在基于 NAP 的治疗期间和之后持续分析 HBsAg 免疫复合物和 cccD

StephenW

在基于 NAP 的治疗期间和之后持续分析 HBsAg 免疫复合物和 cccDNA 活性
Michel Bazinet 1 , Mark Anderson 2 , Victor Pântea 3 , Gheorghe Placinta 3 , Iurie Moscalu 4 , Valentin Cebotarescu 3 , Lilia Cojuhari 3 , Pavlina Jimbei 5 , Liviu Iarovoi 3 , Valentina Smeso 3, Valentina Smeso 4 Dittmer 6、Jeff Gersch 2、Vera Holzmayer 2、Mary Kuhns 2、Gavin Cloherty 2、Andrew Vaillant 1

隶属关系隶属关系    1    Replicor Inc.，加拿大蒙特利尔。    2    雅培诊断，雅培公园，伊利诺伊州，美国。    3    摩尔多瓦共和国基希讷乌 Nicolae Testemiţanu 国立医药大学传染病系。    4    ARENSIA 探索医学，共和国临床医院，摩尔多瓦共和国基希讷乌。    5    Toma Ciorbǎ Infectious Clinical Hospital, Chișinău, 摩尔多瓦共和国。    6    德国埃森杜伊斯堡-埃森大学病毒学研究所。    PMID：34558823 DOI：10.1002/hep4.1767抽象
的核酸聚合物 (NAPs)、富马酸替诺福韦二吡呋酯 (TDF) 和聚乙二醇干扰素 (pegIFN) 治疗在慢性乙型肝炎病毒 (HBV) 感染中实现了高 HBsAg 消失/血清转换和功能性治愈率。研究了乙型肝炎表面抗原 (HBsAg) 血清转化和共价闭合环状 DNA (cccDNA) 失活在建立功能性治愈中的作用。使用雅培 ARCHITECT HBsAg NEXT 检测（伊利诺伊州芝加哥）、雅培研究专用检测 HBsAg 免疫复合物 (HBsAg IC)、循环 HBV RNA 和 Fujirebio 检测乙型肝炎核心 - 对来自 REP 401 研究的存档血清进行分析。相关抗原（HBcrAg；马尔文，宾夕法尼亚州）。在 NAP 暴露期间，23 名参与者的 HBsAg 变为 < 0.005 IU/mL，并且在所有功能治愈的参与者中持续存在。 HBsAg IC 在引入 TDF 单药治疗期间下降，并且与 HBsAg 的轻微下降相关。添加 NAPs 和 pegIFN 后，治疗期间 HBsAg IC 的轻微增加（n = 13）或发作（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。在病毒学控制或功能治愈的参与者中，HBsAg IC 在随访期间普遍下降。无论治疗结果如何，NAP + pegIFN 在 TDF 单药治疗期间 HBV RNA 和 HBcrAg 普遍下降。在治疗结束时，14 名功能治愈的参与者中只有 5 人检测不到 HBV RNA，但在所有功能治愈的参与者中止治疗后都检测不到 HBV RNA。 5 名参与者在治疗结束时检测不到 HBV RNA，随后复发至病毒学控制或病毒反弹。
结论：抗 HBs 非依赖性机制有助于 NAP 治疗期间的 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。功能性治愈的持续 HBsAg 消失也可能反映整合 HBV DNA 的减少/清除。 Clinicaltrials.org 编号 NCT02565719。

StephenW

Analysis of HBsAg Immunocomplexes and cccDNA Activity During and Persisting After NAP-Based Therapy
Michel Bazinet  1 , Mark Anderson  2 , Victor Pântea  3 , Gheorghe Placinta  3 , Iurie Moscalu  4 , Valentin Cebotarescu  3 , Lilia Cojuhari  3 , Pavlina Jimbei  5 , Liviu Iarovoi  3 , Valentina Smesnoi  5 , Tatina Musteata  5 , Alina Jucov  3   4 , Ulf Dittmer  6 , Jeff Gersch  2 , Vera Holzmayer  2 , Mary Kuhns  2 , Gavin Cloherty  2 , Andrew Vaillant  1
Affiliations
Affiliations

    1
    Replicor Inc., Montreal, Canada.
    2
    Abbott Diagnostics, Abbott Park, IL, USA.
    3
    Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova.
    4
    ARENSIA Exploratory Medicine, Republican Clinical Hospital, Chișinău, Republic of Moldova.
    5
    Toma Ciorbǎ Infectious Clinical Hospital, Chișinău, Republic of Moldova.
    6
    Institute for Virology, University of Duisburg-Essen, Essen, Germany.

    PMID: 34558823 DOI: 10.1002/hep4.1767

Abstract

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.

© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

StephenW

https://aasldpubs.onlinelibrary. ... t/10.1002/hep4.1767