Eurosurveillance

Trebbien R, Pedersen SS, Vorborg K, Franck KT, Fischer TK. Development of oseltamivir and zanamivir resistance in influenza A(H1N1)pdm09 virus, Denmark, 2014. Euro Surveill. 2017;22(3):pii=30445. DOI: http://dx.doi.org/10.2807/1560-7917.ES.2017.22.3.30445

“Influenza virus is the cause of annual seasonal epidemics worldwide, and leads to high morbidity in the population. Severe disease and deadly outcome due to influenza virus are recognised in the defined risk groups, in particular elderly persons > 65 years of age and immunocompromised patients. Influenza is normally an acute self-limiting disease with a duration of 5 to 7 days, however, in immunocompromised patients prolonged infections lasting several months have been reported [1–4]. Prevention of severe influenza disease is mainly based on immunisations with split vaccines which are produced annually to accommodate the changing antigenicity of seasonal epidemic viruses [5,6]. The effect of vaccination in immunocompromised patients is questionable and this is why other modes of prevention and/or treatment often are considered for this risk group [7–12]. For treatment of influenza viruses only a few antiviral drugs are available; the neuraminidase (NA) inhibitors and the matrix-2 (M2)-ion channel inhibitors. The current circulating epidemic influenza viruses harbour natural resistance towards the M2-ion channel inhibitors therefore these are not an option for treatment [13–15]. The NA inhibitors bind to the NA surface protein and prevent it from facilitating the release of new virus particles from an infected cell [16]. In Denmark, two different NA inhibitors are approved and available for treatment of influenza: oseltamivir (Tamiflu) and zanamivir (Relenza). Oseltamivir is the drug of choice for treatment due to its easy oral administration whereas zanamivir (intravenous or inhalation) is often used when the effect of oseltamivir is limited, e.g. in case of development of resistance. In the NA gene of the H1N1 viruses a range of amino acid mutations are recognised to confer reduced inhibition by NA inhibitors [16–18]. Among these, two well characterised mutations are the H275Y mutation which results in viruses with highly reduced inhibition by oseltamivir and the I223R mutation which results in reduced inhibition by both oseltamivir and zanamivir [16,17].

Antiviral treatment of immunocompromised patients with prolonged influenza virus infection can lead to multidrug-resistant influenza quasispecies in the same patient [1]. We describe how the emergence of such virus variants poses challenges in the combat of a severe influenza infection in a Danish patient treated with antivirals. The patient had sustained shedding of influenza A(H1N1)pdm09 virus for 6 months and was treated with oseltamivir and subsequently zanamivir. Antiviral resistance mutation profiles were evaluated using conventional Sanger sequencing and next generation sequencing (NGS)…..”