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.
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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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