Mutations in the NS5B region of the hepatitis C virus genome correlate with clinical outcomes of interferon-alpha plus ribavirin combination therapy
Mutations in the NS5B region of the hepatitis C virus genome correlate with clinical outcomes of interferon-alpha plus ribavirin combination therapy
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DOI：
10.1111/j.1440-1746.2005.04024.x
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发表时间：
2005-09-01
影响因子：
4.1
通讯作者：
Watanabe, M
中科院分区：
文献类型：
--
作者：
Hamano, K;Sakamoto, N;Watanabe, M
背景和目的：干扰素-α (IFN) 和利巴韦林 (RBV) 联合治疗丙型肝炎病毒 (HCV) 感染比单独使用 IFN 更有效。然而，联合疗法的作用机制尚不清楚。为了阐明 IFN 联合 RBV 联合治疗的病毒遗传基础，我们对 HCV-1b 的遗传变异进行了分析。 方法：我们对 IFN 联合 RBV 治疗开始前后三名患者血清中的全长 HCV 基因组序列进行了两两比较。随后，我们分析了编码病毒 RNA 依赖性 RNA 聚合酶的 NS5B 区域的氨基酸序列，并将其与 81 名患者的治疗结果进行了比较。 结果：对接受 IFN 加 RBV 治疗的患者的整个 HCV 序列进行分析，未发现治疗开始前后的氨基酸变化一致。 NS5B 序列分析显示，与表现出无反应 (NR) 的患者组相比，表现出持续病毒反应 (SVR) 或治疗结束反应 (ETR) 的患者组中，NS5B 第 300-358 位的突变（包括聚合酶基序 B 到 E）更频繁地发生。仔细检查发现，SVR 加 ETR 组中 NS5B 氨基酸 309、333、338 和 355 的突变发生频率显着高于 NR 组（P = 0.0004）。多变量分析表明，这四个位点的突变数量是 SVR 加 ETR 与 NR 的独立预测因素。结论：HCV NS5B 区域的特定氨基酸变化可能与 IFN 加 RBV 联合治疗的结果相关。 (C) 2005 年布莱克威尔出版亚洲有限公司。
Background and Aim: Combination treatments of interferon-alpha (IFN) and ribavirin (RBV) are more effective than those of IFN alone in hepatitis C virus (HCV) infection. However, mechanisms of the action of the combination regimen are not well understood. To elucidate the viral genetic basis of IFN plus RBV combination therapy, genetic variabilities of HCV-1b were analyzed.Methods: We performed pair-wise comparisons of full-length HCV genomic sequences in three patients' sera before and after initiation of IFN plus RBV treatment. Subsequently, we analyzed amino acid sequences of the NS5B region, which codes for the viral RNA-dependent RNA polymerase, and compared these with the outcomes of the therapy in 81 patients.Results: Analysis of the entire HCV sequence in patients who received IFN plus RBV therapy did not show consistent amino acid changes between before and after the initiation of the therapy. NS5B sequence analyses revealed that mutations at positions 300-358 of NS5B, including polymerase motif B to E, occurred more frequently in a group of patients exhibiting a sustained viral response (SVR) or an end-of-treatment response (ETR) compared with a group of patients exhibiting a non-response (NR). Closer examination revealed that mutations at aa 309, 333, 338 and 355 of NS5B occurred significantly more frequently in the SVR plus ETR group than in the NR group (P = 0.0004). Multivariate analysis showed that the number of mutations at these four sites was an independent predictor of SVR plus ETR versus NR.Conclusions: Particular amino acid changes in the NS5B region of HCV may correlate with outcomes of IFN plus RBV combination therapy. (C) 2005 Blackwell Publishing Asia Pty Ltd.