National Center for AIDS/STD Control and Prevention (NCAIDS), Chinese Center for Disease Control and Prevention (China CDC), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing 102206, China.
J Antimicrob Chemother. 2023 Nov 6;78(11):2743-2751. doi: 10.1093/jac/dkad297.
To assess the impact of pretreatment low-abundance HIV drug-resistant variants (LA-DRVs) on virological outcomes among ART-naive HIV-1-infected Chinese people who initiated ART.
A nested case-control study was conducted among HIV-1-infected individuals who had pretreatment drug resistance (PDR) genotypic results. Cases were defined as individuals with virological failure (HIV-1 RNA viral load ≥1000 copies/mL) after 1 year of ART, and controls were individuals from the same cohort whose viral load was less than 1000 copies/mL. Next-generation sequencing was used to identify low-abundance PDR mutations at detection thresholds of 10%, 2% and 1%. The mutant load was calculated by multiplying the abundance of HIV-1 drug-resistant variants by the pretreatment viral load. The impact of pretreatment low-abundance mutations on virological failure was estimated in logistic regression models.
Participants (43 cases and 100 controls) were included in this study for the analysis. The proportion of participants with PDR was higher in cases than in controls at different detection thresholds (44.2% versus 22.0%, P = 0.007 at 10% threshold; 58.1% versus 31.0%, P = 0.002 at 2% threshold; 90.7% versus 69.0%, P = 0.006 at 1% threshold). Compared with participants without PDR, participants with ≥10% detectable PDR mutations were associated with an increased risk of virological failure (adjusted OR 8.0, 95% CI 2.4-26.3, P = 0.001). Besides this, individuals with pretreatment LA-DRVs (2%-9% abundance range) had 5-fold higher odds of virological failure (adjusted OR 5.0, 95% CI 1.3-19.6, P = 0.021). Furthermore, LA-DRVs at 2%-9% abundance resistant to NRTIs and mutants with abundance of ≥10% resistant to NNRTIs had a 4-fold and 8-fold risk of experiencing virological failure, respectively. It was also found that a mutant load of more than 1000 copies/mL was predictive of virological failure (adjusted OR 7.2, 95% CI 2.5-21.1, P = 0.0003).
Low-abundance PDR mutations ranging from 2% to 9% of abundance can increase the risk of virological failure. Further studies are warranted to define a clinically relevant threshold of LA-DRVs and the role of NRTI LA-DRVs.
评估初治 HIV-1 感染者中治疗前低丰度 HIV 耐药变异体（LA-DRVs）对病毒学结果的影响，这些感染者接受了 ART 治疗。
对具有治疗前耐药（PDR）基因型结果的 HIV-1 感染者进行了嵌套病例对照研究。病例定义为 ART 治疗 1 年后病毒学失败（HIV-1 RNA 病毒载量≥1000 拷贝/mL）的个体，对照组为同一队列中病毒载量小于 1000 拷贝/mL 的个体。下一代测序用于在检测阈值为 10%、2%和 1%的情况下识别低丰度 PDR 突变。通过将 HIV-1 耐药变异体的丰度乘以预处理病毒载量来计算突变负荷。在 logistic 回归模型中估计治疗前低丰度突变对病毒学失败的影响。
本研究共纳入 43 例病例和 100 例对照进行分析。在不同检测阈值下，病例组中 PDR 参与者的比例高于对照组（10%阈值时为 44.2%比 22.0%，P=0.007；2%阈值时为 58.1%比 31.0%，P=0.002；1%阈值时为 90.7%比 69.0%，P=0.006）。与无 PDR 参与者相比，≥10%可检测到 PDR 突变的参与者发生病毒学失败的风险增加（调整后的 OR 8.0，95%CI 2.4-26.3，P=0.001）。此外，具有治疗前 LA-DRVs（丰度 2%-9%）的个体发生病毒学失败的可能性高出 5 倍（调整后的 OR 5.0，95%CI 1.3-19.6，P=0.021）。此外，丰度为 2%-9%且对 NRTIs 耐药的 LA-DRVs 和丰度≥10%且对 NNRTIs 耐药的突变体发生病毒学失败的风险分别增加 4 倍和 8 倍。还发现，突变负荷超过 1000 拷贝/mL 可预测病毒学失败（调整后的 OR 7.2，95%CI 2.5-21.1，P=0.0003）。
丰度为 2%-9%的低丰度 PDR 突变可增加病毒学失败的风险。需要进一步研究来确定 LA-DRVs 的临床相关阈值以及 NRTI LA-DRVs 的作用。
