Background & Aims

Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT).

Methods

We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated.

Results

A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40–90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56–80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88–95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H.

Conclusions

We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals.

Impact and implications

There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

中文翻译：

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DAA 治疗失败后 HCV 耐药相关替代的长期持续存在

背景与目标

用直接作用抗病毒药物 (DAA) 治疗后长期持续存在 HCV 耐药相关替代 (RAS) 的数据有限。本研究评估了 NS3、NS5A 和 NS5B RAS 在治疗结束 (EOT) 后长达 5 年的持续性。

方法

我们纳入了来自欧洲耐药数据库中收集的 678 名 HCV 基因型 (GT) 1 或 3 感染且病毒学 DAA 治疗失败的个体的样本。对 NS3、NS5A 和 NS5B 进行了测序，并评估了临床参数。

结果

总共包括 242 名 HCV GT1a 患者 (36%)、237 名 GT1b (35%) 患者和 199 名 (29%) GT3 患者且 DAA 失败。蛋白酶抑制剂失效后，EOT 后 NS3 RAS 的频率为 40-90%。随访第 3 个月后，GT1b 和 GT3 中的 NS3 RAS 迅速消失，但由于 Q80K，GT1a 中的 NS3 RAS 稳定 (≥60%)。SOF 抗性 NS5B RAS S282T 仅在具有 GT3a 的个体中发现。非核苷 NS5B RAS 在 GT1 中常见 (56–80%)，在 GT1a 中降至 30%，但在 GT1b 中持续存在。NS5A RAS 在 NS5A 抑制剂失败后的所有 GT 中非常常见 (88–95%)，甚至在随访 24 个月后，它们的频率为 65% 或更高。然而，GT1b 中的 RAS 具有稳定的过程，而 GT1a 和 GT3 中的 RAS 在随访 24 个月后略有下降（GT1a，68%；GT1b，95%；GT3，65%），

结论

我们发现低到中等水平的 RASs 持续存在，而高水平的抗性 RASs 随着时间的推移消失。根据 HCV 亚型的不同 RAS 持久性模式可能对第一代 DAAs 的复治和全球 HCV 消除目标有影响。

影响和启示

关于 DAA 治疗失败后 HCV 耐药相关替代 (RAS) 长期持续存在的数据很少，RAS 可能对挽救治疗的疗效产生影响。特别是在 VOX/VEL/SOF 或 G/P/SOF 可用性有限的国家，不同的 RAS 持久性模式可能对第一代 DAA 的再治疗和全球 HCV 消除目标产生影响。本研究中确定的 RAS 持久性的不同模式可用于推导有关 DAA 失败后 RAS 持久性的一般规则，欠发达国家的医生可以应用这些规则来计划个体化 HCV 再治疗。