No emergence of resistance mutations in COVID‐19 patients receiving nirmatrelvir/ritonavir

Abstract

To the Editor, Nirmatrelvir/ritonavir is a combination antiviral drug for the treatment of COVID-19 in high-risk patients prone to severe disease that reduces the likelihood of hospitalization and mortality. [1][2][3][4] It is administered orally and should be taken for 5 days, within 5 days of symptom onset. 5 Different to other COVID-19 treatments, 6 there are few longitudinal genomic analyses of the emergence of nirmatrelvir resistance in clinical samples. Most of the evidence for resistance mutations for this drug comes from in silico, in vitro, and ex vivo studies and they are located in the residues S144, M165, E166, H172, and Q192 of the Mpro gene. [7][8][9][10] The compensatory mutations, T21I and L50F, have been found to offset the effects of substitutions in E166, restoring the cell growth kinetics. 10 Recently, mutations in Mpro (E166V/L50V and E166A/V) have been identified in two immunocompromised patients undergoing prolonged treatment, leading to therapeutic failures. 11,12 The aim of our study was to evaluate the emergence of nirmatrelvir/ritonavir resistance mutations in the clinical setting, in a longitudinal analysis of 60 patients who received it at our institution (April-October 2022), and had ≥1 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nasopharyngeal positive specimen (C t < 32), 3-13 days after starting treatment. Whole-genome sequencing was performed as described elsewhere. 6 The sequences