ECDC Threat Assessment
First isolation of a secondary oseltamivir - resistant A(H1N1)v strain in Denmark, 29 June, 2009
SOURCE: Internal request following a EWRS message from Denmark health authorities
PUBLIC HEALTH ISSUE: Isolation of a mutant A(H1N1)v virus containing a genetic marker of resistance to oseltamivir.
CONSULTED EXPERTS: Internal experts
EVENT BACKGROUND INFORMATION:
Event reported by Danish EWRS Focal point on 29 July 2009 :
In the context of tracing contacts of a cluster of 3 imported cases in Denmark, a female contact who initially tested negative on PCR, was given prophylaxis with oseltamivir (75 mg per day). Five days later, despite reportedly having complied with treatment, she developed flu-like symptoms and was tested positive for A(H1N1)v. Sequencing of the virus showed a single mutation H275Y (H274Y in N2 nomenclature) in the neuraminidase gene. The presence of the resistance marker and the phenotypic (in vitro) resistance was confirmed by a WHO collaborating Centre. The virus is not a re-assortant and is presumed to remain susceptible to zanamivir (another neuraminidase inhibitor). All other virus isolated as part of this cluster investigation, including the presumed source patient, did not show the mutation.
ECDC THREAT ASSESSMENT FOR THE EU
The A(H1N1)v virus related to the ongoing pandemic has always be found sensitive to oseltamivir and zanamivir and resistant to adamantanes (M2 blockers). This is the first observation of a genetic marker of resistance to oseltamivir in a A(H1N1)v virus.
The mutation consists of the substitution of histidine to tyrosine at amino acid position 275 in the neuraminidase segment gene (position 274 in N2 nomenclature). This mutation has been described in the past, associated with secondary resistance to oseltamivir acquired during treatment. This was documented some years back in children in Japan where the drug was used more commonly than in Europe(1). The mutation was detected in up to 16% of oseltamivir-treated children in Japan, perhaps associated with under-dosing(2). Studies have shown that the virus containing this mutation is unfit in terms of transmissibility(3) and possibly also in terms of pathogenicity(4) as demonstrated in animal studies. Therefore, such mutation is of limited public health concern since it has not resulted in the past in a virus that demonstrated sustained person-to-person transmission.
According to the available epidemiological and virological data, this reported event in Denmark is almost certainly secondary resistance acquired during post-exposure prophylaxis. This is supported by the time sequence and the absence of similar genotypic markers in viruses isolated in the other cases of the cluster.
There is no evidence in this case that the isolated resistant virus has transmitted to other persons, meaning that the risk of spread of a resistant virus is nearly zero. It is however likely that such mutation will be observed again in the future. This observation does highlight the increased likelihood of such event arising from widespread use of anti-virals especially in prophylaxis.
Secondary resistance, arising due to treatment, must not be confused with more complex mutations including the H274Y substitution resulting from primary resistance. Such primary resistance was first observed in seasonal A(H1N1) influenza virus in the 2007-2008. It spread worldwide generally displacing other seasonal A(H1N1) viruses (98% resistance in EU in 2008-2009)(5). Following that phenomenon some EU countries have diversified their anti-virals stockpiles adding zanamivir to oseltamivir.
There is always a theoretical risk of re-assortment of A(H1N1)v with primary resistant seasonal viruses notably the seasonal influenza virus A(H1N1) containing the H274Y mutation.
CONCLUSIONS AND RECOMMENDATIONS
The emergence of secondary resistance while on antiviral treatment is a well recognised phenomenon in influenza viruses. As in the past, there is no evidence the mutation has led to a virus capable of transmitting from person to person. Therefore, though resistant viruses are always a concern, the emergence of A(H1N1)v resistant to oseltamivir does not represent a public health threat. It can be expected to happen again.
Surveillance of genetic resistance for detecting early primary resistance is of particular importance for the future course of the pandemic
(1) Whitley RJ, Hayden FG, Reisinger K, Young N, Dutkowski R, Ipe D, et al. Oral oseltamivir treatment of influenza in children. Ped Infect Dis J 2001; 20(2):127-33.
(2) Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu(R)) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother 2005; 55(suppl_1): i5-21.
(3) Compromised transmission: Herlocher ML, Truscon R, Elias S; et al. Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J Infect Dis. 2004;190(9):1627-30
(4) Attenuated pathogenicity: Ives JA, Carr JA, Mendel DB; et al. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res. 2002; 55(2): 307-17
(5) Meijer A, Lackenby A, Hungnes O, Lina B, van der Werf S, Schweiger B, et al. Oseltamivir-resistant influenza A (H1N1) virus, Europe, 2007–08 season. Emerg Infect Dis. 2009; 15(4):552-60