在多名治疗失败患者中，阿扎那韦经利托那韦增效与未经增效时，其基因型耐药评分涉及两种不同的突变模式。

Two different patterns of mutations are involved in the genotypic resistance score for atazanavir boosted versus unboosted by ritonavir in multiple failing patients.

作者信息

Santoro M M, Bertoli A, Lorenzini P, Ceccherini-Silberstein F, Gianotti N, Mussini C, Torti C, Di Perri G, Barbarini G, Bini T, Melzi S, Caramello P, Maserati R, Narciso P, Micheli V, Antinori A, Perno C F

机构信息

Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.

出版信息

Infection. 2009 Jun;37(3):233-43. doi: 10.1007/s15010-008-8065-4. Epub 2009 Jan 23.

DOI:10.1007/s15010-008-8065-4

PMID:19169632

Abstract

OBJECTIVES

The protease inhibitor atazanavir (ATV) can be used either boosted by ritonavir (ATV300/r) or unboosted (ATV400). To date, however, genotypic resistance scores (GRSs) have been developed only for boosted-ATV. We have determined GRS associated with virologic response (VR) for both ATV300/r and ATV400 in highly pre-treated HIV-1 infected patients.

PATIENTS AND METHODS

We analyzed the results of genotypic tests available 0-3 months before the initiation of an ATV-containing regimen in 159 patients with HIV-RNA >or= 500 copies/ml (ATV300/r group: 74; ATV400 group: 85) who were enrolled in the CARe study through an Early Access Program. The impact of baseline protease mutations on VR (>or= 1 log(10)copies/ml HIV-RNA decrease at 12-24 weeks) was analyzed using Fisher's exact test. Mutated protease amino acid positions (MPP) with p < 0.20 were retained for further analysis. The GRSs were determined by a step-by-step analysis using the chi(2) test for trend.

RESULTS

The GRSs for ATV300/r and ATV400 revealed differing sets of mutations. For ATV300/r, 12 MPPs (10C/I/V + 32I + 34Q + 46I/L + 53L + 54A/M/V + 82A/F/I/T + 84V + 90M - 15E/G/L/V - 69K/M/N/Q/R/T/Y - 72M/ T/V; p = 1.38 x 10(-9)) were the most strongly associated with VR (VR: 100%, 78.3%, 83.3%, 75% and 0% of patients with a score of -2/-1, 0, 1, 2, and >or= 3, respectively); the last three MPPs (I15/H69/I72) were associated with a better VR. For ATV400, nine MPPs (16E + 20I/M/R/T/V + 32I + 33F/I/V + 53L/Y + 64L/M/ V + 71I/T/V + 85V + 93L/M; p = 9.42 x 10(-8)) were most strongly associated with VR (VR: 83.3%, 66.7%, 5.9%, 0% of patients with 0, 1/2, 3, and >or= 4 MPP, respectively). Differences between GRSs for ATV300/r and ATV400 may be due to different ATV drug levels (boosted vs unboosted), favoring different pathways of escape from antiviral pressure.

CONCLUSIONS

Both GRSs were independent predictors of response in a multivariable logistic regression model. Nevertheless, cross-validation of these GRSs on different patient databases is required before their implementation in clinical practice.

摘要

目的

蛋白酶抑制剂阿扎那韦（ATV）既可以与利托那韦联用（ATV300/r），也可以单独使用（ATV400）。然而，迄今为止，仅针对联用阿扎那韦开发了基因型耐药评分（GRS）。我们已经确定了在接受过大量治疗的HIV-1感染患者中，与阿扎那韦300/r和阿扎那韦400病毒学应答（VR）相关的GRS。

患者和方法

我们分析了159例HIV-RNA≥500拷贝/毫升患者（阿扎那韦300/r组：74例；阿扎那韦400组：85例）在开始含阿扎那韦治疗方案前0 - 3个月的基因型检测结果，这些患者通过早期准入计划参与了CARe研究。使用Fisher精确检验分析基线蛋白酶突变对病毒学应答（12 - 24周时HIV-RNA下降≥1 log₁₀拷贝/毫升）的影响。保留p < 0.20的突变蛋白酶氨基酸位置（MPP）用于进一步分析。通过使用趋势χ²检验的逐步分析确定GRS。

结果

阿扎那韦300/r和阿扎那韦400的GRS显示出不同的突变组合。对于阿扎那韦300/r，12个MPP（10C/I/V + 32I + 34Q + 46I/L + 53L + 54A/M/V + 82A/F/I/T + 84V + 90M - 15E/G/L/V - 69K/M/N/Q/R/T/Y - 72M/T/V；p = 1.38 x 10⁻⁹）与病毒学应答最密切相关（病毒学应答：评分分别为-2/-l、0、1、2和≥3的患者中，应答率分别为100%、78.3%、83.3%、75%和0%）；最后三个MPP（I15/H69/I72）与更好的病毒学应答相关。对于阿扎那韦400，9个MPP（16E + 20I/M/R/T/V + 32I + 33F/I/V + 53L/Y + 64L/M/V + 71I/T/V + 85V + 93L/M；p = 9.42 x 10⁻⁸）与病毒学应答最密切相关（病毒学应答：MPP分别为0、1/2、3和≥4的患者中，应答率分别为83.3%、66.7%、5.9%、0%）。阿扎那韦300/r和阿扎那韦400的GRS差异可能是由于阿扎那韦药物水平不同（联用与未联用），有利于不同的抗病毒压力逃逸途径。