H1N1 Virus Mutated in Lab: Resistant to Relenza

INFLUENZA VIRUS - RELENZA RESISTANCE LABORATORY MUTATION
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Date: Tue 4 Aug 2009
Source: The Age [edited]



Relenza-resistant flu virus mutation found
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The H1N1 flu virus has mutated into a form resistant to the
Australian-developed antiviral drug Relenza. Researchers said the
mutation posed little threat to humans yet: the virus was not a
strain of swine flu virus [Influenza pandemic (H1N1) 2009 virus] or
bird flu [avian influenza H5N1) virus], and it was found only in the
lab [i.e., only after propagation of patients' samples in the
laboratory], not in patients. There are no known strains of
Relenza-resistant influenza in humans. In contrast, virtually all the
flu cases in the US and Europe last year [2008], much of Australia's
seasonal flu and even a few cases of swine flu have proven resistant
to the other leading antiviral drug, Tamiflu.

A team at North Melbourne's WHO Collaborating Centre for Reference
and Research on Influenza analysed 391 influenza A(H1N1) viruses
found in humans in Australasia and South-East Asia between 2006 and
2008, before the spread of swine flu [i.e., the isolates screened
were all seasonal influenza viruses - Mod.CP]. 9 of the viruses had a
previously unseen mutation that made them 300 times more resistant to
zanamivir (sold as Relenza), according to results reported in the
Journal of Virology [see below].

The mutation was not found when the specimens were taken from
patients, only later when the viruses multiplied in the lab. "That
could mean there were very low levels of this mutation in the
patient," said Dr Ian Barr, one of the researchers involved and
deputy director of the WHO centre. "We wouldn't say it's a clinical
problem, but it's an interesting finding. We know [the mutation] can
survive, and it's stable."

The recent spread of Tamiflu-resistant A(H1N1) viruses showed that
antiviral-resistant viruses could spread rapidly and travel widely
around the world, the study authors warned. A spokeswoman for Biota,
which developed Relenza, said the discovery was "not clinically
relevant, because it's an in vitro discovery -- there's no evidence
that this mutated virus has infected patients." A spokeswoman for
Relenza manufacturer GSK said the "clinical significance is yet to be
determined." GSK announced a week ago that it planned to triple
production of Relenza in the face of the spread of swine flu
[influenza pandemic (H1N1) 2009] virus infection and rising demand
from government stockpiles.

Last week Japan identified its 3rd case of Tamiflu-resistant swine
flu, making a total of 6 worldwide. Scientists have warned that the
massive worldwide use of Tamiflu since the outbreak of swine flu
could hasten the spread of resistant mutations. No Relenza-resistant
swine flu has yet been found.

[Byline: Nick Miller]

--
Communicated by:
ProMED-mail Rapporteur Mary Marshall

[The research refered to in above newspaper article is published in
the Journal of Virology:

Ref: Zanamivir-Resistant Influenza Viruses with a Novel Neuraminidase Mutation.
J Virol. 2009 Jul 29. (Epub ahead of print)

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Authors: Hurt AC, Holien JK, Parker M, Kelso A, Barr IG.
At: The WHO Collaborating Centre for Reference and Research on
Influenza, 10 Wreckyn St, North Melbourne, Victoria 3051, Australia;
Monash University, School of Applied Sciences, Churchill, Victoria
3842, Australia; Structural Biology Laboratory, St. Vincent's
Institute of Medical Research, Fitzroy, Victoria 3065, Australia;
Department of Biochemistry and Molecular Biology, Bio21 Molecular
Science and Biotechnology Institute, The University of Melbourne,
Parkville, Victoria 3052, Australia.

Abstract: "The neuraminidase inhibitors zanamivir and oseltamivir are
marketed for the treatment and prophylaxis of influenza, and have
been stockpiled by many countries for use in a pandemic. Although
recent surveillance has identified a striking increase in the
frequency of oseltamivir resistant seasonal A(H1N1) viruses in
Europe, USA, Oceania and South Africa, to date there have been no
reports of significant zanamivir resistance among A(H1N1) viruses or
any other human influenza viruses. We investigated the frequency of
oseltamivir and zanamivir resistance in circulating seasonal A(H1N1)
influenza viruses in Australasia and South East Asia. Analysis of 391
A(H1N1) influenza viruses isolated between 2006 and early 2008 from
Australasia and South East Asia revealed 9 viruses (2.3 percent)
which demonstrated markedly reduced zanamivir susceptibility and
contained a previously undescribed Gln136Lys (Q136K) neuraminidase
mutation. The mutation had no effect on oseltamivir susceptibility,
but caused approximately a 300-fold and a 70-fold reduction in
zanamivir and peramivir susceptibility, respectively. The role of the
Q136K mutation in conferring zanamivir resistance was confirmed using
reverse genetics. Interestingly, the mutation was not detected in the
primary clinical specimens from which these mutant isolates were
grown, suggesting that the resistant viruses either occurred in very
low proportions in the primary clinical specimens or arose during
MDCK cell culture passage. Compared to susceptible A(H1N1) viruses,
the Q136K mutant strains displayed greater viral fitness than the
wildtype virus in MDCK cells, but equivalent infectivity and
transmissibility in a ferret model."

In view of the relatively restricted clinical use of Relenza relative
to the more easily administered Tamiflu, it is not surprising that a
Relenza-resistant mutant has yet to be isolated directly from
seasonal or pandemic influenza virus infected patients. It is likely
that in time the Q136K mutation will appear be recovered directly
from patients as a consequence of increased clinical use of Relenza. - Mod.CP]

[see also:
2007
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Influenza B virus, neuraminidase inhibitor resistance 20070404.1143
2001
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Influenza virus, neuraminidase inhibitor resistance (02) 20010928.2372
Influenza virus, neuraminidase inhibitor resistance 20010926.2350]
....................cp/ejp/dk

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