Institut de Recerca de la SIDA irsiCaixa-HIVACAT, Badalona, Spain.
PLoS One. 2011;6(5):e19461. doi: 10.1371/journal.pone.0019461. Epub 2011 May 13.
To explore the potential of deep HIV-1 sequencing for adding clinically relevant information relative to viral population sequencing in heavily pre-treated HIV-1-infected subjects.
In a proof-of-concept study, deep sequencing was compared to population sequencing in HIV-1-infected individuals with previous triple-class virological failure who also developed virologic failure to deep salvage therapy including, at least, darunavir, tipranavir, etravirine or raltegravir. Viral susceptibility was inferred before salvage therapy initiation and at virological failure using deep and population sequencing genotypes interpreted with the HIVdb, Rega and ANRS algorithms. The threshold level for mutant detection with deep sequencing was 1%.
7 subjects with previous exposure to a median of 15 antiretrovirals during a median of 13 years were included. Deep salvage therapy included darunavir, tipranavir, etravirine or raltegravir in 4, 2, 2 and 5 subjects, respectively. Self-reported treatment adherence was adequate in 4 and partial in 2; one individual underwent treatment interruption during follow-up. Deep sequencing detected all mutations found by population sequencing and identified additional resistance mutations in all but one individual, predominantly after virological failure to deep salvage therapy. Additional genotypic information led to consistent decreases in predicted susceptibility to etravirine, efavirenz, nucleoside reverse transcriptase inhibitors and indinavir in 2, 1, 2 and 1 subject, respectively. Deep sequencing data did not consistently modify the susceptibility predictions achieved with population sequencing for darunavir, tipranavir or raltegravir.
In this subset of heavily pre-treated individuals, deep sequencing improved the assessment of genotypic resistance to etravirine, but did not consistently provide additional information on darunavir, tipranavir or raltegravir susceptibility. These data may inform the design of future studies addressing the clinical value of minority drug-resistant variants in treatment-experienced subjects.
探索深度 HIV-1 测序相对于病毒群体测序在大量预处理的 HIV-1 感染患者中增加临床相关信息的潜力。
在一项概念验证研究中，深度测序与 HIV-1 感染个体进行比较，这些个体以前曾经历过三重耐药病毒学失败，并且对深度挽救治疗也发生了病毒学失败，其中至少包括达芦那韦、替普那韦、依曲韦林或拉替拉韦。在挽救治疗开始前和病毒学失败时，使用深度和群体测序基因型，并使用 HIVdb、Rega 和 ANRS 算法进行解释，推断病毒易感性。深度测序检测突变的阈值水平为 1%。
共纳入 7 例既往接受中位数为 15 种抗逆转录病毒药物治疗中位数为 13 年的个体。深度挽救治疗包括达芦那韦、替普那韦、依曲韦林或拉替拉韦，分别在 4、2、2 和 5 例中。4 例患者自述治疗依从性良好，2 例部分依从；1 例患者在随访期间中断治疗。深度测序检测到所有通过群体测序发现的突变，并且除 1 例外，所有个体均检测到了额外的耐药突变，主要是在深度挽救治疗后病毒学失败时。额外的基因型信息导致 2 例、1 例、2 例和 1 例患者的依曲韦林、依非韦伦、核苷逆转录酶抑制剂和茚地那韦预测敏感性分别持续降低。对于达芦那韦、替普那韦或拉替拉韦，深度测序数据并未一致改变群体测序获得的敏感性预测。
在这部分大量预处理的个体中，深度测序改善了对依曲韦林耐药基因型的评估，但并未一致提供关于达芦那韦、替普那韦或拉替拉韦敏感性的额外信息。这些数据可能为未来研究提供信息，以确定治疗经验丰富的患者中少数耐药变异体的临床价值。
