Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P4502B6*6 and*26
Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P4502B6*6 and*26
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DOI：
10.1086/522175
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发表时间：
2007-11-01
影响因子：
11.8
通讯作者：
Oka, Shinichi
中科院分区：
文献类型：
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作者：
Gatanaga, Hiroyuki;Hayashida, Tsunefusa;Oka, Shinichi
背景。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 516 位点 (516G -> T) 的 G -> T 多态性以及频繁的中枢神经系统 (CNS) 相关副作用有关。在这里，我们测试了基于基因型的 EFV 剂量减少的可行性。方法。在 456 名正在接受 EFV 治疗或计划接受含 EFV 治疗的人类免疫缺陷病毒 1 型 (HIV-1) 感染患者中确定了 CYP2B6 基因型。 CYP2B6 516G -> T 携带者在接受标准剂量（600 mg）时血浆 EFV 浓度较高，因此 EFV 剂量减少。用低剂量 EFV 治疗未接触过 EFV 的纯合 CYP2B6 516G -> T 携带者。两组中，当血浆EFV浓度保持高水平时，剂量进一步减少。结果。 CYP2B6 516G -> T 在 * 6 等位基因（在我们的 17.9% 的受试者中发现）和一个新的等位基因 * 26（在我们的 1.3% 的患者中发现）中被鉴定。所有 EFV 治疗的 CYP2B6 * 6/* 6 和 * 6/* 26 携带者在接受标准剂量时均具有极高的血浆 EFV 浓度 (16000 ng/mL)。 11 名患者的 EFV 剂量减少至 400 mg，7 名 HIV-1 负荷持续受到抑制的患者的 EFV 剂量减少至 200 mg。 4 名 CYP2B6 * 6/* 6 携带者和 1 名 * 6/* 26 携带者中以 400 mg 开始含 EFV 的治疗。其中两人在接受该剂量时仍具有较高的血浆 EFV 浓度，并且剂量进一步减少至 200 mg，成功抑制了 HIV-1。 14 名患者中有 10 名患者中，有 10 名患者的中枢神经系统相关症状随着剂量减少而改善，尽管有些患者在初始剂量时并未意识到这些症状。结论。基于基因型的 EFV 剂量减少在 CYP2B6 * 6/* 6 和 * 6/* 26 携带者中是可行的，这可以减轻 EFV 相关的 CNS 症状。
Background. 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.Methods. 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.Results. 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 ( 16000 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.Conclusions. Genotype- based EFV dose reduction is feasible in CYP2B6 * 6/* 6 and * 6/* 26 carriers, which can reduce EFV- associated CNS symptoms.