Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany.
United European Gastroenterol J. 2021 May;9(4):486-496. doi: 10.1177/2050640620976991. Epub 2021 Feb 18.
The risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon-free direct-acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance.
Here, we aimed at evaluating the effects of direct-acting antiviral therapy-induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct-acting antiviral-mediated hepatitis C clearance in cirrhosis patients was investigated.
Employing multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed posttreatment hepatocellular carcinoma and their respective negative controls, before and after direct-acting antiviral treatment.
Elevated pretherapy concentrations of specific soluble immune mediators including MCP-3, GDNF, CDCP1, IL-17C, IL-17A, signalling lymphocytic activation family 1, CCL11, FGF-5, LIF-R, interleukin 10 (IL-10), IL-10RA, IL-15RA, beta NGF, CCL28, CCL25 and NT-3 distinguished patients who developed posttreatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF-5 and IL-15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pretherapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the posttherapy carcinoma-free patients experienced significant ameliorations.
These results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct-acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct-acting antiviral therapies would be superior to the risk of developing carcinoma.
尽管目前无干扰素直接作用抗病毒疗法治疗丙型肝炎可实现持续病毒学应答，但一些患者仍存在肝细胞癌风险。在这种情况下，报道了更高的癌症风险的主题，并正在进行辩论。因此，了解这一悖论与接受抗病毒治疗的肝硬化患者炎症生物标志物动力学之间的关系仍然是一个重要的研究课题。
在这里，我们旨在评估直接作用抗病毒治疗丙型肝炎治愈对治疗前、治疗中和治疗后测量的全身炎症标志物的影响。具体来说，研究了影响肝细胞癌发展几率的直接作用抗病毒介导的丙型肝炎清除后可溶性免疫调节剂表型关联，以及肝硬化患者中出现的相关变化。
采用可测量多达 91 种循环生物标志物蛋白的多重技术，对治疗后发生肝细胞癌的肝硬化患者及其各自的阴性对照患者在直接作用抗病毒治疗前后的血浆可溶性免疫调节剂浓度进行了分析。
在治疗前，特定可溶性免疫调节剂（包括 MCP-3、GDNF、CDCP1、IL-17C、IL-17A、信号淋巴细胞激活家族 1、CCL11、FGF-5、LIF-R、白细胞介素 10（IL-10）、IL-10RA、IL-15RA、βNGF、CCL28、CCL25 和 NT-3）的浓度升高可将发生治疗后肝细胞癌的患者与未发生肝细胞癌的患者区分开来。特别是，GDNF、FGF-5 和 IL-15RA 显示出独立的预测生物标志物属性，可用于区分无论新发生还是复发的患者的癌出现。经过成功的治疗，最终发生肝细胞癌的患者的治疗前可溶性免疫调节剂升高的基础在很大程度上没有受到影响，而在治疗后无癌的患者中，约 38 种可溶性免疫调节剂经历了显著的改善。
这些结果对于在肝硬化患者中开始无干扰素直接作用抗病毒治疗丙型肝炎之前，描绘潜在的肝细胞癌发生具有重要意义。它们为阐明直接作用抗病毒治疗的益处是否超过发生癌症的风险提供了初步贡献。
