Genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor tipranavir
Genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor tipranavir
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DOI：
10.1128/jvi.00712-06
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发表时间：
2006-11-01
影响因子：
5.4
通讯作者：
Mayers, Douglas L.
中科院分区：
文献类型：
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作者：
Baxter, John D.;Schapiro, Jonathan M.;Mayers, Douglas L.
替pranavir是一种新型的人类免疫缺陷病毒1型（HIV-1）的非肽类蛋白酶抑制剂，对来自治疗经验丰富的患者的临床HIV-1分离株具有活性。对有蛋白酶抑制剂经历的替普那韦II期和III期临床试验的HIV-1基因型和表型数据进行分析，以确定蛋白酶突变与降低对替普那韦的易感性和病毒学反应之间的关系。根据II期研究数据集的逐步多元回归分析，确定了特定的蛋白酶突变。验证包括对III期研究数据集的分析，以确定是否会选择相同的突变，并评估这些突变如何有助于替普那韦相关表型和病毒学反应的多元回归模型。根据这些分析，建立了替普那韦突变评分，该评分由16个蛋白酶位置和21个突变（10V、13V、20M/RN、33F、35G、36I、43T、46L、47V、54A/M/V、58E、69K、74P、82L/T、83D和84V）组成。HIV-1分离株显示越来越多的这些替普那韦耐药相关突变，对替普那韦的表型易感性和病毒学反应降低。在III期试验中预测病毒学反应的回归模型显示，在治疗第24周时，替普那韦评分的每一点都与0.16 log(10) copies/ml的低病毒学反应相关。替普那韦得分较低和背景方案中活性药物数量较多预示着病毒学成功。这些分析表明，替普那韦突变评分是预测蛋白酶抑制剂患者对替普那韦的病毒学反应的潜在有价值的工具。
Tipranavir is a novel, nonpeptidic protease inhibitor of human immunodeficiency virus type 1 (HIV-1) with activity against clinical HIV-1 isolates from treatment-experienced patients. HIV-1 genotypic and phenotypic data from phase II and III clinical trials of tipranavir with protease inhibitor-experienced patients were analyzed to determine the association of protease mutations with reduced susceptibility and virologic response to tipranavir. Specific protease mutations were identified based on stepwise multiple-regression analyses of phase II study data sets. Validation included analyses of phase III study data sets to determine if the same mutations would be selected and to assess how these mutations contribute to multiple-regression models of tipranavir-related phenotype and of virologic response. A tipranavir mutation score was developed from these analyses, which consisted of a unique string of 16 protease positions and 21 mutations (10V, 13V, 20M/RN, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, and 84V). HIV-1 isolates displaying an increasing number of these tipranavir resistance-associated mutations had a reduced phenotypic susceptibility and virologic response to tipranavir. Regression models for predicting virologic response in phase III trials revealed that each point in the tipranavir score was associated with a 0.16-log(10) copies/ml-lower virologic response to tipranavir at week 24 of treatment. A lower number of points in the tipranavir score and a greater number of active drugs in the background regimen were predictive of virologic success. These analyses demonstrate that the tipranavir mutation score is a potentially valuable tool for predicting the virologic response to tipranavir in protease inhibitor-experienced patients.