Shrivastava S, Wilson E, Poonia B, Tang L, Osinusi A, Kohli A, Kottilil S
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
Gilead Sciences Inc., Foster City, CA, USA.
J Viral Hepat. 2017 Sep;24(9):742-749. doi: 10.1111/jvh.12702. Epub 2017 May 4.
Treatment for chronic hepatitis C virus (HCV) infection has rapidly evolved into interferon-free directly acting antiviral regimens (DAA) that result in high sustained virologic response. DAAs primarily work by suppressing HCV replication and rely less on the immune system than interferon-based therapies. However, it is unclear whether the immune system recovers with suppression of HCV replication and contributes to HCV clearance with DAA therapy. We previously demonstrated HCV clearance is associated with increased HCV-specific immunity in CHCV-GT-1-infected patients during treatment with sofosbuvir (SOF)+ribavirin (RBV). Here, we aimed to analyse changes in HCV-specific immunological responses associated with viral clearance with combination DAA therapy of SOF+ledipasvir (LDV) for 12 weeks in CHCV-GT1 (N=14) patients who relapsed without augmentation of HCV-specific immunity during treatment with SOF+RBV. Phenotypic and functional changes within the T-cell compartment of PBMCs pre- and post-treatment were analysed. Retreatment of relapsers with LDV/SOF resulted in all patients attaining SVR . Suppression of HCV was associated with a decline in T-cell exhaustion markers (CD57; Tim3; PD1) along with augmented of HCV-specific T-cell IFN-gamma responses post-treatment. Addition of LDV to SOF was associated with augmentation of HCV-specific immunity and SVR in patients who previously failed SOF+RBV therapy without increased immunity. These findings demonstrate a novel effect of DAA in inducing host immune responses to aid HCV clearance and achieve SVR.
慢性丙型肝炎病毒（HCV）感染的治疗已迅速演变为无干扰素的直接抗病毒方案（DAA），可带来高持续病毒学应答。DAA主要通过抑制HCV复制起作用，与基于干扰素的疗法相比，对免疫系统的依赖较少。然而，尚不清楚免疫系统是否会随着HCV复制的抑制而恢复，并在DAA治疗中促进HCV清除。我们之前证明，在接受索磷布韦（SOF）+利巴韦林（RBV）治疗的慢性丙型肝炎基因1型（CHCV-GT-1）感染患者中，HCV清除与HCV特异性免疫增强有关。在此，我们旨在分析在接受SOF+RBV治疗期间未增强HCV特异性免疫而复发的CHCV-GT1（N=14）患者中，接受12周SOF+来迪派韦（LDV）联合DAA治疗后与病毒清除相关的HCV特异性免疫反应变化。分析了治疗前后外周血单个核细胞（PBMC）T细胞区室的表型和功能变化。复发患者再次接受LDV/SOF治疗后，所有患者均实现了持续病毒学应答（SVR）。HCV的抑制与T细胞耗竭标志物（CD57；Tim3；PD1）的下降以及治疗后HCV特异性T细胞干扰素-γ反应的增强有关。在先前接受SOF+RBV治疗但免疫未增强而失败的患者中，将LDV添加到SOF中与HCV特异性免疫增强和SVR相关。这些发现证明了DAA在诱导宿主免疫反应以帮助HCV清除并实现SVR方面的新作用。
