Antiviral treatment of influenza

Antivirals can be useful to reduce the duration of disease or severity of symptoms due to influenza virus infection. This is important, especially for persons at risk of developing severe disease, as well as situations in which the vaccine fails, for example, due to: 

•    antigenic mismatch with the circulating virus; 
•    waning immunity in the elderly population; 
•    immunocompromised patients; 
•    current unavailability of the vaccine; 
•    an outbreak of ‘avian’ influenza or an emerging pandemic, as post-exposure for exposed people and in particular possible cases of avian influenza infection according to national guidelines.

Influenza-specific antiviral drugs administered as therapy or prophylaxis are an important addition to the influenza vaccine, but they cannot be used to replace influenza vaccination. 

Currently, three drugs are authorised and recommended for the treatment of influenza in Europe:

•    oseltamivir (Tamiflu)
•    zanamivir (Relenza and Dectova)
•    baloxavir marboxil (Xofluza). 

In addition, Matrix-2 (M2) inhibitors such as adamantanes are authorised at the national level in the EU. However, adamantanes are not active against influenza B strains and there is widespread resistance among all currently circulating influenza A strains. Therefore, M2 inhibitors should not be used for the treatment of influenza. 

None of these medications can be obtained without a prescription. They are often only recommended as treatment for influenza for individuals considered to be ‘at risk’ of developing more serious complications:  the elderly or those living with underlying conditions, like asthma or heart disease. Individuals ‘at risk’ may particularly benefit from starting the treatment within 48 hours of the onset of symptoms of an influenza-like illness. 

Zanamivir and oseltamivir belong to the neuraminidase inhibitor family of drugs. Neuraminidase is a protein on the surface of the virus. When the neuraminidases are blocked, the virus cannot spread. Both oseltamivir and zanamivir are effective on the neuraminidases of influenza A and B viruses.

Oseltamivir (e.g.Tamiflu)  can be used for the treatment of influenza in adults and children, including full-term neonates, when the influenza virus is circulating in the community. For post-exposure prophylaxis, to prevent flu, it can be used in adults and children aged one year and older who have been in contact with someone who has flu. The decision to use oseltamivir is generally taken on a case-by-case basis. In exceptional circumstances, e.g., a pandemic situation, seasonal prevention could be considered, also in infants younger than one year.

Relenza (inhaled Zanamivir) is approved for the treatment of adults and children aged five years and older. It is also approved for the post-exposure prophylaxis of influenza in adults and paediatric patients aged 5 years and older, who have been in contact with someone who has flu. In exceptional circumstances, e.g., a pandemic situation, seasonal prevention could be considered.

Dectova (intravenous Zanamivir) can be used in adults and children from 6 months of age for the treatment of complicated and potentially life-threatening influenza. 

Baloxavir marboxil inhibits an enzyme known as cap-dependent endonuclease (CEN) in the acidic subunit of the viral polymerase complex, resulting in the disruption of viral RNA transcription and virus replication. Xoflusa (Baloxavir marboxil) can be used for the treatment or post-exposure prophylaxis of individuals aged one year and older.  

Can influenza viruses develop resistance to antiviral drugs?

Neuraminidase inhibitors (oseltamivir and zanamivir) constitute the primary type of antiviral drugs against influenza. Strains that are no longer sensitive to the neuraminidase inhibitors are sporadically detected each season due to mutations in the neuraminidase (NA) gene. However, resistant viruses that spread to others are very rare. 

Matrix-2 (M2) inhibitors such as adamantanes (amantadine and rimantadine) are authorised at the national level in the EU. However, resistant mutants to the Matrix-2 (M2) inhibitors have been detected and spread globally.  All currently circulating influenza type A viruses are resistant to M2 inhibitors and therefore should not be used for the treatment of influenza. 

The polymerase (PA) inhibitor baloxavir marboxil, which belongs to a new class of antivirals with different mechanisms of action, has been approved in the EU/EEA. Reduced sensitivity to this drug due to mutations in the PA gene has also been observed sporadically. 

The analysis of resistance is performed phenotypically by measuring IC50 values and/or by genotyping of viruses for detection of known drug resistance mutations, or genotypically by looking for specific mutations that have been associated with reduced susceptibility to the drugs. 

Antiviral resistance in Europe is monitored by ECDC and the World Health Organization Regional Office for Europe (WHO/Europe) based on the reports sent by influenza national reference laboratories to The European Surveillance System (TESSy). ECDC routinely collects, analyses and disseminates information on antiviral resistance from influenza viruses isolated from all the EU/EEA countries through the European respiratory virus surveillance summary (ERVISS).  

The practice regarding the use of antivirals varies between European countries, with 21 EU/EEA Member States having national recommendations in place for influenza antiviral use. According to the ECDC technical report, 'Seasonal influenza vaccination and antiviral use in EU/EEA Member States' (2018), 16 EU/EEA countries recommended the use of neuraminidase inhibitors as treatment for outpatients who might have a higher risk of severe outcomes of influenza and they are usually not recommended for otherwise healthy adults with ordinary influenza. Health professionals typically assess each case individually to determine the necessity and potential benefits of antiviral treatment.

For people in risk groups (people with chronic disease, pregnant women, immunocompromised persons, or persons 65 years and above), the most effective way of preventing serious complications of influenza is to get vaccinated against influenza. However, people belonging to a risk group who have contracted an influenza infection should seek early advice from healthcare professionals who can provide guidance on the need for antivirals, as they can shorten the duration of the illness or reduce the severity of the symptoms.  

Scientific evidence suggests that antivirals are more effective if they are taken early on during the illness. Antiviral drugs should be taken within the first 48 hours of the symptom onset as this is a key period to inhibit the replication of the virus. The effectiveness of the antivirals decreases with the time elapsed from the symptom onset. Early administration of antivirals after contracting an influenza infection has greater benefits.  

However, according to the ECDC expert opinion on the use of neuraminidase inhibitors for treatment and prevention of influenza, there is also evidence to suggest they can be beneficial even when started later than 48 hours after symptom onset, especially in certain settings. This is particularly relevant in cases involving severe influenza, hospitalized patients, or those at high risk for complications from influenza. In these cases, the benefits of starting antiviral treatment may outweigh the reduced efficacy due to the delayed initiation.

If antivirals are so good, why don’t doctors give them out more often? 

There are good reasons for this. If doctors use antivirals a lot, then the influenza viruses that are circulating may develop resistance to them. Also, like many other medicines, antivirals against influenza should be prescribed by doctors based on their clinical assessment and in adherence to national guidelines and recommendations. Excessive, inappropriate use of antivirals may also affect their availability during crises e.g. an influenza pandemic. Some European countries have policies in place that allow or recommend doctors to use antivirals against influenza only when it has been shown that influenza is circulating in the population at a certain level. 

Would it not be best if we all had antivirals at home to use when we need them? 

As with antibiotics, antivirals require a medical prescription and are not over-the-counter drugs. They should be given according to the national guidelines and taken only under medical supervision. 

This may happen in special circumstances where people in a risk group have been exposed to influenza. The most common situation is when there is a proven influenza outbreak in a long-term care facility, a nursing home or a hospital ward. Then antivirals may be given to all the people at risk as prophylaxis or early treatment.