Infectious Diseases and Vaccines, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Antimicrob Agents Chemother. 2022 May 17;66(5):e0222321. doi: 10.1128/aac.02223-21. Epub 2022 May 2.
Doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor (NNRTI), was approved for treatment of HIV-1 infection in 2018. In the pivotal phase 3 trials, DRIVE-FORWARD and DRIVE-AHEAD, 7 out of 747 (0.9%) treatment-naive participants treated with DOR plus two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) met protocol-defined virologic failure criteria and showed phenotypic resistance to DOR at week 48. The most common DOR resistance-associated mutation (RAM) detected in 5 of the 7 resistant isolates was F227C. Six isolates bearing NRTI RAMs (M184V and/or K65R) were resistant to lamivudine (3TC) and emtricitabine (FTC) but not to other approved NRTIs. All DOR-resistant isolates were susceptible or hypersusceptible (fold change of <0.25) to islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor (NRTTI). Isolate hypersusceptibility to ISL required F227C, in contrast to zidovudine, an NRTI, which required M184V. Based on the frequent emergence of F227C, we hypothesized that DOR and ISL would create a combination (DOR/ISL) with a high barrier to resistance. In resistance selection studies in MT4-GFP cells (MT4 cells engineered to express green fluorescent protein), DOR/ISL synergistically prevented viral breakthrough at a threshold of 2× the half-maximal inhibitory concentration (IC). DOR/ISL exhibited a higher barrier to resistance than DOR/3TC and dolutegravir (DTG)/3TC. Resistance analysis showed no emergence of substitutions at F227, an observation consistent with its ability to confer hypersusceptibility to ISL. Overall, the data demonstrate that DOR/ISL creates a 2-drug combination with a higher barrier to resistance, consistent with the reported clinical activity.
多伟拉韦（DOR）是一种非核苷类逆转录酶抑制剂（NNRTI），于 2018 年被批准用于治疗 HIV-1 感染。在关键的 3 期临床试验 DRIVE-FORWARD 和 DRIVE-AHEAD 中，接受 DOR 加两种核苷（酸）逆转录酶抑制剂（NRTIs）治疗的 747 名初治参与者中有 7 名（0.9%）达到方案定义的病毒学失败标准，并在第 48 周表现出对 DOR 的表型耐药。在 7 个耐药分离株中检测到的最常见的 DOR 耐药相关突变（RAM）是 F227C。6 个携带 NRTI RAM（M184V 和/或 K65R）的分离株对拉米夫定（3TC）和恩曲他滨（FTC）耐药，但对其他批准的 NRTIs 敏感。所有 DOR 耐药分离株对伊拉司韦（ISL）敏感或超敏（倍比变化<0.25），ISL 是一种核苷逆转录酶转位抑制剂（NRTTI）。与齐多夫定（一种 NRTI）需要 M184V 不同，ISL 对 DOR 耐药分离株的超敏性需要 F227C。基于 F227C 的频繁出现，我们假设 DOR 和 ISL 将形成一种具有高耐药屏障的组合（DOR/ISL）。在 MT4-GFP 细胞（工程化表达绿色荧光蛋白的 MT4 细胞）中的耐药选择研究中，DOR/ISL 以 2×半最大抑制浓度（IC）的阈值协同阻止病毒突破。DOR/ISL 比 DOR/3TC 和多替拉韦（DTG）/3TC 具有更高的耐药屏障。耐药性分析显示 F227 没有出现替代，这一观察结果与其对 ISL 具有超敏性的能力一致。总的来说，数据表明 DOR/ISL 形成了一种具有更高耐药屏障的 2 药组合，与报告的临床活性一致。
