在未经抗逆转录病毒治疗的慢性HIV感染患者中，低丰度耐药病毒变体对治疗结果有显著影响。

Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes.

作者信息

Simen Birgitte B, Simons Jan Fredrik, Hullsiek Katherine Huppler, Novak Richard M, Macarthur Rodger D, Baxter John D, Huang Chunli, Lubeski Christine, Turenchalk Gregory S, Braverman Michael S, Desany Brian, Rothberg Jonathan M, Egholm Michael, Kozal Michael J

机构信息

454 Life Sciences, a Roche Company, Branford, Connecticut, USA.

出版信息

J Infect Dis. 2009 Mar 1;199(5):693-701. doi: 10.1086/596736.

DOI:10.1086/596736

PMID:19210162

Abstract

BACKGROUND

Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important.

OBJECTIVES

To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF).

METHODS

The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified.

RESULTS

Mutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, "NNRTI strategy"), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17-5.36]).

CONCLUSIONS

Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.

摘要

背景

耐药性较低（即流行率<20%）的人类免疫缺陷病毒（HIV）变异株可能未被检测到，但在临床上可能很重要。

目的

比较通过标准测序和超深度测序（检测流行率低至1%）检测到的耐药变异株的流行率，并确定低水平耐药变异株对病毒学失败（VF）的影响。

方法

灵活初始逆转录病毒抑制疗法（FIRST）研究（N = 1397）比较了3种初始抗逆转录病毒治疗（ART）策略。一个随机子集（n = 491）使用标准测序方法进行了耐药性突变的基线检测。对病毒含量充足的样本（N = 264）进行了超深度测序。使用比例风险模型比较了有和没有检测到突变的患者的VF发生率。

结果

通过标准测序和超深度测序均检测到了突变（分别在14%和28%的参与者中检测到；P <.001）。在开始使用核苷类和非核苷类逆转录酶抑制剂联合的ART方案（以下简称“非核苷类逆转录酶抑制剂策略”）进行治疗的个体中，所有通过超深度测序鉴定出非核苷类逆转录酶抑制剂耐药突变的个体均出现了VF。当将这些个体与开始使用非核苷类逆转录酶抑制剂策略但没有非核苷类逆转录酶抑制剂耐药突变的个体进行比较时，两种方法均检测到非核苷类逆转录酶抑制剂耐药突变的个体的VF风险更高（风险比[HR]，12.40[95%置信区间{CI}，3.41 - 45.10]），仅通过超深度测序检测到突变的个体的VF风险也更高（HR，2.50[95%CI，1.17 - 5.36]）。