Temporal dynamics of inflammatory cytokines/chemokines during sofosbuvir and ribavirin therapy for genotype 2 and 3 hepatitis C infection
Temporal dynamics of inflammatory cytokines/chemokines during sofosbuvir and ribavirin therapy for genotype 2 and 3 hepatitis C infection
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DOI：
10.1002/hep.27971
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发表时间：
2015-10-01
期刊：
影响因子：
13.5
通讯作者：
Wyles, David L.
中科院分区：
文献类型：
--
作者：
Carlin, Aaron F.;Aristizabal, Paula;Wyles, David L.
丙型肝炎病毒（HCV）感染过程中产生的炎性细胞因子和趋化因子的分析，提高了我们对病毒-宿主相互作用的理解，并确定了治疗反应的预测因子。干扰素（IFN）的管理使得难以解释治疗期间免疫激活的生物标志物。无干扰素的直接作用抗病毒（DAA）方案目前正用于治疗HCV，具有良好的疗效。为了深入了解HCV治疗之前、期间和之后发生的HCV-宿主相互作用，我们进行了一项病例对照研究，测量了IFN-诱导蛋白10（IP-10）、单核细胞趋化蛋白1（MCP-1）、巨噬细胞炎性蛋白1 β（MIP-1）、131例慢性丙型肝炎患者接受索非布韦（SOF）联合利巴韦林（RBV）治疗后，血清白细胞介素18（IL-18）水平的变化。使用基线因素进行线性回归分析，发现丙氨酸氨基转移酶升高与治疗前IP-10之间以及肝硬化与治疗前IL-18升高之间存在强正相关性。平均IP-10、MCP-1、MIP-1和IL-18水平均在治疗后下降，但在治疗后期和停止治疗后显示出不同的动力学。在治疗中，IP-10和MIP-1水平在达到持续病毒学应答（SVR）的个体中显著较高。对所有患者的治疗反应进行Logistic回归分析，结果显示较高的基线MIP-1水平与治疗早期MIP-1的较小下降和SVR之间存在显著相关性。在肝硬化患者和基因型3（GT3）感染的个体中，早期较高的MIP-1水平也与SVR显著相关，这两个因素与治疗反应性降低相关。结论：IP-10水平的变化反映了HCV RNA，提示IP-10是先天免疫病毒识别的指标。MIP-1水平在达到SVR的GT 2/3患者中保持升高，表明对SOF/RBV治疗有反应的患者中存在差异性免疫激活，并在预测治疗反应中具有潜在作用。（肝病学2015;62：1047-1058）
The analysis of inflammatory cytokines and chemokines produced during hepatitis C virus (HCV) infection has advanced our understanding of viral-host interactions and identified predictors of treatment response. Administration of interferons (IFNs) made it difficult to interpret biomarkers of immune activation during treatment. Direct-acting antiviral (DAA) regimens without IFN are now being used to treat HCV with excellent efficacy. To gain insight into HCV-host interactions occurring before, during, and after HCV treatment, we performed a case-control study that measured serial plasma levels of IFN--inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 beta (MIP-1), and interleukin-18 (IL-18) in 131 patients with chronic HCV treated with sofosbuvir (SOF) plus ribavirin (RBV). A linear regression analysis using baseline factors identified strong positive associations between elevated alanine aminotransferase and pretreatment IP-10 and between the presence of cirrhosis and elevated pretreatment IL-18. Mean IP-10, MCP-1, MIP-1, and IL-18 levels all decline on therapy, but display different dynamics late in treatment and after cessation of therapy. On treatment, IP-10 and MIP-1 levels were significantly higher in individuals who achieved sustained virological response (SVR). Logistic regression analyses examining treatment response in all patients demonstrated significant associations between higher baseline MIP-1 levels and smaller decreases in MIP-1 early in treatment and SVR. Higher early MIP-1 levels were also significantly associated with SVR in subsets of patients with cirrhosis and individuals with genotype 3 (GT3) infection, two factors associated with decreased responsiveness to treatment. Conclusion: Changes in IP-10 levels mirror HCV RNA, suggesting that IP-10 is an indicator of innate immune viral recognition. MIP-1 levels remain elevated in GT2/3 patients who achieved SVR, suggesting differential immune activation in those who respond to SOF/RBV therapy and a potential role in predicting treatment responses. (Hepatology 2015;62:1047-1058)