人类免疫缺陷病毒1型（HIV-1）对达芦那韦的基因型耐药性解读及病毒学反应：现有系统和新评分的验证

Interpretation of genotypic HIV-1 resistance to darunavir and virological response: validation of available systems and of a new score.

作者信息

De Luca Andrea, Di Giambenedetto Simona, Maserati Renato, Gianotti Nicola, Narciso Pasquale, Antinori Andrea, Di Perri Giovanni, Prosperi Mattia C F, Baldanti Fausto, Micheli Valeria, Zazzi Maurizio, Perno Carlo F, Santoro Maria M

机构信息

Institute of Clinical Infectious Diseases, Catholic University, Rome, Italy.

出版信息

Antivir Ther. 2011;16(4):489-97. doi: 10.3851/IMP1799.

DOI:10.3851/IMP1799

PMID:21685536

Abstract

BACKGROUND

There is not yet consensus on interpretation of genotypic HIV-1 resistance to darunavir (DRV). We validated existing rules and a newly derived score.

METHODS

Protease inhibitor (PI)-failing patients starting a DRV/ritonavir-based regimen, with available baseline resistance genotypes, were extracted from three Italian databases. Virological response (VR) was analysed between 4 and 32 follow-up weeks, defined as a drop from baseline HIV RNA of ≥2 log(10) or a value <50 copies/ml if the last measurement had been obtained at ≤12 weeks and as HIV RNA<50 copies/ml if it had been obtained at >12 weeks of follow-up. DRV/ritonavir resistance was interpreted by seven algorithms. A new weighted score (DRV-2009) was derived and validated, analysing associations of protease mutations with VR.

RESULTS

A total of 217 patients were analysed, with a mean (±sd) follow-up time of 17 (±9) weeks. At baseline, median HIV RNA was 4.26 log(10) copies/ml (IQR 3.11-5.03); VR was achieved in 135/217 (62%) patients. Adjusting for use of a new drug class, number of previous PIs experienced, CD4(+) T-cell count and HIV RNA, only the Rega DRV/ritonavir interpretation was significantly associated with VR (per increase in susceptibility category, OR 1.94, 95% CI 1.32-2.86; P<0.001). The DRV-2009 score V11I+L33F+R41K+I47V+2I50V+2I54M+K55R+D60E+L74P+L76V+N88D+2*L89V-L10I/V-I13V-G16E-G48V-F53I/L-I62V-I66F-V77I (<0 indicating susceptibility, 0-1 intermediate resistance and ≥2 resistance) correlated with VR in the derivation set (n=132, R=0.395; P<0.001). In the validation set (n=85), after adjusting for mutual interpretation and new use of enfuvirtide, DRV-2009 (P=0.017) and Rega (P=0.013) were both independently associated with VR.

CONCLUSIONS

In contrast to the other algorithms, both the DRV-2009 score and Rega interpretation showed a robust predictive capacity of VR to DRV/ritonavir-containing regimens.

摘要

背景

对于人类免疫缺陷病毒1型（HIV-1）对达芦那韦（DRV）的基因型耐药性的解读尚未达成共识。我们对现有的规则和新得出的评分进行了验证。

方法

从三个意大利数据库中提取开始基于DRV/利托那韦方案治疗且有可用基线耐药基因型的蛋白酶抑制剂（PI）治疗失败患者。在随访4至32周期间分析病毒学应答（VR），定义为若最后一次测量在≤12周时进行，则HIV RNA较基线下降≥2 log(10)或值<50拷贝/毫升；若在随访>12周时进行，则定义为HIV RNA<50拷贝/毫升。采用七种算法解读DRV/利托那韦耐药性。得出并验证了一个新的加权评分（DRV-2009），分析蛋白酶突变与VR的关联。

结果

共分析了217例患者，平均（±标准差）随访时间为17（±9）周。基线时，HIV RNA中位数为4.26 log(10)拷贝/毫升（四分位间距3.11 - 5.03）；135/217（62%）例患者实现了VR。在对新药类别使用、既往使用PI的数量、CD4(+) T细胞计数和HIV RNA进行校正后，仅Rega DRV/利托那韦解读与VR显著相关（易感性类别每增加一级，比值比1.94，95%置信区间1.32 - 2.86；P<0.001）。DRV-2009评分V11I + L33F + R41K + I47V + 2I50V + 2I54M + K55R + D60E + L74P + L76V + N88D + 2*L89V - L10I/V - I13V - G16E - G48V - F53I/L - I62V - I66F - V77I（<0表示敏感，0 - 1为中度耐药，≥2为耐药）与推导集（n = 132，R = 0.395；P<0.001）中的VR相关。在验证集（n = 85）中，在对相互解读和恩夫韦肽新使用情况进行校正后；DRV-2009（P = 0.017）和Rega（P = 0.013）均与VR独立相关。