Department of Specialized and Internal Medicine, Tropical and Infectious Diseases Unit, University Hospital of Siena, Siena, Italy.
Department of Specialized and Internal Medicine, Tropical and Infectious Diseases Unit, University Hospital of Siena, Siena, Italy; Department of Medical Biotechnologies, University of Siena, Siena, Italy.
Infez Med. 2021 Jun 1;29(2):242-251.
Despite the high efficacy of direct-acting antivirals (DAAs), the selection of resistance-associated substitutions (RASs) after virological failure of hepatitis C virus (HCV) DAAs can impair the cure of chronic HCV. The aim of the study was to characterize RASs after virological failure of DAAs in Italy over the years. Within the Italian network VIRONET-C, the change in prevalence of NS3/4A-NS5A-NS5B RASs was retrospectively evaluated in patients who failed a DAA regimen over the years 2015-2019. NS3, NS5A and NS5B Sanger sequencing was performed using homemade protocols and the geno2pheno system was used to define HCV-genotype/subtype and predict drug resistance. The changes in the prevalence of RASs over time were evaluated using the chi-square test for trend. Predictors of RASs at failure were analysed by logistic regression. Among 468 HCV-infected patients, HCV genotype 1 was the most prevalent (1b in 154, 33% and 1a in 109, 23%). DAA regimens were: ledipasvir (LDV)/sofosbuvir (SOF) in 131 patients (28%), daclatasvir (DCV)/SOF in 109 (23%), ombitasvir/paritaprevir/ritonavir+dasabuvir (3D) in 89 (19%), elbasvir (EBR)/grazoprevir (GRZ) in 52 (10.5%), velpatasvir (VEL)/SOF in 53 (11%), glecaprevir (GLE)/pibrentasvir (PIB) in 27 (6%) and ombitasvir/paritaprevir/ritonavir (2D) in 7 (1.5%); ribavirin was administered in 133 (28%). The NS5A fasta sequence was available for all patients, NS5B and NS3/4A both for 93%. The prevalence of NS5A and NS3/4A RASs significantly declined from 2015 to 2019; NS5B RAS remained stable. Independent predictors of any RASs included older age and genotype 1a (vs G2 and vs G4). Notably, at least partial susceptibility to all the agents included in the GLE/PIB and VEL/SOF/Voxilaprevir (VOX) combinations was predicted in >95% of cases. As RASs remain common at the failure of DAAs, their identification could play a crucial role in optimizing re-treatment strategies. In Italy RAS prevalence has been decreasing over the years and susceptibility to the latest developed drug combinations is maintained in most cases.
尽管直接作用抗病毒药物（DAAs）的疗效很高，但丙型肝炎病毒（HCV）DAAs 病毒学失败后出现的耐药相关替代（RASs）可损害慢性 HCV 的治愈。本研究的目的是描述意大利多年来 DAA 病毒学失败后 RASs 的特征。在意大利网络 VIRONET-C 中，回顾性评估了 2015 年至 2019 年间 DAA 方案失败的患者中 NS3/4A-NS5A-NS5B RASs 的流行率变化。使用自制方案进行 NS3、NS5A 和 NS5B Sanger 测序，并使用 geno2pheno 系统定义 HCV 基因型/亚型并预测药物耐药性。使用趋势卡方检验评估随时间变化的 RASs 流行率。通过逻辑回归分析 RASs 失败的预测因素。在 468 例 HCV 感染患者中，最常见的 HCV 基因型为 1 型（1b 为 154 例，占 33%，1a 为 109 例，占 23%）。DAA 方案为：ledipasvir（LDV）/sofosbuvir（SOF）在 131 例患者中（28%），daclatasvir（DCV）/SOF 在 109 例患者中（23%），ombitasvir/paritaprevir/ritonavir+dasabuvir（3D）在 89 例患者中（19%），elbasvir（EBR）/grazoprevir（GRZ）在 52 例患者中（10.5%），velpatasvir（VEL）/SOF 在 53 例患者中（11%），glecaprevir（GLE）/pibrentasvir（PIB）在 27 例患者中（6%），ombitasvir/paritaprevir/ritonavir（2D）在 7 例患者中（1.5%）；133 例患者（28%）接受了利巴韦林治疗。所有患者均提供 NS5A fasta 序列，93%的患者均提供 NS5B 和 NS3/4A。2015 年至 2019 年，NS5A 和 NS3/4A RASs 的流行率显著下降；NS5B RAS 保持稳定。任何 RASs 的独立预测因素包括年龄较大和基因型 1a（与 G2 和 G4 相比）。值得注意的是，在 >95%的情况下，预测对包括 glecaprevir/PIB 和 velpatasvir/SOF/Voxilaprevir（VOX）组合在内的所有药物均具有部分敏感性。由于 DAA 失败后 RASs 仍然很常见，因此识别它们可能在优化再治疗策略方面发挥关键作用。在意大利，RASs 的流行率多年来一直在下降，而且在大多数情况下，对最新开发的药物组合的敏感性得以维持。
