Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Clin Pharmacol Ther. 2014 Jun;95(6):627-35. doi: 10.1038/clpt.2014.20. Epub 2014 Jan 31.
Using hepatitis C virus (HCV) and interferon (IFN) resistance as a proof of concept, we have devised a new method for calculating the effect of a drug on a viral population, as well as the resistance of the population's individual intrahost variants. By means of next-generation sequencing, HCV variants were obtained from sera collected at nine time points from 16 patients during the first 48 h after injection of IFN-α. IFN-resistance coefficients were calculated for individual variants using changes in their relative frequencies, and for the entire intrahost viral population using changes in viral titer. Population-wide resistance and presence of IFN-resistant variants were highly associated with pegylated IFN-α2a/ribavirin treatment outcome at week 12 (P = 3.78 × 10(-5) and 0.0114, respectively). This new method allows an accurate measurement of resistance based solely on changes in viral titer or the relative frequency of intrahost viral variants during a short observation time.
利用丙型肝炎病毒（HCV）和干扰素（IFN）耐药性作为概念验证，我们设计了一种新方法来计算药物对病毒群体以及该群体个体宿主内变异体的耐药性的影响。通过下一代测序，从 16 名患者在 IFN-α 注射后 48 小时内的 9 个时间点采集的血清中获得 HCV 变异体。使用相对频率的变化为个体变异体计算 IFN 耐药系数，并使用病毒滴度的变化为整个宿主内病毒群体计算 IFN 耐药系数。整个病毒群体的耐药性和 IFN 耐药变异体的存在与聚乙二醇化 IFN-α2a/利巴韦林治疗 12 周时的结果高度相关（P=3.78×10(-5)和 0.0114，分别）。这种新方法仅基于短观察时间内病毒滴度或宿主内病毒变异体相对频率的变化，就可以准确测量耐药性。
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