Department of Hepatology, Toranomon Hospital, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
J Clin Microbiol. 2014 Jan;52(1):193-200. doi: 10.1128/JCM.02371-13. Epub 2013 Nov 6.
The clinical usefulness of detecting telaprevir-resistant variants is unclear. Two hundred fifty-two Japanese patients infected with hepatitis C virus (HCV) genotype 1b received triple therapy with telaprevir-peginterferon (PEG-IFN)-ribavirin and were evaluated for telaprevir-resistant variants by direct sequencing at baseline and at the time of reelevation of the viral load. An analysis of the entire group indicated that 76% achieved a sustained virological response. Multivariate analysis identified a PEG-IFN dose of <1.3 μg/kg of body weight, an IL28B rs8099917 genotype (genotype non-TT), detection of telaprevir-resistant variants of amino acid (aa) 54 at baseline, nonresponse to prior treatment, and a leukocyte count of <5,000/mm(3) as significant pretreatment factors for detection of telaprevir-resistant variants at the time of reelevation of the viral load. In 63 patients who showed nonresponse to prior treatment, a higher proportion of patients with no detected telaprevir-resistant variants at baseline (54%) achieved a sustained virological response than did patients with detected telaprevir-resistant variants at baseline (0%). Furthermore, 2 patients who did not have a sustained virological response from the first course of triple therapy with telaprevir received a second course of triple therapy with telaprevir. These patients achieved a sustained virological response by the second course despite the persistence of very-high-frequency variants (98.1% for V36C) or a history of the emergence of variants (0.2% for R155Q and 0.2% for A156T) by ultradeep sequencing. In conclusion, this study indicates that the presence of telaprevir-resistant variants at the time of reelevation of viral load can be predicted by a combination of host, viral, and treatment factors. The presence of resistant variants at baseline might partly affect treatment efficacy, especially in those with nonresponse to prior treatment.
检测特拉匹韦耐药变异体的临床实用性尚不清楚。252 例感染丙型肝炎病毒 (HCV) 基因型 1b 的日本患者接受特拉匹韦-聚乙二醇干扰素 (PEG-IFN)-利巴韦林三联治疗，并在基线和病毒载量再次升高时通过直接测序评估特拉匹韦耐药变异体。对整个组的分析表明，76%的患者获得持续病毒学应答。多变量分析确定 PEG-IFN 剂量<1.3μg/kg 体重、IL28B rs8099917 基因型（非 TT 基因型）、基线时检测到氨基酸 (aa) 54 位的特拉匹韦耐药变异体、对先前治疗无应答以及白细胞计数<5000/mm(3)为病毒载量再次升高时检测到特拉匹韦耐药变异体的重要预处理因素。在 63 例对先前治疗无应答的患者中，基线时未检测到特拉匹韦耐药变异体的患者（54%）比基线时检测到特拉匹韦耐药变异体的患者（0%）获得持续病毒学应答的比例更高。此外，2 例在首次接受特拉匹韦三联治疗时未获得持续病毒学应答的患者接受了第二次特拉匹韦三联治疗。尽管存在超高频率变异体（V36C 为 98.1%）或变异体出现史（R155Q 为 0.2%，A156T 为 0.2%），这 2 例患者通过深度测序仍在第二疗程中获得持续病毒学应答。总之，本研究表明，病毒载量再次升高时存在特拉匹韦耐药变异体可通过宿主、病毒和治疗因素的组合进行预测。基线时存在耐药变异体可能会部分影响治疗效果，尤其是在对先前治疗无应答的患者中。
