KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), College of Health Sciences, University of KwaZulu-Natal, Doris Duke Medical Research Institute, Durban, South Africa.
Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
J Antimicrob Chemother. 2020 Nov 1;75(11):3319-3326. doi: 10.1093/jac/dkaa343.
To determine the impact of pretreatment low-abundance HIV-1 drug-resistant variants (LA-DRVs) on virological failure (VF) among HIV-1/TB-co-infected individuals treated with NNRTI first-line ART.
We conducted a case-control study of 170 adults with HIV-1/TB co-infection. Cases had at least one viral load (VL) ≥1000 RNA copies/mL after ≥6 months on NNRTI-based ART, and controls had sustained VLs <1000 copies/mL. We sequenced plasma viruses by Sanger and MiSeq next-generation sequencing (NGS). We assessed drug resistance mutations (DRMs) using the Stanford drug resistance database, and analysed NGS data for DRMs at ≥20%, 10%, 5% and 2% thresholds. We assessed the effect of pretreatment drug resistance (PDR) on VF.
We analysed sequences from 45 cases and 125 controls. Overall prevalence of PDR detected at a ≥20% threshold was 4.7% (8/170) and was higher in cases than in controls (8.9% versus 3.2%), P = 0.210. Participants with PDR at ≥20% had almost 4-fold higher odds of VF (adjusted OR 3.7, 95% CI 0.8-18.3) compared with those without, P = 0.104. PDR prevalence increased to 18.2% (31/170) when LA-DRVs at ≥2% were included. Participants with pretreatment LA-DRVs only had 1.6-fold higher odds of VF (adjusted OR 1.6, 95% CI 0.6-4.3) compared with those without, P = 0.398.
Pretreatment DRMs and LA-DRVs increased the odds of developing VF on NNRTI-based ART, although without statistical significance. NGS increased detection of DRMs but provided no additional benefit in identifying participants at risk of VF at lower thresholds. More studies assessing mutation thresholds predictive of VF are required to inform use of NGS in treatment decisions.
确定预处理低丰度 HIV-1 耐药变异体（LA-DRVs）对接受 NNRTI 一线 ART 治疗的 HIV-1/TB 合并感染者发生病毒学失败（VF）的影响。
我们对 170 名 HIV-1/TB 合并感染者进行了病例对照研究。病例组在接受 NNRTI 为基础的 ART 治疗至少 6 个月后至少有一次病毒载量（VL）≥1000 RNA 拷贝/ml，对照组 VLs<1000 拷贝/ml。我们采用 Sanger 和 MiSeq 下一代测序（NGS）对血浆病毒进行测序。我们使用斯坦福耐药数据库评估耐药突变（DRMs），并在≥20%、10%、5%和 2%的阈值下分析 NGS 数据中的 DRMs。我们评估了预处理耐药（PDR）对 VF 的影响。
我们分析了 45 例病例和 125 例对照的序列。在≥20%的阈值下检测到的 PDR 总发生率为 4.7%（8/170），病例组高于对照组（8.9%比 3.2%），P=0.210。与无 PDR 者相比，PDR≥20%的参与者发生 VF 的几率几乎高 4 倍（校正 OR 3.7，95%CI 0.8-18.3），P=0.104。当包括≥2%的 LA-DRVs 时，PDR 的发生率增加到 18.2%（31/170）。与无 PDR 者相比，仅存在预处理 LA-DRVs 的参与者发生 VF 的几率高 1.6 倍（校正 OR 1.6，95%CI 0.6-4.3），P=0.398。
在接受 NNRTI 为基础的 ART 治疗时，预处理 DRMs 和 LA-DRVs 增加了发生 VF 的几率，但无统计学意义。NGS 增加了 DRMs 的检出率，但在较低阈值下识别发生 VF 风险的参与者方面没有提供额外的益处。需要更多评估预测 VF 的突变阈值的研究，以指导 NGS 在治疗决策中的应用。
