慢性HCV肝炎抗病毒疗效预测及临床.ppt

Natural History of HCV infection Biological Activities of IFN Antagonism of IFN by HCV proteins * Exposure Self Resolution 15% Chronic Infection Liver Cirrhosis End Stage Liver Disease Liver Transplant Hepatocellular Carcinoma Death 85% Stable 80% (68%) 20% (17%) 25% (4%) Slowly Progressive 75% (13%) 20-30 yr Alcohol HIV HBV Immunosuppression Older age B cell CD8+ CTL Hepatocyte CD4+ Th cell Y Y Y Y Y NK NKT cells Immune response to HCV infection : Role largely unknown - early, vigorous, multi- specific response - strong NS3-response in resolving acute HCV - TH1 in recovery - TH2 in chronic - vigorous, multi- specific response - CTL exert some control on viral load antibodies to most structural and non-structural viral proteins are made Signal ISG IFN-induced protein Inhibition of viral replication Inhibition of Cell Growth Regulation of Cell differentiation Activation of Immune System IFN非特异型抗病毒功能 IFN Receptor 2‘-5’OAS RNA Rnase L Single-Strand RNAs 降解 M x protein virus 多聚酶 抑制 PKR protein synthesisi 抑制 IFN immunomodulatory effects 增加 MHC I 激活M NK CTL cells 诱导Th 1 cells 减少Th 2 cells 抑制 IL-1、8、10和TNF → 抗炎 IFN Protein Kinase PKR inactive Initiation Factor eIF-2a Phosphorylated Initiation Factor eIF-2a P Phosphatase (soluble) Pi mRNA translation inhibition Protein Kinase PKR active dsRNA ssRNA Reduced capacity of mature DC from HCV patients to induce allogeneic T cell proliferation. Bain et al. Gastroenterology 120:51-524, 2001 IFN Protein Kinase PKR inactive Initiation Factor eIF-2a Phosphorylated Initiation Factor eIF-2a P Phosphatase (soluble) Pi mRNA translation inhibition Protein Kinase PKR active dsRNA ssRNA HCV E2 HCV NS5A 影响IFN抗HCV治疗的因素 ? 性别 ? 年龄 ? 种族 ? 体重 ? 感染HCV时间 ? 细胞免疫状态、 ? 肝脏纤维化程度、脂肪变程度、胰岛素抵抗 ? HCV基因型、准种、病毒含量 ? ISDR变异、E2胞膜蛋白与eIF-2a的同源性 ? 病毒下降的速度 ? 以前是否治疗 ? 治疗药物、剂量、给药方法 、联合用药 PP人群197例临床特征 临床特征和病毒学指标 数值 男/女 134/63 年龄 ≥50/50岁 49/148 HCV感