Donovan-Banfield, I'ah 
ORCID: 0000-0002-5124-2427, Penrice-Randal, Rebekah ORCID: 0000-0002-0653-2097, Goldswain, Hannah ORCID: 0000-0003-4194-8714, Rzeszutek, Aleksandra M, Pilgrim, Jack, Bullock, Katie, Saunders, Geoffrey, Northey, Josh, Dong, Xiaofeng, Ryan, Yan ORCID: 0000-0002-4708-5350 et al (show 24 more authors)
(2022)
Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial.
NATURE COMMUNICATIONS, 13 (1).
7284-.
Abstract
Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)-2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Antiviral Agents, Genomics, SARS-CoV-2, COVID-19 Drug Treatment |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 30 Nov 2022 12:20 |
| Last Modified: | 10 Jan 2023 13:21 |
| DOI: | 10.1038/s41467-022-34839-9 |
| Open Access URL: | https://doi.org/10.1038/s41467-022-34839-9 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3166454 |
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