A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes

Abstract

Molnupiravir, an antiviral medication widely used against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus and many will be lethal; thus, molnupiravir-induced elevated mutation rates reduce viral load1,2. However, if some patients treated with molnupiravir do not fully clear the SARS-CoV-2 infections, there could be the potential for onward transmission of molnupiravir-mutated viruses. Here we show that SARS-CoV-2 sequencing databases contain extensive evidence of molnupiravir mutagenesis. Using a systematic approach, we find that a specific class of long phylogenetic branches, distinguished by a high proportion of G-to-A and C-to-T mutations, are found almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and age groups with widespread use of the drug. We identify a mutational spectrum, with preferred nucleotide contexts, from viruses in patients known to have been treated with molnupiravir and show that its signature matches that seen in these long branches, in some cases with onward transmission of molnupiravir-derived lineages. Finally, we analyse treatment records to confirm a direct association between these high G-to-A branches and the use of molnupiravir.

Protracted COVID‐19 pneumonitis early post‐ABO incompatible kidney transplantation: Management considerations and the role of whole genome sequencing

“…By virtue of its mechanism of action, molnupiravir induces viral mutagenesis and, as was noted in our patient, an increased genetic diversity has been observed in surviving viral populations of SARS-CoV-2 from patients treated with molnipiravir. 5 The impact of molnupiravir-associated genetic diversity, particularly in immunocompromised hosts where endogenous mechanisms of viral clearance are impaired, is unclear. We prescribed remdesivir rather than nirmatrelvir/ritonavir due to CYP-3A4 interactions 6 interferon gamma release assay was weakly positive, indicating an inadequate T cell response, due to transplant immunosuppression.…”

“…4 GenXpert ® Xpress SARS-CoV-2. 5 WGS: Long-read sequencing was performed on the Oxford Nanopore Technologies platform and consensus genomes were generated using ARTIC workflows. SARS-CoV-2 genomic lineages were inferred using Phylogenetic Assignment of Named Global Outbreak Lineages (PANGOLIN).…”

Alterations of SARS-CoV-2 Evolutionary Dynamics by Pharmaceutical Factors

“…[27] Although a lack of directionality in selection is evident, [53] the emergence of molnupiravir-induced escape mutations is possible. [54] For instance, a retrospective analysis revealed a 6-fold increase in substitution rates in patients treated with molnupiravir than in those who were untreated. [53] This is consistent with other studies showing higher SARS-CoV-2 genetic variation among patients receiving molnupiravir treatment.…”

“…These sequences have also linked to continued transmission in many cases. [54] 4. The development of drug resistance Antivirals acting by lethal mutagenesis are not a novel concept.…”

Two short approaches to the COVID-19 drug β-d-N4-hydroxycytidine and its prodrug molnupiravir

“…8 The FDA determined that molnupiravir does not have drug–drug interactions and, on the basis of genotoxicity data, that it posed a low risk for 5 days of treatment. 7,9 Although there has been a recent claim that transmission of a mutated virus could occur from molnupiravir-treated patients in whom the virus is not completely cleared, 10 the US has a plan to purchase 1.7 million doses of molnupiravir. 11 Recently, both N 4 -hydroxycytidine and molnupiravir have been found to show broad-spectrum activity against enterovirus in vitro and in vivo .…”