Use of whole genome sequencing to identify low‐frequency mutations in SARS‐CoV‐2 patients treated with remdesivir

Abstract

BackgroundRemdesivir (RDV) has been shown to reduce hospitalization and mortality in COVID‐19 patients. Resistance mutations caused by RDV are rare and have been predominantly reported in patients who are on prolonged therapy and immunocompromised. We investigate the effects of RDV treatment on intra‐host SARS‐CoV‐2 diversity and low‐frequency mutations in moderately ill hospitalized COVID‐19 patients and compare them to patients without RDV treatment.MethodsFrom March 2020 to April 2022, sequential collections of nasopharyngeal and mid‐turbinate swabs were obtained from 14 patients with and 30 patients without RDV treatment. Demographic and clinical data on all patients were reviewed. A total of 109 samples were sequenced and mutation analyses were performed.ResultsPreviously reported drug resistant mutations in nsp12 were not identified during short courses of RDV therapy. In genes encoding and surrounding the replication complex (nsp6‐nsp14), low‐frequency minority variants were detected in 7/14 (50%) and 18/30 (60%) patients with and without RDV treatment, respectively. We did not detect significant differences in within‐host diversity and positive selection between the RDV‐treated and untreated groups.ConclusionsMinimal intra‐host variability and stochastic low‐frequency variants detected in moderately ill patients suggests little selective pressure in patients receiving short courses of RDV. The barrier to RDV resistance is high in patients with moderate disease. Patients undergoing short regimens of RDV therapy should continue to be monitored.

Clinico-Virological Outcomes and Mutational Profile of SARS-CoV-2 in Adults Treated with Ribavirin Aerosol for COVID-19 Pneumonia

“…However, sequence analysis of nasopharyngeal samples did not show a clear effect of RDV on viral evolution by comparison of mutational patterns at T1 (before remdesivir administration), T2 (corresponding to first administration of remdesivir), and BL administration of RBV (corresponding to the completion of a 5-day course of RDV treatment) ( Supplementary Figure S1 ). In this regard, a recent study showed no resistance mutations and minimal intra-host diversity in serial samples of patients receiving short courses of RDV for moderate COVID-19 disease, suggesting that the barrier to RDV resistance is high in patients with moderate disease under short-term treatment [ 40 ].…”