Gane Edward J, Metivier Sophie, Nahass Ronald, Ryan Michael, Stedman Catherine A, Svarovskaia Evguenia S, Mo Hongmei, Doehle Brian, Dvory-Sobol Hadas, Hedskog Charlotte, Lin Ming, Brainard Diana M, Yang Jenny C, McHutchison John G, Sulkowski Mark, Younes Ziad, Lawitz Eric
Auckland Clinical Studies Auckland New Zealand.
Centre Hospitalier Universitaire-Purpan Toulouse France.
Hepatol Commun. 2017 Jun 22;1(6):538-549. doi: 10.1002/hep4.1060. eCollection 2017 Aug.
S282T in NS5B is the primary amino acid substitution associated with resistance to sofosbuvir (SOF) but has rarely been detected in patients treated with a SOF-based regimen. Here, the emergence and fitness of the S282T substitution in virologic failure patients administered SOF-based regimens across the SOF and ledipasvir (LDV)/SOF phase 2 and 3 programs was evaluated. Plasma samples collected at baseline and at virologic failure were amplified and deep sequenced (1% cutoff). To date, over 12,000 patients have been treated in SOF or LDV/SOF phase 2 and 3 studies. Of these, deep sequencing was available at baseline in 8598 patients (62.4% genotype [GT] 1, 10.7% GT2, 20.9% GT3, and 6.0% GT4-6) and at virologic failure in 901 patients. In the 8598 patients, no S282T substitution was detected at baseline; at virologic failure, 10 of the 901 (1%) patients had S282T detected. The SOF-based regimen associated with treatment-emergent S282T was SOF monotherapy in two patients, retreatment with LDV/SOF in prior LDV/SOF failures in three patients, LDV/SOF for 8 weeks in 1 GT1 patient, LDV/SOF for 12 weeks in 1 patient each with GT3, GT4, and GT5, and LDV/SOF + ribavirin for 12 weeks in 1 GT6 patient. Nine of 10 patients with emergent S282T received an SOF-based retreatment regimen, eight of whom achieved sustained virologic response 12 weeks after treatment and one of whom failed retreatment. : The emergence of S282T substitution was rare in patients who fail SOF-based regimens. Successful retreatment of prior SOF failure patients is possible in the presence of S282T substitution with SOF in combination with various direct-acting antiviral agents. ( 2017;1:538-549).
NS5B 中的 S282T 是与对索磷布韦（SOF）耐药相关的主要氨基酸替代，但在接受基于索磷布韦方案治疗的患者中很少检测到。在此，对在索磷布韦和来迪派韦（LDV）/索磷布韦 2 期和 3 期项目中接受基于索磷布韦方案治疗的病毒学失败患者中 S282T 替代的出现情况和适应性进行了评估。收集基线和病毒学失败时的血浆样本进行扩增和深度测序（截断值为 1%）。迄今为止，超过 12000 名患者已在索磷布韦或来迪派韦/索磷布韦 2 期和 3 期研究中接受治疗。其中，8598 名患者（62.4%为基因 1 型[GT]、10.7%为 GT2、20.9%为 GT3、6.0%为 GT4 - 6）在基线时有深度测序数据，901 名患者在病毒学失败时有深度测序数据。在 8598 名患者中，基线时未检测到 S282T 替代；在病毒学失败时，901 名患者中有 10 名（1%）检测到 S282T。与治疗中出现 S282T 相关的基于索磷布韦的方案为：两名患者接受索磷布韦单药治疗，三名在先前来迪派韦/索磷布韦治疗失败后接受来迪派韦/索磷布韦再治疗，一名 GT1 患者接受来迪派韦/索磷布韦治疗 8 周，一名 GT3、一名 GT4 和一名 GT5 患者各接受来迪派韦/索磷布韦治疗 12 周，一名 GT6 患者接受来迪派韦/索磷布韦 + 利巴韦林治疗 12 周。10 名出现 S282T 的患者中有 9 名接受了基于索磷布韦的再治疗方案，其中 8 名在治疗 12 周后实现了持续病毒学应答，1 名再治疗失败。：在接受基于索磷布韦方案治疗失败的患者中，S282T 替代的出现很罕见。在存在 S282T 替代的情况下，使用索磷布韦联合各种直接作用抗病毒药物对先前索磷布韦治疗失败的患者进行成功再治疗是可能的。（2017；1：538 - 549）
