Delaugerre Constance, Pavie Juliette, Palmer Pierre, Ghosn Jade, Blanche Stephane, Roudiere Laurent, Dominguez Stephanie, Mortier Emmanuel, Molina Jean-Michel, de Truchis Pierre
Virology Department, Saint Louis Hospital-APHP, Paris, France.
AIDS. 2008 Sep 12;22(14):1809-13. doi: 10.1097/QAD.0b013e328307f24a.
Ritonavir-boosted darunavir (DRV/r) has proven potent efficacy when used in heavily pretreated patients, harboring protease inhibitor-associated resistance mutations. Limited data are available on resistance pattern emerging in patients failing DRV/r and on subsequent remaining protease inhibitor options.
Analysis of baseline and failure resistance genotypes were performed in patients experiencing virologic failure (>200 copies/ml) after at least 3 months on a DRV/r (600/100 mg twice daily)-containing regimen.
Twenty-five highly protease inhibitor-experienced patients were included. Baseline median human immunodeficiency virus type 1 RNA was 5 log10 copies/ml and number of total-protease inhibitor, major-protease inhibitor and DRV-associated-resistance mutations was 13, 4 and 3, respectively. Median viral replication duration on DRV/r selective pressure was 34 weeks. Emergence of DRV-associated-resistance mutations was observed in 72% (18/25) of patients, at codons L89I/M/V (32%), V32I (28%), V11I (20%), I47V/A (20%), I54L/M (20%), L33F/I (16%) and I50V (16%). A high risk of DRV resistance was observed in patients with 2 and 3 baseline DRV-associated-resistance mutations and in patients with more than 24 weeks of ongoing viral replication. According to 2007 ANRS algorithm, isolates classified as susceptible to ritonavir-boosted tipranavir decreased from baseline to failure from 76 to 60% and susceptible to DRV/r from 32 to 12%.
Emerging mutations observed after DRV/r failure were those already described to impact the DRV efficacy. Our study provided recommendations to firstly, reconsider lowering the cutoff number of DRV mutations to two; secondly, avoid keeping patients on a DRV-failing regimen for more than 24 weeks and thirdly, to examine the efficacy of using tipranavir after DRV failure.
对于携带蛋白酶抑制剂相关耐药突变的经大量治疗的患者，利托那韦增强的达芦那韦（DRV/r）已被证明具有强大的疗效。关于DRV/r治疗失败患者出现的耐药模式以及后续剩余蛋白酶抑制剂选择的数据有限。
对接受含DRV/r（600/100mg，每日两次）方案治疗至少3个月后出现病毒学失败（>200拷贝/ml）的患者进行基线和失败时耐药基因型分析。
纳入了25例有大量蛋白酶抑制剂治疗经验的患者。基线时，人类免疫缺陷病毒1型RNA中位数为5 log10拷贝/ml，蛋白酶抑制剂总数、主要蛋白酶抑制剂和DRV相关耐药突变数分别为13、4和3。在DRV/r选择压力下，病毒复制的中位数持续时间为34周。在72%（18/25）的患者中观察到DRV相关耐药突变的出现，发生在L89I/M/V（32%）、V32I（28%）、V11I（20%）、I47V/A（20%）、I54L/M（20%）、L33F/I（16%）和I50V（16%）密码子处。在有2个和3个基线DRV相关耐药突变的患者以及病毒持续复制超过24周的患者中，观察到DRV耐药的高风险。根据2007年法国国家艾滋病研究机构（ANRS）算法，从基线到失败时，分类为对利托那韦增强的替拉那韦敏感的分离株从76%降至60%，对DRV/r敏感的分离株从32%降至12%。
DRV/r治疗失败后观察到的新出现的突变是那些已被描述会影响DRV疗效的突变。我们的研究提供了以下建议：首先，重新考虑将DRV突变的截断数降至2个；其次，避免让患者在DRV治疗失败的方案上持续超过24周；第三，研究DRV治疗失败后使用替拉那韦的疗效。
