New resistance-associated substitutions and failure of dual oral therapy with daclatasvir and asunaprevir
New resistance-associated substitutions and failure of dual oral therapy with daclatasvir and asunaprevir
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DOI：
10.1007/s00535-016-1303-0
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发表时间：
2017-07-01
影响因子：
6.3
通讯作者：
Ido, Akio
中科院分区：
文献类型：
--
作者：
Mawatari, Seiichi;Oda, Kohei;Ido, Akio
背景达卡他韦（DCV）和阿舒那匹韦（ASV）联合治疗主要用于治疗前无NS 5A L31或Y 93耐药相关置换（RAS）的患者。我们检查了没有这些基线RAS的患者的特征，这些患者用DCV和ASV联合治疗没有达到丙型肝炎病毒根除，并确定了与联合治疗失败密切相关的新的基线NS 5A RAS。入选DCV和ASV联合治疗前和NS 3 D168 RAS，且无蛋白酶抑制剂治疗史。结果297例患者（89%）在12周时达到持续病毒学应答（SVR 12）。具有NS 5A Q24、L28和/或R30 RAS或伴随的NS 5A F37和Q54 RAS的患者比没有这些RAS的患者具有显著更低的SVR 12率（分别为70%对92%，p < 0.001和79%对92%，p = 0.002）。多变量分析显示，NS 5A Q24、L28和/或R30 RAS以及伴随的NS 5A F37和Q54 RAS与病毒学失败显著相关。在没有NS 5A Q24、L28和/或R30 RAS以及伴随NS 5A F37和Q54 RAS的患者中，SVR 12率为96.2%（202/210）。和/或R30 RAS以及伴随的NS 5A F37和Q54 RAS与DCV和ASV联合治疗失败相关。除NS 5A L31和Y 93之外的基线RAS共存可能会影响DCV和ASV联合治疗的疗效。
Background Daclatasvir (DCV) and asunaprevir (ASV) combination therapy has been primarily used in patients without NS5A L31 or Y93 resistance-associated substitutions (RASs) before treatment. We examined the characteristics of patients without these baseline RASs who did not achieve hepatitis C virus eradication with DCV and ASV combination therapy and identified new baseline NS5A RASs that are closely associated with failure of combination therapy.Methods Three hundred thirty-five patients with hepatitis C virus genotype 1 infection with no NS5A L31, NS5A Y93, and NS3 D168 RASs before DCV and ASV combination therapy and no history of protease inhibitor therapy were enrolled. All RASs were evaluated by direct sequencing.Results Sustained virologic response at 12 weeks (SVR12) was achieved in 297 patients (89%). Patients with NS5A Q24, L28, and/or R30 RASs or concomitant NS5A F37 and Q54 RASs had a significantly lower SVR12 rate than patients without these RASs (70% vs 92%, p < 0.001 and 79% vs 92%, p = 0.002 respectively). Multivariate analysis showed that NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs were significantly associated with virologic failure. The SVR12 rate in patients without NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs was 96.2% (202/210).Conclusions In patients without NS5A L31 or Y93 RASs, the presence of NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs at the baseline was associated with failure of DCV and ASV combination therapy. The coexistence of baseline RASs other than NS5A L31 and Y93 may affect the therapeutic effectiveness of DCV and ASV combination therapy.