Lineberger Comprehensive Cancer Center.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill.
J Infect Dis. 2024 Jul 25;230(1):86-94. doi: 10.1093/infdis/jiae131.
The association between low-frequency human immunodeficiency virus type 1 (HIV-1) drug resistance mutations (DRMs) and treatment failure (TF) is controversial. We explore this association using next-generation sequencing (NGS) methods that accurately sample low-frequency DRMs.
We enrolled women with HIV-1 in Malawi who were either antiretroviral therapy (ART) naive (cohort A), had ART failure (cohort B), or had discontinued ART (cohort C). At entry, cohorts A and C began a nonnucleoside reverse transcriptase inhibitor-based regimen and cohort B started a protease inhibitor-based regimen. We used Primer ID MiSeq to identify regimen-relevant DRMs in entry and TF plasma samples, and a Cox proportional hazards model to calculate hazard ratios (HRs) for entry DRMs. Low-frequency DRMs were defined as ≤20%.
We sequenced 360 participants. Cohort B and C participants were more likely to have TF than cohort A participants. The presence of K103N at entry significantly increased TF risk among A and C participants at both high and low frequency, with HRs of 3.12 (95% confidence interval [CI], 1.58-6.18) and 2.38 (95% CI, 1.00-5.67), respectively. At TF, 45% of participants showed selection of DRMs while in the remaining participants there was an apparent lack of selective pressure from ART.
Using accurate NGS for DRM detection may benefit an additional 10% of patients by identifying low-frequency K103N mutations.
低频人类免疫缺陷病毒 1 型（HIV-1）耐药突变（DRMs）与治疗失败（TF）之间的关联存在争议。我们使用能够准确检测低频 DRMs 的下一代测序（NGS）方法来探讨这种关联。
我们招募了马拉维的 HIV-1 感染女性，她们要么是抗逆转录病毒治疗（ART）初治者（队列 A），要么是 ART 失败（队列 B），要么是已停止 ART（队列 C）。入组时，队列 A 和 C 开始使用非核苷类逆转录酶抑制剂为基础的方案，队列 B 开始使用蛋白酶抑制剂为基础的方案。我们使用 Primer ID MiSeq 在入组和 TF 血浆样本中鉴定方案相关的 DRMs，并使用 Cox 比例风险模型计算入组 DRMs 的风险比（HR）。低频 DRMs 的定义为≤20%。
我们对 360 名参与者进行了测序。队列 B 和 C 的 TF 发生率高于队列 A。入组时存在 K103N 与 A 和 C 参与者的 TF 风险显著相关，高频和低频时的 HR 分别为 3.12（95%置信区间 [CI]，1.58-6.18）和 2.38（95% CI，1.00-5.67）。在 TF 时，45%的参与者出现 DRMs 的选择，而在其余参与者中，ART 没有明显的选择压力。
使用准确的 NGS 检测 DRM 可能会通过识别低频 K103N 突变使另外 10%的患者受益。
