Session:

Update on Influenza

Abstract No.:

24.003

Title:

Newer influenza antivirals and biotherapeutics

Author(s):

F. Hayden; University of Virginia School of Medicine, Medicine, Charlottesville, VA/US

Abstract:

The limitations of availabe antiviral agents, the M2 ion channel and neuraminidase inhibitors (NAIs), including resistance issues indicate the need for developing alternative agents.Novel antivirals presently in clinical development include intravenous NAIs (oseltamivir, peramivir, zanamivir), long-acting inhaled NAIs (laninamivir), attachment blockers (e.g., DAS181), viral RNA polymerase inhibitors (e.g., ribavirin, favipiravir), passive immunotherapy (convalescent plasma, heterosubtypic neutralizing anti-HA stem monoclonals, anti-M2 monoclonals), and interferons.  Intravenous zanamivir and peramivir are undergoing active-controlled study in patients hospitalized with serious influenza.  One-time treatment with intravenous peramivir or inhaled laninamivir appears comparable to a standard 5-day regimen of oral oseltamivir in uncomplicated influenza, and both agents are approved for use in Japan (peramivir also in South Korea). Of note, zanamivir and laninamivir are inhibitory for H275Y-containing N1 viruses. Orally inhalation of the HA receptor-destroying sialidase DAS 181 showed antiviral effects in uncomplicated influenza, and the oral anti-parasitic agent nitazoxanide was recently reported to have beneficial effects in a phase 2 study in ambulatory patients. Other novel approaches include RNA interference, with one construct targeting influenza M gene now in clinical study, and agents that inhibit host cell functions essential for influenza replication. Combinations of influenza antivirals with differing mechanisms of action can enhance antiviral activity and reduce resistance emergence. One nonrandomized study of convalescent plasma for pandemic 2009 A(H1N1) patients reported significantly reduced mortality compared to NAI therapy alone, and an NIAID-sponsored controlled study in hospitalized patients is in progress. One triple regimen of oral amantadine, ribavirin, and oseltamivir (termed TCAD) shows greater antiviral activity than each dual combination, and a controlled study comparing TCAD to oseltamivir monotherapy is underway in at-risk ambulatory patients.  One controlled study in adults with uncomplicated influenza (primarily A/H3N2) found that oseltamivir alone was superior to a combination of oseltamivir and inhaled zanamivir. Combination studies involving antivirals and immunomodulatory interventions that might address excessive or inadequate host responses are also needed.Newer agents will provide opportunities for studying drug combinations, coping with the problem of antiviral resistance, and expanding the therapeutic repertoire for influenza management, especially in seriously ill patients and immunocompromised hosts.