Gatanaga Hiroyuki, Hayashida Tsunefusa, Tsuchiya Kiyoto, Yoshino Munehiro, Kuwahara Takeshi, Tsukada Hiroki, Fujimoto Katsuya, Sato Isao, Ueda Mikio, Horiba Masahide, Hamaguchi Motohiro, Yamamoto Masahiro, Takata Noboru, Kimura Akiro, Koike Takao, Gejyo Fumitake, Matsushita Shuzo, Shirasaka Takuma, Kimura Satoshi, Oka Shinichi
AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan.
Clin Infect Dis. 2007 Nov 1;45(9):1230-7. doi: 10.1086/522175. Epub 2007 Sep 24.
Efavirenz (EFV) is metabolized primarily by cytochrome P450 2B6 (CYP2B6), and high plasma concentrations of the drug are associated with a G-->T polymorphism at position 516 (516G-->T) of CYP2B6 and frequent central nervous system (CNS)-related side effects. Here, we tested the feasibility of genotype-based dose reduction of EFV.
CYP2B6 genotypes were determined in 456 human immunodeficiency virus type 1 (HIV-1)-infected patients who were receiving EFV treatment or were scheduled to receive EFV-containing treatment. EFV dose was reduced in CYP2B6 516G-->T carriers who had high plasma EFV concentrations while receiving the standard dosage (600 mg). EFV-naive homozygous CYP2B6 516G-->T carriers were treated with low-dose EFV. In both groups, the dose was further reduced when plasma EFV concentration remained high.
CYP2B6 516G-->T was identified in the *6 allele (found in 17.9% of our subjects) and a novel allele, *26 (found in 1.3% of our patients). All EFV-treated CYP2B6 *6/*6 and *6/*26 carriers had extremely high plasma EFV concentrations (>6000 ng/mL) while receiving the standard dosage. EFV dose was reduced to 400 mg for 11 patients and to 200 mg for 7 patients with persistently suppressed HIV-1 loads. EFV-containing treatment was initiated at 400 mg in 4 CYP2B6 *6/*6 carriers and one *6/*26 carrier. Two of them still had a high plasma EFV concentration while receiving that dose, and the dose was further reduced to 200 mg, with successful HIV-1 suppression. CNS-related symptoms improved with dose reduction in 10 of the 14 patients, although some had not been aware of the symptoms at initial dosage.
Genotype-based EFV dose reduction is feasible in CYP2B6 *6/*6 and *6/*26 carriers, which can reduce EFV-associated CNS symptoms.
依非韦伦（EFV）主要通过细胞色素P450 2B6（CYP2B6）代谢，该药物的高血浆浓度与CYP2B6第516位（516G→T）的G→T多态性以及频繁出现的中枢神经系统（CNS）相关副作用有关。在此，我们测试了基于基因型降低EFV剂量的可行性。
在456例接受EFV治疗或计划接受含EFV治疗的1型人类免疫缺陷病毒（HIV-1）感染患者中确定CYP2B6基因型。对于在接受标准剂量（600mg）时血浆EFV浓度较高的CYP2B6 516G→T携带者，降低其EFV剂量。未接受过EFV治疗的纯合CYP2B6 516G→T携带者接受低剂量EFV治疗。在两组中，当血浆EFV浓度仍然较高时，进一步降低剂量。
在6等位基因中鉴定出CYP2B6 516G→T（在我们的受试者中占17.9%）以及一个新的等位基因26（在我们的患者中占1.3%）。所有接受EFV治疗的CYP2B6 *6/6和6/*26携带者在接受标准剂量时血浆EFV浓度极高（>6000 ng/mL）。11例HIV-1病毒载量持续受到抑制的患者的EFV剂量降至400mg，7例患者降至200mg。4例CYP2B6 *6/6携带者和1例6/*26携带者以400mg开始含EFV治疗。其中2例在接受该剂量时血浆EFV浓度仍然较高，剂量进一步降至200mg，HIV-1得到成功抑制。14例患者中有10例随着剂量降低CNS相关症状有所改善，尽管有些患者在初始剂量时并未意识到这些症状。
对于CYP2B6 *6/6和6/*26携带者，基于基因型降低EFV剂量是可行的，这可以减轻与EFV相关的CNS症状。
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