Oluka Margaret Ngwono, Okalebo Faith Apolot, Guantai Anastasia Nkatha, McClelland R Scott, Graham Susan M
Department of Pharmacology and Pharmacognosy, University of Nairobi, P.O. BOX 19498, Nairobi, 00202 Kenya.
Departments of Medicine, Global Health, and Epidemiology, University of Washington, Seattle, USA and Institute of Tropical and Infectious Diseases, University of Nairobi, Nairobi, Kenya.
AIDS Res Ther. 2015 Apr 15;12:10. doi: 10.1186/s12981-015-0052-0. eCollection 2015.
Polymorphisms in cytochrome P450 2B6 (CYP2B6) affect the steady state plasma concentration of nevirapine. CYP2B6 516G>T and 983T>C are common in African populations, but data on their influence on plasma nevirapine concentration and clinical response in African women are limited. We investigated the impact of CYP 516G>T and 983T>C on plasma nevirapine concentration and clinical outcomes in a prospective cohort study of HIV-infected Kenyan women.
Study subjects were 66 HIV-1-seropositive women taking nevirapine-based antiretroviral therapy. Plasma collected at week 12 was analyzed for nevirapine concentration by high performance liquid chromatography. Baseline samples were genotyped for CYP2B6 516G>T and 983T>C single nucleotide polymorphisms by real-time polymerase chain reaction. CD4 cell count, plasma viral load, and genotypic drug resistance in plasma and genital secretions were assessed at baseline and during follow up. We evaluated the effect of each genotype on plasma nevirapine concentration at week 12 and on change in CD4 cell count at months 3, 6 and 12. Associations between plasma nevirapine concentration and clinical outcomes were analyzed by logistic or linear regression.
Women with CYP2B6 516TT genotype (n=9) had higher mean nevirapine plasma levels (14.33 μg/mL) compared to those with heterozygous 516GT (9.18 μg/mL; n=25) and wild- type 516GG (7.95 μg/mL; n=32) genotypes (P=0.01). Women heterozygous for the CYP2B6 983TC genotype (n=13) had higher mean nevirapine plasma levels (12.94 μg/mL), compared to women with the homozygous 983TT (8.35 μg/mL; n=53) genotype (P=0.007). In Generalized Estimating Equation analysis, plasma nevirapine levels predicted greater change in CD4 cell count after ART initiation (adjusted beta 119.4 cells/μL, 95% CI, 27.3-211.5 cells/μL, P=0.01). The CYP2B6 983TT genotype also predicted greater change in CD4 cell count (adjusted beta 68.6 cells/μL, 95% CI, 3.9-133.4 cells/μL, P=0.04). We found no associations between CYP2B6 genotypes and virologic response or toxicity.
CYP2B6 516G>T and CYP2B6 983T>C genotypes were strongly associated with plasma nevirapine concentration, which predicted immunologic response in women on nevirapine-based antiretroviral therapy. These data support continued work on the potential utility of human genetic testing to inform nevirapine dosage optimization for individual patients.
细胞色素P450 2B6（CYP2B6）基因多态性会影响奈韦拉平的稳态血药浓度。CYP2B6 516G>T和983T>C在非洲人群中很常见，但关于它们对非洲女性血浆奈韦拉平浓度及临床反应影响的数据有限。我们在一项针对感染HIV的肯尼亚女性的前瞻性队列研究中，调查了CYP 516G>T和983T>C对血浆奈韦拉平浓度及临床结局的影响。
研究对象为66名接受以奈韦拉平为基础的抗逆转录病毒治疗的HIV-1血清阳性女性。采用高效液相色谱法分析第12周采集的血浆中的奈韦拉平浓度。通过实时聚合酶链反应对基线样本进行CYP2B6 516G>T和983T>C单核苷酸多态性基因分型。在基线和随访期间评估CD4细胞计数、血浆病毒载量以及血浆和生殖道分泌物中的基因型耐药情况。我们评估了每种基因型对第12周时血浆奈韦拉平浓度以及第3、6和12个月时CD4细胞计数变化的影响。通过逻辑回归或线性回归分析血浆奈韦拉平浓度与临床结局之间的关联。
与携带杂合子516GT（9.18μg/mL；n = 25）和野生型516GG（7.95μg/mL；n = 32）基因型的女性相比，携带CYP2B6 516TT基因型（n = 9）的女性的奈韦拉平血浆平均水平更高（14.33μg/mL）（P = 0.01）。与携带纯合子983TT（8.35μg/mL；n = 53）基因型的女性相比，携带CYP2B6 983TC基因型杂合子（n = 13）的女性的奈韦拉平血浆平均水平更高（12.94μg/mL）（P = 0.007）。在广义估计方程分析中；血浆奈韦拉平水平预示着抗逆转录病毒治疗开始后CD4细胞计数有更大变化（校正β值为119.4细胞/μL，95%可信区间为27.3 - 211.5细胞/μL，P = 0.01）。CYP2B6 983TT基因型也预示着CD4细胞计数有更大变化（校正β值为68.6细胞/μL，95%可信区间为3.9 - 133.4细胞/μL，P = 0.04）。我们未发现CYP2B6基因型与病毒学反应或毒性之间存在关联。
CYP2B6 516G>T和CYP
