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PHE guidance on use of antiviral agents for the treatment and prophylaxis of seasonal influenza

This Guidelines summary provides the key points for primary care, please refer to the full guideline for the complete set of recommendations. Please refer to the PHE website to ensure you are using the most recent version of this document

Definitions

  • Uncomplicated influenza: influenza presenting with fever, coryza, generalised symptoms (headache, malaise, myalgia, arthralgia) and sometimes gastrointestinal symptoms, but without any features of complicated influenza
  • Complicated influenza: influenza requiring hospital admission and/or with symptoms and signs of lower respiratory tract infection (hypoxaemia, dyspnoea, lung infiltrate), central nervous system involvement and/or a significant exacerbation of an underlying medical condition.
  • Risk factors for complicated influenza:
    • neurological, hepatic, renal, pulmonary and chronic cardiac disease
    • diabetes mellitus
    • severe immunosuppression
    • age over 65 years
    • pregnancy (including up to two weeks post partum)
    • children under 6 months of age
    • morbid obesity (BMI ≥40)
  • For full details refer to Immunisation against infectious disease, known as the Green Book
  • Severe immunosuppression: Examples of severe immunosuppression relevant to this guidance are given below. Degrees of immunosuppression are difficult to quantify and individual variation exists, therefore this list is not comprehensive
    • severe primary immunodeficiency
    • current or recent (within six months) chemotherapy or radiotherapy for malignancy
    • solid organ transplant recipients on immunosuppressive therapy
    • bone marrow transplant recipients currently receiving immunosuppressive treatment, or within 12 months of receiving immunosuppression
    • patients with current graft-versus-host disease
    • patients currently receiving high dose systemic corticosteroids (equivalent to ≥40 mg prednisolone per day for >1 week in an adult, or ≥ 2 mg/kg/day for ≥1 week in a child), and for at least three months after treatment has stopped
    • HIV infected patients with severe immunosuppression (CD4<200/μl or <15% of total lymphocytes in an adult or child over five; CD4< 500/μl or <15% of total lymphocytes in a child aged one to five; expert clinical opinion in a child aged under one)
    • patients currently or recently (within six months) on other types of highly immunosuppressive therapy or where the patient’s specialist regards them as severely immunosuppressed

Treatment of suspected or confirmed influenza

Algorithm for the selection of antiviral therapy for treatment of influenza 1280x1238

Algorithm for the selection of antiviral therapy for treatment of influenza*

  • Some influenza subtypes are associated with a greater risk of developing oseltamivir resistance. The risk of resistance is greatest in people who are severely immunosuppressed. The selection of first line antivirals in severely immunosuppressed individuals should take account of the subtype of influenza causing infection, or if not yet known, the dominant strain of influenza that is circulating during the current influenza season
  • In general, influenza A (H1N1) is considered to be a higher risk for the development of oseltamivir resistance, whilst influenza A(H3N2) and influenza B are considered lower risk. This list is not exhaustive of all possible subtypes causing human infection, and further advice on the risk of individual subtypes can be obtained from a Consultant Microbiologist or Consultant Virologist
  • The dominant circulating strain of influenza is obtainable from the PHE weekly influenza reports. Table 1 (below) provides guidance on the selection of antivirals for severely immunosuppressed patients, taking into account the dominant circulating strain of influenza, and the risk of developing oseltamivir resistance
Table 1: Selection of antivirals for severely immunosuppressed patients
 Dominant circulating strain has a lower risk of oseltamivir resistance, eg A(H3N2), influenza B§Dominant circulating strain has a higher risk of oseltamivir resistance, e.g. A(H1N1)§

Uncomplicated influenza

Oseltamivir PO and clinical follow up. 
Commence therapy within 48 hours of onset (or later at clinical discretion)

Zanamivir INH (Diskhaler®

Commence therapy within 36 hours of onset (or later at clinical discretion)

or  if unable to take inhaled preparation use oseltamivir PO and clinical follow up

Commence therapy within 48 hours of onset (or later at clinical discretion)

Complicated influenza

First line: oseltamivir PO/NG
Second line: zanamivir INH, NEB or IV
Consider switching to zanamivir if:
– poor clinical response
– subtype testing confirms a strain with potential oseltamivir resistance, e.g. A(H1N1)

Zanamivir INH, NEB or IV

Commence therapy within 48 hours of onset (36 hours for children) or later at clinical discretion

(if there are delays in obtaining aqueous zanamivir, use oseltamivir as a bridging treatment until zanamivir is available)

§ also applicable if this is the strain known to be infecting patient; treatment however, should not be delayed while waiting for test results

Treatment of adults and children in community/A&E with uncomplicated influenza

  • All patients should be advised of the symptoms of complicated influenza and told to seek medical help should their condition worsen. The following recommendations for adults refer to dosages in Box 1.For paediatric dosing, see full guideline
    • previously healthy people (excluding pregnant women): No antiviral treatment, or if physician feels patient is at serious risk of developing serious complications from influenza, then oseltamivir PO
    • at risk population, including pregnant women (but excluding the severely immunosuppressed): Oseltamivir (PO). Do not wait for laboratory confirmation. Treatment should be started as soon as possible, ideally within 48 hours of onset. There is evidence that treatment may reduce the risk of mortality even if started up to five days after onset. Treatment after 48 hours is an off-label use of oseltamivir and clinical judgement should be exercised
    • severely immunosuppressed patients: Some influenza subtypes are associated with a greater risk of developing oseltamivir resistance, and the selection of first line antivirals in severely immunosuppressed individuals should take account of the dominant circulating strain of influenza (Table 1). The risk of resistance is highest in people who are severely immunosuppressed and have complicated influenza, who are given antivirals. Oseltamivir PO is the first line treatment, unless the dominant circulating strain is influenza A(H1N1) which has a higher risk for developing oseltamivir resistance, in which case use zanamivir (INH) (Table 1). Treatment should start as soon as possible. If clinical condition does not improve, continue with Zanamivir, take a specimen for resistance testing and consider other possible causes for a failure to improve
    • suspected or confirmed oseltamivir resistant influenza in a patient who requires treatment: Zanamivir (INH). Treatment should be started as soon as possible
    • management of patients for whom zanamivir is indicated, who are unable to self-administer inhaled zanamivir: Some patients who would normally receive inhaled zanamivir are unable to use it, either due to underlying severe respiratory disease or inability to effectively self-administer the Diskhaler® (this includes children under 5, for whom zanamivir is unlicensed). Patients who are severely immunosuppressed and cannot take inhaled zanamivir should receive oseltamivir PO. As they are at increased risk of developing oseltamivir resistant influenza, they should be reviewed clinically to assess response to therapy. Patients who have suspected or confirmed oseltamivir resistant infection and cannot take inhaled zanamivir should be considered for nebulised aqueous zanamivir. This is an unlicensed medication and the dose is provided on the manufacturer’s guidance supplied with the drug (see full guideline)
Box 1. Dosage in adults for treatment of uncomplicated influenza

Oseltamivir 75 mg PO twice daily for 5 days  

Zanamivir 10 mg INH twice daily for 5 days 

Note: dose adjustments for obesity, renal dysfunction and use in children are provided in the full guideline

Treatment of adults and children with complicated influenza

  • All patients with complicated influenza should receive treatment, often in hospital. Rapid testing for respiratory viruses including influenza virus is recommended for all patients fulfilling the clinical criteria for complicated infection. Treatment should be started as early as possible; do not wait for laboratory confirmation of influenza virus infection
  • Ensure that appropriate infection control precautions are applied to the patients (see PHE guidance on Infection control precautions to minimize transmission of acute respiratory tract infections in healthcare settings for further details
  • A history of influenza immunisation does not exclude influenza as a possible diagnosis. The duration of therapy depends on clinical response. Test for antiviral resistance in patients who do not respond after five days of treatment
  • The following recommendations include the use of IV antivirals and nebulised aqueous zanamivir, which are unlicensed medications (see full guideline)
    • first line treatment: Oseltamivir PO or NG (see exceptions below). There is evidence that PO/NG oseltamivir is adequately absorbed in critical illness at standard doses
    • second line treatment: If there is a poor clinical response to first line treatment switch to zanamivir. If there is evidence of gastrointestinal dysfunction, which could cause decreased absorption of enterically-administered medications, use zanamivir. Examples include known gastroparesis, clinical evidence of malabsorption, uncontrollable vomiting, and gastrointestinal bleeding. Some patients who are considered to have good respiratory function despite their illness may be able to use inhaled zanamivir. Those who cannot use a zanamivir Diskhaler® should be considered for nebulised aqueous zanamivir. The following patients may be considered for IV zanamivir: patients who have already failed to respond to nebulised zanamivir; patients who have developed respiratory conditions affecting nebuliser delivery (eg airways disease, pulmonary oedema); patients who have multi-organ involvement or who require intensive care

Exceptions:

  • Severely immunosuppressed patients: Oseltamivir (PO or NG) is the first line treatment, unless the dominant circulating strain is influenza A(H1N1) (Table 1) Treatment should start as soon as possible. Arrange influenza A subtype testing and monitor clinical condition closely. If there is a poor clinical response, consider switching to zanamivir and test for oseltamivir resistance.
  • If the dominant circulating strain is influenza A(H1N1), use zanamivir (INH or NEB) as first line treatment (Table 1). Patients who cannot use inhaled zanamivir should be considered for nebulised aqueous zanamivir (unlicensed). IV zanamivir (unlicensed) may be considered for patients who have already failed to respond to nebulised zanamivir; patients who have developed respiratory conditions affecting nebuliser delivery; patients who have multi-organ involvement or who require intensive care.
  • Suspected or confirmed oseltamivir resistance: for example, contact of known oseltamivir resistant case. Do not use oseltamivir. Some patients considered to have good respiratory function despite their illness may be able to use inhaled zanamivir (Diskhaler®). Those who cannot should be considered for nebulised aqueous zanamivir (unlicensed). IV zanamivir (unlicensed) may be considered for patients who have already failed to respond to nebulised zanamivir; patients who have developed respiratory conditions affecting nebuliser delivery; patients who have multi-organ involvement or who require intensive care.

Post exposure prophylaxis

  • NICE has provided guidance stating that oseltamivir and zanamivir may be used for prophylaxis of persons in at risk groups (see definitions above) following exposure to a person in the same household or residential setting with influenza-like illness when influenza is circulating in the community
  • As per NICE guidance, prophylaxis should be issued if the contact is not adequately protected by vaccination, that is:
    • the vaccination is not well matched to the circulating strain, or
    • there has been less than 14 days between vaccination and date of first contact with influenza
  • In addition, the guidance also states that—if the individual has been exposed as part of a localised outbreak (such as in a care home), antiviral prophylaxis may be given regardless of vaccination status. For further guidance on care home outbreaks, see PHE guidance on the management of outbreaks of influenza like illness (ILI ) in care homes
Table 2: Selection of antivirals for post-exposure prophylaxis
 If identified strain in index case or dominant circulating strain is lower risk for oseltamivir resistance e.g. influenza A (H3N2), influenza BIf identified strain in index case or dominant circulating strain is known to higher risk for oseltamivir resistance e.g. influenza A (H1N1)Exposed to suspected or confirmed oseltamivir resistant influenza

Previously healthy (excluding pregnant women)

No prophylaxis

No prophylaxis

No prophylaxis

At risk of complicated influenza (including pregnant women but excluding severely immunosuppressed patients and excluding children under 5 years)

Oseltamivir PO once daily for 10 days, if therapy can be started within 48 hours of exposure; or after 48 hours on specialist advice only

Oseltamivir PO once daily for 10 days, if therapy can be started within 48 hours of exposure; or after 48 hours on specialist advice only

Zanamivir INH once daily for 10 days, if therapy can be started within 36 hours of exposure; or after 36 hours on specialist advice only

Severely immunosuppressed patients (excluding children under 5 years)

Oseltamivir PO once daily for 10 days, if therapy can be started within 48 hours of exposure; or after 48 hours on specialist advice only

Zanamivir INH once daily for 10 days, if therapy can be started within 36 hours of exposure; or after 36 hours on specialist advice only. If unable to administer zanamivir INH, oseltamivir PO once daily for 10 days, if therapy can be started within 48 hours of exposure; or after 48 hours on specialist advice only

Zanamivir INH once daily for 10 days, only if therapy can be started within 36 hours of exposure; or after 36 hours on specialist advice only. If unable to administer zanamivir INH, discuss with specialist and consider nebulised aqueous zanamivir (unlicensed) after individual risk assessment

Children under 5 years in at risk groups including severely immunocompromised children

Oseltamivir PO once daily for 10 days, if therapy can be started within 48 hours of exposure; or after 48 hours on specialist advice only

Oseltamivir PO once daily for 10 days, if therapy can be started within 48 hours of exposure; or after 48 hours on specialist advice only

Discuss with specialist. Consider nebulised aqueous zanamivir (unlicensed) after individual risk assessment

Note: Commencing prophylaxis with oseltamivir later than 48 hours after exposure, or with zanamivir, later than 36 hours after exposure is an off-label use. Specialist advice referred to in the table above may be obtained from a local infection specialist such as a virologist

  • Specialist advice is available from local health protection teams and public health virologists for prophylaxis in healthcare settings where repeated or ongoing exposure is suspected
  • An alternative to prophylaxis in some clinical settings may be to monitor persons exposed to an influenza case and start antiviral treatment promptly when symptoms of influenza start. It is recommended that such an arrangement is undertaken only when:
    • the patient (or their carer) has been provided with information on symptoms prompting antiviral use, potential adverse events, and has decided to take antiviral medicines for treatment rather than prophylaxis and
    • the clinician has made arrangements in advance for the patient to promptly receive and start antiviral treatment within 48 hours of symptom onset (or 36 hours for zanamivir treatment in children)

Summary algorithm for prescribing antiviral treatment for influenza

Summary algorithm for prescribing antiviral treatment for influenza 1280x1776

Summary algorithm for prescribing antiviral treatment for influenza|

Prescribing in primary care 

  • GPs may only prescribe antiviral medicines for the prophylaxis and treatment of influenza under the General Medical Services (GMS) regulations when the Chief Medical Officer (CMO) has confirmed that influenza is circulating in the community. The CMO announcement is issued to the NHS through the DH Central Alerting System (CAS)
  • GPs have the discretion to prescribe antiviral medicines for people who are not in the specified at-risk groups but who are considered to be at risk of complications if not treated with an antiviral medicine

full guideline available from…

www.gov.uk/government/publications/influenza-treatment-and-prophylaxis-using-anti-viral-agents

Public Health England. PHE guidance on use of antiviral agents for the treatment and prophylaxis of seasonal influenza.  September 2017.

First included: November 2017.