Direct acting antiviral agents (DAAs) are potent inhibitors of Hepatitis C virus (HCV) that have revolutionized the treatment landscape for this important viral disease. There are currently four classes of DAAs that inhibit HCV replication via distinct mechanisms of action: nonstructural protein (NS) 3/4a protease inhibitors, NS5A inhibitors, NS5B nucleoside polymerase inhibitors, and NS5B non-nucleoside polymerase inhibitors. Combination therapy with two or more DAAs has great potential to further enhance antiviral potency. The purpose of this study was to identify optimal combinations of DAAs against genotype 1 HCV replicons that maximized the inhibition of replicon replication. All possible two-drug combinations were evaluated against genotype 1a and 1b HCV replicons using a 96-well plate luciferase-based assay in triplicate. The Greco Universal Response Surface Area mathematical model was fit to the luciferase data to identify drug-drug interactions (i.e.: synergy, additivity, and antagonism) for antiviral effect against both genotypes. This information was used to rank-order combinations of DAAs based on their ability to inhibit replicon replication against genotype 1a and 1b HCV. These preclinical findings can provide information as to which antiviral regimens should move on in the development process.

直接作用抗病毒药（DAA）是丙型肝炎病毒（HCV）的有效抑制剂，已经彻底改变了这种重要病毒性疾病的治疗方法。当前有四类通过不同作用机制抑制HCV复制的DAA：非结构蛋白（NS）3 / 4a蛋白酶抑制剂，NS5A抑制剂，NS5B核苷聚合酶抑制剂和NS5B非核苷聚合酶抑制剂。两种或两种以上DAA的联合治疗具有进一步增强抗病毒效力的巨大潜力。这项研究的目的是确定针对基因型1 HCV复制子的DAA的最佳组合，从而最大程度地抑制复制子的复制。使用基于96孔板荧光素酶的一式三份，针对基因型1a和1b HCV复制子评估所有可能的两种药物组合。希腊通用反应表面积数学模型适合荧光素酶数据，以鉴定针对两种基因型的抗病毒作用的药物-药物相互作用（即：协同作用，加和作用和拮抗作用）。基于DAA抑制针对基因型1a和1b HCV的复制子复制的能力，该信息用于对DAA进行组合排序。这些临床前研究结果可提供有关在开发过程中应继续进行哪些抗病毒治疗的信息。