Remdesivir resistance in transplant recipients with persistent COVID-19

Abstract

The medical community currently lacks robust data regarding the incidence, prevalence, and clinical significance of mutations associated with resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) therapeutics. This report describes two renal transplant recipients who, after remdesivir exposure, developed a de novo V792I RNA-dependent RNA polymerase (RdRp) mutation that has recently been found to confer resistance to remdesivir in vitro . To the best of our knowledge, this publication is the first to document the emergence of V792I in patients treated with remdesivir. Our work underscores the critical need for augmented efforts to identify concerning mutations and address their clinical implications.

Figure 1

Independent acquisition of the remdesivir resistance mutation nsp-V792I in two immunocompromised patients. Full genome mutation profiles of SARS-CoV-2 viruses in longitudinal specimens of two immunocompromised patients treated with remdesivir. Basepair (bp) mutations compared to the Wuhan- Hu-1 reference are shown as ticks, color-coded according to the legend on the lower left. Bp and corresponding amino acid (aa) mutations in nsp12 (RNA-dependent RNA polymerase [RdRp]) and nsp14 (containing 3'-to-5' exoribonuclease proofreading activity) are labeled and shown in bold if non-synonymous. The longitudinal acquisition of mutations in nsp12 and 14 are highlighted by colored asterisks. Full genome maps are shown on top. The timeline is shown on the y-axis where time points are indicated on the left and days (d) elapsed since the first COVID-19 sampling per patient on the right of each plot. A 3D protein structure of the multi-domain polymerase complex is shown in its active dimeric form. Each domain is colored differently and labeled in the protomer that is shown in ribbon representation, whereas the other domains are shown in sphere representation, respectively. Nsp14 (exonuclease activity) and its co-factor nsp10 convey RNA proofreading in trans and are thus highlighted/shown as ribbons in protomer b together with the other domains in protomer a. The non-synonymous mutations in nsp12 and 14 as well as remdesivir are highlighted and labeled. The structure of the polymerase complex dimer is based on pdb 7egq with remdesivir added by structural overlay of a remdesivir-bound nsp12 complex (pdb 7l1f)^,.

Figure 2

2A Relation between the timing of remdesivir exposure and the subsequent development of the de novo RdRp V792I mutation in Case 1. Select Ct values are provided at points when the patient was symptomatic. A Ct of 34.1 was obtained 153 days after the diagnosis of COVID-19 when the patient experienced durable resolution of all symptoms associated with SARS-CoV-2 infection. 2B Case 1 CT of the abdomen demonstrating mass-like thickening along the renal graft (arrow) contiguous with the abdominal wall. 2C Case 1 cutaneous findings along the left abdomen overlying the renal graft. Biopsy yielded cells consistent with PTLD. 2D Relation between the timing of remdesivir exposure and the subsequent development of the de novo RdRp V792I mutation in Case 2. A Ct value of 17.4 was obtained when the patient was readmitted with worsening pulmonary symptoms. A Ct value of 26 was obtained 32 days after the diagnosis of COVID-19 when the patient experienced marked improvement in symptoms and their oxygen requirement had resolved. 2E Case 2 CT of the chest demonstrating multifocal nodules, many of which are surrounded by ground-glass opacities. Arrow indicates a cavitary lesion. An elevated galactomannan level from bronchoalveolar lavage fluid suggested the diagnosis of pulmonary aspergillosis.