Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima 734-8551, Japan.
Viruses. 2018 Sep 28;10(10):531. doi: 10.3390/v10100531.
Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.
尽管直接作用抗病毒 (DAA) 药物在治疗慢性丙型肝炎病毒 (HCV) 感染方面取得了成功，但预计在未来五年内，与 HCV 相关的肝细胞癌 (HCC) 的病例数量将会增加。HCC 的发展需要几十年的时间，并且与纤维化阶段密切相关。HCV 既直接又间接地建立了有利于病毒复制的促炎环境。反复的细胞死亡和再生导致基因组不稳定和细胞周期控制的丧失。DAA 治疗提供了 >90%的持续病毒学应答 (SVR) 率，副作用和限制比干扰素少。虽然消除 HCV 有助于恢复肝功能并逆转轻度纤维化，但 SVR 后患者仍处于 HCC 风险升高的状态。一系列报告 DAA 治疗患者 HCC 发生率高于预期的研究引发了关于与干扰素相比，DAA 是否会增加 HCC 风险的争论。然而，最近基于更大患者队列的前瞻性和回顾性研究发现，在考虑其他因素后，DAA 和干扰素治疗之间的 HCC 风险无显著差异。尽管已经阐明了参与肝癌发生的许多机制和途径，但我们对 SVR 后肝癌发生的特定驱动因素的理解仍然有限，缺乏合适的体内和体外实验系统阻碍了对病因特异性机制的研究，这些机制可能有助于更全面地回答这个问题。需要进一步的研究来确定 SVR 后 HCC 的风险因素和生物标志物，并根据对参与肝癌发生的分子和途径的更全面了解开发靶向治疗。
