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首页> 外文期刊>Journal of Clinical Microbiology >Limited Marginal Utility of Deep Sequencing for HIV Drug Resistance Testing in the Age of Integrase Inhibitors
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Limited Marginal Utility of Deep Sequencing for HIV Drug Resistance Testing in the Age of Integrase Inhibitors

机译：在整合酶抑制剂时代，用于HIV耐药性检测的深度测序有限的边际效用

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HIV drug resistance genotyping is a critical tool in the clinical management of HIV infections. Although resistance genotyping has traditionally been conducted using Sanger sequencing, next-generation sequencing (NGS) is emerging as a powerful tool due to its ability to detect low-frequency alleles. ABSTRACT HIV drug resistance genotyping is a critical tool in the clinical management of HIV infections. Although resistance genotyping has traditionally been conducted using Sanger sequencing, next-generation sequencing (NGS) is emerging as a powerful tool due to its ability to detect low-frequency alleles. However, the clinical value added from NGS approaches to antiviral resistance testing remains to be demonstrated. We compared the variant detection capacity of NGS versus Sanger sequencing methods for resistance genotyping in 144 drug resistance tests (105 protease-reverse transcriptase tests and 39 integrase tests) submitted to our clinical virology laboratory over a four-month period in 2016 for Sanger-based HIV drug resistance testing. NGS detected all true high-frequency drug resistance mutations (&20% frequency) found by Sanger sequencing, with greater accuracy in one instance of a Sanger-detected false positive. Freely available online NGS variant callers HyDRA and PASeq were superior to Sanger methods for interpretations of allele linkage and automated variant calling. NGS additionally detected low-frequency mutations (1 to 20% frequency) associated with higher levels of drug resistance in 30/105 (29%) protease-reverse transcriptase tests and 4/39 (10%) integrase tests. In clinical follow-up of 69 individuals for a median of 674?days, we did not find a difference in rates of virological failure between individuals with and without low-frequency mutations, although rates of virological failure were higher for individuals with drug-relevant low-frequency mutations. However, all 27 individuals who experienced virological failure reported poor adherence to their drug regimen during the preceding follow-up time, and all 19 who subsequently improved their adherence achieved viral suppression at later time points, consistent with a lack of clinical resistance. In conclusion, in a population with low antiviral resistance emergence, NGS methods detected numerous instances of minor alleles that did not result in subsequent bona fide virological failure due to antiviral resistance.
机译：HIV耐药性基因分型是HIV感染临床管理中的关键工具。尽管抗性基因分型传统上是使用Sanger测序进行的，但下一代测序（NGS）由于具有检测低频等位基因的能力而正在成为一种强大的工具。摘要HIV耐药基因型是临床管理HIV感染的关键工具。尽管抗性基因分型传统上是使用Sanger测序进行的，但下一代测序（NGS）由于具有检测低频等位基因的能力而正在成为一种强大的工具。但是，NGS方法在抗病毒耐药性测试中的临床价值仍有待证明。我们比较了NGS和Sanger测序方法在2016年四个月期间针对我们的临床病毒学实验室提交的144种耐药性测试（105种蛋白酶逆转录酶测试和39种整合酶测试）的耐药基因型分型检测能力，用于基于Sanger的HIV耐药性测试。 NGS检测到由Sanger测序发现的所有真正的高频耐药性突变（频率> 20％），在Sanger检测到的假阳性的一种情况下，准确性更高。免费提供的在线NGS变异调用者HyDRA和PASeq在解释等位基因连锁和自动变异调用方面优于Sanger方法。 NGS在30/105（29％）蛋白酶逆转录酶测试和4/39（10％）整合酶测试中还检测到了与较高耐药水平相关的低频突变（频率为1％至20％）。在69位患者的临床随访中位，平均中位时间为674天，我们发现没有和没有低频突变的个体之间的病毒学失败率没有差异，尽管与药物相关的个体的病毒学失败率更高低频突变。然而，在过去的随访期间，所有27名经历病毒学衰竭的个体均报告了对药物治疗的依从性差，并且随后改善其依从性的所有19个人在较晚的时间点均实现了病毒抑制，这与缺乏临床抵抗力一致。总之，在低抗病毒耐药性出现的人群中，NGS方法检测到许多次要等位基因实例，这些实例未因抗病毒耐药性而导致随后的真正的病毒学失败。

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