Inhibitory effects of caffeic Acid phenethyl ester derivatives on replication of hepatitis C virus.
Inhibitory effects of caffeic Acid phenethyl ester derivatives on replication of hepatitis C virus.
复制标题
咖啡酸苯乙酯衍生物对丙型肝炎病毒复制的抑制作用。
DOI：
10.1007/s00535-013-0926-7
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Moriishi K.
中科院分区：
文献类型：
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作者：
Shen H;Yamashita A;Nakakoshi M;Yokoe H;Sudo M;Kasai H;Tanaka T;Fujimoto Y;Ikeda M;Kato N;Sakamoto N;Shindo H;Maekawa S;Enomoto N;Tsubuki M;Moriishi K.
丙型肝炎病毒 (HCV) 是慢性肝炎、肝硬化和肝细胞癌 (HCC) 的主要原因，估计全球感染者总数为 1.85 亿。在日本，每年约有200万人感染HCV，并且每年有超过2万人死于HCV诱发的HCC。虽然抗病毒治疗根除病毒是减少 HCV 引起的 HCC 相关死亡的最重要和最有效的选择，但直到最近，完全根除病毒仍然相当困难，特别是对于基因 1 型 HCV 感染的患者，因为对基于干扰素 (IFN) 的治疗的反应率较低 [1, 2]。在此背景下，针对 HCV 的新型直接作用抗病毒药物 (DAA) 的开发确实是一个革命性事件。 2011年，两种第一代NS3蛋白酶抑制剂（PI）特拉匹韦和博普瑞韦在美国和欧洲的所有DAA中首次被批准与聚乙二醇干扰素和利巴韦林（PR）联合用于临床用于治疗基因1型HCV，特拉匹韦也于2011年同期在日本获得批准。正如预期的那样，特拉匹韦联合聚乙二醇干扰素和利巴韦林的治疗方案显着提高了基因 1 型 HCV 感染的持续病毒应答 (SVR) 率，高达 80%。另一方面，特拉匹韦也有一些不良问题。其中，贫血和皮疹等不良事件（AE）是特拉匹韦的严重问题，可能会发生3/4级皮肤病，包括史蒂文斯-约翰逊综合征和伴有嗜酸性粒细胞增多和全身症状的药疹，以及3级贫血（\8.0 g/dL）[3, 4]。此外，每天三次（每 7-9 小时）频繁给药可能会导致药物依从性差。在这种情况下，引入和监测这种基于特拉匹韦的方案对患者和临床医生来说都是相当有压力的。Simeprevir（SMV，TMC435）被归类为第二代大环结构PI，与线性结构的第一代PI相比，在对NS3蛋白酶的结合亲和力和特异性方面具有优势。由于结构上的差异，其耐药性与特拉匹韦有些不同。尽管 simeprevir 在 155 和 156 个氨基酸位置与 telaprevir 表现出交叉耐药性，但大多数耐药突变发生在 simeprevir 特异性氨基酸位置 168 [5]。尽管 simeprevir 对所有病毒基因型（基因型 1-6）均有效，但它对基因型 1a 和 1b HCV 感染具有最强的抗病毒活性。特别是，除了其强大的抗病毒活性外，低AE发生率和患者友好的每日一次剂量是西美普韦的重要特征。在 simeprevir 与 PegIFNa-2a/RBV 联合治疗初治患者（PILLAR 研究）[6] 和已接受治疗的患者（ASPIRE 研究）[7] 中，针对基因 1 型 HCV 感染患者进行的国际 II 期试验表明，simeprevir 总体耐受性良好，并且具有支持每日一次 (QD) 给药的药代动力学特征，可带来高病毒学应答率。在本期《胃肠病学杂志》中，Hayashi 等人[8]报告了抗病毒剂 TMC435 在基因型 1 HCV 治疗初治患者中的 II 期剂量和持续时间范围研究的重要结果（DRAGON 研究；TMC435-C215），评估每日一次 simeprevir
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC), and it is estimated that infected individuals total 185 million people worldwide. In Japan, around 2 million are infected with HCV, and more than 20 thousand die from HCV-induced HCC annually. Though viral eradication with antiviral therapies is the most important and effective choice for decreasing HCC-related deaths induced by HCV, complete viral eradication has been quite difficult till recently, especially in patients with genotype-1 HCV infection because of the low response rate to interferon (IFN)-based therapy [1, 2]. In this background, development of novel direct-acting antiviral agents (DAAs) specific for HCV was truly a revolutionary event. In 2011, two first-generation NS3 protease inhibitors (PIs), telaprevir and boceprevir, were firstly approved among all the DAAs for clinical use in USA and Europe for genotype-1 HCV in combination with pegylated-interferon and ribavirin (PR), while telaprevir was approved in Japan in the same 2011 period. As expected, a regimen including telaprevir in combination with pegylated-interferon and ribavirin dramatically improved the sustained viral response (SVR) rate to as high as 80% in genotype-1 HCV infection. On the other hand, telaprevir has several undesirable problems. Among all, adverse events (AEs) of anemia and skin rash are serious problems of telaprevir, and Grade 3/4 skin disorders, including Stevens–Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (\8.0 g/dL), might occur [3, 4]. Moreover, cumbersome frequent dosing three times a day (every 7–9 h) could induce poor medication adherence. Under the circumstances, it has been quite stressful for patients as well as clinicians to introduce and monitor this telaprevir-based regimen.Simeprevir (SMV, TMC435) is classified as a secondgeneration PI with the macrocyclic structure having an advantage in the binding affinity and specificity for NS3 protease compared to the first-generation PI with the linear structure. Due to the difference in the structure, the drugresistance profile is somewhat different from that of telaprevir. Though simeprevir shows cross-resistance with telaprevir at amino acid positions of 155 and 156, most of the resistant mutation occurs at the simeprevir-specific amino acid position of 168 [5]. Though simeprevir is effective in all viral genotypes (genotype 1–6), it has the strongest antiviral activity for genotype-1a and-1b HCV infection. In particular, low AE rate and its patient-friendly once-daily dosing are the important characters of simeprevir aside from its strong antiviral activity. In the international phase II trials of simeprevir in combination with PegIFNa-2a/RBV for treatment-naıve (PILLAR study)[6] and treatment-experienced patients (ASPIRE study)[7] for HCV genotype 1-infected patients, it was demonstrated that simeprevir was generally well tolerated and had a pharmacokinetic profile supporting once-a-day (QD) dosing resulting in high virologic response rates. In this issue of the Journal of Gastroenterology, Hayashi et al.[8] reported the important results of the phase II Dose and duration Ranging study of Antiviral agent TMC435 in Genotype One HCV treatment-Naıve patients (DRAGON study; TMC435-C215) evaluating once-daily simeprevir