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Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study

Fountain-Jones et al., The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2
Mar 2024  
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Analysis of immunocompromised COVID-19 showing rapid creation of new variants with molnupiravir. Some mutations became fixed in the viral population and the distinctive mutational pattern, dominated by G-to-A and C-to-T transitions, persisted up to 44 days post-treatment. Treated patients maintained PCR positivity for the duration of monitoring, indicating potential for transmission of mutated virus and subsequent emergence of novel variants. 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 cancer1-9. Multiple analyses have identified variants potentially created by molnupiravir10-13.
Fountain-Jones et al., 22 Mar 2024, Australia, peer-reviewed, 7 authors. Contact: nick.fountainjones@utas.edu.au.
This PaperMolnupiravirAll
Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study
PhD, R Vanhaeften BSc Nicholas M Fountain-Jones, Robert Vanhaeften, PhD, J Maskell BAppSc Jan Williamson, Janelle Maskell, MBBS I-Ly J Chua, Michael Charleston, MBBS Louise Cooley
doi:10.1016/S2666-5247(23)00393-
Introduction Continued SARS-CoV-2 infection among immunocompromised individuals is likely to play a role in generating genomic diversity and the emergence of novel variants. Antiviral treatments such as molnupiravir are used to mitigate severe COVID-19 outcomes, but the extended effects of these drugs on viral evolution in patients with chronic infections remain uncertain. This study investigates how molnupiravir affects SARS-CoV-2 evolution in immunocompromised patients with prolonged infections. Methods The study included five immunocompromised patients treated with molnupiravir and four patients not treated with molnupiravir (two immunocompromised and two non-immunocompromised). We selected patients who had been infected by similar SARS-CoV-2 variants and with high-quality genomes across timepoints to allow comparison between groups. Throat and nasopharyngeal samples were collected in patients up to 44 days post treatment and were sequenced using tiled amplicon sequencing followed by variant calling. The UShER pipeline and University of California Santa Cruz genome viewer provided insights into the global context of variants. Treated and untreated patients were compared, and mutation profiles were visualised to understand the impact of molnupiravir on viral evolution. Findings Patients treated with molnupiravir showed a large increase in low-to-mid-frequency variants in as little as 10 days after treatment, whereas no such change was observed in untreated patients. Some of these variants became fixed in the viral population, including non-synonymous mutations in the spike protein. The variants were distributed across the genome and included unique mutations not commonly found in global omicron genomes. Notably, G-to-A and C-to-T mutations dominated the mutational profile of treated patients, persisting up to 44 days post treatment. Interpretation Molnupiravir treatment in immunocompromised patients led to the accumulation of a distinctive pattern of mutations beyond the recommended 5 days of treatment. Treated patients maintained persistent PCR positivity for the duration of monitoring, indicating clear potential for transmission and subsequent emergence of novel variants.
References
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