Department of Hepatology, Toranomon Hospital, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
J Clin Microbiol. 2013 Sep;51(9):2862-8. doi: 10.1128/JCM.01129-13. Epub 2013 Jun 19.
It is often difficult to predict the response to telaprevir-pegylated interferon (PEG-IFN)-ribavirin triple therapy and the appearance of telaprevir-resistant variants. The present study determined the predictive factors of a sustained virological response (SVR) to 12- or 24-week triple therapy (T12PR12 or T12PR24, respectively) in 194 Japanese patients infected with hepatitis C virus genotype 1b (HCV-1b). The study also evaluated whether ultradeep sequencing technology can predict at baseline the emergence of resistant variants after the start of therapy. Analysis of the data of the entire group indicated that an SVR was achieved in 78% of the patients. Multivariate analysis identified IL28B rs8099917 (genotype TT), the substitution of amino acid (aa) 70 (Arg70), response to prior treatment (naive or relapse), PEG-IFN dose (≥ 1.3 μg/kg of body weight), and treatment regimen (T12PR24) as significant determinants of SVR. Among patients of the T12PR24 group, 92% with genotype TT achieved an SVR, irrespective of a substitution at aa 70. In patients with the non-TT genotype, an SVR was achieved in 76% of those with Arg70, while only 14% of patients with the non-TT genotype, Gln70(His70), and nonresponse to ribavirin combination therapy achieved an SVR. Ultradeep sequencing was conducted for 17 patients who did not achieve an SVR to determine the emergence of resistant variants during therapy. De novo resistant variants were detected in 16 of 17 patients (94%), regardless of the variant frequencies detected at baseline. In conclusion, the results indicate that the response to triple therapy can be predicted by the combination of host, viral, and treatment factors and that it is difficult to predict at baseline the telaprevir-resistant variants that emerge during triple therapy, even with the use of ultradeep sequencing.
预测 telaprevir-聚乙二醇干扰素（PEG-IFN）-利巴韦林三联疗法的反应和 telaprevir 耐药变异体的出现通常较为困难。本研究旨在确定 194 例感染丙型肝炎病毒 1b 型（HCV-1b）的日本患者接受 12 周或 24 周三联治疗（T12PR12 或 T12PR24）的持续病毒学应答（SVR）的预测因素。本研究还评估了超深度测序技术是否能在治疗开始前预测耐药变异体的出现。对全组数据的分析表明，78%的患者实现了 SVR。多变量分析确定 IL28B rs8099917（基因型 TT）、氨基酸 70 位取代（Arg70）、既往治疗反应（初治或复发）、PEG-IFN 剂量（≥1.3μg/kg 体重）和治疗方案（T12PR24）为 SVR 的显著决定因素。在 T12PR24 组的患者中，92%的 TT 基因型患者实现了 SVR，无论 aa70 位的取代情况如何。在非 TT 基因型的患者中，Arg70 的患者中 76%实现了 SVR，而非 TT 基因型、Gln70（His70）和利巴韦林联合治疗无反应的患者中仅有 14%实现了 SVR。对 17 例未实现 SVR 的患者进行了超深度测序，以确定治疗过程中耐药变异体的出现情况。17 例患者（94%）均检测到新出现的耐药变异体，无论基线时检测到的变异频率如何。综上所述，结果表明，三联治疗的反应可以通过宿主、病毒和治疗因素的组合来预测，即使使用超深度测序，也很难在基线时预测三联治疗过程中出现的 telaprevir 耐药变异体。
