The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-na⟨ve HIV-1 infected patients
The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-na⟨ve HIV-1 infected patients
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DOI：
10.1007/s00228-009-0763-z
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发表时间：
2010-04-01
影响因子：
2.9
通讯作者：
Bottiger, Ylva
中科院分区：
文献类型：
--
作者：
Josephson, Filip;Andersson, Maria C. H.;Bottiger, Ylva
在NORTHIV试验的药代动力学/药效学分研究中，研究了治疗结果与EFV、ATV和LPV的低谷血浆浓度之间的关系。NORTHIV试验是一项随机的IV期疗效试验，比较了(1)EFV+2核苷逆转录酶抑制剂(2NRTI)每天一次、(2)利托那韦增强的ATV+2NRTI每天一次或(3)利托那韦增强的LPV+2NRTI每天两次治疗抗逆转录病毒感染的患者。这些结果与通常提到的每种药物的最低有效浓度水平(EFV 1,000 ng/ml，ATV 150 ng/ml，LPV 1,000 ng/ml)有关。阿扎那韦诱导的高胆红素血症与病毒学疗效的关系也被研究。药物浓度在4周和48周采样，可选在12周采样，并用高效液相色谱-紫外检测器进行分析。必要时，通过假设各自药物的平均半衰期来推算低谷值。EFV、ATV或LPV的血浆浓度与病毒学失败、因不良反应而停止治疗或抗病毒效力(病毒载量从基线下降至第4周)之间没有相关性。很少有样本低于建议的最低疗效截止值，它们对治疗失败的预测价值无法得到验证。在服用ATV的患者中，血清胆红素平均升高25mU/l的患者有增加病毒学失败风险的趋势。绝大多数接受标准剂量EFV、利托那韦增强的ATV和利托那韦增强的LPV的初治和依从性患者的药物浓度高于各自药物的最大疗效。这些结果不支持使用常规的治疗药物监测(TDM)来优化使用这些药物治疗初治患者的疗效，尽管TDM在某些药代动力学改变、不良事件或药物相互作用的情况下可能仍然有价值。血清胆红素可能是ATV治疗依从性的有用标记物。
The relation between treatment outcome and trough plasma concentrations of efavirenz (EFV), atazanavir (ATV) and lopinavir (LPV) was studied in a pharmacokinetic/pharmacodynamic substudy of the NORTHIV trial-a randomised phase IV efficacy trial comparing antiretroviral-na < ve human immunodeficiency virus-1-infected patients treated with (1) EFV + 2 nucleoside reverse transcriptase inhibitors (2NRTI) once daily, (2) ritonavir-boosted ATV + 2NRTI once daily or (3) ritonavir-boosted LPV + 2NRTI twice daily. The findings were related to the generally cited minimum effective concentration levels for the respective drugs (EFV 1,000 ng/ml, ATV 150 ng/ml, LPV 1,000 ng/ml). The relation between atazanavir-induced hyperbilirubinemia and virological efficacy was also studied.Drug concentrations were sampled at weeks 4 and 48 and optionally at week 12 and analysed by high-performance liquid chromatography with UV detector. When necessary, trough values were imputed by assuming the reported average half-lives for the respective drugs. Outcomes up to week 48 are reported.No relation between plasma concentrations of EFV, ATV or LPV and virological failure, treatment withdrawal due to adverse effects or antiviral potency (viral load decline from baseline to week 4) was demonstrated. Very few samples were below the suggested minimum efficacy cut-offs, and their predictive value for treatment failure could not be validated. There was a trend toward an increased risk of virological failure in patients on ATV who had an average increase of serum bilirubin from baseline of < 25 mu mol/l.The great majority of treatment-na < ve and adherent patients on standard doses of EFV, ritonavir-boosted ATV and ritonavir-boosted LPV have drug concentrations above that considered to deliver the maximum effect for the respective drug. The results do not support the use of routine therapeutic drug monitoring (TDM) for efficacy optimisation in treatment-na < ve patients on these drugs, although TDM may still be of value in some cases of altered pharmacokinetics, adverse events or drug interactions. Serum bilirubin may be a useful marker of adherence to ATV therapy.