Department of Chemical Pathology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2001, Republic of South Africa.
AIDS Res Ther. 2010 Aug 19;7:32. doi: 10.1186/1742-6405-7-32.
The 516G > T polymorphism in exon 4 of the CYP2B6 gene has been associated with increased plasma Efavirenz (EFV) concentrations. EFV concentrations greater than the recommended therapeutic range have been associated with the increased likelihood of developing adverse CNS effects. The aims of this study were to a) determine the presence of the 516G > T and other CYP2B6 exon 4 polymorphisms in a South African group of HIV-infected individuals b) investigate the relationship between the EFV plasma concentrations, the CYP2B6 516G > T polymorphism and the occurrence of CNS related side effects in this group of patients and c) develop and validate a rapid method for determination of EFV in plasma.
Data from 80 patients is presented. Genetic polymorphisms in exon 4 of the CYP2B6 gene were identified using PCR amplification of this region followed by sequencing of the amplification products. EFV concentrations were analysed by UPLC-MS/MS. Assessment of the presence of CNS related side effects following EFV initiation were elicited with the use of a questionnaire together with physical examination.
Plasma EFV concentrations displayed high inter-individual variability amongst subjects with concentrations ranging from 94 mug/l to 23227 mug/l at 2 weeks post initiation of treatment. For the 516G > T polymorphism the following frequencies were observed 23% of patients were TT homozygous, 36% GG and 41% GT. The TT homozygous patients had significantly higher EFV concentrations vs. those with the wild (GG) genotype (p < 0.05). Patients who experienced no side effects had significantly lower EFV plasma concentrations vs. the group of patients which experienced the most severe side effects (p < 0.05).
The significant association between the 516G > T polymorphism and plasma EFV concentrations has been demonstrated in this study. A rapid and sensitive method for the measurement of plasma EFV concentration was developed and validated.
CYP2B6 基因exon4 的 516G>T 多态性与依非韦伦（EFV）的血浆浓度升高有关。EFV 浓度超过推荐的治疗范围与发生 CNS 不良反应的可能性增加有关。本研究的目的是：a）确定南非 HIV 感染个体中 CYP2B6 exon4 多态性的存在；b）研究该组患者 EFV 血浆浓度、CYP2B6 516G>T 多态性与 CNS 相关不良反应发生的关系；c）开发和验证一种快速测定血浆中 EFV 的方法。
共纳入 80 例患者的数据。采用该区域的 PCR 扩增，然后对扩增产物进行测序，鉴定 CYP2B6 基因exon4 的遗传多态性。采用 UPLC-MS/MS 分析 EFV 浓度。使用问卷和体格检查评估 EFV 起始后 CNS 相关不良反应的发生情况。
治疗 2 周后，个体的 EFV 血浆浓度显示出高度的个体间变异性，浓度范围为 94μg/L 至 23227μg/L。对于 516G>T 多态性，观察到以下频率：23%的患者为 TT 纯合子，36%为 GG，41%为 GT。TT 纯合子患者的 EFV 浓度明显高于野生（GG）基因型（p<0.05）。未发生不良反应的患者的 EFV 血浆浓度明显低于发生最严重不良反应的患者（p<0.05）。
本研究证实了 516G>T 多态性与 EFV 血浆浓度之间的显著相关性。建立并验证了一种快速、灵敏的 EFV 血浆浓度测定方法。
