慢性乙型肝炎功能性治愈新疗法的临床前景。
完整摘要 · 中文译文
背景：慢性乙型肝炎（CHB）仍是全球主要健康问题。功能性治愈定义为治疗停止后24周持续乙型肝炎表面抗原（HBsAg）清除且HBV DNA检测不到。它已成为具有临床意义的终点，与肝纤维化逆转、降低肝细胞癌（HCC）风险及较低的治疗负担相关。然而，当前CHB治疗，包括核苷（酸）类似物（NUCs）和聚乙二醇干扰素α（Peg-IFNα），尽管病毒抑制充分，却很少实现功能性治愈，导致相当一部分患者仍面临不良肝脏相关结局风险，包括肝功能失代偿和HCC。因此，新型治疗药物旨在加速实现功能性治愈。它们被分为病毒靶向治疗和免疫调节治疗。方法：本综述总结了旨在实现功能性治愈的新兴疗法的临床证据，特别关注RNA靶向治疗。它还讨论了与治疗选择相关的实践考虑。结果：在这些新型疗法中，RNA靶向治疗目前最有前景，其中bepirovirsen（一种非偶联反义寡核苷酸）作为唯一完成III期研究并显示有效结果的药物脱颖而出。以RNA靶向治疗为骨架的联合方案日益受到追求，利用潜在协同效应以获得更高的HBsAg清除率。结论：RNA靶向治疗及联合方案 这些药物为慢性乙型肝炎（CHB）实现功能性治愈提供了有前景的方法。进一步的研究应着重于这些新型药物的长期疗效和安全性。
完整摘要 · 英文原文
BACKGROUND: Chronic hepatitis B (CHB) remains a major global health problem. Functional cure is defined as sustained hepatitis B surface antigen (HBsAg) seroclearance with undetectable HBV DNA 24 weeks after cessation of therapy. It has emerged as a clinically meaningful endpoint, associated with regression of liver fibrosis, reduced hepatocellular carcinoma (HCC) risk, and a lower treatment burden. However, current CHB therapies, including nucleos(t)ide analogues (NUCs) and pegylated interferon-α (Peg-IFNα), rarely lead to functional cure despite adequate viral suppression, leading to a notable portion of patients remaining at risk for adverse liver-related outcomes, including hepatic decompensation and HCC. Hence, novel therapeutic agents are aimed at accelerating towards functional cure. They are categorized as virus-targeting and immunomodulatory therapies. METHODS: This review summarizes the clinical evidence for emerging therapies aimed at acheiving functional cure, with a particular focus on RNA-targeting therapies. It also discusses practical considerations relevant to treatment selection. RESULTS: Among these novel therapies, RNA-targeting therapies are currently the most promising, with bepirovirsen (an unconjugated antisense oligonucleotide) standing out as the only agent completed in Phase III study showing efficacious results. Combination regimens that use RNA-targeting therapies as backbone are increasingly pursued, leveraging potential synergistic effects to achieve higher rates of HBsAg seroclearance. CONCLUSION: RNA-targetting therapies and combination regimens offer promising approaches in attaining functional cure in CHB. Further research should emphasize on the long-term efficacy and safety for these novel agents.