Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites influencing the response to peginterferon and ribavirin therapy
Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites influencing the response to peginterferon and ribavirin therapy
复制标题
DOI：
10.1007/s12072-011-9267-x
复制
发表时间：
2011-09-01
影响因子：
6.6
通讯作者：
Enomoto, Nobuyuki
中科院分区：
文献类型：
--
作者：
Kadokura, Makoto;Maekawa, Shinya;Enomoto, Nobuyuki
目的：部分2a型丙型肝炎病毒感染患者对聚乙二醇化干扰素联合利巴韦林治疗不能取得持续的病毒学应答(SVR)，但其原因尚不清楚。方法采用直接测序法对两组患者(43例患者为检测患者，35例患者为验证组，35例患者为验证组)的2a型丙型肝炎患者治疗前的完整开放阅读框序列进行测定，并分析其与最终结果的相关性。结果58例重型肝炎患者和20例非重型肝炎患者治疗前丙型肝炎病毒核糖核酸水平(P=0.002)、肝纤维化评分(P=0.047)和累积RBV剂量(P=0.003)差异有统计学意义。比较完整的丙型肝炎病毒开放阅读框架的所有氨基酸位置，核心区第110位的苏氨酸在SVR中出现的频率非常高(第1组p=0.004，第2组p=0.004，P=5e-05)。滑动窗口分析显示，SVR患者NS5AA2258-2306区氨基酸变异总数显著高于非SVR患者(P=0.006，P=0.0006)。多因素分析显示核心AA110(p=0.02)、NS5A AA2258-2306(p=0.03)和累积RBV剂量(p=0.02)是影响最终结果的独立变量。结论2a型丙型肝炎病毒感染者的核心和NS5A区变异显著影响了聚乙二醇干扰素/RBV治疗的疗效。
Purpose A proportion of patients infected with genotype 2a hepatitis C virus (HCV) cannot achieve a sustained virological response (SVR) to pegylated-interferon plus ribavirin therapy (PEG-IFN/RBV) but the reason remains unclear. The present study aimed to clarify the possible correlation between viral sequence variations and final outcome.Methods The pretreatment complete open reading frame (ORF) sequences of genotype 2a HCV were determined by direct sequencing for two independent groups of patients (43 patients as test; group 1 and 35 as validation; group 2), and the correlation with the final outcome was explored.Results Patients with SVR (n = 58) and with non-SVR (n = 20) differed significantly in pretreatment HCV RNA level (p = 0.002), fibrosis score (p = 0.047), and cumulative RBV dosage (p = 0.003). By comparison of all amino acid positions in the complete HCV ORFs, threonine at amino acid (aa) 110 in the core region was remarkably frequent in SVR (p = 0.01 for group 1, p = 0.004 for group 2, and p = 5E-05 for combined). A sliding window analysis revealed that the total number of amino acid variations within the NS5A aa 2258-2306 region were significantly high in SVR compared to non-SVR patients (p = 0.01 for group 1, p = 0.006 for group 2, and p = 0.0006 for combined). Multivariate analyses revealed that core aa 110 (p = 0.02), NS5A aa 2258-2306 (p = 0.03), and cumulative RBV dosage (p = 0.02) were identified as independent variables associated with the final outcome.Conclusions The outcome of PEG-IFN/RBV therapy is significantly influenced by variation in the core and NS5A regions in genotype 2a HCV infection.