There are two main classes of antiviral drugs that have been used for the treatment and prophylaxis of influenza – neuraminidase inhibitors and adamantanes. Multiple novel therapies are currently in development.
Neuraminidase inhibitors are the mainstay of antiviral therapy against influenza. However, they need to be started within 48 hours of symptom onset and are most effective within 24 hours.
They inhibit the viral neuraminidase enzyme, preventing the virus from escaping the host cell.20 Three neuraminidase inhibitors are currently registered in Australia – oral oseltamivir, inhaled zanamivir and intravenous peramivir.21
Oseltamivir shortens the duration of symptoms in uncomplicated influenza by approximately one day.22,23 The majority of studies were in healthy adults, and this effect has not been shown in asthmatic children.22,23 Inhaled zanamivir has shown a similar reduction in duration of symptoms in adults but has no significant effect in children.22,23 Single-dose intravenous peramivir is non-inferior to oseltamivir in adults and is a potential alternative for those who cannot take oral or inhaled medicines.24
A newer long-acting neuraminidase inhibitor, laninamivir, achieves high concentrations in lung tissue with the potential to treat influenza following a single inhaled dose. It has comparable efficacy to oseltamivir in adults.25,26 An intravenous form of zanamivir has been recently studied in populations with severe influenza and also shows similar outcomes to oseltamivir.27 While these two drugs are not currently registered in Australia, intravenous zanamivir has been used through the Special Access Scheme for critically ill patients with influenza.21
The role of neuraminidase inhibitors in reducing influenza complications is less clear.22,23 While oseltamivir has been shown to reduce unverified pneumonia, this has not been confirmed in trials with robust diagnostic criteria.23It has also not been shown to reduce the rate of hospital admissions.22
Zanamivir has not been found to reduce pneumonia complications and its effect on hospital admissions has not been studied.22,23 In patients with influenza the use of neuraminidase inhibitors has been associated with a mortality benefit, with delayed treatment resulting in increased mortality.28
Recommendations for treatment
Prompt commencement of neuraminidase inhibitors is recommended for patients with confirmed or suspected influenza who require hospitalisation, or are at risk of complications (including children <5 years, adults ≥65 years, pregnant women, immunosuppressed patients or significant comorbidities), or have severe, complicated or progressive disease.29-31 Therapy should begin within 48 hours of the onset of illness, but in severe disease treatment may still be beneficial if given outside this timeframe.28,30 Treatment should also be considered in those who have household contacts who are at high risk of influenza complications.30,31 The recommended duration of therapy (oseltamivir and zanamivir) is five days.29 In healthy outpatients with uncomplicated influenza, treatment can be of limited benefit.29,30 Antibiotics are only indicated when patients have bacterial complications.29,31
Antiviral resistance has been well described in at-risk populations including immunocompromised hosts and young children due to a high virus burden and prolonged replication promoting resistance mutations.32Factors that increase the risk of resistance include suboptimal antiviral dosing and cross-transmission of resistant strains in outbreaks.32,33 The H275Y mutation is commonly associated with oseltamivir-resistant influenza A strains, but laninamivir and zanamivir rarely show cross-resistance to strains expressing this mutation.32
Adamantanes work by inhibiting the M2 ion channel.20They are not recommended due to widespread resistance in circulating influenza viruses.20,29 Currently amantadine is the only drug to be registered in Australia for influenza. Its use is limited to prophylaxis of influenza A.21,34 When used for treatment, amantadine shortens the duration of fever by approximately one day, but has no effect on nasal shedding or upper airways viral clearance.34