Replicor Inc.MontrealCanada.
Abbott DiagnosticsAbbott ParkILUSA.
Hepatol Commun. 2021 Nov;5(11):1873-1887. doi: 10.1002/hep4.1767. Epub 2021 Jul 10.
Therapy with nucleic acid polymers (NAPs), tenofovir disoproxil fumarate (TDF), and pegylated interferon (pegIFN) achieve high rates of HBsAg loss/seroconversion and functional cure in chronic hepatitis B virus (HBV) infection. The role of hepatitis B surface antigen (HBsAg) seroconversion and inactivation of covalently closed circular DNA (cccDNA) in establishing functional cure were examined. Archived serum from the REP 401 study was analyzed using the Abbott ARCHITECT HBsAg NEXT assay (Chicago, IL), Abbott research use-only assays for HBsAg immune complexes (HBsAg ICs), circulating HBV RNA, and the Fujirebio assay for hepatitis B core-related antigen (HBcrAg; Malvern, PA). HBsAg became < 0.005 IU/mL in 23 participants during NAP exposure, which persisted in all participants with functional cure. HBsAg IC declined during lead-in TDF monotherapy and correlated with minor declines in HBsAg. Following the addition of NAPs and pegIFN, minor HBsAg IC increases (n = 13) or flares (n = 2) during therapy were not correlated with HBsAg decline, hepatitis B surface antibody (anti-HBs) titers, or alanine aminotransferase. HBsAg IC universally declined during follow-up in participants with virologic control or functional cure. Universal declines in HBV RNA and HBcrAg during TDF monotherapy continued with NAP + pegIFN regardless of therapeutic outcome. At the end of therapy, HBV RNA was undetectable in only 5 of 14 participants with functional cure but became undetectable after removal of therapy in all participants with functional cure. Undetectable HBV RNA at the end of therapy in 5 participants was followed by relapse to virologic control or viral rebound. Conclusion: Anti-HBs-independent mechanisms contribute to HBsAg clearance during NAP therapy. Inactivation of cccDNA does not predict functional cure following NAP-based therapy; however, functional cure is accompanied by persistent inactivation of cccDNA. Persistent HBsAg loss with functional cure may also reflect reduction/clearance of integrated HBV DNA. Clinicaltrials.org number NCT02565719.
核酸聚合物 (NAPs)、替诺福韦二吡呋酯 (TDF) 和聚乙二醇干扰素 (pegIFN) 的治疗在慢性乙型肝炎病毒 (HBV) 感染中实现了高乙型肝炎表面抗原 (HBsAg) 丢失/转换率和功能性治愈。研究了 HBsAg 转换和共价闭合环状 DNA (cccDNA) 失活在建立功能性治愈中的作用。使用 Abbott ARCHITECT HBsAg NEXT 检测试剂盒（芝加哥，IL）、Abbott 用于研究的 HBsAg 免疫复合物 (HBsAg IC) 检测试剂盒、循环 HBV RNA 检测试剂盒和 Fujirebio 乙型肝炎核心相关抗原 (HBcrAg；Malvern，PA）检测试剂盒分析了 REP 401 研究中的存档血清。在 NAP 暴露期间，23 名参与者的 HBsAg 降至 <0.005 IU/mL，所有功能性治愈的参与者均持续存在。在 TDF 单药治疗的导入期，HBsAg IC 下降，并与 HBsAg 的轻微下降相关。加入 NAPs 和 pegIFN 后，13 名参与者的 HBsAg IC 出现轻微增加（n=13）或爆发（n=2），与 HBsAg 下降、乙型肝炎表面抗体 (抗-HBs) 滴度或丙氨酸氨基转移酶无关。在具有病毒学控制或功能性治愈的参与者中，在随访期间 HBsAg IC 普遍下降。在 NAP + pegIFN 治疗期间，无论治疗结果如何，TDF 单药治疗期间 HBV RNA 和 HBcrAg 的普遍下降仍在继续。在治疗结束时，只有 14 名功能性治愈的参与者中有 5 名的 HBV RNA 检测不到，但在所有功能性治愈的参与者中，在停止治疗后 HBV RNA 检测不到。在 5 名参与者中，治疗结束时 HBV RNA 检测不到，随后病毒学控制或病毒反弹。结论：NAP 治疗期间，抗-HBs 非依赖性机制有助于 HBsAg 清除。cccDNA 的失活并不能预测基于 NAP 的治疗后的功能性治愈；然而，功能性治愈伴随着 cccDNA 的持续失活。在功能性治愈的情况下，持续的 HBsAg 丢失也可能反映了整合的 HBV DNA 的减少/清除。Clinicaltrials.gov 编号 NCT02565719。
