Transient SARS-CoV-2 RNA-Dependent RNA Polymerase Mutations after Remdesivir Treatment for Chronic COVID-19 in Two Transplant Recipients: Case Report and Intra-Host Viral Genomic Investigation

Abstract

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.

In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants

“…A strong argument for combining drugs with different mechanisms of action is the need to limit the emergence of drug resistance, which is clearly a major issue with persistent viruses. However, there have been reports of rapid selection of drug resistance also with exposure of SARS-CoV-2 to mAb or DAA, particularly in immunocompromised subjects requiring prolonged treatment [ 28 , 29 , 30 , 31 ]. Combination therapy with SARS-CoV-2 has been so far limited to mAb cocktails, including casirivimab/imdevimab, bamlanivimab/etesevimab, and CIL/TIX.…”

An Update on SARS-CoV-2 Clinical Trial Results—What We Can Learn for the Next Pandemic

“…In addition, drug-induced viral mutations have been described for SARS-CoV-2 therapeutics, however, so far mostly in immunosuppressed individuals. Further, circulating viruses may harbour variants that are resistant to DAA, such as G15S and T21I that confer resistance to the M Pro inhibitor Paxlovid [ 277 , 278 , 279 ]. The ongoing identification and characterisation of drug-resistant signatures within the SARS-CoV-2 genome will be crucial for clinical management and virus surveillance [ 280 ].…”