Yang Shangxin, Multani Ashrit, Garrigues Jacob M, Oh Michael S, Hemarajata Peera, Burleson Taylor, Green Nicole M, Oliai Caspian, Gaynor Pryce T, Beaird Omer E, Winston Drew J, Seet Christopher S, Schaenman Joanna M
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Microorganisms. 2023 Aug 16;11(8):2096. doi: 10.3390/microorganisms11082096.
Remdesivir is the first FDA-approved drug for treating severe SARS-CoV-2 infection and targets RNA-dependent RNA polymerase (RdRp) that is required for viral replication. To monitor for the development of mutations that may result in remdesivir resistance during prolonged treatment, we sequenced SARS-CoV-2 specimens collected at different treatment time points in two transplant patients with severe COVID-19. In the first patient, an allogeneic hematopoietic stem cell transplant recipient, a transient RdRp catalytic subunit mutation (nsp12:A449V) was observed that has not previously been associated with remdesivir resistance. As no in vitro study had been conducted to elucidate the phenotypic effect of nsp12:A449V, its clinical significance is unclear. In the second patient, two other transient RdRp mutations were detected: one in the catalytic subunit (nsp12:V166A) and the other in an accessory subunit important for processivity (nsp7:D67N). This is the first case report for a potential link between the nsp12:V166A mutation and remdesivir resistance in vivo, which had only been previously described by in vitro studies. The nsp7:D67N mutation has not previously been associated with remdesivir resistance, and whether it has a phenotypic effect is unknown. Our study revealed SARS-CoV-2 genetic dynamics during remdesivir treatment in transplant recipients that involved mutations in the RdRp complex (nsp7 and nsp12), which may be the result of selective pressure. These results suggest that close monitoring for potential resistance during the course of remdesivir treatment in highly vulnerable patient populations may be beneficial. Development and utilization of diagnostic RdRp genotyping tests may be a future direction for improving the management of chronic COVID-19.
瑞德西韦是首个获美国食品药品监督管理局（FDA）批准用于治疗严重新型冠状病毒2（SARS-CoV-2）感染的药物，其作用靶点是病毒复制所需的RNA依赖性RNA聚合酶（RdRp）。为监测在长期治疗期间可能导致瑞德西韦耐药的突变的发生情况，我们对两名患有严重冠状病毒病2019（COVID-19）的移植患者在不同治疗时间点采集的SARS-CoV-2样本进行了测序。在首例患者（一名异基因造血干细胞移植受者）中，观察到一个短暂的RdRp催化亚基突变（nsp12:A449V），该突变此前未被发现与瑞德西韦耐药有关。由于尚未进行体外研究以阐明nsp12:A449V的表型效应，其临床意义尚不清楚。在第二例患者中，检测到另外两个短暂的RdRp突变：一个在催化亚基（nsp12:V166A），另一个在对持续性很重要的辅助亚基中（nsp7:D67N）。这是关于nsp12:V166A突变与体内瑞德西韦耐药之间潜在联系的首例病例报告，此前该联系仅在体外研究中有描述。nsp7:D67N突变此前未被发现与瑞德西韦耐药有关，其是否具有表型效应尚不清楚。我们的研究揭示了移植受者在接受瑞德西韦治疗期间SARS-CoV-2的基因动态变化，其中涉及RdRp复合物（nsp7和nsp12）中的突变，这可能是选择性压力的结果。这些结果表明，在高度脆弱的患者群体接受瑞德西韦治疗期间密切监测潜在耐药情况可能有益。开发和利用诊断性RdRp基因分型检测可能是改善慢性COVID-19管理的未来方向。
