■我们的目的是阐明HCV基因型1b感染中多种无干扰素(IFN)方案失败后耐药性相关替代(RAS)的特征。
■共有1,193名直接抗病毒(DAA)治疗失败的HCV患者来自日本的67个机构。非结构蛋白(NS)3、NS5A、和NS5B通过群体测序确定。
■在1,101;80;和12名患者中观察到1、2和3个方案的失败,分别。在1个方案失败的患者中,在Paritaprevir失效后,NS3中的Y56H和D168V更频繁地被检测到,而D168E在包括asunaprevir在内的方案失败后更常见。在包括daclatasvir在内的方案失败后,经常检测到NS5A中的R30H和L31-RAS。与治疗方案无关,Y93-RAS的患病率很高。NS5B中的S282TRAS在3.9%的ledipasvir/sofosbuvir失败中检测到。D168-RAS的患病率根据失败的方案数显著增加(p<0.01),这与L31-RAS和Y93-RAS相似。在NS3或NS5A中使用RAS的患者的患病率,或者两者,随着失败方案数量的增加,显着增加。P32del,这是DAA失败的患者所独有的,与Y93H的缺失有关,L31F的存在,和以前接触过IFN+蛋白酶抑制剂方案。
■多种DAA方案的失败可导致在HCV1b基因组的NS3和NS5A区域中产生多种RAS。这些突变有助于病毒对多种治疗方案的抗性,因此,在决定治疗慢性HCV时应该考虑。
丙型肝炎病毒基因组中的抗性相关替换(RAS)是导致治疗失败的主要原因之一。我们调查了慢性丙型肝炎的各种治疗失败后的RAS,并发现在连续治疗失败的情况下,病毒基因组中积累了更复杂的RAS。在DAA治疗失败的患者中,NS5A区域的高抗性P32delRAS独特地发现,并且与特定RAS的存在和不存在有关。
UNASSIGNED: We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections.
UNASSIGNED: A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing.
UNASSIGNED: Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p <0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens.
UNASSIGNED: Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV.
UNASSIGNED: Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.