The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in severe models of COVID-19
The central aim of this study was to risk-assess the impact of administering a mutagenic antiviral compound, molnupiravir, to patients believed to already be at risk of generating increased viral diversity, which could have severe implications for antiviral resistance development. Combination therapy has a long history of mitigating antiviral resistance risk and was used in this study to demonstrate its potential usefulness in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) context. Animals treated with molnupiravir showed an increase in transition/transversion ratios over time, consistent with the drug's mechanism of action and a recent UK-wide phase II clinical trial assessing the efficacy of molnupiravir in humans. The addition of nirmatrelvir increased viral clearance, which in turn reduces the probability of viral persistence and rapid intra-host evolution of SARS-CoV-2.
Authors
- Chloe Bramwell (ORCID: https://orcid.org/0000-0001-8274-457X)
- Joanne Sharp (ORCID: https://orcid.org/0000-0001-8482-5736)
- Julian A. Hiscox (ORCID: https://orcid.org/0000-0002-6582-0275)
- Adam Kirby (ORCID: https://orcid.org/0009-0007-2708-3909)
- Daniele F. Mega (ORCID: https://orcid.org/0009-0004-4700-353X)
- I’ah Donovan-Banfield (ORCID: https://orcid.org/0000-0002-5124-2427)
- Andrew Owen (ORCID: https://orcid.org/0000-0002-9819-7651)
- Anja Kipar (ORCID: https://orcid.org/0000-0001-7289-3459)
- Eleanor G. Bentley
- Rebekah Penrice-Randal (ORCID: https://orcid.org/0000-0002-0653-2097)
- Parul Sharma (ORCID: https://orcid.org/0009-0007-4989-0381)
- James P. Stewart
Institutions
- Agency for Science, Technology and Research (SG)
- University of Liverpool (GB)
- University of Zurich (CH)
- Star Technology and Research (United States) (US)
- Health Protection Research Unit in Emerging and Zoonotic Infections at University of Liverpool (GB)
Publication Details
- Journal
- Microbiology Spectrum
- Published
- 2025-03-25
- DOI
- https://doi.org/10.1128/spectrum.01829-24
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Medical Research Council Canada
- National Institutes of Health
- U.S. Food and Drug Administration
- Biotechnology and Biological Sciences Research Council
- Innovate UK
- Centre For Medical Engineering, King’s College London