| Summary: | Persistent SARS-CoV-2 infections may act as viral reservoirs that could seed future outbreaks 1–5, give rise to highly divergent lineages 6–8, and contribute to cases with post-acute COVID-19 sequelae (Long Covid) 9,10. However, the population prevalence of persistent infections, their viral load kinetics, and evolutionary dynamics over the course of infections remain largely unknown. Using viral sequence data collected as part of a national infection survey, we identified 381 individuals with SARS-CoV-2 RNA at high titre persisting for at least 30 days, of which 54 had viral RNA persisting at least 60 days. We refer to these as ‘persistent infections’ since available evidence suggests they represent ongoing viral replication, although the persistence of non-replicating RNA cannot be ruled out in all. Persistently infected individuals had more than 50% higher odds of self-reporting Long Covid compared to non-persistently infected individuals. We estimate that 0.1- 0.5% of infections may become persistent with typically rebounding high viral loads and last for at least 60 days. In some individuals, we identified many viral amino acid substitutions, indicating periods of strong positive selection, while others had no consensus change in the sequences for prolonged periods, consistent with weak selection. Substitutions included mutations that are lineage-defining for SARS-CoV-2 variants, at target sites for monoclonal antibodies, and/or commonly found in immunocompromised patients 11–14. This work has significant implications for understanding and characterising SARS-CoV-2 infection, epidemiology, and evolution.
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