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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; [...]

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

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  • Media type: E-Article
  • Title: Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial
  • Contributor: 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; [...]
  • Published: Springer Science and Business Media LLC, 2022
  • Published in: Nature Communications, 13 (2022) 1
  • Language: English
  • DOI: 10.1038/s41467-022-34839-9
  • ISSN: 2041-1723
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>n</jats:italic> = 59 for molnupiravir and <jats:italic>n</jats:italic> = 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.</jats:p>
  • Access State: Open Access