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ECDC On Oseltamivir Resistance

 

 

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Oseltamivir (Tamiflu) is one of two commonly stockpiled antivirals that has been shown effective against the H1N1 pandemic virus, with the other being the inhaled powder zanamivir. A third antiviral, the injectable peramivir, has recently been granted EUA (Emergency Use Authorization), but is in limited supply.

 

Oseltamivir, being either in pill or liquid form, is by far the most commonly used antiviral against this flu.   And there are concerns that the novel H1N1 virus could eventually develop resistance to it, as its seasonal cousin has done over the past 2 years.

 

Resistance is generally caused by a mutation, known as H274Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 274.

 

Thus far, we’ve only seen scattered reports of Tamiflu resistance, but it is likely that we are missing some cases.  For now, however, the overwhelming majority of H1N1 cases respond well to the drug.

 

Since the US, along with many other countries, have mainly stockpiled oseltamivir for use against a pandemic virus, any indication that the virus is becoming resistant is taken seriously. 

 

Routine surveillance (which, admittedly, is conducted on a very small subset of virus samples) has failed to show that any resistant strains are circulating at the community level.  According to the ECDC:

 

For the 2009–10 season starting September 2009, only three out of 1076 viruses tested in the USA as part of the routine surveillance were resistant and only two additional resistant viruses have so far been identified by other laboratories [3]. In Canada, two out of 69 tested viruses were resistant [4].

 

The WHO (World Health Organization), it its WER (Weekly Epidemiological Record) report of October 31st, examined 32 known cases of oseltamivir resistant H1N1 viruses detected through Oct 22nd.

 

oseltamivir-resistant pandemic (H1N1) 2009 infuenza virus, October 2009


The  earliest  isolates  of  pandemic  (H1N1) 2009  influenza virus were  shown  to be  sensitive  to  the  influenza  virus  neuraminidase inhibitors oseltamivir and zanamivir but resistant to the M2inhibitors amantadine and rimantadine. 1 WHO and other organizations have developed guidelines for the use of antiviral  drugs  in  the  clinical management  of pandemic  (H1N1)  2009  influenza  virus  infections on  the basis of  these data.2,3

 

(Continue . . . )

 

The ECDC today has released a summary and comment on the WER report, which I’ve excerpted below.  Follow the link to read it in its entirety.

 

 

Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009

18 Nov 2009

Description:


The World Health Organization has recently published a review of all the cases of 2009 A(H1N1) pandemic influenza viruses reported as resistant to the neuraminidase inhibitor oseltamivir as of 22 October 2009 [1]. The information on cases was derived from published reports, notifications under the International Health Regulations and information provided by WHO collaborating centres. It covers a total of 39 cases.

 

Among the 32 cases for whom detailed information was available 16 were associated with antiviral treatment of influenza, 13 with antiviral prophylaxis, and three had no history of exposure to oseltamivir.

 

Common features of all cases were the following:

  • Resistance was associated with the histidine to tyrosine point mutation at position 275 (N1 numbering) in the neuraminidase glycoprotein (H275Y).
  • None of those tested by a phenotypic assay were resistant to the other neuraminidase inhibitor zanamivir.
  • None has arisen as result of reassortment with the seasonal A(H1N1) influenza virus that has become naturally resistant to oseltamivir.
  • There is no evidence that oseltamivir-resistant viruses transmitted beyond the close proximity of cases.
  • Apart from some severely immunosuppressed patients and two children who developed pneumonia, all other cases experienced an uncomplicated influenza illness.

There are two factors that can be considered as associated with the isolation of an oseltamivir-resistant pandemic virus in this case series:

 

a) Immunosuppression. This was observed in seven cases and had also been previously observed for seasonal influenza viruses. Experts suggest that prolonged virus replication in immunosuppressed individuals under oseltamivir treatment favours the emergence and selection of resistant viruses [2].

b) Oseltamivir given for prophylaxis. This was observed in 13 cases and deserves some attention. Oseltamivir resistance has not been considered a common event during prophylaxis for seasonal influenza. However the number of individuals receiving antiviral prophylaxis during a pandemic is likely to be larger.

 

The WHO article recommends that antiviral resistance testing is considered for patients with persistent and complicated illness after five or more days of antiviral treatment and for patients presenting with an influenza-like illness despite having received antiviral prophylaxis.

 

Finally, in order to monitor antiviral resistance at community level, the selection of samples undergoing testing should be done in an unbiased way and include a sufficient number of post-treatment samples.

ECDC comment (17-11- 2009):


This article describes the first cases of 2009 A(H1N1) influenza viruses that tested resistant to the neuraminidase inhibitor oseltamivir worldwide.

In general the patients described in this article have been geographically dispersed, cases were sporadic and not linked to one another and the viruses tested by a phenotypic test were all susceptible to the other neuraminidase inhibitor zanamivir.

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