Yao Kaijie, Feng Hao, Chen Ying, Bao Yun, Yan Mengxia, Li Wen, Wu Bin
Department of Pharmacy, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Clin Drug Investig. 2025 Sep 17. doi: 10.1007/s40261-025-01477-0.
Chronic hepatitis B virus infection remains a Major global public health challenge, affecting over 254 million individuals and causing substantial mortality owing to the limited curative potential of current therapies. This horizon scanning review aims to comprehensively analyze emerging trends and future directions in novel anti-hepatitis B virus therapeutic development, evaluating their progress and potential to achieve functional or complete cures.
We conducted a systematic horizon scanning review from January 2020 to June 2025, searching databases (PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure [CNKI], and WanFang), clinical trial registries (ClinicalTrials.gov, EU Clinical Trials Register, World Health Organization International Clinical Trials Registry, Chinese Clinical Trial Registry, and chinadrugtrials.org), hepatology conference abstracts (American Association for the Study of Liver Diseases, European Association for the Study of the Liver), and pharmaceutical company websites. Inclusion criteria focused on studies detailing novel anti-hepatitis B virus treatments, with data extracted on category, target, clinical phase, and discontinuation reasons.
Our analysis identified 161 unique anti-hepatitis B virus treatments: 75 in clinical trials, 34 in preclinical development, and 52 discontinued post-clinical trials because of safety or insufficient efficacy. The pipeline reveals a diversification of targets, with capsid assembly modulators, therapeutic vaccines, and monoclonal antibodies being most prevalent. Three therapies representing novel mechanisms have reached phase III-bepirovirsen (an antisense oligonucleotide), canocapavir (a capsid assembly modulator), and εPA-44 (a therapeutic vaccine), illustrating diversification of late-stage pipelines; however, 6-month off-treatment endpoints should be interpreted cautiously across modalities until durability is established.
The robust and diverse pipeline of novel anti-hepatitis B virus treatments offers promise for improving functional cure rates, but definitive conclusions await longer off-treatment follow-up and durability data. Continued research, rational combination strategies, and global collaboration are crucial to overcome challenges and ensure equitable access to these transformative therapies worldwide.
慢性乙型肝炎病毒感染仍然是一项重大的全球公共卫生挑战，影响着超过2.54亿人，并且由于当前疗法的治愈潜力有限而导致大量死亡。本前瞻性综述旨在全面分析新型抗乙型肝炎病毒治疗药物研发的新趋势和未来方向，评估它们实现功能性治愈或完全治愈的进展和潜力。
我们于2020年1月至2025年6月进行了一项系统性前瞻性综述，检索了数据库（PubMed、Embase、Cochrane图书馆、中国知网[CNKI]和万方）、临床试验注册库（ClinicalTrials.gov、欧盟临床试验注册库、世界卫生组织国际临床试验注册库、中国临床试验注册中心和药物临床试验登记与信息公示平台）、肝病学会议摘要（美国肝病研究协会、欧洲肝脏研究协会）以及制药公司网站。纳入标准聚焦于详细介绍新型抗乙型肝炎病毒治疗的研究，并提取有关类别、靶点、临床阶段和停药原因的数据。
我们的分析确定了161种独特的抗乙型肝炎病毒治疗药物：75种处于临床试验阶段，34种处于临床前研发阶段，52种因安全性或疗效不足在临床试验后停止研发。研发管线显示靶点呈现多样化，衣壳组装调节剂、治疗性疫苗和单克隆抗体最为普遍。三种代表新机制的疗法已进入III期——贝派维林（一种反义寡核苷酸）、卡诺卡韦（一种衣壳组装调节剂）和εPA - 44（一种治疗性疫苗），这说明了后期研发管线的多样化；然而，在确定疗效持久性之前，对于所有治疗方式，6个月停药终点的解读都应谨慎。
强大且多样的新型抗乙型肝炎病毒治疗药物研发管线有望提高功能性治愈率，但确切结论有待更长时间的停药随访和疗效持久性数据。持续的研究、合理的联合策略以及全球合作对于克服挑战并确保在全球范围内公平获得这些变革性疗法至关重要。
