Mutations associated with virological response to darunavir/ritonavir in HIV-1-infected protease inhibitor-experienced patients
Mutations associated with virological response to darunavir/ritonavir in HIV-1-infected protease inhibitor-experienced patients
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DOI：
10.1093/jac/dkn544
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发表时间：
2009-03-01
影响因子：
5.2
通讯作者：
Brun-Vezinet, Francoise
中科院分区：
文献类型：
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作者：
Descamps, Diane;Lambert-Niclot, Sidonie;Brun-Vezinet, Francoise
该研究的目的是确定与达芦那韦/利托那韦治疗方案的病毒学反应相关的蛋白酶基因突变模式。我们分析了 153 名接受达芦那韦/利托那韦挽救方案作为唯一蛋白酶抑制剂 (PI) 的有治疗经验的患者。病毒学应答定义为第 3 个月时 HIV-1 RNA 载量 < 200 拷贝/mL。检查了单个蛋白酶基因突变对达芦那韦/利托那韦病毒学应答的影响，并确定了与病毒学应答最密切相关的突变组合。基线中位 HIV RNA 水平为 4.7 log10 拷贝/mL，中位 CD4 细胞计数为 142 个细胞/mm3。第 3 个月，55% 的患者出现病毒学应答，病毒载量较基线下降的中位数为 1.7 log10 拷贝/mL。所有患者在第 3 个月时均检测到达芦那韦浓度。Cochran-Armitage 程序鉴定出 8 个对病毒学反应有负面影响的突变，即 K14R、K20I、E34Q、I47V、I54M、K55R、T74P 和 I84V；两个突变（E35D 和 V82A）具有积极影响。在多变量分析中，我们的基因型评分高度预测第3个月的病毒学反应，以及基线血浆病毒载量和恩夫韦肽首次使用患者的恩夫韦肽联合处方。在对病毒学反应有负面影响的八个突变中，I47V、I54M、T74P和I84V先前被描述为达芦那韦耐药相关突变。一些 PI 耐药突变对病毒学反应有积极影响。这些发现可能有助于解释达芦那韦/利托那韦对 PI 耐药 HIV 的功效。
The aim of the study was to identify a pattern of protease gene mutations associated with the virological response to darunavir/ritonavir-based regimens.We analysed 153 treatment-experienced patients receiving a darunavir/ritonavir salvage regimen as a sole protease inhibitor (PI). Virological response was defined as an HIV-1 RNA load of < 200 copies/mL at month 3. The impact of individual protease gene mutations on the virological response to darunavir/ritonavir was examined, and the combination of mutations most strongly associated with the virological response was identified.The baseline median HIV RNA level was 4.7 log10 copies/mL and the median CD4 cell count was 142 cells/mm3. At month 3, 55% of patients had a virological response and the median fall in viral load from baseline was 1.7 log10 copies/mL. All the patients had detectable darunavir concentrations at month 3. Cochran-Armitage procedure identified eight mutations with a negative impact on the virological response, namely K14R, K20I, E34Q, I47V, I54M, K55R, T74P and I84V; and two mutations (E35D and V82A) with a positive impact. In multivariate analyses, our genotypic scores were highly predictive of the virological response at month 3, along with the baseline plasma viral load and enfuvirtide co-prescription to enfuvirtide-naive patients.Among the eight mutations with a negative impact on the virological response, I47V, I54M, T74P and I84V were previously described as darunavir resistance-associated mutations. Some PI resistance mutations had a positive impact on the virological response. These findings might help to explain the potency of darunavir/ritonavir on PI-resistant HIV.