502例raltegravir治疗失败患者对elvitegravir和dolutegravir的交叉耐药性：一项针对有raltegravir治疗经验的HIV-1感染患者的法国全国性研究。
Cross-resistance to elvitegravir and dolutegravir in 502 patients failing on raltegravir: a French national study of raltegravir-experienced HIV-1-infected patients.
作者信息
Fourati Slim, Charpentier Charlotte, Amiel Corinne, Morand-Joubert Laurence, Reigadas Sandrine, Trabaud Mary-Anne, Delaugerre Constance, Nicot Florence, Rodallec Audrey, Maillard Anne, Mirand Audrey, Jeulin Hélène, Montès Brigitte, Barin Francis, Bettinger Dominique, Le Guillou-Guillemette Hélène, Vallet Sophie, Signori-Schmuck Anne, Descamps Diane, Calvez Vincent, Flandre Philippe, Marcelin Anne-Genevieve
机构信息
AP-HP, Hôpital Pitié-Salpêtrière, INSERM-Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Paris, France.
INSERM, IAME, UMR 1137, F-75018 Paris, France Université de Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France AP-HP, Hôpital Bichat, Laboratoire de Virologie, F-75018 Paris, France.
出版信息
J Antimicrob Chemother. 2015 May;70(5):1507-12. doi: 10.1093/jac/dku535. Epub 2015 Jan 3.
OBJECTIVES
The objectives of this study were to determine the prevalence and patterns of resistance to integrase strand transfer inhibitors (INSTIs) in patients experiencing virological failure on raltegravir-based ART and the impact on susceptibility to INSTIs (raltegravir, elvitegravir and dolutegravir).
PATIENTS AND METHODS
Data were collected from 502 treatment-experienced patients failing a raltegravir-containing regimen in a multicentre study. Reverse transcriptase, protease and integrase were sequenced at failure for each patient. INSTI resistance-associated mutations investigated were those included in the last ANRS genotypic algorithm (v23).
RESULTS
Among the 502 patients, at failure, median baseline HIV-1 RNA (viral load) was 2.9 log10 copies/mL. Patients had been previously exposed to a median of five NRTIs, one NNRTI and three PIs. Seventy-one percent harboured HIV-1 subtype B and the most frequent non-B subtype was CRF02_AG (13.3%). The most frequent mutations observed were N155H/S (19.1%), Q148G/H/K/R (15.4%) and Y143C/G/H/R/S (6.7%). At failure, viruses were considered as fully susceptible to all INSTIs in 61.0% of cases, whilst 38.6% were considered as resistant to raltegravir, 34.9% to elvitegravir and 13.9% to dolutegravir. In the case of resistance to raltegravir, viruses were considered as susceptible to elvitegravir in 11% and to dolutegravir in 64% of cases. High HIV-1 viral load at failure (P < 0.001) and low genotypic sensitivity score of the associated treatment with raltegravir (P < 0.001) were associated with the presence of raltegravir-associated mutations at failure. Q148 mutations were selected more frequently in B subtypes versus non-B subtypes (P = 0.004).
CONCLUSIONS
This study shows that a high proportion of viruses remain susceptible to dolutegravir in the case of failure on a raltegravir-containing regimen.
目的
本研究的目的是确定在基于拉替拉韦的抗逆转录病毒治疗（ART）中出现病毒学失败的患者对整合酶链转移抑制剂（INSTIs）的耐药率和耐药模式，以及对INSTIs（拉替拉韦、埃替拉韦和多替拉韦）敏感性的影响。
患者与方法
在一项多中心研究中，收集了502例接受过治疗且含拉替拉韦方案失败的患者的数据。对每位患者失败时的逆转录酶、蛋白酶和整合酶进行测序。研究的与INSTI耐药相关的突变是纳入最新ANRS基因分型算法（v23）中的那些突变。
结果
在这502例患者中，失败时HIV-1 RNA（病毒载量）的中位数基线为2.9 log10拷贝/mL。患者此前平均接受过五种核苷类逆转录酶抑制剂（NRTIs）、一种非核苷类逆转录酶抑制剂（NNRTI）和三种蛋白酶抑制剂（PIs）的治疗。71%的患者感染的是HIV-1 B亚型，最常见的非B亚型是CRF02_AG（13.3%）。观察到的最常见突变是N155H/S（19.1%）、Q148G/H/K/R（15.4%）和Y143C/G/H/R/S（6.7%）。失败时，61.0%的病例中的病毒被认为对所有INSTIs均完全敏感，而38.6%的病例中的病毒被认为对拉替拉韦耐药，34.9%对埃替拉韦耐药，13.9%对多替拉韦耐药。在对拉替拉韦耐药的情况下，11%的病例中的病毒被认为对埃替拉韦敏感，64%对多替拉韦敏感。失败时的高HIV-1病毒载量（P＜0.001）以及与拉替拉韦相关治疗的低基因敏感性评分（P＜0.001）与失败时拉替拉韦相关突变的存在有关。Q148突变在B亚型中比在非B亚型中更频繁地被选择（P = 0.004）。
结论
本研究表明，在含拉替拉韦方案失败的情况下，很大一部分病毒对多替拉韦仍敏感。
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