Genotypic correlates of resistance to the HIV-1 strand transfer integrase inhibitor cabotegravir.
Genotypic correlates of resistance to the HIV-1 strand transfer integrase inhibitor cabotegravir.
复制标题
HIV-1 链转移整合酶抑制剂 cabotegravir 耐药性的基因型相关性。
DOI：
10.1016/j.antiviral.2022.105427
复制
发表时间：
2022
影响因子：
7.6
通讯作者：
Shafer,RobertW
中科院分区：
文献类型：
--
作者：
Rhee,Soo-Yon;Parkin,Neil;Harrigan,PRichard;Holmes,Susan;Shafer,RobertW
Cabotegravir (CAB) 是一种整合酶链转移抑制剂 (INSTI)，作为长效注射药物被批准用于暴露前预防，并与长效利匹韦林制剂一起用于治疗病毒学抑制患者。然而，目前尚未对CAB耐药的遗传机制进行全面综述。对报告 CAB 耐药突变 (DRM) 选择和体外 CAB 药敏试验结果的研究进行了回顾。使用正则化回归分析评估整合酶突变对 CAB 易感性的影响。在接受 CAB 时发生病毒学失败的 24 名患者中，最常见的突变包括 Q148R (n = 15)、N155H (n = 7) 和 E138K (n = 5)。 T97A、G118R、G140 A/R/S 和 R263K 各由 1-2 人开发。除了T97A、G118R和G140 A/R之外，这些DRM也是在体外选择的，而G140R是在SIV猕猴模型中选择的。尽管这些 DRM 与接受相关 INSTI 多替拉韦治疗的患者中发生的类似，但 Q148R 更可能与 CAB 一起发生，而 G118R 和 R263K 更可能与多替拉韦一起发生。正则回归分析确定了 14 个与降低 CAB 敏感性显着相关的 DRM，其中包括 6 个本身降低敏感性的主要 DRM，包括 G118R、Q148 H/K/R、N155H 和 R263K，以及 8 个辅助 DRM，包括 M50I、L74 F/M、T97A、E138K 和 G140 A/C/S。使用 Q148 H/K/R 与 L74M、E138 A/K、G140 A/S 和 N155H 组合的分离株通常可将 CAB 敏感性降低 10 倍以上。 M50I、L74M 和 T97A 是多态性突变，单独使用这些突变似乎不会增加接受含 CAB 方案的患者病毒学失败的风险。需要仔细的患者筛查，以防止在病毒活跃复制期间使用 CAB。需要进行密切的病毒学监测，以尽量减少 CAB 暴露于主动复制，以防止与其他 INSTI 交叉耐药相关的 DRM 的出现。
Cabotegravir (CAB) is an integrase strand transfer inhibitor (INSTI) formulated as a long-acting injectable drug approved for pre-exposure prophylaxis and use with a long acting rilpivirine formulation for therapy in patients with virological suppression. However, there has been no comprehensive review of the genetic mechanisms of CAB resistance. Studies reporting the selection of drug resistance mutations (DRMs) by CAB and the results ofin vitroCAB susceptibility testing were reviewed. The impact of integrase mutations on CAB susceptibility was assessed using regularized regression analysis. The most commonly selected mutations in the 24 persons developing virological failure while receiving CAB included Q148R (n = 15), N155H (n = 7), and E138K (n = 5). T97A, G118R, G140 A/R/S, and R263K each developed in 1–2 persons. With the exception of T97A, G118R, and G140 A/R, these DRMs were also selectedin vitrowhile G140R was selected in the SIV macaque model. Although these DRMs are similar to those occurring in persons receiving the related INSTI dolutegravir, Q148R was more likely to occur with CAB while G118R and R263K were more likely to occur with dolutegravir. Regularized regression analysis identified 14 DRMs significantly associated with reduced CAB susceptibility including six primary DRMs which reduced susceptibility on their own including G118R, Q148 H/K/R, N155H, and R263K, and eight accessory DRMs including M50I, L74 F/M, T97A, E138K, and G140 A/C/S. Isolates with Q148 H/K/R in combination with L74M, E138 A/K, G140 A/S, and N155H often had >10-fold reduced CAB susceptibility. M50I, L74M, and T97A are polymorphic mutations that alone did not appear to increase the risk of virological failure in persons receiving a CAB-containing regimen. Careful patient screening is required to prevent CAB from being used during active virus replication. Close virological monitoring is required to minimize CAB exposure to active replication to prevent the emergence of DRMs associated with cross-resistance to other INSTIs.