Abstract
The prolonged treatment of immunosuppressed (IS) individuals with anti-influenza monotherapies may lead to the emergence of drug-resistant variants. Herein, we evaluated oseltamivir and polymerase inhibitors combinations against influenza A/H3N2 infections in an IS mouse model. Mice were IS with cyclophosphamide and infected with 3 × 103 PFU of a mouse-adapted A/Switzerland/9715293/2013 (H3N2) virus. Forty-eight hours post-infection, the animals started oseltamivir, favipiravir or baloxavir marboxil (BXM) as single or combined therapies for 10 days. Weight losses, survival rates and lung viral titers (LVTs) were determined. The neuraminidase (NA) and polymerase genes from lung viral samples were sequenced. All untreated animals died. Oseltamivir and favipiravir monotherapies only delayed mortality (the mean day to death (MDD) of 21.4 and 24 compared to 11.4 days for those untreated) while a synergistic improvement in survival (80%) and LVT reduction was observed in the oseltamivir/favipiravir group compared to the oseltamivir group. BXM alone or in double/triple combination provided a complete protection and significantly reduced LVTs. Oseltamivir and BXM monotherapies induced the E119V (NA) and I38T (PA) substitutions, respectively, while no resistance mutation was detected with combinations. We found that the multiple dose regimen of BXM alone provided superior benefits compared to oseltamivir and favipiravir monotherapies. Moreover, we suggest the potential for drug combinations to reduce the incidence of resistance.
Highlights
Influenza viruses (IVs) are among the most important pathogens causing severe respiratory infections
We confirmed that the lymphoproliferative response and number of total T, B and neutrophil cells was reduced. We used such an IS mouse model and we evaluated whether the combination of Oseltamivir phosphate (OS) and polymerase inhibitors (FA or baloxavir marboxil (BXM)) would improve therapeutic efficacy and reduce the emergence of resistance mutations compared with single therapy following lethal infection with a contemporary mouse-adapted influenza A/H3N2 virus [29]
Efficacy of Single and Combined Therapies In IS mice infected with the mouse-adapted A/Switzerland/9715293/2013 (H3N2) virus, the body weight loss was observed earliest in the untreated group, whereas the OS- or FA-treated mice started losing body weight on days 18 and 20 p.i., respectively (Figure 1)
Summary
Influenza viruses (IVs) are among the most important pathogens causing severe respiratory infections. Two classes of antivirals targeting the viral neuraminidase (NA) and the polymerase complex are currently clinically available for the treatment of influenza infections. Oseltamivir phosphate (OS), a NA inhibitor (NAI), is the most frequently prescribed compound and has demonstrated efficacy against influenza A and B viruses [2,3]. In 2018, the novel antiviral, baloxavir marboxil (BXM) was approved in the USA, Japan and several other countries for the treatment of uncomplicated influenza in otherwise healthy individuals [4,5]. Its active form, baloxavir acid (BXA), potently inhibits the influenza cap-dependent endonuclease encoded by the PA gene, preventing viral replication [6]
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