Prevalence and clinical impact of minority resistant variants in patients failing an integrase inhibitor-based regimen by ultra-deep sequencing
Prevalence and clinical impact of minority resistant variants in patients failing an integrase inhibitor-based regimen by ultra-deep sequencing
复制标题
通过超深度测序分析整合酶抑制剂治疗方案失败的患者中少数耐药变异的患病率和临床影响
DOI：
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发表时间：
2018
影响因子：
5.2
通讯作者：
A. Marcelin
中科院分区：
文献类型：
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作者：
Thuy Nguyen;D. Fofana;M. Lê;Charlotte Charpentier;G. Peytavin;M. Wirden;S. Lambert;Nathalie Désiré;M. Grudé;L. Morand‐Joubert;P. Flandre;Christine Katlama;Diane Descamps;Vincent Calvez;E. Todesco;A. Marcelin
背景
整合酶链转移抑制剂(INSTI)被国际指南推荐作为抗逆转录病毒初治和有经验的HIV-1感染患者的一线治疗。
目标
这项研究旨在评估INSTI耐药变异的失败率以及基线少数耐药变异(MIRV)对基于INSTI方案的病毒学应答的影响。
方法
用桑格测序和超深测序对134例失败的患者样本进行了测序。这些患者分别接受了含Raltegravir方案(n = 65例)、含elvitegravir方案(n = 20例)或含多洛替格韦方案(n = 49例)失败。对INSTI治疗的病毒学失败(VF)患者(n = 34例)和病毒学成功(VS)患者(n = 31例)的基线样本进行UDS测序。使用Smartgene平台分析数据，并根据ANRS算法版本27解释抗性。
结果
失败时，根据Sanger测序和UDS测序，至少有一个INSTI耐药变异的发生率为39.6%和57.5%，改变了17/134(13%)患者对耐药的解释。在两种方法检测到至少一个耐药突变的53例患者中，最主要的INSTI耐药突变是N155H(45%)、Q148H/K/R(23%)、T97A(19%)和Y143C(11%)。VF患者和VS患者之间基线MIRV的发生率没有差异。在VF患者中基线发现的MIRV在失败时未被检测到，无论是在大多数或少数突变中。
结论
在检测治疗失败时INSTI MIRV方面，UDS比Sanger测序更敏感。故障时MIRV的存在可能对决定改用其他INSTI很重要。然而，在我们的研究中，基线MIRV的存在与基于INSTI的治疗的反应之间没有关联。
Background
Integrase strand transfer inhibitors (INSTIs) are recommended by international guidelines as first-line therapy in antiretroviral-naive and -experienced HIV-1-infected patients.
Objectives
This study aimed at evaluating the prevalence at failure of INSTI-resistant variants and the impact of baseline minority resistant variants (MiRVs) on the virological response to an INSTI-based regimen.
Methods
Samples at failure of 134 patients failing a raltegravir-containing (n = 65), an elvitegravir-containing (n = 20) or a dolutegravir-containing (n = 49) regimen were sequenced by Sanger sequencing and ultra-deep sequencing (UDS). Baseline samples of patients with virological failure (VF) (n = 34) and of those with virological success (VS) (n = 31) under INSTI treatment were sequenced by UDS. Data were analysed using the SmartGene platform, and resistance was interpreted according to the ANRS algorithm version 27.
Results
At failure, the prevalence of at least one INSTI-resistant variant was 39.6% by Sanger sequencing and 57.5% by UDS, changing the interpretation of resistance in 17/134 (13%) patients. Among 53 patients harbouring at least one resistance mutation detected by both techniques, the most dominant INSTI resistance mutations were N155H (45%), Q148H/K/R (23%), T97A (19%) and Y143C (11%). There was no difference in prevalence of baseline MiRVs between patients with VF and those with VS. MiRVs found at baseline in patients with VF were not detected at failure either in majority or minority mutations.
Conclusions
UDS is more sensitive than Sanger sequencing at detecting INSTI MiRVs at treatment failure. The presence of MiRVs at failure could be important to the decision to switch to other INSTIs. However, there was no association between the presence of baseline MiRVs and the response to INSTI-based therapies in our study.