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Antivirals: Treatment, Prophylaxis and Pandemic Control

Figure 22 The mechanism by which antiviral drugs interrupt the replicative cycle of influenza is illustrated. M2 inhibitors prevent the M2-mediated acidification of the interior of the virus while it resides in endosomes and the subsequent uncoating of the viral genome, thus inhibiting viral replication. Neuraminidase inhibitors (NAIs) prevent cleavage of sialic acid residues and thus newly formed virus cannot be released from the cell surface to infect adjacent cells; also, virus particles remain associated to one another. source: “The treatment of influenza with antiviral drugs” – Reprinted from CMAJ 07-Jan-03; 168(1): 49–57 by permission of the publisher. © 2003 CMA Media Inc.

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  • The mechanisms of action of the four available specific anti-influenza viral drugs are summarized in Figure 22.
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  • In addition, within the infected cell, M2 protects newly synthesized HA against premature exposure to low pH by transiently neutralizing the pH of the trans-Golgi network, while HA is in transit to the cell surface.4 Amantadine and rimantadine counteract this protection and thus indirectly induce a premature conformational change in HA, inactivating the protein (Figure 22).
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  • In addition, within the infected cell, M2 protects newly synthesized HA against premature exposure to low pH by transiently neutralizing the pH of the trans-Golgi network, while HA is in transit to the cell surface.4 Amantadine and rimantadine counteract this protection and thus indirectly induce a premature conformational change in HA, inactivating the protein (Figure 22).
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Figure 23 The neuraminidase inhibitors zanamivir and oseltamivir are structural analogs of sialic acid, which is the substrate of neuraminidase (NA) and the receptor for the influenza virus HA. Zanamivir and oseltamivir bind to the substrate binding site of NA, thus blocking its enzymatic activity. Zanamivir (GG167 or Relenza®) is inhaled or administered intranasally. Oseltamivir is given as the oral prodrug oseltamivir phosphate (GS4104 or Tamiflu®), which is converted in the liver to oseltamivir carboxylate GS4071, the active drug.

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  • Zanamivir and oseltamivir are analogues of sialic acid, as shown in Figure 23.2 These compounds specifically inhibit all nine NA subtypes in nature, including the subtypes contained in the avian strains of influenza A H5N1, H7N7 and H9N2 that have infected humans (see also Chapter 3).
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Table 13 Comparison of antiviral drugs for prophylaxis and treatment of influenza. source: Reproduced from La Rosa AM and Whimbey E. Respiratory viruses. In: Cohen J, Powderly WG, editors. Infectious Diseases, 2nd edn, 2003 with permission from Elsevier.

Comparison of antiviral drugs for prophylaxis and treatment of influenza
Drug Trade name Influenza type Dosing for prophylaxis Dosing for treatment Main side effects
Amantadine Symmetrel® A Age 1–9 years: Age 1–9 years: Central nervous system
5 mg/kg/day, p.o. div b.i.d. 5 mg/kg/day, p.o. div b.i.d.
Age 9 and up: Age 9 and up:
100 mg p.o. b.i.d. 100 mg p.o. b.i.d.
Rimantadine Flumadine® A Age 1–10 years: Adults: Central nervous
5 mg/kg/day, p.o. q.d. 100 mg p.o. b.i.d. system
Age 10 and up:
100 mg p.o. b.i.d.
Zanamivir Relenza® A and B N/A Age >7 years: Bronchial
10 mg inhaled b.i.d.
Oseltamivir Tamiflu® A and B Age 1–12 years: Age 1–12 years: Gastrointestinal
dose per weight dose per weight
Age ≥ 13 years: Age 13 and up:
75 mg p.o. q.d. 75 mg p.o. b.i.d.

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  • Table 13 presents a comparison between the different antiviral drugs available for treatment (amantadine, rimantadine and oseltamivir) and prophylaxis (amantadine, rimantadine, oseltamivir and zanamivir) of influenza.
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*For children who weigh <15 kg the dose is 30 mg b.i.d.; for those who weigh 15–23 kg, it is 45 mg b.i.d.; for those who weigh 23–40 kg, it is 60 mg b.i.d.; and for those who weigh >40 kg, it is 75 mg b.i.d.

Table 14 Indications for antiviral drugs against influenza. source: Adapted from CDC, Prevention and control of influenza. Recommendations ACIP. MMWR Recomm Rep 2004; 53 (RR-6): 1–40.

Indications for antiviral drugs against influenza
  • Patients at risk and their household contacts, who have not (yet) been vaccinated at the time when influenza infections are becoming widespread in an area.
  • Control of an outbreak in a (semi-)closed community (e.g. nursing home).
  • Patients at risk with a known hypersensitivity to chicken proteins (contraindication for vaccination).
  • Vaccine mismatch between vaccine component and circulating virus strain.
  • Pandemic threat with no vaccine (yet) available.

References in context

  • The influenza antiviral drugs should only be used to treat patients if the clinical picture meets the criteria for influenza-like illness (ILI) and if influenza activity has been reported in the area. Table 14 lists indications for influenza antivirals.
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