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Successful treatment would need to inhibit viral considered as first-line empiric treatment of seasonal influenza, although
replication sufficiently in order for this repair mechanism to remain intact. they may have a role in the prophylaxis and/or treatment of known
H5N1 infections in humans produced up to three times greater viral load than
seasonal influenza, with relatively higher viral titers in the throat and lungs.
In H5N1 viruses from Vietnam, Malaysia, and Cambodia contained mutations
addition, H5N1 virus is a more systemic disease, with viral RNA detected in associated with resistance to rimantadine and amantadine, while strains from
lung, intestine, and spleen tissues, though virus replication appears to be Indonesia were mixed with some strains retaining susceptibility to these
confined to the lung and intestine.
Successful treatment, therefore, would drugs.
Generally, these drugs should not be used for avian or pandemic
need to limit viral replication effectively, as well as to be distributed systemically. influenza unless the circulating strain is known to be susceptible.
H5N1 disease in humans is also associated with a marked increase in Neuraminidase inhibitors are sialic acid analogs that inhibit the viral
pro-inflammatory cytokines compared with H3N2.
It is unclear whether neuraminidases by competitively binding with the active enzyme site of
the hypercytokinemia is an appropriate response to the severity of infection influenza A and B viruses. Currently available agents include zanamivir and
and viral replication, or whether this represents immune dysregulation. This oseltamivir. The adult treatment trials of oseltamivir and zanamivir studied
ambulatory individuals who presented within 36 hours of developing
symptoms of seasonal influenza. Treatment was associated with improved
time to improvement of symptoms: 1–1.9 days faster than placebo.
Discussions of potential influenza
effect on viral titers was conclusively shown in any of these trials, as subjects
pandemic viruses should consider that
in the placebo arms stopped shedding influenza virus without any
pharmacological intervention in two to four days.
any of these viruses or other influenza
viruses may have the potential to acquire
The majority of H5N1 viruses are fully sensitive to the neuraminidase
inhibitors, with IC
values similar to those of commonly circulating human
the ability for sustained human-to-human
While circulating animal viruses have infrequently been
transmission, and thus any of these
found to be resistant,
resistant strains have not yet been found in humans
infected with avian viruses. Resistance may, however, develop on therapy
viruses could be a pandemic virus.
with oseltamivir if viral replication is not adequately suppressed.
Zanamivir may be effective based on virus sensitivities. To date, there have
hypercytokinemia—the so-called cytokine storm—has been invoked as a been no cases of avian influenza infections in humans treated with
cause of the high mortality in avian influenza.
However, in animal models zanamivir. In addition, avian influenza virus is systemically disseminated,
the cytokine response was necessary for control of viral replication, and and zanamivir systemic bioavailability after inhalation is less than 20%.
cytokine knockout mice did not have improved outcomes after being Therefore, the clinical utility of zanamivir for a systemic infection with avian
infected with H5N1.
influenza is yet to be established.
Control of viral replication is critical for successful outcomes. Fatal outcomes New Approaches
have been shown to be associated with failure to control viral replication.
Several new approaches may be available in the near future. While many of
While hypercytokinemia is associated with poor outcomes, the these are still in the pre-clinical stage, the following will highlight several
hypercytokinemia is proportional to viral load.
Additionally, the systemic approaches that are in clinical testing and may be available within the next
spread of the virus and the associated organ damage are due to unabated several years.
viral replication. Therefore, medical options for treating avian and pandemic
influenza should focus on control of viral replication.
Discussion of the medical options for an
Discussion of the medical options for an influenza pandemic is limited by a
influenza pandemic is limited by a lack of
lack of knowledge as to what virus would cause the pandemic. There are no
controlled trials to guide therapeutic decisions in humans infected with avian
knowledge as to what virus would cause
influenza viruses. Therefore, extrapolations must be made from what we
know about therapeutics in seasonal and zoonotic avian influenza infections.
Amantadine and rimantadine are tricyclic amines that inhibit the ion
channel function of the M2 protein of influenza A, thereby interfering Similar to oseltamivir and zanamivir, peramivir is a novel neuraminidase
with the uncoating of the virus. Resistance to these compounds was inhibitor in development. Peramivir is unique as it is being developed for
uncommon in community isolates until recently, but in 2005–2006 the intravenous (IV) and intramuscular (IM) administration. In an in vitro
resistance frequency in H3N2 was 92% in the US.
Due to this circulating comparison of peramivir, oseltamivir, and zanamivir, all agents had similar
level of resistance, amantadine and rimantadine should not be ability to inhibit the neuraminidase enzyme.
Dissociation studies indicate
32 US INFECTIOUS DISEASE 2007
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