Medizinische Klinik 1, Goethe University Hospital, Frankfurt, Germany.
Gilead Sciences, Inc, Foster City, California.
Gastroenterology. 2016 Sep;151(3):501-512.e1. doi: 10.1053/j.gastro.2016.06.002. Epub 2016 Jun 11.
BACKGROUND & AIMS: We evaluated the effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions (RASs) on response to the combination of ledipasvir and sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infection.
We analyzed data from 2144 participants in phase 2 and 3 studies of patients with HCV genotype 1a or b infection who received the combination of ledipasvir (90 mg) and sofosbuvir (400 mg) (ledipasvir/sofosbuvir) once daily, with or without ribavirin twice daily. Population and/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at baseline.
Overall, 16.0% of patients had detectable baseline RASs in NS5A. Among patients with HCV genotype 1b infection, there was no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end of treatment (SVR12) with ledipasvir/sofosbuvir and only a small effect in patients with HCV genotype 1a infection. RASs in NS5A that increased the half-maximal effective concentration to ledipasvir by more than 100-fold reduced the rate of SVR12 in treatment-naive patients given ledipasvir/sofosbuvir for 8 weeks (P = .011), but not for 12 weeks. These same baseline NS5A RASs reduced the percentage of treatment-experienced patients who achieved an SVR12 to 12 weeks (but not 24 weeks) ledipasvir/sofosbuvir (P < .001). These RASs had a small effect in patients given ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks. Overall, 2.5% of patients had baseline NS5B nucleotide inhibitor RASs (L159F, N142T, S282G, or L320S) and all achieved an SVR12. Of patients previously treated with protease inhibitors, 53.7% had RASs in NS3 and 96.5% achieved an SVR12.
Baseline RASs in NS5A have minimal effects on patient responses to ledipasvir/sofosbuvir therapy. When these RASs do have effects, they could be largely overcome by extending treatment duration or through treatment intensification.
我们评估了基线丙型肝炎病毒（HCV）NS5A、NS5B 和 NS3 耐药相关取代（RAS）对索磷布韦和 ledipasvir 联合治疗伴或不伴利巴韦林治疗 HCV 基因 1 型感染患者的影响。
我们分析了 2144 名 HCV 基因 1a 或 b 感染患者接受索磷布韦（400mg）和 ledipasvir（90mg）联合治疗的 2 期和 3 期研究数据，每日一次，伴或不伴利巴韦林每日两次。在基线时采集血样进行 HCV NS3、NS5A 和 NS5B 基因的群体和/或深度测序分析。
总体而言，16.0%的患者在 NS5A 中检测到基线 RAS。在 HCV 基因 1b 感染患者中，基线 NS5A 的 RAS 对索磷布韦和 ledipasvir 治疗结束后 12 周持续病毒学应答（SVR12）没有显著影响，而在 HCV 基因 1a 感染患者中仅有轻微影响。将 ledipasvir 的半最大有效浓度增加 100 倍以上的 NS5A RAS 降低了无利巴韦林治疗 8 周的 ledipasvir/sofosbuvir 治疗初治患者的 SVR12 率（P =.011），但不能降低 12 周的 SVR12 率。这些相同的基线 NS5A RAS 降低了治疗经验患者在 ledipasvir/sofosbuvir 治疗 12 周时获得 SVR12 的比例（但不是 24 周）（P <.001）。利巴韦林联合治疗 12 周时，这些 RAS 对患者的影响较小。总体而言，2.5%的患者有基线 NS5B 核苷酸抑制剂 RAS（L159F、N142T、S282G 或 L320S），所有患者均获得 SVR12。在以前接受过蛋白酶抑制剂治疗的患者中，53.7%的患者有 NS3 中的 RAS，96.5%的患者获得 SVR12。
基线 NS5A 的 RAS 对 ledipasvir/sofosbuvir 治疗的患者反应影响较小。当这些 RAS 确实有影响时，通过延长治疗时间或通过治疗强化可以在很大程度上克服。
