Liver Diseases-Viral Hepatitis, Liver Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
J Viral Hepat. 2021 Sep;28(9):1319-1324. doi: 10.1111/jvh.13497. Epub 2021 Mar 22.
Direct-acting antivirals (DAAs) resolve chronic HCV infection in >95% of patients, but a small percentage do not respond to DAA-based therapy. These may be difficult to treat because of resistance-associated substitutions (RAS) emerging after treatment failure. Triple therapy with sofosbuvir (SOF)/velpatasvir (VEL)/voxilaprevir (VOX) is the recommended retreatment after DAA-based failure. However, in rare cases, failure to triple therapy occurs, and there is little information characterizing the viruses that relapse. To determine the RAS profile after failing SOF/VEL/VOX, and seek suitable alternatives for retreatment, samples from 5 patients were analysed using MiSeq Illumina deep sequencing before and after triple therapy. All patients were men, aged 59-78 years, 2 HCV genotype (G) 1b and 3 G3a. The most prevalent NS3 substitutions after SOF/VEL/VOX failure were Y56F and A166T. Four patients had the NS5A RAS, Y93H, after triple failure, and Y93H was observed in both G1b patients before retreatment and after SOF/ledipasvir failure. In 2 G3a patients, Y93H appeared at triple failure, and on the other G3a, A30K persisted in 100% of viral genomes. Finally, G1b patients showed C316N in NS5B, associated with SOF failure, but G3a patients had no known NS5B substitutions. HCV RAS analysis identified the following substitutions present at higher rates after triple failure: Y56F in NS3 (G1b), A166T in NS3 (G3a), A30K or Y93H in NS5A, and C316N in NS5B (G1b). A RAS-based salvage treatment (SOF + glecaprevir/pibrentasvir + RBV) was successfully used in one G3a patient.
直接作用抗病毒药物（DAA）可使超过 95%的慢性 HCV 感染患者得到治愈，但仍有一小部分患者对 DAA 治疗无应答。这些患者可能由于治疗失败后出现耐药相关替换（RAS）而难以治疗。索磷布韦（SOF）/维帕他韦（VEL）/伏西瑞韦（VOX）三联治疗是 DAA 治疗失败后的推荐补救治疗。然而，在极少数情况下，三联治疗会失败，而且对于复发病毒的特征描述信息较少。为了确定 SOF/VEL/VOX 治疗失败后的 RAS 谱，并寻找合适的补救治疗方案，对 5 例患者的样本进行了 MiSeq Illumina 深度测序，分别在三联治疗前后进行了分析。所有患者均为男性，年龄 59-78 岁，2 例 HCV 基因型（G）1b 和 3 例 G3a。SOF/VEL/VOX 治疗失败后最常见的 NS3 替换是 Y56F 和 A166T。4 例患者在三联治疗失败后出现 NS5A RAS，Y93H，在 G1b 患者的双重治疗前和 SOF/ledipasvir 失败后均观察到 Y93H。在 2 例 G3a 患者中，Y93H 在三联治疗失败时出现，而另一位 G3a 患者的 100%病毒基因组中持续存在 A30K。最后，G1b 患者的 NS5B 中出现 C316N，与 SOF 失败相关，但 G3a 患者的 NS5B 中没有已知的替换。HCV RAS 分析确定了以下在三联治疗失败后更高频率出现的替换：NS3 中的 Y56F（G1b）、NS3 中的 A166T（G3a）、NS5A 中的 A30K 或 Y93H 以及 NS5B 中的 C316N（G1b）。一位 G3a 患者成功地使用了基于 RAS 的挽救治疗（SOF+glecaprevir/pibrentasvir+RBV）。
