乙型肝炎病毒表达抑制剂与恩替卡韦和干扰素-α联用对慢性

StephenW

Efficacy of an Inhibitor of Hepatitis B Virus Expression in Combination With Entecavir and Interferon-α in Woodchucks Chronically Infected With Woodchuck Hepatitis Virus
Stephan Menne  1 , Steffen Wildum  2 , Guido Steiner  2 , Manasa Suresh  1 , Kyle Korolowicz  1 , Maria Balarezo  1 , Changsuek Yon  1 , Marta Murreddu  1 , Xupeng Hong  1 , Bhaskar V Kallakury  3 , Robin Tucker  4 , Song Yang  5 , John A T Young  2 , Hassan Javanbakht  2
Affiliations
Affiliations

    1
    Department of Microbiology and Immunology Georgetown University Medical Center Washington DC.
    2
    Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland.
    3
    Department of Pathology Georgetown University Medical Center Washington DC.
    4
    Department of Pharmacology Georgetown University Medical Center Washington DC.
    5
    Roche Pharma Research and Early Development Roche Innovation Center Shanghai Shanghai China.

    PMID: 32490326 PMCID: PMC7262289 DOI: 10.1002/hep4.1502

Abstract

RG7834 is a small-molecule inhibitor of hepatitis B virus (HBV) gene expression that significantly reduces the levels of hepatitis B surface antigen (HBsAg) and HBV DNA in a humanized liver HBV mouse model. In the current study, we evaluated the potency of RG7834 in the woodchuck model of chronic HBV infection, alone and in combination with entecavir (ETV) and/or woodchuck interferon-α (wIFN-α). RG7834 reduced woodchuck hepatitis virus (WHV) surface antigen (WHsAg) by a mean of 2.57 log10 from baseline and WHV DNA by a mean of 1.71 log10. ETV + wIFN-α reduced WHsAg and WHV DNA by means of 2.40 log10 and 6.70 log10, respectively. The combination of RG7834, ETV, and wIFN-α profoundly reduced WHsAg and WHV DNA levels by 5.00 log10 and 7.46 log10, respectively. However, both viral parameters rebounded to baseline after treatment was stopped and no antibody response against WHsAg was observed. Effects on viral RNAs were mainly seen with the triple combination treatment, reducing both pregenomic RNA (pgRNA) and WHsAg RNA, whereas RG7834 mainly reduced WHsAg RNA and ETV mainly affected pgRNA. When WHsAg was reduced by the triple combination, peripheral blood mononuclear cells (PBMCs) proliferated significantly in response to viral antigens, but the cellular response was diminished after WHsAg returned to baseline levels during the off-treatment period. Consistent with this, Pearson correlation revealed a strong negative correlation between WHsAg levels and PBMC proliferation in response to peptides covering the entire WHsAg and WHV nucleocapsid antigen. Conclusion: A fast and robust reduction of WHsAg by combination therapy reduced WHV-specific immune dysfunction in the periphery. However, the magnitude and/or duration of the induced cellular response were not sufficient to achieve a sustained antiviral response.

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

StephenW

乙型肝炎病毒表达抑制剂与恩替卡韦和干扰素-α联用对慢性感染土拨鼠肝炎病毒的土拨鼠的功效
斯蒂芬·曼妮（Stephan Menne）1，斯特芬·威登姆（Steffen Wildum）2，圭多·斯坦纳（Guide Steiner）2，马纳萨·苏雷什（Manasa Suresh）1，凯尔·科罗洛维奇（Kyle Korolowicz）1，玛丽亚·巴拉雷佐（Maria Balarezo）1，昌硕尹（Chantsuek Yon）1，玛塔·默瑞杜（Marta Murreddu）1，许鹏洪1，巴哈卡·V·加拉库里（Bhaskar V Kallakury）3，罗宾·塔克（Robin Tucker）4，宋扬5，约翰AT Young 2，哈桑Javanbakht 2
隶属关系
隶属关系

    1个
    华盛顿特区乔治敦大学医学中心微生物学和免疫学系。
    2
    罗氏制药研究与早期开发罗氏创新中心，瑞士巴塞尔。
    3
    华盛顿乔治敦大学医学中心病理学系。
    4
    华盛顿特区乔治敦大学医学中心药理学系。
    5
    罗氏制药研究与早期开发罗氏创新中心上海上海中国。

    PMID：32490326 PMCID：PMC7262289 DOI：10.1002 / hep4.1502

抽象

RG7834是乙型肝炎病毒（HBV）基因表达的小分子抑制剂，可在人源化肝HBV小鼠模型中显着降低乙型肝炎表面抗原（HBsAg）和HBV DNA的水平。在本研究中，我们评估了RG7834在单独或与恩替卡韦（ETV）和/或土拨鼠干扰素-α（wIFN-α）结合的慢性HBV感染的土拨鼠模型中的效力。 RG7834与基线相比平均降低了2.57 log10的土拨鼠肝炎病毒（WHV）表面抗原（WHsAg），平均降低了1.71 log10的WHV DNA。 ETV +wIFN-α分别通过2.40 log10和6.70 log10降低WHsAg和WHV DNA。 RG7834，ETV和wIFN-α的组合分别将WHsAg和WHV DNA水平分别降低了5.00 log10和7.46 log10。但是，在停止治疗后，两种病毒参数均反弹至基线，并且未观察到针对WHsAg的抗体反应。对病毒RNA的影响主要是通过三联治疗，减少了前体组RNA（pgRNA）和WHsAg RNA，而RG7834主要减少了WHsAg RNA，而ETV主要影响了pgRNA。当通过三联组合降低WHsAg时，外周血单核细胞（PBMC）对病毒抗原的反应明显增生，但是在非治疗期间WHsAg恢复到基线水平后，细胞反应减弱。与此一致的是，Pearson相关性揭示了WHsAg水平与PBMC增殖之间强烈的负相关性，这是对覆盖整个WHsAg和WHV核衣壳抗原的肽的反应。结论：通过联合疗法快速而有力地降低WHsAg可以减少外周WHV特异性免疫功能障碍。然而，诱导的细胞应答的大小和/或持续时间不足以实现持续的抗病毒应答。

©2020作者。 Wiley Periodicals，Inc.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/hep4.1502