Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), AP-HP, Hôpital Pitié-Salpêtrière, Laboratoire de virologie, F-75013 Paris, France.
Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), AP-HP, Hôpital Saint-Antoine, Laboratoire de virologie, F-75012 Paris, France.
J Antimicrob Chemother. 2018 Sep 1;73(9):2485-2492. doi: 10.1093/jac/dky198.
Integrase strand transfer inhibitors (INSTIs) are recommended by international guidelines as first-line therapy in antiretroviral-naive and -experienced HIV-1-infected patients.
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.
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.
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.
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.
整合酶链转移抑制剂（INSTIs）被国际指南推荐为初治和经治 HIV-1 感染患者的一线治疗药物。
本研究旨在评估 INSTI 耐药变异体的失败率以及基线少数耐药变异体（MiRVs）对 INSTI 为基础方案的病毒学应答的影响。
对 134 例因拉替拉韦（n=65）、艾维雷格（n=20）或多替拉韦（n=49）方案治疗失败的患者的样本进行测序，方法为 Sanger 测序和超深度测序（UDS）。对 INSTI 治疗失败（VF）（n=34）和病毒学成功（VS）（n=31）患者的基线样本进行 UDS 测序。使用 SmartGene 平台分析数据，并根据 ANRS 算法版本 27 解释耐药性。
通过 Sanger 测序和 UDS 检测，失败时至少有一种 INSTI 耐药变异体的流行率分别为 39.6%和 57.5%，这改变了 134 例患者中的 17 例（13%）的耐药性解释。在 53 例至少通过两种技术检测到一种耐药突变的患者中，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 患者的基线 MiRVs 流行率无差异。VF 患者的基线 MiRVs 在失败时无论是在主要还是次要突变中均未检出。
UDS 比 Sanger 测序更敏感地检测到治疗失败时的 INSTI MiRVs。失败时 MiRVs 的存在可能对决定改用其他 INSTIs 很重要。然而，在我们的研究中，基线 MiRVs 的存在与 INSTI 为基础的治疗反应之间没有关联。
