M49L and other drug resistance mutations emerging in individuals after administration of ensitrelvir in Japanese clinical settings

Recent in-vitro and in-vivo studies and analysis of genomic information registered in GISAID have raised concerns about drug resistance mutations such as M49L after treatment with the 3C-like protease inhibitor ensitrelvir. The aim of this study was to identify resistance gene mutations to 3C-like protease inhibitors, including M49L mutations, in Japanese clinical settings. Genomic analysis of samples from our hospital admissions showed M49L mutations associated with ensitrelvir treatment in two cases and M49L mutation unrelated to ensitrelvir treatment in three cases. In a study of cases with persistent infection or rebound in viral load after 5 days of ensitrelvir treatment, 10 of 16 patients had M49L mutations and 5 had M49I mutations. Resistance gene mutations following treatment with ensitrelvir were shown to emerge even within individual patients who were not immunocompromised. In a study of persistent SARS-CoV-2 infection in severely immunocompromised patients, various drug resistance mutations emerged, with the M49L mutation especially showing a tendency to be a majority mutation. The current status of drug resistance mutations occurring in individuals following administration of ensitrelvir in Japanese clinical settings was clinically investigated for the first time. Genomic analysis of SARS-CoV-2 should continue, and the occurrence of ensitrelvir resistance gene mutations should be closely monitored.