TY - JOUR
T1 - Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial
AU - Donovan-Banfield, I’ah
AU - Penrice-Randal, Rebekah
AU - Goldswain, Hannah
AU - Rzeszutek, Aleksandra M.
AU - Pilgrim, Jack
AU - Bullock, Katie
AU - Saunders, Geoffrey
AU - Northey, Josh
AU - Dong, Xiaofeng
AU - Ryan, Yan
AU - Reynolds, Helen
AU - Tetlow, Michelle
AU - Walker, Lauren E.
AU - FitzGerald, Richard
AU - Hale, Colin
AU - Lyon, Rebecca
AU - Woods, Christie
AU - Ahmad, Shazaad
AU - Hadjiyiannakis, Dennis
AU - Periselneris, Jimstan
AU - Knox, Emma
AU - Middleton, Calley
AU - Lavelle-Langham, Lara
AU - Shaw, Victoria
AU - Greenhalf, William
AU - Edwards, Thomas
AU - Lalloo, David G.
AU - Edwards, Christopher J.
AU - Darby, Alistair C.
AU - Carroll, Miles W.
AU - Griffiths, Gareth
AU - Khoo, Saye H.
AU - Hiscox, Julian A.
AU - Fletcher, Thomas
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85142939554&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-34839-9
DO - 10.1038/s41467-022-34839-9
M3 - Article
C2 - 36435798
AN - SCOPUS:85142939554
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7284
ER -