Reay Riaan, Dandara Collet, Viljoen Michelle, Rheeders Malie
1 Division of Pharmacology, Centre of Excellence for Pharmaceutical Sciences (Pharmacen), North-West University , Potchefstroom, South Africa .
2 Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
OMICS. 2017 Aug;21(8):465-473. doi: 10.1089/omi.2017.0078.
South Africa has the highest burden of the human immunodeficiency virus (HIV) infection globally. Efavirenz (EFV), a frequently used drug against HIV infection, displays a relationship between drug concentration and pharmacodynamics effects clinically. However, haplotype-based genetic variation in drug metabolism in a pediatric sample has been little considered in a longitudinal long-term context. CYP2B6 plays a key role in variation of EFV plasma concentration through altered drug metabolism. We report here on a prospective clinical pharmacogenomics/pharmacokinetic study of Bantu-speaking children, importantly, over a period of 24 months post-initiation of EFV-based treatment in South Africa. We characterized the HIV-1-infected children (n = 60) for the CYP2B6 c.516G>T, c.785A>G, c.983T>C, and c.1459C>T single nucleotide polymorphisms (SNPs). These SNPs were determined using polymerase chain reaction/restricted fragment length polymorphism and SNaPshot genotyping. Longitudinal mid-dose EFV plasma concentrations were determined by LC-MS/MS and association analyses with genotypes and haplotypes at 1, 3, and 24 months were performed. The CYP2B6 c.516T/T genotype showed significantly higher EFV plasma concentrations (p < 0.001) compared to non 516T-allele carriers at all three time points. The minor allele frequencies (MAF) for CYP2B6 c.516T, c.785G, c.983C, and c.1459T were 0.410, 0.408, 0.110, and 0.000 respectively. Haplotypes were constructed using CYP2B6 c.516G>T,-c.785A>G and c.983T>C. The haplotype T-G-T presented with significantly increased EFV plasma concentrations compared to the reference G-A-T haplotype at 1, 3, and 24 months (p = 0.009; p = 0.003; p = 0.001), suggesting that the T-G-T haplotype predisposes a risk of EFV plasma concentrations >4 μg/mL. The clinical implications of these pharmacogenomics observations for EFV toxicity and treatment resistance warrant further future research.
南非是全球人类免疫缺陷病毒（HIV）感染负担最高的国家。依法韦仑（EFV）是一种常用的抗HIV感染药物，临床上显示出药物浓度与药效学效应之间的关系。然而，在长期纵向研究中，很少考虑儿科样本中基于单倍型的药物代谢基因变异。CYP2B6通过改变药物代谢在EFV血浆浓度变异中起关键作用。我们在此报告一项针对讲班图语儿童的前瞻性临床药物基因组学/药代动力学研究，重要的是，该研究在南非开始基于EFV的治疗后的24个月内进行。我们对60名HIV-1感染儿童的CYP2B6基因c.516G>T、c.785A>G、c.983T>C和c.1459C>T单核苷酸多态性（SNP）进行了特征分析。这些SNP通过聚合酶链反应/限制性片段长度多态性和SNaPshot基因分型来确定。通过液相色谱-串联质谱法测定纵向中剂量EFV血浆浓度，并在1、3和24个月时进行基因型和单倍型的关联分析。在所有三个时间点，CYP2B6基因c.516T/T基因型的EFV血浆浓度均显著高于非516T等位基因携带者（p<0.001）。CYP2B6基因c.516T、c.785G、c.983C和c.1459T的次要等位基因频率（MAF）分别为0.410、0.408、0.110和0.000。使用CYP2B6基因c.516G>T、c.785A>G和c.983T>C构建单倍型。在1、3和24个月时，单倍型T-G-T的EFV血浆浓度相比参考单倍型G-A-T显著升高（p=0.009；p=0.003；p=0.001），表明T-G-T单倍型易导致EFV血浆浓度>4μg/mL的风险。这些药物基因组学观察结果对EFV毒性和治疗耐药性的临床意义值得未来进一步研究。
