Pellegrin Isabelle, Breilh Dominique, Ragnaud Jean-Marie, Boucher Sébastien, Neau Didier, Fleury Hervé, Schrive Marie-Hélène, Saux Marie-Claude, Pellegrin Jean-Luc, Lazaro Estibaliz, Vray Muriel
Department of Virology, Bordeaux University Hospital, Bordeaux, France.
Antivir Ther. 2006;11(4):421-9.
To assess the impact of baseline HIV-1 substitutions, individual pharmacokinetic (PK) parameters (Cmin, Cmax, area under the curve [AUC0-->24 h]) and genotype-inhibitory quotient (GIQ) on virological responses (VR) to atazanavir-ritonavir (300 mg/100 mg)-based highly active antiretroviral therapy (HAART) in 71 antiretroviral-experienced, atazanavir-naive patients in virological failure (VF) on HAART.
VR was defined as HIV RNA <1.7 log10 copies/ml at week 12 (W12). A clinically relevant genotype-substitutions score for atazanavir-ritonavir was developed and validated (Reyaphar substitutions score). Previously published substitutions scores were also tested.
Patients had a median (Q1; O3) of 6 (3; 8) previous treatment lines during 9 (7; 11) years. Baseline (WO) values were as follows: 262 (187; 435) CD4+/microl, 3.9 (2.6; 4.9) log10 HIV-1 RNA copies/ml, 4 (2; 6) protease substitutions and 3 (1; 4) NRTI-related substitutions. Respective steady-state Cmin, Cmax and AUC0-->24 h were 300 (200; 700) ng/ml, 620 (430; 750) ng/ml and 78,000 (61,000; 94,000) ng.h/ml. At W12, 49% of the patients had VR with a median decrease of -1.2 (-0.5; -2.3) log10 HIV-1 RNA copies/ml. The Reyaphar score included 12 baseline protease substitutions from the International AIDS Society USA list that were associated with poorer VR: L10I/F/R/V, K20I/M/R, L241, M461/L, 154L/M/T/V, L63P, A71I/L/V/T, G73A/C/F/T, V771, V82A/F/S/T, 184V, L90M and the polymorphism substitution Q58E. Comparing <5 versus > or =5 Reyaphar substitutions, the W12-W0 HIV-1 RNA decrease was - 1.4 (-0.7; -2.3) versus -0.5 (-1.2; +0.5) log10 copies/ml (P=0.009) with VR in 63% versus 110% (P<10(-4)), respectively. This score predicted VF at W12 with 46% sensitivity, compared to 33% and 28% for the ANRS 2004 and 2005 scores. PK parameters alone were not associated with VR, but GIQ was associated with virological outcome (P=0.04). 150L, known to be correlated with atazanavir-specific resistance, emerged in 2 (8%) of the 24 failing patients with paired genotypes at WO and VF.
These findings highlight the need to cross-validate genotype-based algorithms to interpret substitution impact on virological outcome using different patient databases before their implementation in routine clinical practice.
评估71例接受过抗逆转录病毒治疗、初治且处于病毒学失败（VF）状态的患者，其基线HIV-1置换、个体药代动力学（PK）参数（Cmin、Cmax、曲线下面积[AUC0→24 h]）和基因型抑制商（GIQ）对基于阿扎那韦-利托那韦（300 mg/100 mg）的高效抗逆转录病毒治疗（HAART）病毒学应答（VR）的影响。
VR定义为第12周（W12）时HIV RNA<1.7 log10拷贝/ml。制定并验证了阿扎那韦-利托那韦的临床相关基因型置换评分（Reyaphar置换评分）。还测试了先前发表的置换评分。
患者在9（7；11）年中接受过的治疗方案中位数（Q1；Q3）为6（3；8）种。基线（W0）值如下：262（187；435）个/μl CD4+细胞，3.9（2.6；4.9）log10 HIV-1 RNA拷贝/ml，4（2；6）个蛋白酶置换和3（1；4）个与核苷类逆转录酶抑制剂（NRTI）相关的置换。稳态时Cmin、Cmax和AUC0→24 h分别为300（200；700）ng/ml、620（430；750）ng/ml和78,000（61,000；94,000）ng·h/ml。在W12时，49%的患者实现了VR，HIV-1 RNA拷贝数中位数下降-1.2（-0.5；-2.3）log10。Reyaphar评分包括美国国际艾滋病协会列表中的12个基线蛋白酶置换，这些置换与较差的VR相关：L10I/F/R/V、K20I/M/R、L24I、M46I/L、I54L/M/T/V、L63P、A71I/L/V/T、G73A/C/F/T、V77I、V82A/F/S/T、I84V、L90M以及多态性置换Q58E。比较Reyaphar置换数<5与≥5的情况，W12-W0时HIV-1 RNA下降分别为-1.4（-0.7；-2.3）与-0.5（-1.2；+0.5）log10拷贝/ml（P=0.009），VR分别为63%与11%（P<10-4）。该评分预测W12时VF的敏感性为46%，而ANRS 2004和2005评分的敏感性分别为33%和28%。单独的PK参数与VR无关，但GIQ与病毒学结局相关（P=0.04）。在24例治疗失败且在W0和VF时具有配对基因型的患者中，2例（8%）出现了已知与阿扎那韦特异性耐药相关的I50L。
这些发现强调，在将基于基因型的算法应用于常规临床实践之前，需要使用不同患者数据库对其进行交叉验证，以解释置换对病毒学结局的影响。
