高剂量Myrcludex-B单药治疗HDV相关性肝硬化48周的出色安全性和

StephenW

Excellent safety and effectiveness of high-dose myrcludex-B monotherapy administered for 48 weeks in HDV-related compensated cirrhosis: A case report of 3 patients
Alessandro Loglio1
, Peter Ferenci2
, Sara Colonia Uceda Renteria3
, Christine Y.L. Tham4
, Florian van Bömmel5
, Marta Borghi1
, Heidemarie Holzmann6
, Riccardo Perbellini1
, Elena Trombetta7
, Silvia Giovanelli8
, Letizia Greco3
, Laura Porretti7
, Daniele Prati8
, Ferruccio Ceriotti3
, Giovanna Lunghi3
, Antonio Bertoletti4
, Pietro Lampertico1,low asterisk,'Correspondence information about the author Pietro LamperticoEmail the author Pietro Lampertico
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DOI: https://doi.org/10.1016/j.jhep.2019.07.003 |

Summary

Short-term administration of the entry inhibitor myrcludex-B (MyrB) has been shown to be safe and effective in phase II studies in patients coinfected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). However, its effectiveness and safety are unknown during long-term and high-dose treatment of patients with compensated cirrhosis in real-life settings. Herein, we describe the first 3 European patients with HDV-related compensated cirrhosis who were treated with MyrB 10 mg/day for 48 weeks as a compassionate therapy. Liver function tests, bile acids, and virological markers were monitored every 4 weeks. HBV/HDV-specific T cell quantity (up to 48 and 36 weeks) and HBV RNA levels were also assessed in 2 cases. During MyrB treatment, HDV RNA levels progressively declined from 4.4 and 5.6 logs IU/ml to undetectability in 2 cases, and from 6.8 log copies/ml to 500 copies/ml for the other patient. Alanine aminotransferase normalised after 20, 12 and 28 weeks, respectively. A significant improvement in features of portal hypertension, liver function tests and alpha-fetoprotein levels were documented in 2 cases. In the male patient with histological and clinical stigmata of autoimmune hepatitis, IgG and immunoglobulins rapidly normalised. No significant changes in HBV surface antigen levels and circulating HBV/HDV-specific T cells were demonstrated; HBV DNA and HBV RNA levels remained undetectable throughout the study period. MyrB was well tolerated; patients remained fully asymptomatic despite a significant increase of bile acids. In conclusion, this report shows excellent safety and effectiveness of a 48-week course of MyrB 10 mg/day, combined with tenofovir disoproxil fumarate, for the treatment of HDV-related compensated cirrhosis.

StephenW

高剂量Myrcludex-B单药治疗HDV相关性肝硬化48周的出色安全性和有效性：3例病例报告
亚历山德罗·洛格里奥1
彼得·费伦奇2
，萨拉·科洛尼亚Uceda Renteria3
克里斯汀·Y·L· Tham4
，Florian vanBömmel5
玛尔塔·伯格（Marta Borghi）1
，海德玛莉·霍尔兹曼（Heidemarie Holzmann）6
里卡多·佩尔贝里尼1
，埃琳娜·特隆贝塔（Elena Trombetta）7
，西尔维亚·乔瓦内利8
，莱蒂齐亚·格雷科3
劳拉·波雷蒂（Laura Porretti）7
，丹妮（Daniele Prati）8
，Ferruccio Ceriotti3
，乔万娜·隆吉3
安东尼奥·贝托莱蒂4
，Pietro Lampertico1，低星号，有关作者Pietro Lampertico的通讯信息给作者发送电子邮件Pietro Lampertico
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DOI：https：//doi.org/10.1016/j.jhep.2019.07.003 |

摘要

在II期研究中，对于合并感染了乙型肝炎病毒（HBV）和丙型肝炎三角洲病毒（HDV）的患者，短期施用进入抑制剂myrcludex-B（MyrB）已被证明是安全有效的。但是，在现实生活中长期和大剂量治疗代偿性肝硬化患者期间，其有效性和安全性尚不清楚。本文中，我们描述了头3例HDV相关性肝硬化的欧洲患者，他们接受了10毫克/天的MyrB每天治疗48周作为同情疗法。每4周监测一次肝功能检查，胆汁酸和病毒学指标。还对2例患者的HBV / HDV特异性T细胞数量（长达48和36周）和HBV RNA水平进行了评估。在MyrB治疗期间，HDV RNA水平逐渐从4.4和5.6 log IU / ml下降2例无法检测到，另一例患者从6.8 log拷贝/ ml至500拷贝/ ml。丙氨酸氨基转移酶分别在20、12和28周后恢复正常，有2例患者的门脉高压，肝功能检查和甲胎蛋白水平明显改善。在患有自身免疫性肝炎的组织学和临床污名的男性患者中，IgG和免疫球蛋白迅速恢复正常。 HBV表面抗原水平和循环HBV / HDV特异性T细胞未见明显变化；在整个研究期间，HBV DNA和HBV RNA的水平仍然无法检测到。 MyrB的耐受性良好；尽管胆汁酸显着增加，患者仍完全无症状。总而言之，该报告显示了MyrB 10 mg /天的48周疗程与替诺福韦二吡呋酯富马酸酯联合用于治疗HDV相关性肝硬化的卓越安全性和有效性

StephenW

这是一项非常有意义的研究:
12个月使用Myrcludex-B, Myrcludex-B抑制HDV和HBV进入肝细胞, 这个被"HDV RNA水平逐渐从4.4和5.6 log IU / ml下降2例无法检测到，另一例患者从6.8 log拷贝/ ml至500拷贝/ ml" 证明了.

但是 "HBV表面抗原水平和循环HBV / HDV特异性T细胞未见明显变化".

因此，长期抑制HBV再感染/新感染似乎不足以治愈HBV?
这个对核心蛋白抑制剂的含义是什么?

乙肝人1949

是不是可以解释，乙肝病毒使用Mycvibx药后不再被允许进入肝细胞，切断重新感染新肝细胞的渠道?

StephenW

回复 乙肝人1949 的帖子

myrcludex-B（MyrB）可以安全使用12个月是重要的临床结果.
TDF / ETF / TAF等药物也可以长期使用，可以将血清hbvdna降至无法检测的水平，但仍无法治愈. 主要原因是因为这些药物无法100％停止生产新的病毒粒子。 一些新的病毒体循环到细胞核以补充cccDNA .一些新的病毒可能被释放以重新感染肝细胞, 补充cccDNA .

myrcludex-B（MyrB）+ TDF 应该停止重新感染(外部), 但仍然不能治愈.

核心蛋白抑制剂是否可以长期使用（正在临床试验中测试). 如果长期使用安全, 核心蛋白抑制剂必须停止新病毒粒子的内部再循环，以便能够治愈. 如果成功，则血清HBsAg应降低，因为无补充ccccDNA库.

乙肝人1949

回复 StephenW 的帖子

防止重新污染新鲜肝细胞和杜绝CcCDNA补充，是组合的作用。数据成功就好了。那就直接等待CCCDNA衰减完，继而HBsAg降至O(转阴)。嗯思路很好。