Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens.
Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens.
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DOI：
10.1371/journal.pone.0177352
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Ceccherini-Silberstein F
中科院分区：
文献类型：
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作者：
Cento V;Nguyen THT;Di Carlo D;Biliotti E;Gianserra L;Lenci I;Di Paolo D;Calvaruso V;Teti E;Cerrone M;Romagnoli D;Melis M;Danieli E;Menzaghi B;Polilli E;Siciliano M;Nicolini LA;Di Biagio A;Magni CF;Bolis M;Antonucci FP;Di Maio VC;Alfieri R;Sarmati L;Casalino P;Bernardini S;Micheli V;Rizzardini G;Parruti G;Quirino T;Puoti M;Babudieri S;D'Arminio Monforte A;Andreoni M;Craxì A;Angelico M;Pasquazzi C;Taliani G;Guedj J;Perno CF;Ceccherini-Silberstein F
细胞内HCV-RNA减少是直接作用抗病毒药物（DAA）的作用机制，可替代聚乙二醇化干扰素加利巴韦林（PR）消除肝细胞。我们对目前使用的全DAA组合治疗的丙型肝炎患者的ALT和HCV-RNA动力学进行了建模，以评估其作用模式和细胞毒性，并与特拉匹韦（TVR）+PR进行了比较。在111名HCV-1型丙型肝炎患者中进行了ALT和HCV-RNA动力学的数学建模，81例接受全DAA方案治疗，30例接受TVR+ PR方案治疗。动力学模型和Cox分析用于评估ALT衰减和正常化的决定因素。HCV-RNA动力学是双相的，反映了阻断病毒产生的平均有效性> 99.8%。与TVR+PR或索非布韦+西美瑞韦相比，接受NS 5A抑制剂的患者中病毒下降的第一阶段更快（p<0.001），反映了阻断组装/分泌的更高功效。与NS 5A抑制剂相比，接受TVR+PR或索非布韦+西米普韦的患者的第二时相（记为δ，归因于感染细胞丢失）更快（分别为0.27 vs 0.21 d-1，p = 0.0012）。相反，与NS 5A抑制剂相比，接受TVR+PR或索非布韦+西米匹韦的患者ALT正常化速率（记为λ）较慢（分别为0.17 vs 0.27 d-1，p<0.001）。病毒下降的第二阶段和ALT正常化率之间没有显著相关性，对于给定的病毒减少水平，ALT正常化在接受DAA，特别是NS 5A的患者中比TVR+ PR更深刻。我们的数据支持通过NS 5A抑制剂增强的所有DAA方案的HCV清除过程，并且比含IFN的方案更少依赖于肝细胞死亡。这可能强调了DAA的“细胞治愈”过程，导致肝脏稳态的快速改善。
Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted δ and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted λ, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of “cell-cure” by DAAs, leading to a fast improvement of liver homeostasis.