Durant J, Clevenbergh P, Garraffo R, Halfon P, Icard S, Del Giudice P, Montagne N, Schapiro J M, Dellamonica P
Archet Hospital, Infectious Diseases Department, Nice, France.
AIDS. 2000 Jul 7;14(10):1333-9. doi: 10.1097/00002030-200007070-00005.
In a prospective randomized study, the impact of plasma protease inhibitor (PI) trough levels on changes in HIV RNA were assessed in patients treated with genotypic-guided therapy.
Patients failing combination therapy (HIV-1 RNA > 10,000 copies/ml, and at least 6 months of therapy with nucleoside analogues and 3 months with PI) were randomly assigned into two arms: control group (C) in which the treatment was modified according to the standard of care; genotypic group (G) in which the treatment was modified according to resistance mutation profiles. Serial PI plasma levels were performed in patients throughout the 12 month study. PI levels were determined by high performance liquid chromatography. 'Suboptimal' concentration (SOC) was defined as at least two PI plasma levels below 2 x IC95. Others were defined as 'optimal' concentration (OC). Patients were categorized into four groups: G1 (SOC/control); G2 (OC/control); G3 (SOC/genotype); G4 (OC/genotype). An intent-to-treat analysis was performed with viral load as the primary endpoint.
A total of 81 patients [mean age 39.7 +/- 8 years, 59 men, 52.7% Centers for Disease Control and Prevention (CDC) stage C] were included in the pharmacological substudy. The two groups according to randomization arms were comparable in terms of risk factor, age, sex, previous treatments, baseline CD4 cell count, HIV-1 RNA and mean PI plasma concentrations. Linear regression analysis showed a significant relationship between PI concentration and HIV RNA in the plasma. OC and SOC were found in 67.9% (55/81) and 32.1% (26/81) of patients, respectively. Mean changes in HIV RNA from baseline at month 6 were: -0.23 +/- 0.29 log10 copies/ml (G1); -0.97 +/- 0.28 (G2); -0.68 +/- 0.37 (G3); -1.38 +/- 0.20 (G4). Multivariate analysis showed PI plasma concentrations to be an independent predictor of HIV-RNA evolution (P = 0.017).
Multiple parameters determine the response to antiretroviral therapy and causes other than the development of drug resistance should be considered in the setting of therapeutic failure. Suboptimal concentrations of PI limit the response to antiretroviral therapy. Therapeutic drug monitoring of the PI plasma concentration may therefore prove useful in optimizing antiretroviral therapy.
在一项前瞻性随机研究中，评估了接受基因型指导治疗的患者血浆蛋白酶抑制剂（PI）谷浓度对HIV RNA变化的影响。
联合治疗失败的患者（HIV-1 RNA>10,000拷贝/ml，接受核苷类似物治疗至少6个月且接受PI治疗3个月）被随机分为两组：对照组（C），其治疗根据标准治疗方案进行调整；基因型组（G），其治疗根据耐药突变谱进行调整。在整个12个月的研究中对患者进行连续的PI血浆水平检测。PI水平通过高效液相色谱法测定。“次优”浓度（SOC）定义为至少有两个PI血浆水平低于2×IC95。其他则定义为“最佳”浓度（OC）。患者被分为四组：G1（SOC/对照组）；G2（OC/对照组）；G3（SOC/基因型组）；G4（OC/基因型组）。以病毒载量作为主要终点进行意向性分析。
共有81例患者[平均年龄39.7±8岁，59例男性，52.7%为疾病控制与预防中心（CDC）C期]纳入了药物亚研究。根据随机分组，两组在危险因素、年龄、性别、既往治疗、基线CD4细胞计数、HIV-1 RNA和平均PI血浆浓度方面具有可比性。线性回归分析显示血浆中PI浓度与HIV RNA之间存在显著关系。分别在67.9%（55/81）和32.1%（26/81）的患者中发现了OC和SOC。第6个月时HIV RNA相对于基线的平均变化为：-0.23±0.29 log10拷贝/ml（G1）；-0.97±0.28（G2）；-0.68±0.37（G3）；-1.38±0.20（G4）。多变量分析显示PI血浆浓度是HIV-RNA演变的独立预测因素（P = 0.017）。
多个参数决定了对抗逆转录病毒治疗的反应，在治疗失败的情况下应考虑除耐药性产生之外的其他原因。PI次优浓度会限制对抗逆转录病毒治疗的反应。因此，对PI血浆浓度进行治疗药物监测可能有助于优化抗逆转录病毒治疗。
