Haas David W, Severe Patrice, Jean Juste Marc Antoine, Pape Jean William, Fitzgerald Daniel W
Vanderbilt University School of Medicine, Nashville, TN, USA
GHESKIO Centers, Port-au-Prince, Haiti.
J Antimicrob Chemother. 2014 Aug;69(8):2187-90. doi: 10.1093/jac/dku088. Epub 2014 Apr 2.
Efavirenz is widely prescribed for HIV-1 infection. Three polymorphisms in CYP2B6 define plasma efavirenz trough concentration strata that vary across an ∼10-fold range. We characterized associations between human genetic polymorphisms and virologic response among participants who received efavirenz-containing regimens in a prospective clinical trial.
We genotyped 76 polymorphisms in CYP2B6 (including those that define efavirenz concentration strata), CYP2A6, CYP3A4, CYP3A5 and ABCB1 and week 48 virologic responses in 360 Haitians who initiated efavirenz-containing regimens in protocol HT 001. Associations were characterized by logistic regression analysis and Fisher's exact test.
Proportions with HIV-1 RNA <50 or <200 copies/mL did not differ across 10 CYP2B6 metabolizer strata. In analyses that combined strata into three metabolizer levels (extensive, intermediate and slow), the respective proportions were 0.79, 0.79 and 0.81 (<50 copies/mL cut-off) and 0.84, 0.86 and 0.87 (<200 copies/mL cut-off). Genetic associations were not identified after controlling for baseline variables or with other polymorphisms after adjusting for multiple comparisons.
Virologic failures in HT 001 were not explained by genetic polymorphisms known to define the lowest plasma efavirenz concentration stratum.
依法韦仑被广泛用于治疗HIV-1感染。细胞色素P450 2B6（CYP2B6）基因的三种多态性决定了血浆中依法韦仑谷浓度的分层，其变化范围约为10倍。在一项前瞻性临床试验中，我们对接受含依法韦仑治疗方案的参与者的人类基因多态性与病毒学反应之间的关联进行了特征分析。
我们对参与HT 001方案并开始接受含依法韦仑治疗方案的360名海地人的CYP2B6基因（包括那些决定依法韦仑浓度分层的基因）、CYP2A6、CYP3A4、CYP3A5和ABCB1基因的76种多态性以及第48周的病毒学反应进行了基因分型。通过逻辑回归分析和Fisher精确检验对关联进行特征分析。
在10种CYP2B6代谢型分层中，HIV-1 RNA<50或<200拷贝/毫升的比例没有差异。在将分层合并为三种代谢型水平（快代谢型、中间代谢型和慢代谢型）的分析中，相应比例分别为0.79、0.79和0.81（<50拷贝/毫升临界值）以及0.84、0.86和0.87（<200拷贝/毫升临界值）。在控制基线变量后或在进行多重比较校正后，未发现与其他多态性的基因关联。
HT 001试验中的病毒学失败不能用已知决定最低血浆依法韦仑浓度分层的基因多态性来解释。
