1型慢性丙型肝炎患者外周血单个核细胞中USP18表达下调预示对基于干扰素的三联疗法无反应：一项初步研究
USP18 downregulation in peripheral blood mononuclear cells predicts nonresponse to interferon-based triple therapy in patients with chronic hepatitis C, genotype 1: a pilot study.
作者信息
Frankova Sona, Jirsa Milan, Merta Dusan, Neroldova Magdalena, Urbanek Petr, Senkerikova Renata, Spicak Julius, Sperl Jan
机构信息
Department of Hepatogastroenterology, Resuscitation and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Laboratory of Experimental Hepatology, Resuscitation and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
出版信息
Ther Clin Risk Manag. 2015 Dec 17;11:1853-61. doi: 10.2147/TCRM.S94010. eCollection 2015.
BACKGROUND AND AIMS
Patients with advanced liver fibrosis owing to chronic hepatitis C virus genotype 1 represent a difficult-to-treat group even if a protease inhibitor is added to pegylated interferon alpha and ribavirin. Therefore, only patients with a high chance of cure should be treated with interferon-based treatment.
PATIENTS AND METHODS
Expression of IFNG, IFNLR1, and interferon-sensitive genes CXCL9, IFI16, IFI27, ISG15, and USP18 in peripheral blood mononuclear cells was assessed before and during the initial 12 weeks of treatment. The studied group consisted of 26 treatment-experienced patients of average age of 50 years with advanced liver fibrosis compared to seven healthy volunteers. Fourteen patients were treated with pegylated interferon alpha 2b, ribavirin, and boceprevir and 12 patients with telaprevir. The overall sustained virological response (SVR) rate was 69% (18/26).
RESULTS
A significant difference in the initial expression (median, interquartile range [IQR]) of CXCL9 2.9×, IQR: 1.7-12.4 vs 1.2×, IQR: 0.5-1.8; (P=0.01) IFNG 7.3×, IQR: 1.7-32.6 vs 0.7×, IQR: 0.4-1.3; P=0.002 and USP18 3.7×, IQR: 2.1-7.7 vs 1.4×, IQR: 0.9-1.6; (P=0.03) was found between the SVR and non-SVR groups. Expression of all analyzed genes was progressively increasing during the first 12 weeks of therapy, but a significant difference between SVR and non-SVR group was found only in USP18 expression at week 12 (P=0.001). Initial expression of four genes predicted SVR in univariate analysis (CXCL9 [OR: 12.00, 95% CI: 1.21-118.89], IFI27 [OR: 12.00, 95% CI: 1.21-118.89], IFNG [OR: 10.50, 95% CI: 1.50-73.67], USP18 [OR: 21.00, 95% CI: 2.05-215.18]). In multivariate analysis, only the initial expression of USP18 was identified as a predictor of SVR (P=0.047).
CONCLUSION
Initial expression of USP18 and the course of its activation could be a reliable predictor of SVR achievement.
背景与目的
即使在聚乙二醇化干扰素α和利巴韦林基础上加用蛋白酶抑制剂，丙型肝炎病毒1型所致晚期肝纤维化患者仍是难以治疗的群体。因此，只有治愈机会高的患者才应接受基于干扰素的治疗。
患者与方法
在治疗的最初12周之前及期间，评估外周血单个核细胞中IFNG、IFNLR1以及干扰素敏感基因CXCL9、IFI16、IFI27、ISG15和USP18的表达。研究组由26例有治疗经验、平均年龄50岁的晚期肝纤维化患者组成，另有7名健康志愿者作为对照。14例患者接受聚乙二醇化干扰素α 2b、利巴韦林和博赛匹韦治疗，12例患者接受特拉匹韦治疗。总体持续病毒学应答（SVR）率为69%（18/26）。
结果
SVR组与非SVR组在CXCL9初始表达（中位数，四分位间距[IQR]）上存在显著差异，分别为2.9倍，IQR：1.7 - 12.4 vs 1.2倍，IQR：0.5 - 1.8；（P = 0.01）；IFNG分别为7.3倍，IQR：1.7 - 32.6 vs 0.7倍，IQR：0.4 - 1.3；P = 0.002；USP18分别为3.7倍，IQR：2.1 - 7.7 vs 1.4倍，IQR：0.9 - 1.6；（P = 0.03）。在治疗的前12周内，所有分析基因的表达均逐渐增加，但仅在第12周时USP18表达在SVR组与非SVR组之间存在显著差异（P = 0.001）。在单因素分析中，4个基因的初始表达可预测SVR（CXCL9 [比值比（OR）：12.00，95%置信区间（CI）：1.21 - 118.89]，IFI27 [OR：12.00，95% CI：1.21 - 118.89]，IFNG [OR：10.50，95% CI：1.50 - 73.67]，USP18 [OR：21.00，95% CI：2.05 - 215.18]）。在多因素分析中，仅USP18的初始表达被确定为SVR的预测因子（P = 0.047）。
结论
USP18的初始表达及其激活过程可能是实现SVR的可靠预测指标。
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