Hepatitis C antivirals: Mechanism of action, combination efficacy and resistance

丙型肝炎抗病毒药物：作用机制、联合疗效和耐药性

• 批准号: 8646873
• 负责人: Charles M Rice
• 金额: $ 73.54万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646873
• 关键词: Address; Adult; Affect; African American; Antiviral Agents; Antiviral Response; Antiviral resistance; Automobile Driving; Biological; Biological Process; Cell Culture System; Cell Line; Cells; Clinic; Clinical; Clinical Research; Combined Modality Therapy; Complex; Cyclophilins; Data; Detection; Development; Double-Stranded RNA; Drug Combinations; Effectiveness; Frequencies; Genotype; Hepatitis C; Hepatitis C Antiviral; Hepatitis C virus; Hepatocyte; Hispanics; Human; Image; In Vitro; Individual; Infection; Infectious hepatitides; Investigation; Kinetics; Knowledge; Life; Life Cycle Stages; Liver; Liver diseases; Luciferases; Measures; Metabolism; Methods; Modeling; Molecular; Pathway interactions; Patients; Pattern; Pegylated Interferon Alfa; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Polymerase; Preclinical Testing; Primary carcinoma of the liver cells; Production; Proteins; Public Health; RNA; Recombinants; Regimen; Replicon; Reporter; Reporting; Resistance; Resistance profile; Ribavirin; Single Nucleotide Polymorphism; Support System; System; Therapeutic; United States; Viral; Viral Proteins; Virus; Virus Replication; Withdrawal; analytical method; base; cellular imaging; chronic liver disease; design; fetal; fitness; hepatoma cell; in vitro Model; inhibitor/antagonist; insight; liver transplantation; mathematical model; pathogen; pre-clinical; resistance mechanism; response; tool; treatment response; viral RNA; viral resistance; virus culture

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide (1) and is the major indication for liver transplantation in the United States (2, 3). While therapy with PEGylated Interferon-alpha (PEG-IFN) plus ribavirin (RBV) provides sustained virologic response (SVR) in 40-50% of patients overall, the SVR rate is only about 20% in African Americans and Hispanics, who have a higher frequency of single nucleotide polymorphisms associated with poor response (4, 5). Addition of direct-acting antivirals (DAAs) targeting the HCV NS3/4A protease increases SVR rates to 68-75% in previously untreated patients, but such regimens still suffer from the limitations of PEG-IFN/RBV. Thus, drug developers are seeking combinations of DAAs that will reduce or eliminate the need for PEG-IFN and/or RBV while providing an adequate barrier to resistance. It was recently reported that a small number of genotype 1a and 1b patients achieved SVR following treatment with a combination of two DAAs targeting NS3/4A and NS5A. While these results provide proof of concept for SVR without use of PEG-IFN/RBV, biological data to inform the selection of such DAA combinations are limited. The preponderance of preclinical characterization of DAAs and combinations has been obtained using subgenomic HCV replicons in Huh-7 hepatoma-derived cell lines, a recombinant system that omits important features of the viral life cycle. Systems have been developed that recapitulate the complete HCV life cycle in hepatoma lines and primary human hepatocytes/hepatoblasts. This study proposes to interrogate the effects of DAAs in cell systems that support the complete HCV life cycle. These studies will deepen our understanding of key biological processes involved in viral replication and provide new insights into DAA mechanisms of action that will be translatable to clinical studies.

描述（由申请人提供）：丙型肝炎病毒（HCV）是全球慢性肝病的主要病因(1)，也是美国肝移植的主要适应症（2,3）。虽然聚乙二醇化干扰素- α (PEG-IFN)加利巴韦林（RBV）治疗在40-50%的患者中提供了持续的病毒学反应（SVR），但在非洲裔美国人和西班牙裔美国人中，SVR率仅为20%左右，他们的单核苷酸多态性频率较高，与不良反应相关（4,5）。添加靶向HCV NS3/4A蛋白酶的直接作用抗病毒药物（DAAs）可将先前未治疗的患者的SVR率提高至68-75%，但此类方案仍然受到PEG-IFN/RBV的限制。因此，药物开发人员正在寻求DAAs的组合，以减少或消除对PEG-IFN和/或RBV的需求，同时提供足够的耐药屏障。最近有报道称，少数基因型1a和1b患者在接受靶向NS3/4A和NS5A的两种daa联合治疗后实现了SVR。虽然这些结果为不使用PEG-IFN/RBV的SVR提供了概念证明，但用于选择此类DAA组合的生物学数据有限。在hh -7肝癌来源细胞系中，利用HCV亚基因组复制子获得了DAAs及其组合的临床前特征优势，这是一种重组系统，忽略了病毒生命周期的重要特征。已经开发出系统，可以概括肝癌系和原代人肝细胞/肝母细胞中HCV的完整生命周期。本研究拟探讨DAAs在支持HCV完整生命周期的细胞系统中的作用。这些研究将加深我们对病毒复制的关键生物学过程的理解，并为DAA的作用机制提供新的见解，这些见解将可转化为临床研究。