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Favipiravir induces HuNoV viral mutagenesis and infectivity loss with clinical improvement in immunocompromised patients

Kreins, Alexandra Y; Roux, Emma; Pang, Juanita; Cheng, Iek; Charles, Oscar; Roy, Sunando; Mohammed, Reem; ... Breuer, Judith; + view all (2024) Favipiravir induces HuNoV viral mutagenesis and infectivity loss with clinical improvement in immunocompromised patients. Clinical Immunology , Article 109901. 10.1016/j.clim.2024.109901. Green open access

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Abstract

Chronic human norovirus (HuNoV) infections in immunocompromised patients result in severe disease, yet approved antivirals are lacking. RNA-dependent RNA polymerase (RdRp) inhibitors inducing viral mutagenesis display broad-spectrum in vitro antiviral activity, but clinical efficacy in HuNoV infections is anecdotal and the potential emergence of drug-resistant variants is concerning. Upon favipiravir (and nitazoxanide) treatment of four immunocompromised patients with life-threatening HuNoV infections, viral whole-genome sequencing showed accumulation of favipiravir-induced mutations which coincided with clinical improvement although treatment failed to clear HuNoV. Infection of zebrafish larvae demonstrated drug-associated loss of viral infectivity and favipiravir treatment showed efficacy despite occurrence of RdRp variants potentially causing favipiravir resistance. This indicates that within-host resistance evolution did not reverse loss of viral fitness caused by genome-wide accumulation of sequence changes. This off-label approach supports the use of mutagenic antivirals for treating prolonged RNA viral infections and further informs the debate surrounding their impact on virus evolution.

Type: Article
Title: Favipiravir induces HuNoV viral mutagenesis and infectivity loss with clinical improvement in immunocompromised patients
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.clim.2024.109901
Publisher version: http://dx.doi.org/10.1016/j.clim.2024.109901
Language: English
Additional information: © 2024 The Authors. Published by Elsevier Inc. under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Favipiravir, Human norovirus infection, Immunodeficiency, Mutagenic antivirals, Virus whole-genome-sequencing, Zebrafish larvae
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10185705
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