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Influenza Antivirals

There are three principal classes of antivirals licensed for prophylaxis and treatment of influenza, those targeted against the M2 proton channel, those against the neuraminidase and those against the RNA polymerase. An inhibitor of the membrane fusion activity of the HA, which represents a fourth class, is licensed in a number of countries. 

M2 inhibitors

Amantadine (Symmetrel®), developed in the 1960s, and rimantadine (Flumadine®) inhibit the function of the M2 protein of influenza A in virus uncoating, but are not effective against influenza B viruses.  They have not been widely used and resistance of currently circulating A(H1N1)pdm09 and A(H3N2) viruses has removed their usefulness against seasonal influenza.

Neuraminidase Inhibitors

Zanamivir (Relenza®) and oseltamivir (Tamiflu®) were developed in the 1990s against the neuraminidase, which is involved in the release and spread of progeny virus.  They are effective against both influenza A and B viruses, and are widely available.  Whereas zanamivir is administered by inhalation, oseltamivir is administered orally, as a prodrug, and has proved to be more widely accepted, and has been the principal choice for antiviral stockpiles as a component of pandemic preparedness.  However resistance to oseltamivir has occurred more frequently than resistance to zanamivir. Two other neuraminidase inhibitors have been licensed more recently: laninamivir (Inavir®) a long-lasting analogue of zanamivir, administered by inhalation as a single therapeutic dose, has been licensed in Japan; peramivir, which possesses the active moieties of both zanamivir and oseltamivir, has been licensed in Japan (Rapiacta®) and Korea (PeramiFlu®) for intravenous administration.

Polymerase inhibitors

Baloxavir Marboxil (XofluzaTM) an oral prodrug that targets the PA, cap-dependent endonuclease, subunit of the RNA polymerase was approved in Japan and the USA in 2018 for treatment of uncomplicated influenza A and B infections.

Favipiravir (T705) targets the RNA polymerase and has a broad spectrum of activity against a variety of RNA virus families and is effective against all three types of influenza, A, B and C. It has been approved in Japan for use against novel or re-emerging influenza viruses.

Pimodivir (VX-787) which inhibits the PB2 cap-binding subunit of the RNA polymerase of influenza A viruses, but not influenza B, has not yet been approved for clinical use.

HA inhibitors

Arbidol targets the membrane fusion activity of the HA in vitro.  It exhibits a broad spectrum of antiviral activity in vitro, including against influenza A and B, and has been shown to have immunomodulatory activity in vivo; the basis of its clinical efficacy against influenza has therefore yet to be established.  Arbidol was initially licensed for use against influenza in Russia and has since been licensed in China and a number of other countries.

A variety of other antivirals, against both virus and host targets, are in development by a number of companies, including broadly-reactive monoclonal antibodies, as illustrated by the ‘landscape’ of influenza antiviral development in the USA (Fig 1).

Fig 1. Influenza Antiviral Landscape 2022, provided by the Biomedical Advanced Research & Development Authority (BARDA), HHS Office of the Assistant Secretary for Preparedness and Response, USA