Combined Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 Reduces Molnupiravir-Induced Mutagenicity and Prevents Selection for Nirmatrelvir/Ritonavir Resistance Mutations

J Infect Dis. 2024 Dec 16;230(6):1380-1383. doi: 10.1093/infdis/jiae213.

Abstract

We investigated the mutation profiles of severe acute respiratory syndrome coronavirus 2 in samples collected from a molnupiravir and nirmatrelvir/ritonavir combination therapy in macaques. We found that molnupiravir induced several nirmatrelvir resistance mutations at low abundance that were not further selected in combination therapy. Coadministration of nirmatrelvir/ritonavir lowered the magnitude of the mutagenetic effect of molnupiravir.

Keywords: SARS-CoV-2; combination therapy; lethal mutagenesis; molnupiravir; nirmatrelvir.

MeSH terms

  • Animals
  • Antiviral Agents* / pharmacology
  • Antiviral Agents* / therapeutic use
  • COVID-19 Drug Treatment*
  • Cytidine* / analogs & derivatives
  • Cytidine* / pharmacology
  • Cytidine* / therapeutic use
  • Drug Resistance, Viral* / genetics
  • Drug Therapy, Combination
  • Hydroxylamines* / pharmacology
  • Hydroxylamines* / therapeutic use
  • Indazoles / pharmacology
  • Lactams
  • Leucine* / analogs & derivatives
  • Leucine* / pharmacology
  • Mutation*
  • Nitriles
  • Proline / analogs & derivatives
  • Proline / pharmacology
  • Proline / therapeutic use
  • Ritonavir* / pharmacology
  • Ritonavir* / therapeutic use
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / genetics
  • Uridine / pharmacology
  • Uridine / therapeutic use

Substances

  • molnupiravir
  • Ritonavir
  • Hydroxylamines
  • Antiviral Agents
  • Cytidine
  • nirmatrelvir
  • Leucine
  • Proline
  • Uridine
  • Indazoles
  • Lactams
  • Nitriles