目的探索基于利益相关者视角的罕见病用药医保准入价值评估准则,为决策部门的罕见病用药评估提供参考。方法计算机检索PubMed、EMbase、CINAHL Plus、ProQuest、Web of Science、CNKI和WanFang Data数据库关于罕见病用药评估的研究,检...目的探索基于利益相关者视角的罕见病用药医保准入价值评估准则,为决策部门的罕见病用药评估提供参考。方法计算机检索PubMed、EMbase、CINAHL Plus、ProQuest、Web of Science、CNKI和WanFang Data数据库关于罕见病用药评估的研究,检索时限均为1983年1月1日至2018年12月31日。基于SPIDER模型构建问题并制定纳入排除标准,采用CASP对纳入文献进行方法学质量评价,利用NVivo 11软件并通过主题分析法归纳总结罕见病用药价值评估准则的一级描述性主题、二级分析性主题和三级分析性主题,运用CERQual证据分级工具对主题分析结果进行证据分级。结果最终纳入涵盖近二十个国家的10篇文献,识别了50个一级描述性主题,经归纳后嵌入14个二级分析性主题和3个三级分析性主题。罕见病用药价值评估准则包括:①疾病相关准则,如受影响人群特征、疾病严重性、未满足需要、疾病负担和道德与伦理考虑等;②药物相关准则,如安全性、有效性、经济性、创新性和证据质量等;③其他外部相关准则,如其他国家或机构报销情况、政府目标与优先项、药企保证供应、对环境影响等。结论除常规的临床效果和药物经济学等考虑因素外,利益相关者更倾向于采用更广泛视角去定义罕见病用药价值,全面了解其价值驱动因素可以更好地辅助罕见病用药医保决策。展开更多
OBJECTIVE: To define the mechanism of acute hepatitis in non-human primates after liver directed gene therapy. METHODS: Differences in immune response exhibited by 8 rhesus monkeys receiving adenovirus (Ad) or lipofec...OBJECTIVE: To define the mechanism of acute hepatitis in non-human primates after liver directed gene therapy. METHODS: Differences in immune response exhibited by 8 rhesus monkeys receiving adenovirus (Ad) or lipofectamine-mediated gene transfer by various routes, the time course, and the nature of the specific immune responses to both adenoviral vectors and transgene products were studied using HE staining (H&E) and immunohistochemical staining. RESULTS: The monkeys developed mild to moderate acute hepatitis 1 to 3 weeks after intravenous or intrabiliary injection of first generation replication-defective adenoviruses carrying the Escherichia coli lacZ gene. This was accompanied by adenovirus-mediated T-cell proliferation and neutralizing antibodies to the adenovirus. Increased numbers of CD3(+), CD4(+) and CD8(+) T-lymphocytes were detected in the diseased livers, while B-lymphocytes were absent. Hepatocytes demonstrated increased expression of beta 2-microglobulins (beta 2-MG) and HLA-DR antigens in the plasma membranes. The development of acute hepatitis and the accompanying immune abnormalities were delayed in immunosuppressed monkeys until after the discontinuation of immunosuppressive therapy. The monkeys infused with Ad. CMVluc showed more significant and longer durations of hepatitis than the monkeys infused with adenoviruses carrying the lacZ gene. Lipofectamine-mediated gene transfer was inefficient. There was neither lacZ expression nor significant immune response in the liver of monkeys infused with lipofectamine via the portal vein or the common bile duct. CONCLUSION: Immune response to the hepatocytes in liver directed gene therapy is MHC class I restricted and T-cell mediated. Both adenoviral vectors and foreign genes are related to the liver damage. Mild to moderate hepatic inflammation seen with the E-1 deleted vector is reversible. Immunosuppression regimens may prolong transgene expression and delay the development of acute adenoviral hepatitis.展开更多
文摘OBJECTIVE: To define the mechanism of acute hepatitis in non-human primates after liver directed gene therapy. METHODS: Differences in immune response exhibited by 8 rhesus monkeys receiving adenovirus (Ad) or lipofectamine-mediated gene transfer by various routes, the time course, and the nature of the specific immune responses to both adenoviral vectors and transgene products were studied using HE staining (H&E) and immunohistochemical staining. RESULTS: The monkeys developed mild to moderate acute hepatitis 1 to 3 weeks after intravenous or intrabiliary injection of first generation replication-defective adenoviruses carrying the Escherichia coli lacZ gene. This was accompanied by adenovirus-mediated T-cell proliferation and neutralizing antibodies to the adenovirus. Increased numbers of CD3(+), CD4(+) and CD8(+) T-lymphocytes were detected in the diseased livers, while B-lymphocytes were absent. Hepatocytes demonstrated increased expression of beta 2-microglobulins (beta 2-MG) and HLA-DR antigens in the plasma membranes. The development of acute hepatitis and the accompanying immune abnormalities were delayed in immunosuppressed monkeys until after the discontinuation of immunosuppressive therapy. The monkeys infused with Ad. CMVluc showed more significant and longer durations of hepatitis than the monkeys infused with adenoviruses carrying the lacZ gene. Lipofectamine-mediated gene transfer was inefficient. There was neither lacZ expression nor significant immune response in the liver of monkeys infused with lipofectamine via the portal vein or the common bile duct. CONCLUSION: Immune response to the hepatocytes in liver directed gene therapy is MHC class I restricted and T-cell mediated. Both adenoviral vectors and foreign genes are related to the liver damage. Mild to moderate hepatic inflammation seen with the E-1 deleted vector is reversible. Immunosuppression regimens may prolong transgene expression and delay the development of acute adenoviral hepatitis.
