Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial

Donovan-Banfield, I’ah, Penrice-Randal, Rebekah, Goldswain, Hannah, Rzeszutek, Aleksandra M., Pilgrim, Jack, Bullock, Katie, Saunders, Geoffrey, Northey, Josh, Dong, Xiaofeng, Ryan, Yan, Reynolds, Helen, Tetlow, Michelle, Walker, Lauren E., FitzGerald, Richard, Hale, Colin, Lyon, Rebecca, Woods, Christie, Ahmad, Shazaad, Hadjiyiannakis, Dennis, Periselneris, Jimstan, Knox, Emma, Middleton, Calley, Lavelle-Langham, Lara, Shaw, Victoria, Greenhalf, William, Edwards, Thomas, Lalloo, David ORCID: https://orcid.org/0000-0001-7680-2200, Edwards, Christopher J., Darby, Alistair C., Carroll, Miles W., Griffiths, Gareth, Khoo, Saye H., Hiscox, Julian A. and Fletcher, Tom (2022) 'Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial'. Nature Communications, Vol 13, Issue 1, e7284.

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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
Subjects:	QU Biochemistry > Genetics > QU 460 Genomics. Proteomics QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 250 Anti-infective agents (General) WC Communicable Diseases > Virus Diseases > Viral Respiratory Tract Infections. Respirovirus Infections > WC 506 COVID-19
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1038/s41467-022-34839-9
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	20 Dec 2022 15:51
Last Modified:	20 Dec 2022 15:51
URI:	https://archive.lstmed.ac.uk/id/eprint/21555

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