Remdesivir Resistance in Transplant Recipients With Persistent Coronavirus Disease 2019

Abstract

New mutations conferring resistance to SARS-CoV-2 therapeutics have important clinical implications. We describe the first cases of an independently acquired V792I RNA-dependent RNA polymerase mutation developing in renal transplant recipients after remdesivir exposure. Our work underscores the need for augmented efforts to identify concerning mutations and address their clinical implications.

Keywords: antiviral resistance; immunocompromise; remdesivir; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); solid-organ transplant.

Figure 1.

A, Timeline of SARS-CoV-2 infection and relation between remdesivir exposure and the subsequent development of the de novo RdRp V792I mutation in Case 1 and Case 2. Ct values are provided at points when the patient was symptomatic and a high-quality SARS-CoV-2 genomic sequence was obtained (circles). For Case 1, 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; and for case 2, 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. Case 1 CT of the abdomen demonstrating mass-like thickening along the renal graft (white arrow) contiguous with the abdominal wall is shown above the timeline (left); and Case 2 CT of the chest (right) demonstrating multifocal nodules, many of which are surrounded by ground-glass opacities. The black arrow indicates a cavitary lesion. An elevated galactomannan level from bronchoalveolar lavage fluid suggested the diagnosis of pulmonary aspergillosis. B, Full genome mutation profiles of SARS-CoV-2 viruses in longitudinal specimens of 2 immunocompromised patients treated with remdesivir (Case 1, left; Case 2, right). Base-pair (bp) mutations compared with the Wuhan-Hu-1 reference are shown as ticks, color-coded according to the legend on the lower left. The 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 nonsynonymous. The longitudinal acquisition of mutations in nsp12 and 14 is 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 as black circles and days (d) elapsed since the first COVID-19 sampling per patient on the right of each plot. A 3D protein structure of the multidomain polymerase complex is shown in its active dimeric form (bottom right). 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 cofactor 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 nonsynonymous mutations in nsp12 and 14 as well as remdesivir are highlighted and labeled. Abbreviations: COVID-19, coronavirus disease 2019; Ct, cycle threshold; CT, computed tomography; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; seq, sequence.