Prevalence and characteristics of naturally occurring sofosbuvir resistance-associated variants in patients with hepatitis C virus genotype 1b infection
Prevalence and characteristics of naturally occurring sofosbuvir resistance-associated variants in patients with hepatitis C virus genotype 1b infection
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DOI：
10.1111/hepr.12685
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发表时间：
2016-12-01
影响因子：
4.2
通讯作者：
Sakamoto, Naoya
中科院分区：
文献类型：
--
作者：
Ito, Jun;Suda, Goki;Sakamoto, Naoya
目的：核苷酸类似物索布韦(SOF)以丙型肝炎病毒(HCV)NS5B聚合酶为靶点，因其高效、良好的耐药性而显示出治疗丙型肝炎病毒感染的潜力。然而，除了罕见的非结构蛋白NS5B S282T的抗药性相关变异体(RAV)外，已有几个新的潜在的SOF RAV被报道，特别是与丙型肝炎病毒1b相关的RAV。方法：我们分析了96例接受西美普韦(SMV)联合治疗的患者中NS3/NS5A/NS5B区变异的发生率，并通过直接测序法或深层测序法确定治疗失败的患者中RAV的发生率。结果：NS5B RAV C316N携带率较高(46.9%，45/96)，而NS5B L159F携带率较低(1.04%，1/96)，但深层测序显示30.0%的C316N患者同时携带NS5B RAV L159F。此外，潜在的NS5B的存在与NS5A或NS3RAV之间没有显著的关系。然而，NS5B C316N的存在与丙型肝炎病毒核心氨基酸91位替换显著相关。在西美普韦联合治疗中，每种RAV和持续病毒学应答之间没有显著差异。结论：我们提供了两种潜在的自然发生的NS5B RAV(C316N和L159F)在日本的高流行率的明确证据。重要的是要特别注意这些新的潜在的RAV，特别是在使用基于SOF的治疗时，由于先前的直接作用抗病毒治疗失败而导致的RAV患者。
Aim: Sofosbuvir (SOF), a nucleotide analog pro-drug, targets hepatitis C virus (HCV) NS5B polymerase and shows potential for treating HCV infection, given its high efficacy and good barrier to resistance. However, in addition to the rare resistant-associated variant (RAV) of non-structural protein NS5B S282T, several new potential RAVs of SOF have been reported, especially related to HCV genotype 1b. However, the prevalence and characteristics of these RAVs have not been clarified.Methods: We analyzed the prevalence of variants in the NS3/NS5A/NS5B regions in 96 patients treated with simeprevir (SMV) combination therapy, and the prevalence of RAVs in patients showing treatment failure was determined by direct- or deep-sequencing methods. Associations between these potential RAVs and clinical factors were also analyzed.Results: Prevalence of NS5B RAV C316N was high (46.9%, 45/96), whereas that of NS5B L159F was relatively low (1.04%, 1/96); however, deep sequencing showed that 30.0% of patients with C316N also had NS5B RAV L159F. Additionally, there was no significant relationship between the existence of potential NS5B and NS5A or NS3 RAVs. However, the presence of NS5B C316N was significantly associated with an HCV core amino acid 91 substitution. No significant difference was detected between each RAV and sustained virological response in simeprevir combination therapy.Conclusion: We provide clear evidence of the high prevalence of two potential naturally occurring NS5B RAVs (C316N and L159F) in Japan. It may be important to pay particular attention to these new potential RAVs, especially when using SOF-based therapy in patients with RAVs due to previous direct-acting antiviral therapy failure.