Antiviral treatments lead to the rapid accrual of hundreds of SARS-CoV-2 mutations in immunocompromised patients
Fountain-Jones et al.,
Antiviral treatments lead to the rapid accrual of hundreds of SARS-CoV-2 mutations in immunocompromised..,
medRxiv, doi:10.1101/2022.12.21.22283811 (Preprint)
Analysis of immunocompromised patients showing rapid creation of new variants with molnupiravir. All patients treated with molnupiravir accrued new mutations in the spike protein of the virus, including non-synonymous mutations that altered the amino acid sequence. Authors note that uncontrolled use may generate new variants with a transmission advantage that prolongs the pandemic and makes other therapeutics less effective.
Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer [Hadj Hassine, Swanstrom]. See [] for analysis of a variant potentially created by molnupiravir.
Fountain-Jones et al., 22 Dec 2022, Australia, preprint, 7 authors.
Abstract: medRxiv preprint doi: https://doi.org/10.1101/2022.12.21.22283811; this version posted December 22, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .
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Antiviral treatments lead to the rapid accrual of hundreds of SARS-CoV-2 mutations in
immunocompromised patients
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Authors: Nicholas M. Fountain-Jones1,2*, Robert Vanhaeften1, Jan Williamson1, Janelle
Maskell1, I-Ly J Chua1, Michael Charleston2 & Louise Cooley1,3
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Affiliations:
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Royal Hobart Hospital, Pathology Department, Hobart Australia 7001.
School of Natural Sciences, University of Tasmania, Hobart Australia 7001.
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School of Medicine, University of Tasmania, Hobart Australia 700.1
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Keywords: Paxlovid, Molnupiravir, Lageviro, virus evolution, resistance
Abstract
The antiviral Molnupiravir (Lageviro) is widely used across the world to treat SARS-CoV-2
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infection. Molnupiravir reduces viral replication by inducing mutations throughout the
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genome, yet in patients that do not clear the infection, the longer-term impact of the drug on
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virus evolution is unclear. Here, we used a case-control approach to monitor SARS-CoV-2
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genomes through time in nine immunocompromised -patients with five treated with
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Molnupiravir. Within days of treatment, we detected a large number of low-frequency
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mutations in patients and that these new mutations could persist and, in some cases, were
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fixed in the virus population. All patients treated with the drug accrued new mutations in the
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spike protein of the virus, including non-synonymous mutations that altered the amino acid
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sequence. Our study demonstrates that this commonly used antiviral can ‘supercharge’ viral
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evolution in immunocompromised patients, potentially generating new variants and
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prolonging the pandemic.
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NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
medRxiv preprint doi: https://doi.org/10.1101/2022.12.21.22283811; this version posted December 22, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .
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Main text:
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Persistent SARS-CoV-2 infection in immunocompromised patients is recognized as an
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important source of genomic variation and is linked to the evolution of novel variants 1–3.
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How commonly used antivirals such as Molnupiravir shape viral evolution is an important
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knowledge gap. As of December 2022, Molnupiravir is routinely used globally to treat
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COVID patients in and outside of hospital settings, including treatment of
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immunocompromised patients 4. Molnupiravir and other similar direct-acting SARS-CoV-2
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antivirals promote mutagenesis by incorporating the prodrug NHC (β-D-N4-hydroxycytidine)
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into the virus-dependent RNA polymerase (RdRp)5. When the RdRp uses the NHC modified
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RNA as a template it promotes an ‘error catastrophe’ 5,6 that inhibits the replication of SARS-
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CoV-2. For immunocompromised patients that do not clear infection after antiviral treatment,
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the impact that these drugs have on..
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