REP 2139-Ca和聚乙二醇化干扰素治疗慢性乙型肝炎病毒D病毒感

StephenW

Persistent Control of Hepatitis B Virus and Hepatitis Delta Virus Infection Following REP 2139-Ca and Pegylated Interferon Therapy in Chronic Hepatitis B Virus/Hepatitis Delta Virus Coinfection
Michel Bazinet  1 , Victor Pântea  2 , Valentin Cebotarescu  2 , Lilia Cojuhari  2 , Pavlina Jimbei  3 , Mark Anderson  4 , Jeff Gersch  4 , Vera Holzmayer  4 , Carina Elsner  5 , Adalbert Krawczyk  5   6 , Mary C Kuhns  4 , Gavin Cloherty  4 , Ulf Dittmer  5 , Andrew Vaillant  1
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    PMID: 33553968 PMCID: PMC7850315 DOI: 10.1002/hep4.1633

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Abstract

The nucleic acid polymer REP 2139 inhibits assembly/secretion of hepatitis B virus (HBV) subviral particles. Previously, REP 2139-Ca and pegylated interferon (pegIFN) in HBV/hepatitis delta virus (HDV) coinfection achieved high rates of HDV RNA and hepatitis B surface antigen (HBsAg) loss/seroconversion in the REP 301 study (NCT02233075). The REP 301-LTF study (NCT02876419) examined safety and efficacy during 3.5 years of follow-up. In the current study, participants completing therapy in the REP 301 study were followed for 3.5 years. Primary outcomes were safety and tolerability, and secondary outcomes were HDV functional cure (HDV RNA target not detected [TND], normal alanine aminotransferase [ALT]), HBV virologic control (HBV DNA ≤2,000 IU/mL, normal ALT), HBV functional cure (HBV DNA TND; HBsAg <0.05 IU/mL, normal ALT), and HBsAg seroconversion. Supplemental analysis included high-sensitivity HBsAg (Abbott ARCHITECT HBsAg NEXT), HBV pregenomic RNA (pgRNA), HBsAg/hepatitis B surface antibody (anti-HBs) immune complexes (HBsAg ICs), and hepatitis B core-related antigen (HBcrAg). Asymptomatic grade 1-2 ALT elevations occurred in 2 participants accompanying viral rebound; no other safety or tolerability issues were observed. During therapy and follow-up, HBsAg reductions to <0.05 IU/mL were also <0.005 IU/mL. HBsAg ICs declined in 7 of 11 participants during REP 2139-Ca monotherapy and in 10 of 11 participants during follow-up. HDV functional cure persisted in 7 of 11 participants; HBV virologic control persisted in 3 and functional cure (with HBsAg seroconversion) persisted in 4 of these participants. Functional cure of HBV was accompanied by HBV pgRNA TND and HBcrAg <lower limit of quantitation. Conclusion: REP 2139-Ca + pegIFN is not associated with long-term safety or tolerability issues. The establishment of HDV functional cure and HBV virologic control/functional cure and HBsAg seroconversion are durable over 3.5 years and may reflect removal of integrated HBV DNA from the liver. Further investigation is warranted in larger studies.

© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.

StephenW

REP 2139-Ca和聚乙二醇化干扰素治疗慢性乙型肝炎病毒/三角洲乙肝病毒并发感染后，持久控制乙型肝炎病毒和乙型肝炎三角洲病毒感染
Michel Bazinet 1，VictorPântea2，Valentin Cebotarescu 2，Lilia Cojuhari 2，Pavlina Jimbei 3，Mark Anderson 4，Jeff Gersch 4，Vera Holzmayer 4，Carina Elsner 5，Adalbert Krawczyk 5 6，Mary C Kuhns 4，Gavin Cloherty 4，乌尔夫·迪特默5，安德鲁·威兰特1
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    PMID：33553968 PMCID：PMC7850315 DOI：10.1002 / hep4.1633

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核酸聚合物REP 2139抑制乙型肝炎病毒（HBV）亚病毒颗粒的组装/分泌。以前，在REP 301研究（NCT02233075）中，HBV /肝炎三角洲病毒（HDV）共感染中的REP 2139-Ca和聚乙二醇化干扰素（pegIFN）实现了高比率的HDV RNA和乙型肝炎表面抗原（HBsAg）丢失/血清转化。 REP 301-LTF研究（NCT02876419）在3.5年的随访期间检查了安全性和有效性。在本研究中，对REP 301研究中完成治疗的参与者进行了3.5年的随访。主要结果为安全性和耐受性，次要结果为HDV功能性治愈（未检测到HDV RNA靶标[TND]，丙氨酸氨基转移酶[ALT]正常），HBV病毒学控制（HBVDNA≤2,000IU / mL，ALT正常），HBV功能正常治愈（HBV DNA TND； HBsAg <0.05 IU / mL，ALT正常）和HBsAg血清转化。补充分析包括高敏感性HBsAg（Abbott ARCHITECT HBsAg NEXT），HBV前基因组RNA（pgRNA），HBsAg /乙型肝炎表面抗体（抗HBs）免疫复合物（HBsAg ICs）和乙型肝炎核心相关抗原（HBcrAg）。 2名参与者伴随病毒反弹出现无症状的1-2级ALT升高。没有观察到其他安全性或耐受性问题。在治疗和随访期间，HBsAg降低至<0.05 IU / mL的同时也<0.005 IU / mL。 REP 2139-Ca单药治疗期间，11名参与者中的7名患者的HBsAg ICs下降，随访期间11名参与者中的10名患者的HBsAg ICs下降。 HDV功能治愈持续11名参与者中的7名；在这些参与者中，有3例持续进行了HBV病毒学控制，而4例持续了功能治愈（伴随HBsAg血清转化）。 HBV的功能性治愈伴随着HBV pgRNA TND和HBcrAg <定量下限。结论：REP 2139-Ca + pegIFN与长期安全性或耐受性问题无关。 HDV功能性治疗和HBV病毒学控制/功能性治疗以及HBsAg血清转化的建立可以持续3.5年以上，并且可能反映出肝脏中整合的HBV DNA的去除。较大的研究中有必要做进一步的研究。

©2020作者。 Wiley Periodicals LLC代表美国肝病研究协会出版的《肝病学通讯》。

StephenW

https://aasldpubs.onlinelibrary. ... t/10.1002/hep4.1633