Complex Pattern of Resistance-Associated Substitutions of Hepatitis C Virus after Daclatasvir/Asunaprevir Treatment Failure.
Complex Pattern of Resistance-Associated Substitutions of Hepatitis C Virus after Daclatasvir/Asunaprevir Treatment Failure.
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DOI：
10.1371/journal.pone.0165339
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Izumi N
中科院分区：
文献类型：
--
作者：
Itakura J;Kurosaki M;Hasebe C;Osaki Y;Joko K;Yagisawa H;Sakita S;Okushin H;Satou T;Hisai H;Abe T;Tsuji K;Tamada T;Kobashi H;Mitsuda A;Ide Y;Ogawa C;Tsuruta S;Takaguchi K;Murakawa M;Asahina Y;Enomoto N;Izumi N
我们的目的是阐明NS 5A抑制剂达卡他韦（DCV）联合NS 3/4A抑制剂阿舒那匹韦（ASV）治疗慢性丙型肝炎病毒基因型1b感染失败后耐药相关置换（RAS）的特征。这是一项由日本红十字会肝脏研究小组进行的全国性多中心研究。从68例DCV/ASV治疗24周后病毒学失败的患者中获得血清。通过群体测序确定NS 5A和NS 3中的RAS。在NS 3的D168位置处的签名RAS的频率为68%，并且在NS 5A的L31和Y 93位置处的签名RAS的频率分别为79%和76%。NS 5A（L31-RAS和Y 93-RAS）中双重签名RAS的频率为63%。除双重特征RAS外，分别在5、5、1、22、2和0例患者中检测到L28、R30、P32、Q54、P58和A92的RAS。总体而言，分别在35、10和1.5%的患者中检测到三重、四重和五重RAS联合双重特征RAS。这些RAS在基线无RAS或提前停止治疗的患者中检测到。在62%的患者中观察到NS 3中的D168 RAS和NS 5A中的L31和/或Y 93 RAS共存。在超过50%的患者中，DCV/ASV联合治疗失败后出现的RAS非常复杂。复杂RAS模式的鉴定（可能表明对NS 5A抑制剂的高水平耐药）强调了在考虑使用包括NS 5A抑制剂的方案进行再治疗时对RAS测序的需求。
We aimed to clarify the characteristics of resistance-associated substitutions (RASs) after treatment failure with NS5A inhibitor, daclatasvir (DCV) in combination with NS3/4A inhibitor, asunaprevir (ASV), in patients with chronic hepatitis C virus genotype 1b infection. This is a nationwide multicenter study conducted by the Japanese Red Cross Liver Study Group. The sera were obtained from 68 patients with virological failure after 24 weeks of DCV/ASV treatment. RASs in NS5A and NS3 were determined by population sequencing. The frequency of signature RASs at position D168 of NS3 was 68%, and at positions L31 and Y93 of NS5A was 79 and 76%, respectively. The frequency of dual signature RASs in NS5A (L31-RAS and Y93-RAS) was 63%. RASs at L28, R30, P32, Q54, P58, and A92 in addition to dual signature RAS were detected in 5, 5, 1, 22, 2, and 0 patients, respectively. In total, triple, quadruple, and quintuple RASs in combination with dual signature RAS were detected in 35, 10, and 1.5% patients, respectively. These RASs were detected in patients without baseline RASs or who prematurely discontinued therapy. Co-existence of D168 RAS in NS3 and L31 and/or Y93 RAS in NS5A was observed in 62% of patients. Treatment-emergent RASs after failure with DCV/ASV combination therapy are highly complex in more than 50% of the patients. The identification of complex RAS patterns, which may indicate high levels of resistance to NS5A inhibitors, highlights the need for RAS sequencing when considering re-treatment with regimens including NS5A inhibitors.
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