Leth F Van, Kappelhoff B S, Johnson D, Losso M H, Boron-Kaczmarska A, Saag M S, Livrozet J-M, Hall D B, Leith J, Huitema A D R, Wit F W, Beijnen J H, Lange J M A
International Antiviral Therapy Evaluation Center, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, 1005 Amsterdam, The Netherlands.
AIDS Res Hum Retroviruses. 2006 Mar;22(3):232-9. doi: 10.1089/aid.2006.22.232.
Optimal adherence is essential for successful antiretroviral therapy. We analyzed the relation between minimum plasma drug concentration (Cmin) and total drug exposure over 24 hr (AUC24) with virologic failure for therapy-adherent patients in the nevirapine (NVP) and efavirenz (EFV) groups of the double nonnucleoside study (2NN), which compared the efficacy of NVP and/or EFV together with stavudine and lamivudine. The objective was to find cutoff values of the Cmin and AUC24 below which the risk of virologic failure increased. The relation between Cmin and AUC24 with virologic failure (never a plasma viral load [pVL] < 50 copies/ml or a rebound to two consecutive pVL > 50 copies/ml) was analyzed with proportional hazard analyses. Data were censored at end of study or change of allocated treatment. The risk of virologic failure with NVP (n = 511) started to increase at a Cmin < 3.1 mg/L (hazard ratio [HR], 1.33; 95% confidence interval [CI], 0.89-1.97), but there was no cutoff value below which a statistically significant increased risk occurred. Neither was such a cutoff point identified for the AUC24. The risk of virologic failure with EFV (n = 312) was significantly increased at a Cmin < 1.1 mg/L (HR, 1.95; 95% CI, 1.08-3.54) and an AUC24 < 40 mg x hr x L1 (HR, 1.95; 95% CI, 1.07-3.54). Both cutoff values represent the median values for adherent patients. These associations were driven by patients from Thailand. Adjusting for geographical region made the association between Cmin and AUC24 with virologic failure statistically nonsignificant. The sensitivity of the Cmin values was too low (29% for NVP, 64% for EFV) to be an adequate predictor for virologic failure. We conclude that identifying the Cmin value for the sole purpose of predicting virologic failure in patients who report to be adherent to NVP or EFV is questionable because of the absence of a concentration-response relation (NVP) or the low sensitivity for such a cutoff value (NVP and EFV).
最佳依从性对于抗逆转录病毒治疗的成功至关重要。我们分析了双非核苷研究（2NN）中奈韦拉平（NVP）组和依非韦伦（EFV）组中治疗依从性患者的最低血浆药物浓度（Cmin）与24小时总药物暴露量（AUC24）与病毒学失败之间的关系，该研究比较了NVP和/或EFV与司他夫定和拉米夫定联合使用的疗效。目的是找到Cmin和AUC24的临界值，低于该临界值病毒学失败风险会增加。使用比例风险分析来分析Cmin和AUC24与病毒学失败（血浆病毒载量[pVL]从未<50拷贝/ml或连续两次反弹至pVL>50拷贝/ml）之间的关系。数据在研究结束或分配治疗改变时进行删失。NVP组（n = 511）病毒学失败风险在Cmin < 3.1 mg/L时开始增加（风险比[HR]，1.33；95%置信区间[CI]，0.89 - 1.97），但没有低于该值会出现统计学显著增加风险的临界值。AUC24也未确定这样的临界值。EFV组（n = 312）病毒学失败风险在Cmin < 1.1 mg/L（HR，1.95；95%CI，1.08 - 3.54）和AUC24 < 40 mg·hr·L⁻¹（HR，1.95；95%CI，1.07 - 3.54）时显著增加。这两个临界值均代表依从性患者的中位数。这些关联是由泰国患者驱动的。对地理区域进行校正后，Cmin和AUC24与病毒学失败之间的关联在统计学上无显著意义。Cmin值的敏感性过低（NVP为29%，EFV为64%），不足以作为病毒学失败的充分预测指标。我们得出结论，仅为预测报告依从NVP或EFV治疗的患者的病毒学失败而确定Cmin值是值得怀疑的，因为不存在浓度 - 反应关系（NVP）或该临界值的敏感性较低（NVP和EFV）。
