Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
Clin Transl Sci. 2021 Nov;14(6):2521-2531. doi: 10.1111/cts.13120. Epub 2021 Aug 20.
Papua New Guinea (PNG) has a high HIV/AIDS prevalence and very high frequency of the CYP2B6 c.516G>T (rs3745274) variant. We have conducted the first investigation of the impact of c.516G>T and patient demographics on plasma efavirenz (EFV) and 8-hydroxyefavirenz (8OH-EFV) concentrations, metabolic ratio (8OH-EFV/EFV) (MR), and their association with adverse effects, in PNG patients with HIV/AIDS. For 156 PNG patients with HIV/AIDS taking EFV 600 mg/day (for 3-156 months), plasma EFV and 8OH-EFV concentrations were quantified, CYP2B6 c.516G>T genotyped, and demographic and self-reported adverse effects data recorded. Genotype differences in EFV and 8OH-EFV concentrations, MR, and percent within therapeutic range (1000-4000 ng/ml) were examined, in addition to EFV and 8OH-EFV concentration differences between patients experiencing adverse effects. CYP2B6 c.516T allele frequency was 53%. Plasma EFV (p < 0.0001), 8OH-EFV (p < 0.01), and MR (p < 0.0001) differed significantly between genotypes, with genotype explaining 38%, 10%, and 50% of variability, respectively. Plasma EFV concentrations were significantly higher in T/T (median = 5168 ng/ml) than G/G (1036 ng/ml, post hoc p < 0.0001) and G/T (1502 ng/ml, p < 0.0001) genotypes, with all patients above therapeutic range (n = 23) being T/T genotype (p < 0.0001). EFV and 8OH-EFV concentrations were not significantly higher in patients experiencing adverse effects. In PNG HIV/AIDS population where the 516T frequency is very high, it explains a substantial portion of variability (38%) in EFV disposition; however, at least for the patients receiving EFV long term, this does not translate into significant side effects.
巴布亚新几内亚（PNG）艾滋病毒/艾滋病流行率高，细胞色素 P4502B6 c.516G>T（rs3745274）变异频率非常高。我们首次研究了 c.516G>T 及患者人口统计学特征对艾滋病毒/艾滋病患者体内依非韦伦（EFV）和 8-羟基依非韦伦（8OH-EFV）浓度、代谢比（8OH-EFV/EFV）（MR）的影响，以及这些因素与不良反应的相关性。对 156 名服用 EFV 600mg/天（3-156 个月）的巴布亚新几内亚艾滋病毒/艾滋病患者进行了研究，定量检测了患者体内 EFV 和 8OH-EFV 浓度，对 CYP2B6 c.516G>T 进行了基因分型，并记录了人口统计学特征和患者自述的不良反应数据。考察了 EFV 和 8OH-EFV 浓度、MR 以及治疗范围内（1000-4000ng/ml）百分率的基因型差异，还考察了有不良反应患者与无不良反应患者之间 EFV 和 8OH-EFV 浓度的差异。CYP2B6 c.516T 等位基因频率为 53%。EFV（p<0.0001）、8OH-EFV（p<0.01）和 MR（p<0.0001）的基因型差异具有统计学意义，分别解释了 38%、10%和 50%的变异性。T/T 基因型（中位值=5168ng/ml）的 EFV 浓度显著高于 G/G（1036ng/ml，事后检验 p<0.0001）和 G/T（1502ng/ml，p<0.0001）基因型，所有患者（n=23）均高于治疗范围，均为 T/T 基因型（p<0.0001）。有不良反应的患者 EFV 和 8OH-EFV 浓度没有显著升高。在 516T 频率非常高的巴布亚新几内亚艾滋病毒/艾滋病人群中，它解释了 EFV 处置中 38%的显著变异性；然而，至少对于长期接受 EFV 治疗的患者，这并没有转化为显著的副作用。
