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Saturday, March 27, 2010

More Tamiflu Resistant H1N1 Cases

INFLUENZA PANDEMIC (H1N1) (25): OSELTAMIVIR RESISTANCE
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A ProMED-mail post

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International Society for Infectious Diseases


Date: Fri 26 Mar 2010
Source: PHYSORG.com News [edited]



Rapid development of drug-resistant 2009 H1N1 influenza reported in 2 cases
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Doctors from the National Institute of Allergy and Infectious
Diseases (NIAID) report that 2 people with compromised immune systems
who became ill with [pandemic (H1N1) 2009] influenza [virus
infection] developed drug-resistant strains of virus after less than
2 weeks on therapy. Doctors who treat prolonged influenza infection
should be aware that even a short course of antiviral treatment may
lead to drug-resistant virus, say the authors, and clinicians should
consider this possibility as they develop initial treatment
strategies for their patients who have impaired immune function.

Both patients in the new report developed resistance to the key
influenza drug oseltamivir (Tamiflu), and one also demonstrated
clinical resistance to another antiviral agent, now in experimental
testing, intravenous peramivir, note senior authors Matthew J Memoli,
MD, and Jeffery K Taubenberger, MD, PhD. This is the 1st reported
case of clinically significant peramivir-resistant 2009 H1N1 illness,
say the scientists. The report is scheduled to appear in print on 1
May [2010] in Clinical Infectious Diseases and is now online [MJ
Memoli et al: Rapid selection of oseltamivir and peramivir resistant
pandemic H1N1 during therapy in 2 immunocompromised hosts. Clinical
Infectious Diseases DOI:10. 1086/651605 (2010)]. The people in the
current case report had immune limitations due to blood stem cell
transplants that occurred several years previously. Both recovered
from their influenza infections.

"While the emergence of drug-resistant influenza virus is not in
itself surprising, these cases demonstrate that resistant strains can
emerge after only a brief period of drug therapy," says NIAID
Director Anthony S Fauci, MD. "We have a limited number of drugs
available for treating influenza and these findings provide
additional urgency to efforts to develop antivirals that attack
influenza virus in novel ways."

The pandemic (H1N1) 2009 influenza virus is susceptible to just one
of the 2 available classes of anti-influenza drugs, the neuraminidase
inhibitors. Besides oseltamivir, other neuraminidase inhibitors are
zanamivir (Relenza), which is inhaled, and the intravenously
administered investigational drug peramivir. As the H1N1 influenza
pandemic unfolded, laboratory tests of virus strains isolated from
patients showed that some strains contained a genetic mutation (the
H275Y mutation) that makes the virus less susceptible to some
neuraminidase inhibitors.

The 2 people in the current case study had pre-existing medical
conditions that impaired their immune system function before
contracting 2009 H1N1 flu. Strains of pandemic (H1N1) 2009 virus
containing the H275Y mutation had been reported previously in people
with diminished immune function, but in previous cases the mutation
arose after more than 24 days of continuous therapy. In the newly
described cases, the mutation appeared after 14 days in one
individual and after 9 days in the 2nd. "Although the recommended
length of treatment with oseltamivir is 5 days, it is common for
physicians to continue giving this 1st-line drug longer if the
patient does not improve," says Dr Memoli.

Both people in the current report received oseltamivir for extended
periods but they continued to shed virus in their nasal secretions
throughout treatment. When one patient's condition worsened despite
24 days of oseltamivir treatment, doctors administered peramivir for
10 days. The drug did not reduce viral shedding and the patient
remained ill, demonstrating what the authors described as clinically
significant resistance to peramivir. Next, doctors administered the
only other available flu drug, zanamivir, for 10 days. The person
then fully recovered.

"Additional, larger studies are needed to further refine our
findings," says Dr Memoli. "But these cases of rapid appearance of
drug-resistant 2009 H1N1 influenza in immune-compromised patients are
worrisome and should prompt clinicians to reconsider how they use
available flu drugs."

The mutation that allows the pandemic (H1N1) 2009 influenza virus to
resist oseltamivir also significantly reduces the virus's
susceptibility to peramivir. If a relatively short course of
oseltamivir causes a mutant flu strain to emerge in a particular
patient, that person may not respond to peramivir. Zanamivir might be
a good choice if a patient does not respond within a few days to
oseltamivir, Dr Memoli says. However, because zanamivir must be
inhaled, patients who are very ill and whose breathing is
mechanically supported cannot be given zanamivir.

"As clinicians, we should carefully consider our treatment options
and use all the drugs available to us wisely. This is especially
important in a patient with prolonged infection or when an antiviral
drug fails to cure the patient after the recommended course of
treatment," says Dr Memoli.

--
Communicated by:
ProMED-mail


[Previously it was reported that a kidney transplant patient in
Western Australia developed resistance to oseltamivir and ultimately
the patient's infection was cleared by zanamivir treatment (Medical
Journal of Australia, 11 Jan 2010;
).

Although both oseltamivir and zanamivir are inhibitors of the
activity of the influenza virus neuraminidase protein, the
oseltamivir-resistance (His274Tyr) mutation does not confer
resistance to zanamivir. The interesting feature of the NIAID report
is the rapidity of appearance of oseltamivir resistance and the lack
of response to another antiviral agent, now in experimental testing,
intravenous peramivir, which presumably has the same site of action
as oseltamivir.

One patient's infection was ultimately cleared by zanamivir
treatment. It is not recorded if the patient's virus remained
zanamivir sensitive. - Mod.CP]

[see also:
Influenza pandemic (H1N1) (04): Australia (WA), i/v zanamivir 20100111.0127
2009
----
Influenza pandemic (H1N1) 2009 (77): Taiwan oseltamivir resistance
20091027.3725
Influenza pandemic (H1N1) 2009 (50): oseltamivir resistance 20090917.3260]
....................................sb/cp/mj/dk

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