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This page explores ten questions that Public Health England (PHE) is frequently asked about their guidance on antiviral treatment and prophylaxis for seasonal influenza. Links to the Guidelines summaries of PHE’s guidance are below:

Questions covered on this page

 

1. When should I consider continuing antiviral therapy beyond 5 days?

  • The optimal duration of treatment is not clear for hospitalised patients with influenza. Persistent detection of viral ribonucleic acid (RNA) and ‘rebound’ of previously undetectable viral RNA have been described in patients with severe influenza who received 5 or 7 day courses of oseltamivir. Extending the duration of treatment to at least 10 days may be appropriate in patients with severe influenza (e.g. critically ill patients) and in severely immunosuppressed patients. Prolonged treatment can be associated with the development of antiviral resistance, particularly in immunosuppressed patients, and antiviral resistance monitoring is recommended. Prescribers are reminded that use of oseltamivir as treatment for longer than 5 days is an off-label use

2. What is meant by ‘poor clinical response to first line treatment’?

  • A poor clinical response may manifest as failure to improve, progressive lower respiratory tract signs or symptoms, or new or progressive multi-organ dysfunction in a patient receiving first line antiviral treatment. Antiviral resistance (pre-existing or new on-treatment resistance) is just one potential explanation for a poor clinical response. Antiviral resistance is more likely to occur in patients infected with influenza A(H1N1) virus, rather than infections caused by other seasonal influenza viruses. It is also more likely to occur in patients with known risk factors for antiviral resistance, for example, severely immunosuppressed patients. However, failure to improve or clinical deterioration may also be explained by the natural progression of acute lung injury and the inflammatory response seen in influenza illness, or by secondary infections e.g. bacterial co-infection. Therefore, the assessment of whether a patient has a poor clinical response can only be made by the treating clinician, guided by these considerations

3. In which groups of patients are influenza viruses with reduced antiviral susceptibility more likely to emerge?

  • Patients who are undergoing treatment with influenza antiviral drugs, particularly immunocompromised patients and young children, are more likely to harbour viruses with reduced antiviral drug susceptibility. This might be explained by prolonged durations of infection and/or greater viral burden, compared to other groups. Rapid emergence of oseltamivir resistance (as early as 48h after starting treatment) has been described, particularly in severely immunocompromised patients
  • Between July 2009 and April 2010, 285 oseltamivir-resistant cases of pandemic influenza A (H1N1)pdm09 infection were reported worldwide, including 45 in the UK. Data were available from 34 of the patients from England and Scotland. Of 28 for whom there was information on underlying conditions, 21 (75%) were classified as being immunosuppressed. All but 2 of the immunosuppressed patients had a hematologic cancer, and 8 of them had undergone hematopoietic cell transplantation. The most common condition was leukaemia (11 of 21), of which 5 had chronic lymphocytic leukaemia

4. If zanamivir resistance is suspected, should I switch to oseltamivir?

  • No. Recent antiviral resistance surveillance data for seasonal influenza viruses demonstrate that resistance to oseltamivir remains more common than resistance to zanamivir. Several mutations that confer resistance to zanamivir are also associated with resistance or reduced susceptibility to oseltamivir. If zanamivir resistance is believed to be a possibility (eg as a potential reason for failure to improve), then continue zanamivir treatment and arrange urgent resistance testing. Seek advice from local infection specialists. Additional advice is available from regional public health virologists and from the Respiratory Virus Unit at PHE

5. What is the role of repeat sampling and laboratory testing in patients receiving antivirals?

  • It is recognised that it can be challenging to assess clinical improvement in specific patient groups such as the immunosuppressed or unconscious/ventilated, because they may have atypical or minimal clinical signs and symptoms or be unable to describe symptoms. In such patients with confirmed influenza who are receiving antivirals, repeat or ‘follow-up’ sampling for detection of viral RNA by polymerase chain reaction (PCR) can be considered if the patient:
    • deteriorates or has a non-resolving illness despite at least 5 days of antivirals and may require an extended duration of antiviral treatment
    • develops influenza illness whilst receiving prophylactic-dose antivirals; either test at the outset or test according to non-resolving deterioration
  • When repeat testing has been performed because of suspected treatment failure, antiviral resistance testing should be considered on any positive sample, and is recommended in the context of immunosuppression. Comparing estimated viral load between the initial and repeat sample can be helpful in determining the antiviral effect. Repeat sampling is not routinely recommended for patient groups other than those described above
  • The policy on the surveillance and laboratory diagnosis of antiviral resistant influenza, to support reporting of UK information to WHO is available here
  • If oseltamivir resistance is suspected and further treatment is required, then consider switching to zanamivir before the results of resistance testing are known. Treatment interruption should be avoided (e.g. when awaiting results of follow-up testing), since it can be associated with the development of antiviral resistance
  • Clinicians should be mindful of the potential need for continued infection control measures for inpatients if repeat sampling for PCR testing provides positive results

6. Should healthcare workers with no underlying illness who are unvaccinated be offered antiviral prophylaxis?

  • Currently, prophylaxis is only given to at-risk groups and is not recommended as an alternative to immunisation. The use of prophylactic antivirals in individuals not in riskgroups as a way of controlling an outbreak in hospital settings is not recommended by PHE. Healthcare workers who are not in an at-risk group may continue to work, using appropriate personal protective equipment and should rapidly report any illness. They should then be excluded from work promptly if they develop symptoms consistent with influenza. The importance of seasonal influenza immunisation of healthcare workers needs to be emphasised as does the advice for staff not to come to work if they are ill

7. What is the role of previously diagnosed influenza (laboratory detected) when a person presents with a new influenza-like illness in the same season?

  • The 2 infections should be considered separately and treatment given, if indicated, on both occasions. It is entirely possible that the first infection is with an influenza A virus and the infection later in the season with an influenza B virus so there would not be a protective effect from the first exposure

8. What are the recommendations with regard to use of oseltamivir in neonates exposed to mothers with seasonal influenza? (updated 2018)

  • Clinicians may be faced with particular situations where a pregnant woman develops laboratory confirmed seasonal influenza infection shortly before onset of labour. Questions may then arise about recommendations for the use of antivirals in this situation. It should be noted that the potential mode of influenza transmission in this situation is via direct contact from infected respiratory secretions rather than via breastmilk itself
  • As previously stated in this guidance, pregnant women experience an increased risk of developing complicated influenza and associated severe outcomes, such as ICU admission and death. Therefore, antiviral treatment of a pregnant woman with seasonal influenza should be strongly considered in line with the recommendations featured earlier in this guidance document
  • There are, however, limited data on seasonal influenza infection in neonates. The Influenza Clinical Information Network (Flu-CIN) study reported severe outcomes in 9.3% of children aged <12 months in the UK who were hospitalised with Influenza A(H1N1pdm09) during the 2009–2010 pandemic
  • The summary of product characteristics for Tamiflu® (oseltamivir) oral suspension states that the medicine can be used for post-exposure prevention of influenza in infants aged over 1 year; therefore oseltamivir prophylaxis for infants aged less than 1 year would be an off-label use. Treatment of seasonal influenza in children including full term neonates are however, specified in the summary of product characteristics for capsules and Tamiflu® (oseltamivir) 6 mg/ml Powder for Oral suspension. Relenza® (zanamivir) inhalation powder is not licensed for treatment or prophylaxis in children under 5 years of age
  • In addition to the recommendation for antiviral treatment of pregnant mothers, there are three potential options which may be considered by mothers and clinicians in a joint discussion in these situations in relation to neonates:
    1. oseltamivir oral suspension for post-exposure prophylaxis in the neonate, as an off-label indication
    2. physical separation of the symptomatic mother and asymptomatic neonate until 5 days after the onset of symptoms. The disadvantages for the neonate would include not being able to benefit from breastfeeding-related transfer of immune factors to help protect the baby and nutrients for development; these considerations should be included in the discussion with the mother. Women should be encouraged to express breastmilk so that the neonate can receive the benefits of breastmilk, and to maintain the mother’s milk supply so that breastfeeding can continue once they are reunited
    3. no prophylaxis for the neonate and no separation of neonate and mother. This will require careful monitoring for symptoms of influenza, a discussion in advance with the mother about prompt antiviral treatment of the neonate, and arrangements made in advance for rapidly accessing oseltamivir oral suspension (as this is more readily available via hospital pharmacies than community pharmacies). There should also be consideration of laboratory testing of a symptomatic neonate, as per existing local practice. In this situation, the mother should be advised to wash their hands with soap and water, particularly before breast feeding or touching any other item that the neonate will have contact with. If expressing breast milk using a pump, this should be cleaned as per the manufacturer’s instructions
  • PHE recognises that the decision on which action to take is likely to involve a detailed discussion between the mother and their clinicians about the relative advantages and disadvantages of each potential option in relation to their own individual situation. This advice does not constitute a specific PHE endorsement of the routine use of oseltamivir oral suspension for prophylaxis in neonates, but recognises that this may occur as an off-label use in specific circumstances. Such scenarios highlight the importance of seasonal influenza vaccination of pregnant women; previous research has shown that this was 71% effective in preventing influenza infection in infants aged less than 6 months in England

9. Should diagnostic sampling for influenza be performed when commencing antiviral post‑exposure prophylaxis?

  • When a decision has been made to administer antiviral prophylaxis to contacts of a confirmed case, diagnostic sampling of the contacts for influenza virus detection is recommended before or at the time of commencing antiviral prophylaxis in immunosuppressed patients and critically ill patients
  • This is based on expert advice as symptoms and signs of influenza may be absent or minimal despite influenza virus infection in these patient groups, or may be difficult to assess due to their clinical status. Antivirals administered at prophylactic doses can promote antiviral resistance when given to patients already infected with influenza virus, especially when there is underlying immunosuppression
  • Prophylaxis should not be postponed while the results of influenza testing are awaited and influenza virus testing should be expedited. If testing reveals that a patient commenced on a prophylactic dose of an antiviral is actually infected with influenza virus, then prophylaxis should be stopped and treatment-dose antivirals should be commenced immediately. Any prophylactic doses received should not be counted when determining the duration of treatment-dose antivirals
  • Following the positive influenza test result, clinicians should be reminded that infection control measures should be implemented and it is currently not possible to predict how long shedding of virus may last for individual patients. It should be noted in advance of implementing this advice, that in the absence of influenza symptoms, cessation of these infection control measures will need to be considered locally by an infection specialist, on a case by case basis

10. Should the standard treatment dose of oseltamvir be doubled (‘double‑dosing’) when treating patients with severe illness caused by seasonal influenza infection?

  • An increase in dosage is no longer recommended in patients with severe illness caused by influenza A virus infection, due to a lack of evidence that it is any more effective
  • Although it has been previously reported that higher inhibitory concentrations of oseltamivir carboxylate are required to produce an effect on Influenza B in in-vitro tests, there is insufficient evidence that double-dosing in patients with Influenza B has a clinical benefit

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. January 2019.
Contains public sector information licensed under the Open Government Licence v3.0.

First included: January 2019. 

PHE influenza antiviral treatment guideline