. Lessons were learned from early phase 1 and phase 2 trials regarding the antiviral activity and safety profile of these agents. There is a strong rationale to combine agents to reduce viral replication, reduce viral antigen load, invigorate immune responses, and induce specific adaptive immune responses. Nucleos(t)ide analogs will likely remain an essential backbone of future combinations to control viral replication and prevent resistance to antiviral drugs. In this review, we discuss perspectives on approaches to achieving functional cure, with a review of virological and immunological strategies, highlighting challenges and unresolved questions with the various attempts to achieve cure, as well as exploring alternative endpoints such as partial cure and new noninvasive viral and immunological biomarkers to stratify patients and predict/monitor antiviral response.
慢性乙型肝炎的功能性治愈定义为有限疗程治疗后乙型肝炎表面抗原持续丢失，目前的治疗方法很少能实现，但这是新型治疗方法的目标。对乙型肝炎病毒持续存在的病毒学和免疫学机制的理解，使人们能够确定新的治疗靶点、药物发现，并在临床试验中评估新型药物。早期的 1 期和 2 期试验为这些药物的抗病毒活性和安全性特征提供了经验教训。有充分的理由联合使用药物来降低病毒复制、减少病毒抗原负荷、增强免疫反应，并诱导特异性适应性免疫反应。核苷酸类似物很可能仍然是未来组合治疗的重要基础，以控制病毒复制并防止对抗病毒药物产生耐药性。在这篇综述中，我们讨论了实现功能性治愈的方法，综述了病毒学和免疫学策略，强调了在尝试实现治愈的各种尝试中所面临的挑战和未解决的问题，并探讨了替代终点，如部分治愈和新的非侵入性病毒和免疫学生物标志物，以对患者进行分层，并预测/监测抗病毒反应。
