Abstract
Influenza virus infections and their associated morbidity and mortality are a major threat to global health. Vaccination is an effective influenza prevention measure; however, the effectiveness is challenged by the rapid changes in the influenza virus genome leading to viral adaptation. Emerging viral resistance to the neuraminidase inhibitor oseltamivir limits the treatment of acute influenza infections. Targeting influenza virus-host interactions is a new and emerging field, and therapies based on the combination of virus- and host-directed drugs might significantly improve treatment success. We therefore assessed the combined treatment with oseltamivir and the repurposed antifungal drug itraconazole on infection of polarized broncho-epithelial Calu-3 cells with pdm09 or Panama influenza A virus strains. We detected significantly stronger antiviral activities in the combined treatment compared to monotherapy with oseltamivir, permitting lower concentrations of the drug than required for the single treatments. Bliss independence drug interaction analysis indicated that both drugs acted independently of each other. The additional antiviral effect of itraconazole might safeguard patients infected with influenza virus strains with heightened oseltamivir resistance.
Highlights
With 3–5 million severe cases worldwide and 300,000–700,000 fatalities annually, influenza virus is a major threat to public health, and poses a substantial burden on health care resources.In addition to the annual epidemics, sudden and unpredictable pandemics present global health emergencies
Oseltamivir and itraconazole were added at the indicated combinations 2 h p.i
We analyzed the antiviral effects of combined treatment with the influenza A virus (IAV) neuraminidase-targeting drug oseltamivir and itraconazole, a licensed antifungal that we previously reported to efficiently block
Summary
With 3–5 million severe cases worldwide and 300,000–700,000 fatalities annually, influenza virus is a major threat to public health, and poses a substantial burden on health care resources. While baloxavir marboxil is another success in the development of antiviral medication, especially because of the approval extension for treatment of high-risk patients, oseltamivir is still the leading, most commonly used drug in influenza infection treatment. The use of host-directed therapeutics which interfere with host cell factors that are essentially required for a successful replication process is an emerging approach to counteract viral infection [19,20,21,22,23]. We explored the effect of a combinatory use of the antiviral drug oseltamivir and the host-directed anti-infective drug itraconazole on IAV infection in a cell culture model of polarized bronchial cell monolayers. The additional antiviral effect of itraconazole might safeguard patients infected with influenza strains with heightened oseltamivir resistance
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