Robust Antiviral Efficacy upon Administration of a Nucleoside Analog to Hepatitis C Virus-Infected Chimpanzees
Robust Antiviral Efficacy upon Administration of a Nucleoside Analog to Hepatitis C Virus-Infected Chimpanzees
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DOI：
10.1128/aac.01032-08
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发表时间：
2009-03-01
影响因子：
4.9
通讯作者：
Olsen, David B.
中科院分区：
文献类型：
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作者：
Carroll, Steven S.;Ludmerer, Steven;Olsen, David B.
丙型肝炎病毒（HCV）感染估计全球1.7亿人，并与肝纤维化，肝硬化和肝细胞癌的发病率增加有关。目前批准的治疗HCV感染的疗法包括聚乙二醇化α干扰素和利巴韦林的组合，其在40至60%的患者中导致持续的病毒应答。开发改进的疗法的努力包括开发病毒编码的酶的直接抑制剂，如病毒RNA依赖性RNA聚合酶。核苷类似物2 '-C-甲基-7-脱氮-腺苷（MK-0608）已被证明可抑制亚基因组HCV基因型1b复制子中的病毒RNA复制，50%有效浓度（EC 50）为0.3 μ M（EC 90 = 1.3 μ M）。为了确定体内疗效，将MK-0608给予HCV感染的黑猩猩，导致血浆病毒载量呈剂量和时间依赖性降低。在单独的实验中，给予黑猩猩MK-0608（0.2和2 mg/kg体重/天）静脉给药7天后，病毒载量分别平均降低1.0和>5 log（10）IU/ml。另外两只HCV感染的黑猩猩通过口服给予每日1 mg MK-0608/kg。口服给药37天后，一只初始病毒载量较高的黑猩猩的病毒载量降低了4.6 log（10），另一只黑猩猩的病毒载量低于HCV TaqMan检测的定量限（LOQ）（20 IU/ml）。重要的是，在整个给药期间和给药结束后至少12天，病毒载量保持低于LOQ。结果表明，对HCV感染的黑猩猩给予MK-0608具有稳健的抗病毒作用。
Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide and is associated with an increased incidence of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Currently approved therapies to treat HCV infection consist of combinations of pegylated alpha interferon and ribavirin which result in a sustained viral response in 40 to 60% of patients. Efforts to develop improved therapies include the development of direct inhibitors of virally encoded enzymes such as the viral RNA-dependent RNA polymerase. A nucleoside analog, 2'-C-methyl-7-deaza-adenosine (MK-0608), has been shown to inhibit viral RNA replication in the subgenomic HCV genotype 1b replicon, with a 50% effective concentration (EC50) of 0.3 mu M (EC90 = 1.3 mu M). To determine efficacy in vivo, MK-0608 was administered to HCV-infected chimpanzees, resulting in dose-and time-dependent decreases in plasma viral loads. In separate experiments, chimpanzees dosed for 7 days with MK-0608 at 0.2 and 2 mg per kg of body weight per day by intravenous administration experienced average reductions in viral load of 1.0 and >5 log(10) IU/ml, respectively. Two other HCV-infected chimpanzees received daily doses of 1 mg MK-0608 per kg via oral administration. After 37 days of oral dosing, one chimpanzee with a high starting viral load experienced a reduction in viral load of 4.6 log(10), and the viral load in the other chimpanzee fell below the limit of quantification (LOQ) of the HCV TaqMan assay (20 IU/ml). Importantly, viral load remained below the LOQ throughout the duration of dosing and for at least 12 days after dosing ended. The results demonstrate a robust antiviral effect on the administration of MK-0608 to HCV-infected chimpanzees.