University of Rome 'Tor Vergata', Department of Experimental Medicine, Rome, Italy.
Istituti Ospedalieri di Cremona, Infectious Diseases, Cremona, Italy.
Int J Antimicrob Agents. 2020 Jul;56(1):106027. doi: 10.1016/j.ijantimicag.2020.106027. Epub 2020 May 23.
The aim of this study was to characterize the genotypic and phenotypic resistance profile to the integrase strand transfer inhibitor (INSTI) bictegravir (BIC) and other INSTIs in patients who previously failed twice-daily raltegravir (RAL)-based or twice-daily dolutegravir (DTG)-based regimens. Twenty-two samples were collected after failure on an INSTI-based regimen in 17 highly treatment-experienced patients with HIV-1 with multi-drug-resistant virus, recorded in the Italian PRESTIGIO registry. Genotypic resistance mutations and phenotypic susceptibility to INSTIs were detected by GeneSeqIN and PhenoSenseIN assays, respectively (Monogram Biosciences, San Francisco, CA, USA). The primary INSTI resistance substitutions E138A/K, G140S, Y143C/H/R, Q148H and N155H were detected in 14 of 22 samples and were associated with resistance to one or more INSTIs, with G140S+Q148H present in 11 of 22 samples. Of these 14 samples, all showed high levels of resistance to elvitegravir (EVG) and RAL. Two isolates contained L74M, E138K, G140S and Q148H, or L74M, T97A, S119T, E138K, G140S, Y143R and Q148H, and had high-level resistance to all INSTIs, including BIC and DTG. Intermediate resistance was reported for eight of 14 isolates for BIC and nine of 14 isolates for DTG. Overall, for the 14 INSTI-resistant isolates, the median fold-change values in phenotypic susceptibility were: BIC 3.2 [interquartile range (IQR) 0.6-66], DTG 6.3 (IQR 0.8->186), EVG >164 (IQR 2.6->164) and RAL >188 (IQR 2.7->197). In conclusion, the study findings supported the in-vitro activity of BIC and DTG against most isolates derived from highly treatment-experienced patients who failed INSTI regimens.
本研究旨在描述先前基于每日两次拉替拉韦（RAL）或每日两次多替拉韦（DTG）方案治疗失败的 17 名 HIV-1 高度耐药病毒感染、治疗经验丰富的患者，对整合酶链转移抑制剂（INSTI）比替格韦（BIC）和其他 INSTI 的基因型和表型耐药谱特征。在意大利 PRESTIGIO 登记处记录的 22 个样本是在基于 INSTI 的方案治疗失败后收集的。通过 GeneSeqIN 和 PhenoSenseIN 检测分别检测基因型耐药突变和对 INSTI 的表型敏感性（Monogram Biosciences，旧金山，CA，美国）。在 22 个样本中的 14 个样本中检测到主要的 INSTI 耐药替代物 E138A/K、G140S、Y143C/H/R、Q148H 和 N155H，这些替代物与对一种或多种 INSTI 的耐药性有关，其中 11 个样本中的 22 个样本中存在 G140S+Q148H。在这 14 个样本中，所有样本对埃替格韦（EVG）和 RAL 的耐药水平均较高。两个分离株含有 L74M、E138K、G140S 和 Q148H，或 L74M、T97A、S119T、E138K、G140S、Y143R 和 Q148H，对所有 INSTI 包括 BIC 和 DTG 均具有高水平耐药性。14 个分离株中有 8 个对 BIC 和 14 个分离株中有 9 个对 DTG 显示中度耐药性。总的来说，在 14 个对 INSTI 耐药的分离株中，表型敏感性的中位数折点值为：BIC 3.2（四分位距（IQR）0.6-66）、DTG 6.3（IQR 0.8-186）、EVG >164（IQR 2.6-164）和 RAL >188（IQR 2.7-197）。总之，研究结果支持 BIC 和 DTG 对大多数源自基于 INSTI 方案治疗失败的高度治疗经验丰富的患者的分离株的体外活性。
