初治Nucleos（t）ide治疗的慢性HBV感染患者48周REP 2139或REP 2165，

StephenW

Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy
Michel Bazinet1
, Victor Pântea2
, Gheorghe Placinta2
, Iurie Moscalu3
, Valentin Cebotarescu2
, Lilia Cojuhari2
, Pavlina Jimbei4
, Liviu Iarovoi2
, Valentina Smesnoi4
, Tatiana Musteata4
, Alina Jucov2,3
, Ulf Dittmer5
, Adalbert Krawczyk5,6
, Andrew Vaillant1,∗,'Correspondence information about the author Andrew VaillantEmail the author Andrew Vaillant
DOI: https://doi.org/10.1053/j.gastro.2020.02.058
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    Abstract

Abstract
Background & Aims

Nucleic acid polymers (NAPs) inhibit assembly and secretion of hepatitis B virus (HBV) subviral particles. We performed an open-label, phase 2 study of the safety and efficacy of the NAPs REP 2139 or REP 2165 combined with tenofovir disoproxil fumarate (TDF) and pegylated interferon alfa-2a (pegIFN) in patients with negative chronic HBV infection who were negative for HB e antigen (HBeAg).
Methods

Following 24 weeks TDF therapy, 40 patients were randomly assigned to groups that received 48 weeks of experimental therapy (TDF + pegIFN + REP 2139-Mg or REP 2165-Mg) or 24 weeks of control therapy (TDF + pegIFN) followed by 48 weeks experimental therapy. Patients were then followed for a treatment-free period of 48 weeks. Primary outcomes were the safety and tolerability of REP 2139-Mg or REP 2165-Mg in combination with TDF + pegIFN compared to TDF + pegIFN alone through the first 48 weeks of therapy and subsequently throughout 48 weeks of NAP-based combination therapy (treatment weeks 24-72 in the experimental group and weeks 48-96 in the control group). Secondary outcomes reductions in HBsAg in control and experimental groups over the first 48 weeks of the study and throughout 48 weeks of combination therapy and virologic control (HBsAg positive, HBV DNA below 2000 IU/mL, normal level of alanine aminotransferase) or functional cure (HBsAg below 0.05 IU/mL, HBV DNA target not detected, normal level of alanine aminotransferase) after removal of all therapy.
Results

Levels of HBsAg, anti-HBs, and HBV DNA did not differ significantly between the groups given REP 2139 vs REP 2165. PegIFN-induced thrombocytopenia (P=.299 vs controls) and neutropenia (P=.112 vs controls) were unaffected by NAPs (REP 2139 vs REP 2165). Increases in levels of transaminases were significantly more frequent (P<.001 vs controls) and greater (P=.002 vs controls) in the NAP groups (but did not produce symptoms), correlated with initial decrease in HBsAg, and normalized during therapy and follow up. During the first 24 weeks of TDF and pegIFN administration, significantly higher proportions of patients in NAP groups had decreases in HBsAg to below 1 IU/mL (P<.001 vs control) and HBsAg seroconversion (P=.046 vs control). At the time patients completed the TDF + pegIFN + NAP regimen, HBsAg levels were 0.05 IU/mL or lower in 24/40 participants (all with seroconversion up to 233,055 mIU/mL). During 48 weeks of treatment-free follow up, virologic control persisted in 13/40 participants (2 lost to follow up after 24 weeks), whereas functional cure persisted in with 14/40 participants (all completing 48 weeks of follow-up) with persistent HBsAg seroconversion. One participant had a viral rebound during follow up with hepatic decompensation and was placed on TDF therapy.
Conclusions

In a phase 2 randomized trial, we found that addition of NAPs to TDF + pegIFN did not alter tolerability and significantly increased rates of HBsAg loss and HBsAg seroconversion during therapy and functional cure after therapy. Clinicaltrials.gov no: NCT02565719.
Keywords:
HBV, HBsAg, functional cure, nucleic acid polymer

StephenW

初治Nucleos（t）ide治疗的慢性HBV感染患者48周REP 2139或REP 2165，替诺福韦二甲环素和聚乙二醇化干扰素Alfa-2a的安全性和有效性
米歇尔·巴赞特1
，VictorPântea2
，Gheorghe Placinta2
，Iurie Moscalu3
，Valentin Cebotarescu2
，莉莉亚·科朱哈里2
，帕夫利纳·金贝（Pavlina Jimbei）4
，Liviu Iarovoi2
瓦伦蒂娜（Valentina Smesnoi）4
，塔蒂亚娜·穆斯塔塔4
，阿丽娜·朱可夫2,3
乌尔夫·迪特默（Ulf Dittmer）5
，阿达伯特·克拉维奇5,6
，'Andrew Vaillant1，*，'有关作者Andrew Vaillant的通讯信息通过电子邮件发送给作者Andrew Vaillant
DOI：https：//doi.org/10.1053/j.gastro.2020.02.058
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    抽象

抽象
背景与目标

核酸聚合物（NAP）抑制乙肝病毒（HBV）亚病毒颗粒的组装和分泌。我们对NAP REP 2139或REP 2165联合富马酸替诺福韦酯（TDF）和聚乙二醇化干扰素α-2a（pegIFN）的慢性HBV阴性患者进行了2期安全性和有效性的开放标签研究用于HB e抗原（HBeAg）。
方法

TDF治疗24周后，将40例患者随机分为接受48周实验治疗（TDF + pegIFN + REP 2139-Mg或REP 2165-Mg）或24周对照治疗（TDF + pegIFN）的组，然后进行48周实验疗法。然后，对患者进行48周的免费治疗。主要结局是，在治疗的前48周以及随后整个基于NAP的联合治疗（治疗周）中，REP 2139-Mg或REP 2165-Mg与TDF + pegIFN联合使用与单独使用TDF + pegIFN相比，其安全性和耐受性实验组为24-72周，对照组为48-96周）。在研究的前48周以及联合治疗和病毒学控制（HBsAg阳性，HBV DNA低于2000 IU / mL，丙氨酸转氨酶水平正常）或功能性治愈的整个48周内，对照组和实验组的HBsAg继发结局降低去除所有治疗后，HBsAg低于0.05 IU / mL，未检测到HBV DNA靶点，丙氨酸转氨酶水平正常。
结果

给予REP 2139和REP 2165的组之间HBsAg，抗HBs和HBV DNA的水平没有显着差异。PegIFN诱导的血小板减少症（P = .299 vs对照）和中性粒细胞减少症（P = .112 vs对照）不受这些影响NAP（REP 2139与REP 2165）。在NAP组中转氨酶水平的升高更为频繁（P <.001，对照组），更高（P = .002，对照组）（但未产生症状），与最初的HBsAg降低相关，并在治疗期间恢复正常并跟进。在施用TDF和pegIFN的前24周内，NAP组中较高比例的患者的HBsAg降至1 IU / mL以下（与对照组相比，P <.001）和HBsAg血清转化（与对照组相比，P = .046）。在患者完成TDF + pegIFN + NAP方案时，24/40名参与者的HBsAg水平为0.05 IU / mL或更低（所有患者的血清转化率最高为233,055 mIU / mL）。在48周的无治疗随访中，有13/40名参与者坚持了病毒学控制（2名在24周后失去了随访），而14/40名参与者坚持了功能性治愈（全部完成了48周的随访）。持续的HBsAg血清转化。一名参与者在进行肝失代偿的随访过程中出现病毒反弹，并接受了TDF治疗。
结论

在一项2期随机试验中，我们发现在TDF + pegIFN中添加NAP不会改变耐受性，并且在治疗期间以及治疗后功能治愈的过程中，HBsAg丢失和HBsAg血清转化的比率均显着增加。 Clinicaltrials.gov编号：NCT02565719。
关键字：
HBV，HBsAg，功能性治疗，核酸聚合物

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Clinicaltrials.gov编号：NCT02565719

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