Category:Anti-influenza agents

An anti-influenza agent is a medicine used to treat or prevent infection by influenza A or influenza B virus. The category sits within antivirals and contains three mechanistic classes that have entered clinical use in succession: the M2 ion-channel inhibitors (amantadine, rimantadine; now retired by universal resistance), the neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, laninamivir), and the cap-dependent endonuclease inhibitor baloxavir marboxil.

The first effective anti-influenza medicine was amantadine, synthesised in 1963 at DuPont as a candidate antiviral on the basis of its symmetric tricyclic structure and shown shortly afterwards to inhibit influenza A virus replication. The clinical mechanism was elucidated in the 1980s: amantadine blocks the M2 proton channel of the influenza A virion envelope, preventing the acidification of the viral interior that is required for uncoating after endocytosis. The medicine was active against influenza A only (influenza B has a structurally distinct M2-equivalent that amantadine does not bind), and its clinical use was limited by central-nervous-system adverse effects (insomnia, dizziness, in older adults occasional psychosis) and by the development of resistance through a single S31N substitution in the M2 channel. By the 2005-2006 season, essentially 100 percent of circulating H3N2 influenza A isolates carried the S31N mutation; the medicine has been retired from anti-influenza use since approximately 2008 and is now used principally for Parkinson's disease.

The transformative event of contemporary anti-influenza pharmacology was the development of the neuraminidase inhibitors. The viral neuraminidase, an enzyme on the influenza envelope that cleaves sialic acid residues from cell-surface glycoproteins and so allows release of newly synthesised virions from infected cells, was identified in the 1950s and crystallised in 1983 by Peter Colman at the CSIRO in Melbourne, Australia. Colman's group, working with the GlaxoWellcome team led by Mark von Itzstein, used the crystal-structure-derived knowledge of the active site to design zanamivir (Relenza, GlaxoWellcome 1999), the first structure-based-design success in antiviral pharmacology.^[1] Zanamivir's poor oral bioavailability restricted it to inhalation; oseltamivir (Tamiflu, Gilead/Roche 1999), an oral prodrug whose active metabolite oseltamivir carboxylate binds the same active site, became the standard oral anti-influenza medicine. The intravenous peramivir (Rapivab, BioCryst 2014) and the inhaled long-acting laninamivir (Inavir, Japan 2010) extended the class. The neuraminidase inhibitors are active against both influenza A and B, with substantially lower clinically meaningful resistance than the M2 inhibitors (resistance is reported but has not become epidemic to the extent of M2 resistance).

The clinical effect of neuraminidase inhibitors in influenza is meaningful but modest. In immunocompetent adults treated within 48 hours of symptom onset, oseltamivir reduces symptom duration by approximately one day and reduces the rate of secondary lower-respiratory complications and antibacterial prescription; the absolute benefit is larger in high-risk populations (the elderly, the immunocompromised, pregnant women, those with chronic cardiopulmonary disease) and in severe disease requiring hospitalisation, where intravenous oseltamivir or peramivir may reduce mortality. The 2014 publication of the Cochrane review of the oseltamivir trial data (after a multi-year effort to obtain the full clinical-study reports from Roche) re-evaluated the medicine's benefit downward; the response from the influenza-clinical community has been that the Cochrane analysis underweighted the high-risk-population benefit and that the medicine retains an important role in selected patients.

The most recent addition is the cap-dependent endonuclease inhibitor baloxavir marboxil (Xofluza, Shionogi/Roche 2018). Baloxavir blocks the cap-snatching step of viral mRNA synthesis: the influenza polymerase complex normally cleaves host mRNA cap structures and uses them as primers for viral mRNA, and baloxavir inhibits the endonuclease (PA subunit) responsible for this cleavage. The medicine is administered as a single oral dose and rapidly reduces viral shedding (substantially more rapidly than oseltamivir in head-to-head trials), with comparable effect on symptom duration. The treatment-emergent baloxavir resistance (PA I38T substitution) is a substantial concern: 5-to-10 percent of treated patients develop the mutation, and the clinical implications for the next influenza season are uncertain. Baloxavir is currently used in selected patients rather than as universal first-line.

The contemporary anti-influenza strategy in seasonal practice is therefore: vaccination as the foundation of prevention (described under biologics rather than here); oseltamivir 75 mg twice daily for 5 days as first-line treatment in symptomatic patients within 48 hours of onset, particularly in high-risk populations; intravenous peramivir or oseltamivir in patients unable to tolerate oral medicine; baloxavir as alternative in selected uncomplicated outpatient cases with full discussion of the resistance risk; and monoclonal antibodies (none currently approved but several in trial) as future options. Avian-influenza (H5N1, H7N9) outbreaks raise the question of pandemic preparedness, in which the neuraminidase inhibitors remain the foundational antiviral.

By mechanism:

• Neuraminidase inhibitors (active against influenza A and B):
  • Oseltamivir (Tamiflu; oral; the standard treatment)
  • Zanamivir (Relenza; inhaled; for patients tolerant of inhaler use)
  • Peramivir (Rapivab; intravenous single dose)
  • Laninamivir (Inavir; inhaled long-acting; Japan only)
• Cap-dependent endonuclease inhibitor:
  • Baloxavir (Xofluza; oral single dose; concern for treatment-emergent PA I38T resistance)
• M2 ion-channel inhibitors (largely retired):
  • Amantadine (Symmetrel; influenza A only; not used since 2008 because of universal resistance; current use is Parkinson's disease)
  • Rimantadine (Flumadine; same status)

The boundary of this category is "medicine used to treat or prevent influenza A or B infection." The influenza vaccines (the inactivated trivalent and quadrivalent vaccines, the live attenuated FluMist, the cell-based and recombinant formulations including Flublok, the high-dose Fluzone for adults over 65, the adjuvanted Fluad) are the foundation of prevention; they are biologics rather than antivirals and are listed under biologics. The monoclonal antibody candidates in development for influenza prophylaxis or treatment are biologics in the same sense and are not collected here. The supportive-care medicines used in severe influenza (oxygen, mechanical ventilation, extracorporeal membrane oxygenation, the supportive antibiotics for secondary bacterial pneumonia particularly with Staphylococcus aureus or Streptococcus pneumoniae) are listed under their primary mechanism categories.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.