Dickinson Laura, Amin Janaki, Else Laura, Boffito Marta, Egan Deirdre, Owen Andrew, Khoo Saye, Back David, Orrell Catherine, Clarke Amanda, Losso Marcelo, Phanuphak Praphan, Carey Dianne, Cooper David A, Emery Sean, Puls Rebekah
Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
The Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia.
Clin Pharmacokinet. 2016 Jul;55(7):861-873. doi: 10.1007/s40262-015-0360-5.
ENCORE1 demonstrated non-inferiority of daily efavirenz 400 mg (EFV400) versus 600 mg (EFV600) to 96 weeks in treatment-naïve, HIV-infected adults but concerns regarding lower EFV400 concentrations remained. Therefore, relationships between EFV pharmacokinetics (PK) and key genetic polymorphisms with 96-week efficacy and safety were investigated.
Relationships between EFV PK parameters and single nucleotide polymorphisms (SNP; CYP2B6, CYP2A6, CYP3A4, NR1I3, NR1I2, ABCB1) with plasma HIV-RNA (pVL) <200 copies/mL and EFV discontinuation and adverse events at 96 weeks were explored. Receiver operating characteristic curve analysis evaluated the predictability of mid-dose interval (C12) cutoffs and 96-week pVL.
A total of 606 patients (32 % female; 37 % African, 33 % Asian; n = 311 EFV400, n = 295 EFV600) were included. EFV PK parameters, including C12, were not associated with pVL <200 copies/mL at 96 weeks (odds ratio [OR] 5.25, 95 % confidence interval [CI] 0.41-67.90, p = 0.204). Lower risk of CNS-related adverse events was associated with CYP2B6 983TC/CC (OR 0.35, 95 % CI 0.15-0.81, p = 0.015) and higher risk was associated with CYP2B6 15582CT/TT and ABCB1 3435TT (OR 1.46, 95 % CI 1.02-2.09, p = 0.040; OR 2.31, 95 % CI 1.33-4.02, p = 0.003, respectively). Discontinuation due to adverse events (clinician decision) was independently associated with dose (OR 2.54, 95 % CI 1.19-5.43, p = 0.016). C12 between 0.47 and 0.76 mg/L provided sensitivity/specificity >90 % (100 %/92.3 to 98.9 %/92.3 %) for achieving pVL <200 copies/mL at 96 weeks.
A higher rate of EFV-related adverse events and discontinuations due to these events for EFV600 were not driven by polymorphisms assessed. Although a single threshold concentration associated with HIV suppression may be clinically useful, it was not viable for ENCORE1. Implementation of EFV400 would improve toxicity management whilst still maintaining good efficacy.
在初治的HIV感染成人中，ENCORE1研究表明，每日400mg依非韦伦（EFV400）与600mg依非韦伦（EFV600）相比，至96周时具有非劣效性，但对EFV400浓度较低仍存在担忧。因此，研究了依非韦伦药代动力学（PK）与关键基因多态性之间的关系，以及它们与96周疗效和安全性的关系。
探讨了依非韦伦PK参数与单核苷酸多态性（SNP；CYP2B6、CYP2A6、CYP3A4、NR1I3、NR1I2、ABCB1）与血浆HIV-RNA（pVL）<200拷贝/mL以及96周时依非韦伦停药和不良事件之间的关系。采用受试者工作特征曲线分析评估中剂量间隔（C12）截断值和96周pVL的预测能力。
共纳入606例患者（32%为女性；37%为非洲人，33%为亚洲人；n = 311例EFV400，n = 295例EFV600）。依非韦伦PK参数，包括C12，与96周时pVL<200拷贝/mL无关（比值比[OR]5.25，95%置信区间[CI]0.41 - 67.90，p = 0.204）。CYP2B6 983TC/CC与中枢神经系统相关不良事件风险较低相关（OR 0.35，95%CI 0.15 - 0.81，p = 0.015），而CYP2B6 15582CT/TT和ABCB1 3435TT与较高风险相关（OR分别为1.46，95%CI 1.02 - 2.09，p = 0.040；OR 2.31，95%CI 1.33 - 4.02，p = 0.003）。因不良事件（临床医生决定）停药与剂量独立相关（OR 2.54，95%CI 1.19 - 5.43，p = 0.016）。C12在0.47至0.76mg/L之间对于96周时实现pVL<200拷贝/mL具有>90%的敏感性/特异性（100%/92.3%至98.9%/92.3%）。
EFV60XX年的1月1日，EFV相关不良事件及因这些事件导致的停药发生率较高并非由所评估的多态性所致。尽管与HIV抑制相关的单一阈值浓度在临床上可能有用，但对于ENCORE1研究而言并不可行。采用EFV400可改善毒性管理，同时仍能维持良好疗效。
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