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分析对非结构 5A 抑制剂耐药的难治性丙型肝炎病毒的易感性。

Analysis of the susceptibility of refractory hepatitis C virus resistant to nonstructural 5A inhibitors.

机构信息

Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8‑35‑1 Sakuragaoka, Kagoshima, 890‑8544, Japan.

Division of Biological Information Technology, Joint Research Center for Human Retrovirus Infection, Kagoshima University, 8‑35‑1 Sakuragaoka, Kagoshima, 890‑8544, Japan.

出版信息

Sci Rep. 2024 Jul 16;14(1):16363. doi: 10.1038/s41598-024-67169-5.

DOI:10.1038/s41598-024-67169-5
PMID:39013947
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11252252/
Abstract

Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs.

摘要

丙型肝炎病毒 (HCV) 的耐药相关突变 (RAS) 会影响直接作用抗病毒药物 (DAA) 的疗效。在这项研究中，我们旨在阐明 DAA 治疗失败患者中观察到的非结构 (NS) 5A Q24K/L28M/R30Q（或 R30E）/A92K RAS 共存的敏感性，并考虑新的治疗药物。我们使用亚基因组复制子系统，将 HCV 基因型 1B 株 1B-4 电穿孔到源自 HuH-7 细胞的 OR6c 细胞（野生型 [WT]）中。我们将 WT 基因转换为 NS5A Q24K/L28M/R30Q/A92K 或 Q24/L28K/R30E/A92K。与 WT 相比，Q24K/L28M/R30Q/A92K RAS 对达卡他韦的耐药性高 36000 倍，对来迪帕韦的耐药性高 440000 倍，对伏拉帕韦的耐药性高 6300 倍，对艾尔巴韦的耐药性高 3100 倍，对奥比帕利韦的耐药性高 1.8 倍。与 WT 相比，Q24K/L28M/R30E/A92K RAS 对达卡他韦和来迪帕韦的耐药性高 640000 倍，对伏拉帕韦的耐药性高 150000 倍，对艾尔巴韦的耐药性高 44000 倍，对奥比帕利韦的耐药性高 1500 倍。与 Q24K/L28M/R30Q/A92K RAS 相比，Q24K/L28M/R30E/A92K RAS 对奥比帕利韦的耐药性高 816.3 倍。此外，奥比帕利韦和索磷布韦的联合治疗对这些 RAS 具有治疗效果。联合治疗方案可能根除含有 NS5A Q24K/L28M/R30E/A92K RAS 的 HCV。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da8d/11252252/72ea1fd3280c/41598_2024_67169_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da8d/11252252/5abdf078b099/41598_2024_67169_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da8d/11252252/69c362b98a52/41598_2024_67169_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da8d/11252252/72ea1fd3280c/41598_2024_67169_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da8d/11252252/5abdf078b099/41598_2024_67169_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da8d/11252252/69c362b98a52/41598_2024_67169_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da8d/11252252/72ea1fd3280c/41598_2024_67169_Fig3_HTML.jpg

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本文引用的文献

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Analysis of direct-acting antiviral-resistant hepatitis C virus haplotype diversity by single-molecule and long-read sequencing.单分子和长读测序分析直接作用抗病毒耐药丙型肝炎病毒单倍型多样性。
Hepatol Commun. 2022 Jul;6(7):1634-1651. doi: 10.1002/hep4.1929. Epub 2022 Mar 31.
2
Hepatitis C virus eradication prolongs overall survival in hepatocellular carcinoma patients receiving molecular-targeted agents.丙型肝炎病毒的清除可延长接受分子靶向药物治疗的肝细胞癌患者的总生存期。
J Gastroenterol. 2022 Feb;57(2):90-98. doi: 10.1007/s00535-021-01837-5. Epub 2022 Jan 15.
3
Direct-acting antivirals improve survival and recurrence rates after treatment of hepatocellular carcinoma within the Milan criteria.
直接作用抗病毒药物可提高米兰标准内治疗肝细胞癌的生存率和复发率。
J Gastroenterol. 2021 Jan;56(1):90-100. doi: 10.1007/s00535-020-01747-y. Epub 2020 Dec 5.
4
Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C.丙型肝炎多种直接抗病毒治疗方案失败后与耐药相关替代的特征
JHEP Rep. 2020 Jun 18;2(5):100138. doi: 10.1016/j.jhepr.2020.100138. eCollection 2020 Oct.
5
Japan Society of Hepatology guidelines for the management of hepatitis C virus infection: 2019 update.日本肝脏病学会丙型肝炎病毒感染管理指南：2019年更新版
Hepatol Res. 2020 Jul;50(7):791-816. doi: 10.1111/hepr.13503. Epub 2020 May 29.
6
Viral and host factors are associated with retreatment failure in hepatitis C patients receiving all-oral direct antiviral therapy.病毒和宿主因素与接受全口服直接抗病毒治疗的丙型肝炎患者再次治疗失败有关。
Hepatol Res. 2020 Apr;50(4):453-465. doi: 10.1111/hepr.13474. Epub 2020 Jan 16.
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Study of multiple genetic variations caused by persistent hepatitis C virus replication in long-term cell culture.研究丙型肝炎病毒持续复制引起的长期细胞培养中的多种遗传变异。
Arch Virol. 2020 Feb;165(2):331-343. doi: 10.1007/s00705-019-04461-0. Epub 2019 Dec 12.
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Time-dependent improvement of liver inflammation, fibrosis and metabolic liver function after successful direct-acting antiviral therapy of chronic hepatitis C.慢性丙型肝炎直接抗病毒治疗后肝炎症、纤维化和代谢肝功能的时间依赖性改善。
J Viral Hepat. 2020 Jan;27(1):28-35. doi: 10.1111/jvh.13204. Epub 2019 Oct 2.
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