T-705 (favipiravir) activity against lethal H5N1 influenza A viruses

TLDR

Oseltamivir and zanamivir are used to treat H5N1 influenza, but resistance has emerged and reassortment could render them ineffective, underscoring the need for new antivirals; T‑705 (favipiravir) has shown activity against seasonal influenza and a mouse‑adapted H5N1 strain, though its efficacy against highly pathogenic H5N1 remains uncertain. The study aims to evaluate T‑705 as a novel antiviral for highly pathogenic H5N1 influenza. Biochemical analysis indicates that T‑705 ribofuranosyl triphosphate mimics purines in human cells and does not inhibit DNA synthesis. T‑705 protected mice from lethal infection with both oseltamivir‑sensitive and -resistant highly pathogenic H5N1 viruses, indicating promise as a therapeutic agent.

Abstract

The neuraminidase inhibitors oseltamivir and zanamivi are used to treat H5N1 influenza. However, oseltamivir-resistant H5N1 viruses have been isolated from oseltamivir-treated patients. Moreover, reassortment between H5N1 viruses and oseltamvir-resistant human H1N1 viruses currently circulating could create oseltamivir-resistant H5N1 viruses, rendering the oseltamivir stockpile obsolete. Therefore, there is a need for unique and effective antivirals to combat H5N1 influenza viruses. The investigational drug T-705 (favipiravir; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has antiviral activity against seasonal influenza viruses and a mouse-adapted H5N1 influenza virus derived from a benign duck virus. However, its efficacy against highly pathogenic H5N1 viruses, which are substantially more virulent, remains unclear. Here, we demonstrate that T-705 effectively protects mice from lethal infection with oseltamivir-sensitive or -resistant highly pathogenic H5N1 viruses. Furthermore, our biochemical analysis suggests that T-705 ribofuranosyl triphosphate, an active form of T-705, acts like purines or purine nucleosides in human cells and does not inhibit human DNA synthesis. We conclude that T-705 shows promise as a therapeutic agent for the treatment of highly pathogenic H5N1 influenza patients.