ABSTRACT

Global elimination of HBV is feasible thanks to the availability of a safe, effective and inexpensive vaccine. However, this will not help almost 300 million adults living with chronic HBV infection. Current therapy can reduce complications but is administered life-long and is associated with risk of breakthrough and potential cumulative toxicity. There is therefore great interest in developing new therapies which can achieve sustained disease remission after a finite course of treatment i.e. an HBV CURE. Steps of HBV life cycle other than the polymerase that are targeted by new direct antiviral therapies include HBV entry, HBV capsid assembly, HBV mRNA transcription and translation and HBsAg secretion. As chronic HBV infection is characterised by high viral load and antigen burden and inadequate host immune responses innovative approaches to restore innate and adaptive immune responses against HBV, are currently in clinical development. These include therapeutic vaccines and TLR agonists. It is likely that HBV Cure will require combinations of novel immunomodulatory and antiviral approaches. In the future, strategies which directly silence or eliminate cccDNA could provide a single agent cure. Efficacy, safety, route of administration and cost will ultimately determine the impact of these new regimens on the burden of HBV.

Abbreviations: ACTG: AIDS Clinical Trials Group network; ALT: alanine aminotransferase; ASGPR: Asialoglycoprotein Receptor; ASO: anti-sense oligonucleotide; CAM: capsid assembly modulator; CAM-A: capsid assembly modulator with abhorrent structure; CAM-N: capsid assembly modulator with normal structure; cccDNA: covalently closed circular DNA; CHB: chronic hepatitis B; c-Raf-1/MAP: cellular Rapidly Accelerated Fibrosarcoma-1/mitogen-activated protein kinase; DR1 and DR2: direct repeat sequences 1 and 2; ETV: entecavir; FDA: Food and Drug Administration; GalNAc: N-acetylgalactosamine; HBcrAg: hepatitis B core-related antigen; HBeAg: hepatitis B e antigen; HBIG: hepatitis B immunoglobulin; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HBV DNA: hepatitis B virus deoxyribonucleic acid; HCC: hepatocellular carcinoma; HDV: hepatitis delta virus; ir-AE: immune-related adverse events; LNA: locked nucleic acid; MAD: multiple ascending dose; mRNA: messenger ribonucleic acid; NAPs: nucleic acid polymers; NTCP: sodium taurocholate co-transporting polypeptide; PD-1: programmed death receptor 1; PD-L1: programmed death receptor ligand 1; pgRNA: pregenomic ribonucleic acid; R-CHOP: rituximab plus cyclophosphamide plus doxorubicin plus vincristine plus prednisolone; RISC: RNA-induced silencing complex; RNAi: ribonucleic acid interference; SAD: single ascending dose; siRNA: short (small) interfering ribonucleic acid; STOPs: S-antigen traffic-inhibiting oligonucleotide polymers; TAF: tenofovir alafenamide; TDF: tenofovir disoproxil; USD: United States dollars; WHO: World Health Organization

摘要

由于安全、有效和廉价疫苗的可用性，全球消除 HBV 是可行的。然而，这无助于近 3 亿患有慢性 HBV 感染的成年人。目前的治疗可以减少并发症，但需要终生使用，并且与突破风险和潜在的累积毒性有关。因此，人们对开发能够在有限的治疗过程（即HBV CURE）后实现持续疾病缓解的新疗法非常感兴趣。新的直接抗病毒疗法靶向聚合酶以外的 HBV 生命周期步骤包括 HBV 进入、HBV 衣壳组装、HBV mRNA 转录和翻译以及 HBsAg 分泌。由于慢性 HBV 感染的特点是高病毒载量和抗原负荷以及宿主免疫反应不足，目前正在临床开发中恢复针对 HBV 的先天性和适应性免疫反应的创新方法。这些包括治疗性疫苗和 TLR 激动剂。HBV 治愈很可能需要新的免疫调节和抗病毒方法的组合。将来，直接沉默或消除 cccDNA 的策略可以提供单一药物治疗。疗效、安全性、给药途径和成本将最终决定这些新方案对 HBV 负担的影响。HBV 治愈很可能需要新的免疫调节和抗病毒方法的组合。将来，直接沉默或消除 cccDNA 的策略可以提供单一药物治疗。疗效、安全性、给药途径和成本将最终决定这些新方案对 HBV 负担的影响。HBV 治愈很可能需要新的免疫调节和抗病毒方法的组合。将来，直接沉默或消除 cccDNA 的策略可以提供单一药物治疗。疗效、安全性、给药途径和成本将最终决定这些新方案对 HBV 负担的影响。

缩写：ACTG：艾滋病临床试验组网络；ALT：丙氨酸氨基转移酶；ASGPR：去唾液酸糖蛋白受体；ASO：反义寡核苷酸；CAM：衣壳组装调节剂；CAM-A：具有异常结构的衣壳组装调节剂；CAM-N：具有正常结构的衣壳组装调节剂；cccDNA：共价闭合环状DNA；CHB：慢性乙型肝炎；c-Raf-1/MAP：细胞快速加速纤维肉瘤-1/丝裂原活化蛋白激酶；DR1 和 DR2：直接重复序列 1 和 2；ETV：恩替卡韦；FDA：食品药品监督管理局；GalNAc：N-乙酰半乳糖胺；HBcrAg：乙型肝炎核心相关抗原；HBeAg：乙型肝炎e抗原；HBIG：乙型肝炎免疫球蛋白；HBsAg：乙型肝炎表面抗原；HBV：乙型肝炎病毒；HBV DNA：乙型肝炎病毒脱氧核糖核酸；HCC：肝细胞癌；HDV：丁型肝炎病毒；红外-AE：免疫相关的不良事件；LNA：锁核酸；MAD：多次递增剂量；mRNA：信使核糖核酸；NAPs：核酸聚合物；NTCP：牛磺胆酸钠协同转运多肽；PD-1：程序性死亡受体1；PD-L1：程序性死亡受体配体1；pgRNA：前基因组核糖核酸；R-CHOP：利妥昔单抗加环磷酰胺加多柔比星加长春新碱加泼尼松龙；RISC：RNA诱导的沉默复合物；RNAi：核糖核酸干扰；SAD：单次递增剂量；siRNA：短（小）干扰核糖核酸；STOPs：S-抗原交通抑制寡核苷酸聚合物；TAF：替诺福韦艾拉酚胺；TDF：替诺福韦酯；USD：美元；世界卫生组织：世界卫生组织 NAPs：核酸聚合物；NTCP：牛磺胆酸钠协同转运多肽；PD-1：程序性死亡受体1；PD-L1：程序性死亡受体配体1；pgRNA：前基因组核糖核酸；R-CHOP：利妥昔单抗加环磷酰胺加多柔比星加长春新碱加泼尼松龙；RISC：RNA诱导的沉默复合物；RNAi：核糖核酸干扰；SAD：单次递增剂量；siRNA：短（小）干扰核糖核酸；STOPs：S-抗原交通抑制寡核苷酸聚合物；TAF：替诺福韦艾拉酚胺；TDF：替诺福韦酯；USD：美元；世界卫生组织：世界卫生组织 NAPs：核酸聚合物；NTCP：牛磺胆酸钠协同转运多肽；PD-1：程序性死亡受体1；PD-L1：程序性死亡受体配体1；pgRNA：前基因组核糖核酸；R-CHOP：利妥昔单抗加环磷酰胺加多柔比星加长春新碱加泼尼松龙；RISC：RNA诱导的沉默复合物；RNAi：核糖核酸干扰；SAD：单次递增剂量；siRNA：短（小）干扰核糖核酸；STOPs：S-抗原交通抑制寡核苷酸聚合物；TAF：替诺福韦艾拉酚胺；TDF：替诺福韦酯；USD：美元；世界卫生组织：世界卫生组织 利妥昔单抗加环磷酰胺加多柔比星加长春新碱加泼尼松龙；RISC：RNA诱导的沉默复合物；RNAi：核糖核酸干扰；SAD：单次递增剂量；siRNA：短（小）干扰核糖核酸；STOPs：S-抗原交通抑制寡核苷酸聚合物；TAF：替诺福韦艾拉酚胺；TDF：替诺福韦酯；USD：美元；世界卫生组织：世界卫生组织 利妥昔单抗加环磷酰胺加多柔比星加长春新碱加泼尼松龙；RISC：RNA诱导的沉默复合物；RNAi：核糖核酸干扰；SAD：单次递增剂量；siRNA：短（小）干扰核糖核酸；STOPs：S-抗原交通抑制寡核苷酸聚合物；TAF：替诺福韦艾拉酚胺；TDF：替诺福韦酯；USD：美元；世界卫生组织：世界卫生组织