Analysis of the Virological Response with Respect to Baseline Viral Phenotype and Genotype in Protease Inhibitor-Experienced HIV-1-Infected Patients Receiving Lopinavir/Ritonavir Therapy
Analysis of the Virological Response with Respect to Baseline Viral Phenotype and Genotype in Protease Inhibitor-Experienced HIV-1-Infected Patients Receiving Lopinavir/Ritonavir Therapy
复制标题
接受洛匹那韦/利托那韦治疗的经历过蛋白酶抑制剂的 HIV-1 感染患者的基线病毒表型和基因型的病毒学反应分析
作者：
D. Kempf;J. Isaacson;M. King;S. Brun;J. Sylte;Bruce Richards;B. Bernstein;R. Rode;E. Sun
在接受洛匹那韦/利托那韦+依法韦仑和核苷类逆转录酶抑制剂治疗72周期间，检查了经历过多种蛋白酶抑制剂、非核苷类逆转录酶抑制剂初治、HIV-1感染受试者的病毒学应答（研究M98-957），包括基线病毒表型和基因型。使用“脱落作为删失”分析，分别在93%（25/27）、73%（11/15）和25%（2/8）的受试者中观察到血浆HIV RNA ≤400拷贝/ml，基线时对洛匹那韦的敏感性降低<10倍、10- 40倍和>40倍。此外，分别在91%（21/23）、71%（15/21）和33%（2/6）的基线洛匹那韦突变评分为0-5、6-7和≥8的受试者中观察到病毒学缓解。在72周内，基线分离株含有6个或更多蛋白酶抑制剂突变的所有病毒学失败受试者具有共同的基因型模式，突变位于82、54和10位，沿着出现蛋白酶中4个额外突变的中位数。然而，相同数量的具有相似基因型模式的受试者发生了病毒学应答。进一步分析显示，基线时对洛匹那韦的表型敏感性是预测该受试者亚组缓解的另一个协变量。在多变量分析中，基线对洛匹那韦的敏感性与每个检查时间点（第24、48和72周）的应答相关。这些结果为应用于洛匹那韦/利托那韦时表型和基因型耐药试验的临床相关解释提供了指导。
The virological response of multiple protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor-naive, HIV-1-infected subjects was examined with respect to baseline viral phenotype and genotype through 72 weeks of therapy with lopinavir/ritonavir plus efavirenz and nucleoside reverse transcriptase inhibitors (Study M98-957). Using a ‘dropouts as censored’ analysis, plasma HIV RNA ≤400 copies/ml was observed in 93% (25/27), 73% (11/15) and 25% (2/8) of subjects with <10-fold, 10- to 40-fold, and >40-fold reduced susceptibility to lopinavir at baseline, respectively. In addition, virological response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) of subjects with baseline lopinavir mutation score of 0–5, 6–7 and ≥8, respectively. Through 72 weeks, all subjects experiencing virological failure whose baseline isolates contained six or more protease inhibitor mutations had a common genotypic pattern, with mutations at positions 82, 54 and 10, along with a median of four additional mutations in protease. However, an equal number of subjects with a similar genotypic pattern experienced virological response. Further analysis revealed the baseline phenotypic susceptibility to lopinavir to be an additional covariate predicting response in this subset of subjects. In multivariate analyses, baseline susceptibility to lopinavir was associated with response at each time point examined (weeks 24, 48 and 72). These results provide guidance for clinically relevant interpretation of phenotypic and genotypic resistance tests when applied to lopinavir/ritonavir.