Low-Abundance HIV Drug-Resistant Viral Variants in Treatment-Experienced Persons Correlate with Historical Antiretroviral Use
Low-Abundance HIV Drug-Resistant Viral Variants in Treatment-Experienced Persons Correlate with Historical Antiretroviral Use
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DOI：
10.1371/journal.pone.0006079
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发表时间：
2009-06-29
期刊：
影响因子：
3.7
通讯作者：
Kozal, Michael J.
中科院分区：
文献类型：
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作者：
Le, Thuy;Chiarella, Jennifer;Kozal, Michael J.
背景资料：在经历过抗逆转录病毒治疗的病毒学失败的患者中，在常规基因分型检测限以下水平（< 20%的准种）的低丰度HIV耐药变异体的频率在很大程度上尚不清楚。此外，低丰度耐药变异体在病毒学失败时的临床意义是unknown.Methodology/Principal Findings：从22个抗逆转录病毒经验丰富的受试者在病毒学失败时收集的血浆样本（病毒载量1380至304，000拷贝/mL）从标本库（2004-2007年）获得。使用桑格测序和超深度焦磷酸测序确定耐药突变的患病率和概况。使用斯坦福大学HIV数据库算法解释基因型。抗逆转录病毒治疗史通过病历回顾获得，并与耐药突变相关。通过深度测序在所有22名受试者中检测到低丰度耐药突变，通过桑格测序仅在3名受试者中检测到低丰度耐药突变。它们总共占深度测序检测到的247个突变中的90个（36%）;其中大多数（95%）未被标准基因分型检测到。通过深度测序检测到每个受试者平均4个额外的突变（p < 0.0001，95%Cl：2.85-5.53）。额外的低丰度耐药突变增加了22例受试者中17例（77%）受试者对一种或多种抗逆转录病毒药物的基因型耐药性。当与受试者的抗逆转录病毒治疗史相关时，额外的低丰度耐药突变与21%的受试者的抗逆转录病毒药物治疗失败相关，与79%的受试者的抗逆转录病毒治疗史相关（OR，13.73; 95% CI，2.5-74.3，p = 0.0016）。在病毒学失败时，抗逆转录病毒治疗受试者中的低丰度HIV耐药突变可增加受试者的总体耐药负担，但通常无法被常规基因分型识别。大多数未被识别的耐药突变与抗逆转录病毒药物的历史使用有关。超深度测序可以为临床医生提供重要的历史耐药信息，以便为高度治疗经验的患者计划后续抗逆转录病毒治疗方案，特别是当他们的既往治疗史和纵向基因型不可用时。
Background: It is largely unknown how frequently low-abundance HIV drug-resistant variants at levels under limit of detection of conventional genotyping (< 20% of quasi-species) are present in antiretroviral-experienced persons experiencing virologic failure. Further, the clinical implications of low-abundance drug-resistant variants at time of virologic failure are unknown.Methodology/Principal Findings: Plasma samples from 22 antiretroviral-experienced subjects collected at time of virologic failure (viral load 1380 to 304,000 copies/mL) were obtained from a specimen bank (from 2004-2007). The prevalence and profile of drug-resistant mutations were determined using Sanger sequencing and ultra-deep pyrosequencing. Genotypes were interpreted using Stanford HIV database algorithm. Antiretroviral treatment histories were obtained by chart review and correlated with drug-resistant mutations. Low-abundance drug-resistant mutations were detected in all 22 subjects by deep sequencing and only in 3 subjects by Sanger sequencing. In total they accounted for 90 of 247 mutations (36%) detected by deep sequencing; the majority of these (95%) were not detected by standard genotyping. A mean of 4 additional mutations per subject were detected by deep sequencing (p < 0.0001, 95% Cl: 2.85-5.53). The additional low-abundance drug-resistant mutations increased a subject's genotypic resistance to one or more antiretrovirals in 17 of 22 subjects (77%). When correlated with subjects' antiretroviral treatment histories, the additional low-abundance drug-resistant mutations correlated with the failing antiretroviral drugs in 21% subjects and correlated with historical antiretroviral use in 79% subjects (OR, 13.73; 95% Cl, 2.5-74.3, p = 0.0016).Conclusions/Significance: Low-abundance HIV drug-resistant mutations in antiretroviral-experienced subjects at time of virologic failure can increase a subject's overall burden of resistance, yet commonly go unrecognized by conventional genotyping. The majority of unrecognized resistant mutations correlate with historical antiretroviral use. Ultra-deep sequencing can provide important historical resistance information for clinicians when planning subsequent antiretroviral regimens for highly treatment-experienced patients, particularly when their prior treatment histories and longitudinal genotypes are not available.