Are the currently identified Tamiflu resistance cases significant?

Date: Sat 4 Jul 2009
Source: 660News, All News Radio, The Canadian Press [edited]

All cases of Tamiflu resistance are not created equal. So while the
1st 3 instances of swine flu infection with Tamiflu-resistant viruses
were reported in the past week, it was Number 3, not Number 1 that put
influenza experts on edge. Public health authorities in Hong Kong
announced Friday [3 Jul 2009] they have found a case of Tamiflu
resistance in a woman who hadn't taken the drug. That means she was
infected with swine flu viruses that were already resistant to
Tamiflu, the main weapon in most countries' and companies' pandemic
drug arsenals.

The 2 earlier cases, reported from Denmark and Japan, involved people
who had been taking the medication. While always unwelcome, that type
of resistance is known to occur with seasonal [influenza virus]
strains and may be less of a threat to the long-term viability of this
key flu drug. "It was not at all surprising to see resistance in
patients on treatment, but seeing it in someone who was not treated,
it certainly is more concerning," says Dr. Malik Peiris, a flu expert
at the University of Hong Kong.

There is currently no evidence Tamiflu-resistant viruses are spreading
widely. Still, some experts see the Hong Kong case as a warning that
Tamiflu's role in this pandemic may not be as long-lived as pandemic
planners would like. "I think it's too early to judge," says Dr.
Frederick Hayden, an expert on influenza antivirals who teaches at the
University of Virginia. "But I think that possibility has existed from
the beginning, and it's something that needs to be certainly
considered in making determinations about things like antiviral
stockpiling, management of patients with more serious illness in
hospital and how the available drugs will be used."

Some experts say this early sign of resistance should prompt a rethink
of how often and in which circumstances Tamiflu is used to battle the
novel H1N1 virus. "It ... probably highlights the importance of not
using these antiviral drugs indiscriminately, given that the disease
is relatively mild," says Peiris, whose hospital monitored the woman
who was found to be carrying the resistant virus. "In people who don't
have underlying risk factors, they probably should not be treated with
Tamiflu, basically."

Others suggest countries should limit how often they use the drug to
prevent infection, a regimen known as prophylaxis. In prophylaxis,
people who've been exposed to the virus are given one pill a day for
10 days, compared to the treatment regime of 2 pills a day for 5 days.
Some countries, including Canada, have been reserving prophylaxis for
people at high risk from this flu, such as pregnant women. But others
have taken a different approach, using Tamiflu to try to curb spread
of the virus. For instance, Britain has made the drug widely available
to contacts of confirmed cases, though it announced this past week it
was changing that policy.

The World Health Organization is drafting guidance for countries on
the use of antivirals. While the WHO advises rather than instructs, it
has been stressing that saving these drugs for treatment makes the
most sense, says Dr. Keiji Fukuda, the agency's top flu expert. "In
general we have been pushing the advice that using these drugs for
treatment is definitely the priority use of them," says Fukuda, the
acting assistant director general for health security and environment.
"And I think this is not just from a theoretical resistance
perspective but also from the fact that if you have limited amounts of
antiviral drugs, then you need to make some choices about how you use
them."

From their 1st sighting, the new H1N1 viruses have been resistant to
2 older flu drugs, amantadine and rimantadine. That left the only 2
other influenza drugs, oseltamivir (Tamiflu) and zanamivir (Relenza),
as the sole options for treatment and prophylaxis. There is a risk
inherent in using the drug to prevent illness. If people who are
already infected but aren't yet experiencing symptoms are put on
prophylaxis, there won't be enough drug in their systems to kill all
the viruses they house. Those that survive develop resistance to the
drug. And that, it appears, may be what happened in the resistance
cases in Denmark and Japan. In both instances the women involved had
been given Tamiflu prophylaxis after a contact developed swine flu.

But the Hong Kong case was different. A 16-year-old girl travelling
from San Francisco was stopped in Hong Kong's airport in mid-June
[2009] after setting off a fever detection device. She was taken to
hospital where she tested positive for swine flu. She had not been
taking antivirals and declined to be treated with the drug. She was
kept in isolation until she recovered.

Dr. Jennifer McKimm-Breschkin, an influenza expert from Australia and
a member of the team that developed Relenza, says this case shows
resistant swine flu viruses can spread. It was previously thought flu
viruses that developed resistance to the drug would be crippled in the
process and would not transmit to others. But that belief was
shattered in 2008 when it was discovered Tamiflu-resistant versions of
the seasonal H1N1 viruses were spreading rapidly around the globe.
They have since all but wiped out [replaced] Tamiflu-susceptible
seasonal H1N1 viruses. "This is a patient that hasn't been treated who
has gone from San Francisco to Hong Kong. What that means is that she
has caught a resistant virus in San Francisco," says McKimm-
Breschkin, virology project leader at the Commonwealth Science and
Research Organization -- known as CSIRO -- in Melbourne. "So that
means this virus has been transmitted from somebody who's presumably
been treated. Which means it's been fit enough to transmit -- and that
is of a lot more concern than just resistance in a treated patient."
Experts have worried the seasonal H1N1 viruses might reassort or swap
genes with the swine H1N1. If swine flu picked up the neuraminidase
gene -- the N in a flu virus' name -- from the seasonal H1N1, it would
acquire the resistance its seasonal cousin has developed.

Authorities in Hong Kong have not yet told the WHO whether that is
what has happened in this case. But whether the Hong Kong resistance
case is due to reassortment, or from the fact that some swine flu
viruses have developed resistance on their own, the situation demands
careful monitoring, Fukuda and others say. "The really big question
for any finding of antiviral drug resistance with these viruses is
whether it's an isolated event or whether it's a tip of a larger
phenomenon," he explains. "The bottom line, as is so often the bottom
line with influenza, is that the real answer to the current situation
is monitoring as closely as possible, which in this instance is really
being done, since an extraordinary number of viruses are being
collected and looked at."

[Byline: Helen Branswell]

--
Communicated by:
ProMED-mail Rapporteur Mary Marshall

[The identification in Hong Kong (S.A.R.) of a patient arriving from
the USA harboring Tamiflu-resistant A (H1N1) pandemic influenza virus,
who had not previously received Tamiflu treatment, is a disturbing but
not unexpected development in view of the often indiscriminate use of
the antiviral in some countries. It remains to be seen whether this
Tamiflu-resistant virus will be transmitted more or less efficiently
than Tamiflu-sensitive virus. It may be that Tamiflu will become
largely ineffective in the control and treatment of the A (H1N1)
pandemic virus sooner rather than later. Restriction in future use of
Tamiflu should be considered.

Unlike Tamiflu, which is administered orally in tablet form, the
alternate neuraminidase inhibiter Zanamivir (Relenza) is an antiviral
that must be administered twice a day in powder form through a special
inhaler, with treatment continuing for up to 5 days. This may be an
advantage in reducing the indiscriminate use of the drug. Relenza can
be used by people over 12 years of age who are known or suspected to
have influenza A or influenza B virus infection. - Mod.CP]