Haas David W, Kwara Awewura, Richardson Danielle M, Baker Paxton, Papageorgiou Ioannis, Acosta Edward P, Morse Gene D, Court Michael H
Vanderbilt University School of Medicine, Nashville, TN, USA
Warren Alpert Medical School of Brown University, Providence, RI, USA.
J Antimicrob Chemother. 2014 Aug;69(8):2175-82. doi: 10.1093/jac/dku110. Epub 2014 Apr 11.
Efavirenz is widely prescribed for HIV-1 infection, and CYP2B6 polymorphisms 516G→T and 983T→C define efavirenz slow metabolizer genotypes. To identify genetic predictors of higher plasma efavirenz concentrations beyond these two common functional alleles, we characterized associations with mid-dosing interval efavirenz concentrations in 84 HIV-infected adults, all carrying two copies of these major loss-of-function CYP2B6 alleles.
Study participants had been randomized to efavirenz-containing regimens in prospective clinical trials and had available plasma efavirenz assay data. Analyses focused on secondary metabolism pathway polymorphisms CYP2A6 -48T→G (rs28399433), UGT2B7 735A→G (rs28365062) and UGT2B7 802T→C (rs7439366). Exploratory analyses also considered 196 polymorphisms and 8 copy number variants in 41 drug metabolism/transport genes. Mid-dosing interval efavirenz concentrations at steady-state were obtained ≥8 h but <19 h post-dose. Linear regression was used to test for associations between polymorphisms and log-transformed efavirenz concentrations.
Increased efavirenz concentrations were associated with CYP2A6 -48T→G in all subjects (P = 3.8 × 10(-4)) and in Black subjects (P = 0.027) and White subjects (P = 0.0011) analysed separately; and with UGT2B7 735 G/G homozygosity in all subjects (P = 0.006) and in Black subjects (P = 0.046) and White subjects (P = 0.062) analysed separately. In a multivariable model, CYP2A6 -48T→G and UGT2B7 735 G/G homozygosity remained significant (P < 0.05 for each). No additional polymorphisms or copy number variants were significantly associated with efavirenz concentrations.
Among individuals with a CYP2B6 slow metabolizer genotype, CYP2A6 and possibly UGT2B7 polymorphisms contribute to even higher efavirenz concentrations.
依法韦仑被广泛用于治疗HIV-1感染，CYP2B6基因多态性516G→T和983T→C可定义依法韦仑慢代谢基因型。为了确定除这两个常见功能等位基因外可预测血浆依法韦仑浓度升高的遗传因素，我们对84名HIV感染成人中剂量间隔期依法韦仑浓度的相关因素进行了特征分析，所有受试者均携带两份这些主要的功能缺失型CYP2B6等位基因。
研究参与者在前瞻性临床试验中被随机分配至含依法韦仑的治疗方案，且有可用的血浆依法韦仑检测数据。分析集中于二级代谢途径多态性CYP2A6 -48T→G（rs28399433）、UGT2B7 735A→G（rs28365062）和UGT2B7 802T→C（rs7439366）。探索性分析还考虑了41个药物代谢/转运基因中的196个多态性和8个拷贝数变异。在给药后≥8小时但<19小时时获得稳态下的中剂量间隔期依法韦仑浓度。采用线性回归检验多态性与依法韦仑浓度对数转换值之间的相关性。
依法韦仑浓度升高与所有受试者中的CYP2A6 -48T→G相关（P = 3.8×10⁻⁴），在单独分析的黑人受试者中（P = 0.027）和白人受试者中（P = 0.0011）也相关；在所有受试者中（P = 0.006）以及在单独分析的黑人受试者中（P = 0.046）和白人受试者中（P = 0.062）与UGT2B7 735 G/G纯合性相关。在多变量模型中，CYP2A6 -48T→G和UGT2B7 735 G/G纯合性仍然显著（各P < 0.05）。没有其他多态性或拷贝数变异与依法韦仑浓度显著相关。
在CYP2B6慢代谢基因型个体中，CYP2A6以及可能的UGT2B7多态性导致依法韦仑浓度更高。
