SLCO1B1 521T→C 与艾滋病临床试验组研究 A5146 中利托那韦增效蛋白酶抑制剂的血浆水平之间的不一致关联。
Discordant associations between SLCO1B1 521T→C and plasma levels of ritonavir-boosted protease inhibitors in AIDS clinical trials group study A5146.
机构信息
Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts, USA.
出版信息
Ther Drug Monit. 2013 Apr;35(2):209-16. doi: 10.1097/FTD.0b013e318280d0ad.
OBJECTIVE
Among HIV-positive patients prescribed ritonavir-boosted lopinavir, SLCO1B1 521T→C (rs4149056) is associated with increased plasma lopinavir exposure. Protease inhibitors (PIs) are also substrates for cytochrome P450 (CYP) 3A and ABCB1, which are induced by NR1I2. We characterized relationships between ABCB1, CYP3A4, CYP3A5, NR1I2, and SLCO1B1 polymorphisms and trough PI concentrations among AIDS Clinical Trials Group study A5146 participants.
METHODS
At study entry, subjects with virologic failure on PI-containing regimens initiated new ritonavir-boosted PI regimens. We studied associations between week 2 PI plasma trough concentrations and 143 polymorphisms in these genes, including 4 targeted polymorphisms.
RESULTS
Among 275 subjects with both drug concentrations and genetic data, allelic frequencies of SLCO1B1 521T→C were 15%, 1%, and 8% in whites, blacks, and Hispanics, respectively. Further analyses were limited to 268 white, black, or Hispanic subjects who initiated ritonavir-boosted lopinavir (n = 98), fosamprenavir (n = 69), or saquinavir (n = 99). Of targeted polymorphisms, SLCO1B1 521T→C tended to be associated with higher lopinavir concentrations, with a 1.38-fold increase in the mean per C allele (95% confidence interval, 0.97-1.96; n = 98; P = 0.07). With fosamprenavir, SLCO1B1 521T→C was associated with lower amprenavir concentrations, with a 35% decrease in the mean per C allele (geometric mean ratio 0.65; 95% confidence interval, 0.44-0.94; n = 69; adjusted P = 0.02). There was no significant association with saquinavir concentrations, and none of the remaining 139 exploratory polymorphisms were statistically significant after correcting for multiple comparisons.
CONCLUSIONS
With ritonavir-boosted PIs, a SLCO1B1 polymorphism that predicts higher lopinavir trough concentrations seems to predict lower amprenavir trough concentrations. The mechanism underlying this discordant association is uncertain.
目的
在接受利托那韦增强洛匹那韦治疗的 HIV 阳性患者中，SLCO1B1 521T→C（rs4149056）与血浆洛匹那韦暴露增加有关。蛋白酶抑制剂（PI）也是细胞色素 P450（CYP）3A 和 ABCB1 的底物，而 CYP3A 和 ABCB1 则受 NR1I2 诱导。我们描述了 ABCB1、CYP3A4、CYP3A5、NR1I2 和 SLCO1B1 多态性与 AIDS 临床试验组 A5146 参与者的 PI 谷浓度之间的关系。
方法
在研究开始时，接受含 PI 方案治疗但病毒学失败的患者开始了新的利托那韦增强 PI 方案。我们研究了这些基因中 143 个多态性与 PI 血浆谷浓度之间的关系，包括 4 个靶向多态性。
结果
在 275 名具有药物浓度和遗传数据的受试者中，SLCO1B1 521T→C 的等位基因频率分别为 15%、1%和 8%，分别在白人、黑人和西班牙裔中。进一步的分析仅限于 268 名白人、黑人和西班牙裔患者，他们开始服用利托那韦增强洛匹那韦（n = 98）、福沙那韦（n = 69）或沙奎那韦（n = 99）。在靶向多态性中，SLCO1B1 521T→C 与较高的洛匹那韦浓度有关，每个 C 等位基因的平均增加 1.38 倍（95%置信区间，0.97-1.96；n = 98；P = 0.07）。对于福沙那韦，SLCO1B1 521T→C 与较低的氨普那韦浓度相关，每个 C 等位基因的平均浓度降低 35%（几何平均比 0.65；95%置信区间，0.44-0.94；n = 69；调整后 P = 0.02）。与沙奎那韦浓度无显著相关性，其余 139 个探索性多态性在经过多次比较校正后均无统计学意义。
结论
在使用利托那韦增强的 PI 时，预测洛匹那韦谷浓度较高的 SLCO1B1 多态性似乎预测了氨普那韦谷浓度较低。这种不一致关联的机制尚不清楚。
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