Exploring resistance pathways for first-generation NS3/4A protease inhibitors boceprevir and telaprevir using Bayesian network learning
Exploring resistance pathways for first-generation NS3/4A protease inhibitors boceprevir and telaprevir using Bayesian network learning
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DOI：
10.1016/j.meegid.2017.05.007
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发表时间：
2017-09-01
影响因子：
3.2
通讯作者：
Vandamme, Anne-Mieke
中科院分区：
文献类型：
--
作者：
Cuypers, Lize;Libin, Pieter;Vandamme, Anne-Mieke
耐药相关变异体（RAV）已被证明会影响对直接作用抗病毒药（DAA）和第一代NS 3/4A蛋白酶抑制剂（PI）的治疗反应。丙型肝炎病毒（HCV）基因型耐药性的解释仍然是一个挑战，特别是在既往DAA治疗失败，需要重新治疗第二个DAA为基础的方案的患者。贝叶斯网络（BN）对接受DAA治疗的患者的HCV序列数据的学习可以提供对HCV亚型1a和1b的PI耐药途径的见解，与之前应用于HIV的方式类似。开发了公开可用的“Rega-BN”工具链，以研究各种病原体的关联分析。我们的第一个分析，比较来自PI-初治和PI-经验丰富的患者的序列，确定NS 3取代R155 K和V36 M与HCV 1a感染患者的PI-暴露一起出现，并分别被定义为主要和次要耐药相关变异。NS 3变体174 H新鉴定为可能与PI抗性相关。在第二项分析中，比较了来自在PI治疗期间清除病毒的PI初治患者和来自PI治疗失败的PI初治患者的NS 3序列，表明NS 3基线变体67 S倾向于治疗失败，而变体72 I倾向于治疗成功。如果有足够的治疗注释序列数据在策划的公共数据库中可用，这种方法有可能更好地表征更多RAV的作用。此外，可以使用这种方法鉴定使患者易于治疗失败的基线序列中存在的多态性。(c)2017爱思唯尔B. V.保留所有权利。
Resistance-associated variants (RAVs) have been shown to influence treatment response to direct-acting antivirals (DAAs) and first generation NS3/4A protease inhibitors (PIs) in particular. Interpretation of hepatitis C virus (HCV) genotypic drug resistance remains a challenge, especially in patients who previously failed DAA therapy and need to be retreated with a second DAA based regimen. Bayesian network (BN) learning on HCV sequence data from patients treated with DAAs could provide insight in resistance pathways against PIs for HCV subtypes 1a and 1b, in a similar way as applied before for HIV. The publicly available 'Rega-BN' tool chain was developed to study associative analyses for various pathogens. Our first analysis, comparing sequences from PI-naive and PI-experienced patients, determined that NS3 substitutions R155K and V36M arise with PI-exposure in HCV1a infected patients, and were defined as major and minor resistance-associated variants respectively. NS3 variant 174H was newly identified as potentially related to PI resistance. In a second analysis, NS3 sequences from PI-naive patients who cleared the virus during PI therapy and from PI-naive patients who failed PI therapy were compared, showing that NS3 baseline variant 67S predisposes to treatment-failure and variant 72I to treatment success. This approach has the potential to better characterize the role of more RAVs, if sufficient therapy annotated sequence data becomes available in curated public databases. In addition, polymorphisms present in baseline sequences that predispose patients to therapy failure can be identified using this approach. (c) 2017 Elsevier B.V. All rights reserved.