Developing New Antiviral Agents for Influenza Treatment: What Does the Future Hold?
New Antiviral Agents for Influenza Treatment • CID
Developing New Antiviral Agents for Influenza Treatment: What Does the Future Hold?
Frederick Hayden 0
0 Global Influenza Programme, World Health Organization , Geneva , Switzerland; and University of Virginia School of Medicine , Charlottesville
Antiviral agents for the treatment of influenza are urgently needed to circumvent the limitations of current drugs in several critical areas: high frequencies of resistance to M2 inhibitors among currently circulating strains and variable frequencies of resistance to oseltamivir among A(H1N1) strains, limited efficacy of treatment and treatment-emergent antiviral resistance in cases of avian influenza A(H5N1) illness in humans, and lack of parenteral agents for seriously ill patients. Two neuraminidase inhibitors (NAIs), zanamivir and peramivir, have undergone or are undergoing clinical trials for use by intravenous or intramuscular administration, and one long-acting NAI, designated CS-8958, is under study for use by inhalation. Advances in understanding the mechanisms involved in influenza virus replication have revealed a number of potential targets that might be exploited in the development of new agents. Among these agents are T-705, a polymerase inhibitor, and DAS181, an attachment inhibitor. Combination therapy with currently available agents is supported by data from animal models but has received limited clinical study to date.
Three principal factors drive the medical need for the
development of new antiviral agents for the treatment
of influenza: antiviral resistance; limited antiviral
efficacy in severe cases of influenza, including in influenza
A(H5N1) disease; and a lack of parenteral agents. Since
2003, the frequency of viral resistance to the M2
ionchannel inhibitors (i.e., M2 inhibitors, or
adamantanes)—namely, amantadine (e.g., Symmetrel; Endo
Laboratories) and rimantadine (e.g., Flumadine; Forest
Laboratories)—has increased rapidly among seasonal
influenza A(H3N2) viruses and is now so widespread
that this class of drugs has been rendered mostly
ineffective, although they retain activity against most
influenza A(H1N1) viruses [
]. The 2007–2008
influenza season also was notable for the community
circulation of influenza A(H1N1) viruses resistant to
oseltamivir in many countries . Emergence of
resistance to M2 inhibitors and to neuraminidase inhibitors
(NAIs) also has been a clinical problem in some highly
immunocompromised hosts. Administration of the oral
NAI oseltamivir appears to be beneficial in the
treatment of seasonal influenza in hospitalized patients [
] and of some cases of highly pathogenic avian
influenza A(H5N1) in humans, but it has not reduced the
overall case-fatality rate to below ∼50% for avian
influenza A(H5N1) [
]. Multiple factors likely contribute
to this high mortality, including late presentation for
care, emergence of resistance to oseltamivir, and
possibly reduced bioavailability in some patients. In this
regard, and of particular relevance in the clinical
management of seriously ill, hospitalized patients, no
parenteral agents for the treatment of influenza are
currently available. Each of these factors contributes to the
need for alternative antiviral treatments, particularly
with regard to pandemic preparedness, and for the
consideration of combination therapy. Several of the agents
that are undergoing clinical testing will be highlighted
in this article.
Emergence of resistance during the therapeutic use of M2 inhibitors is well known; estimates of the prevalence of M2-inhibitor resistance that occurs during thera
a Antiviral resistance detected in individual patients, but frequency not reported.
peutic use are shown in table 1 [
9, 10, 12, 15, 17
]. In addition,
in recent years, the prevalence of resistance to M2 inhibitors
among community A(H3N2) isolates has increased
dramatically and spread globally, as shown in figure 1 [
]. In 2006,
this led to changes in the US Advisory Committee on
Immunization Practices recommendations regarding the use of
this entire class of antiviral drugs . Earlier surveillance
studies found that primary resistance occurred at low frequencies
among seasonal isolates and that, historically, the frequency of
resistance was 1%–3%. Increasing frequencies of M2-inhibitor
resistance first appeared among influenza virus A(H3N2)
isolates from China and Hong Kong during the 2003 influenza
season and then spread globally, with rates during the 2005–
2006 influenza season of 190% not only in Asia but also in the
United States and of nearly 50% in Europe. Data from the
2006–2007 influenza season showed rates of M2-inhibitor
resistance of 180% in Asia and the United States and 150% in
parts of Europe. Very high frequencies of resistant A(H3N2)
viruses continued to be detected during the 2007–2008
influenza season in the northern hemisphere. A geographically
variable, increased frequency of resistance among A(H1N1) viruses
also has been observed, although the overall proportion of
resistant A(H1N1) viruses is not as high as that for A(H3N2)
Resistance in recent A(H3N2) and A(H1N1) virus isolates
has been due to a serine-to-asparagine substitution at position
31 in the M2 protein. Unfortunately, resistance to either of the
current M2 inhibitors, amantadine or rimantadine, confers
resistance to the entire class of M2 inhibitors, although M2
inhibitor–resistant viruses are still susceptible to the NAIs. From
a public health perspective, these variants retain their virulence
and their transmissibility from person to person. No loss of
biological fitness has been ascertained in the laboratory or in
Resistance to the M2-inhibitor class of antiviral drugs is also
seen in many A(H5N1) viruses [
]. The clade 1 viruses that
first appeared in Vietnam, Thailand, and Cambodia also are
resistant because of a serine-to-asparagine substitution at
position 31, the same mutation found in the resistant A(H3N2)
viruses. A high frequency of M2-inhibitor resistance also has
been seen in clade 2.1 viruses that circulate in Indonesia,
because of this mutation or of one at position 27. On the other
hand, most (190%) of the clade 2.2 viruses that have spread
across Eurasia to Europe and Africa and clade 2.3 viruses have
retained sensitivity to the M2 inhibitors. Limited data suggest
that amantadine was effective in some individual patients with
M2 inhibitor–susceptible A(H5N1) disease in Hong Kong in
1997, when these viruses were first found to cause illness in
Resistance to NAIs occurs during therapeutic use (table 1) [
11, 13, 14, 16, 21
] and at low frequencies among community
]. New mutations associated with reduced
susceptibility continue to be recognized, as more-detailed
surveillance is used. However, the inhibitory activity of NAIs
against all 9 neuraminidase subtypes recognized in avian viruses
predicts that NAIs would likely be active against a pandemic
strain whether it is an A(H5N1) virus or some other novel virus
that has gained its hemagglutinin and neuraminidase from an
animal virus. Within the NAI class of antiviral drugs, there is
an interesting phenomenon of variable cross-resistance that
depends on the neuraminidase type and subtype, the drug, and
the particular neuraminidase mutation, because of different
interactions of the drugs within the active enzyme site. The
practical consequence is that zanamivir (Relenza;
GlaxoSmithKline) retains full inhibitory activity for several
neuraminidase subtypes when mutations that confer resistance to
oseltamivir (Tamiflu; Roche Laboratories) are present.
Resistance to oseltamivir also has been documented in
outpatient adults, outpatient children, and inpatient children (table
8, 11, 14, 16, 21
]. The frequency of resistance to oseltamivir
is much lower than that observed for M2 inhibitors but is not
insignificant, particularly among children; resistant variants
were detected in nearly 1 in 5 pediatric patients in one study
conducted in Japan [
]. Not surprisingly, the frequency with
which resistant virus is detected in children is substantially
higher than that for adults because, in general, children have
higher viral replication loads and a correspondingly greater
opportunity for the emergence of resistant variants.
NAI-resistant variants usually have reduced infectivity and virulence
in animal models of influenza but not always. Some
oseltamivirresistance mutations are associated with full replication
competence and transmissibility in animal models. Earlier studies
of community isolates found that viruses with resistance
mutations (based on N2 numbering) in influenza A (arginine to
lysine at 292, glutamic acid to valine at 119 in the N2
neuraminidase, and histidine to tyrosine at 274 in the N1
neuraminidase) and B neuraminidases (aspartic acid to asparagine
at 198, isoleucine to threonine at 222, and serine to glycine at
250) probably have been transmitted from person to person
]. Influenza A(H1N1) viruses resistant to oseltamivir
because of the histidine-to-tyrosine mutation at position 274
appeared in many countries for the first time during the 2007–
2008 influenza season . This phenomenon has occurred in
the apparent absence of selective drug pressure and indicates
that these resistant variants are efficiently transmitted from
person to person and capable of causing typical influenza [
Emergence of resistance has been documented in influenza
A(H5N1) virus–infected patients treated with oseltamivir. In a
case-series study of 8 patients from Vietnam, de Jong et al. [
(figure 2) observed that a standard course of oseltamivir therapy
begun a median of 6 days after the onset of illness was associated
temporally with reductions in pharyngeal viral loads in half the
patients and that pharyngeal viral RNA clearance at the end of
the treatment course was linked with survival. In contrast, those
patients who had increasing viral loads over time or failure to
clear virus succumbed to their illness. Two of these individuals
had treatment-emergent oseltamivir-resistant viral variants with
a histidine-to-tyrosine mutation at position 274, the most
common mutation observed in N1 neuraminidase–containing
viruses. N1 neuraminidase with this mutation shows marked
reductions (1400-fold) in susceptibility to oseltamivir but
remains inhibited by zanamivir [
Oseltamivir treatment and prophylaxis has been used with
apparent benefit in immunocompromised hosts with influenza
virus infection [
]. However, emergence of
oseltamivirresistant variants has occurred in some immunocompromised
hosts and appears to be correlated with protracted viral
replication and poor clinical outcomes [
]. In some highly
immunocompromised hosts, sequential therapy with both
antiviral drug classes has been used, in part because viral clearance
failed in these patients. Unfortunately, in this population, dual
resistance to both M2 inhibitors and NAIs has been found [
The approach of sequential drug use in the management of
influenza should be avoided for immunocompromised hosts.
LIMITATIONS OF CURRENT ANTIVIRAL
TREATMENTS FOR INFLUENZA
The efficacy of current antiviral treatments is limited or
uncertain in certain populations and situations. For example,
oseltamivir carboxylate, the active metabolite of oseltamivir, is
substantially less active against influenza B than against
influenza A neuraminidases (table 2). This finding has been
corroborated in several studies from Japan, which have indicated
that among children, particularly young children, the treatment
of influenza B with oseltamivir is associated with delayed
antiviral effects and clinical resolution, compared with the
treatment of influenza A [
]. Furthermore, no controlled
studies have been completed in high-risk or hospitalized
populations, although emerging evidence suggests that even
delayed treatment is beneficial for adults hospitalized with
serious seasonal influenza [
The efficacy of oral oseltamivir is limited in A(H5N1) disease,
for which overall mortality is ∼60% [
]. The case-fatality ratio
among those receiving oseltamivir has hovered around 50%,
compared with nearly 90% among those not receiving antiviral
]. Multiple contributing factors are likely,
particularly delayed time from illness onset to antiviral treatment,
and early administration (within 3–4 days after illness onset)
has been associated with reduced mortality. The World Health
Organization (WHO) updated its clinical management advice
for avian influenza A(H5N1) virus infection in humans in 2006
and again in 2007 [
]. The updated guidelines are based
in part on clinical reports shared at a meeting in Turkey in
March 2007 , and they address both antiviral treatment
and supportive care and discuss the theoretical use of
immunomodulators. These guidelines provide guidance on what
appears to help (i.e., oseltamivir, oxygen therapy, and
lung-protective ventilatory-support strategies) and on what does not
(including antibiotic prophylaxis, high-dose corticosteroids,
and M2-inhibitor monotherapy, especially when the virus strain
is resistant to M2 inhibitors). In fact, use of corticosteroids
appears to be associated with an increased risk of mortality [
NEW ANTIVIRAL AGENTS
FOR INFLUENZA TREATMENT
Multiple potential targets are now being explored actively in
the search for new antiviral treatments for influenza. Some of
the potential sites of intervention are shown in figure 3 [
Several recent review articles have discussed comprehensively
the state of the science with regard to both targets for new
antiviral drug development and the status of some of the
antiviral agents, particularly those in preclinical and early clinical
]. Of the many antiviral agents now in
various stages of development, some agents and formulations
that have shown preclinical activity and that are now being
tested in human trials are listed in table 3.
Parenteral NAIs. Current antiviral treatments are given
either orally or by inhalation. These routes may not provide rapid,
reliable drug delivery in seriously ill patients. For example,
failure of zanamivir therapy for the treatment of pneumonia
in a bone-marrow transplant recipient has been reported, even
though the influenza A(H1N1) virus with which the patient
was infected was sensitive to zanamivir [
]. In addition, the
oral bioavailability of oseltamivir, especially when given by
nonstandard means (e.g., via nasogastric tube), is uncertain,
although a recent report on 3 patients found adequate absorption
under such circumstances [
]. Parenteral administration
would circumvent these limitations by guaranteeing rapid
delivery and high levels in blood to increase the likelihood of
drug delivery to sites of infection, especially in those with
pneumonia or, for patients with influenza A(H5N1) virus infection,
The poor oral bioavailability of zanamivir (∼2%) is well
] and provides the impetus for the
development of alternate administration routes for the drug. Although
an inhaled formulation is approved, intravenous zanamivir has
been evaluated in phase 2a testing [
]. In healthy volunteers
receiving 600 mg zanamivir or placebo intravenously twice daily
for 5 days prior to a virus challenge, zanamivir was found to
be highly protective against experimental infection (14% vs.
100%, respectively, were infected), to reduce viral shedding (0%
vs. 100%, respectively, had viral shedding), and to prevent
]. Intravenous zanamivir is active in a primate model
of A(H5N1) virus infection [
], and the Southeast Asia
Influenza Clinical Research Network [
] is developing a protocol
to study it in patients with avian influenza A(H5N1) illness.
More recently, the NAI peramivir (BioCryst
Pharmaceuticals) is currently in phase 2 trials for both intravenous and
New Antiviral Agents for Influenza Treatment • CID 2009:48 (Suppl 1) • S7
intramuscular routes of administration. In vitro IC50 data for
oseltamivir, zanamivir, and peramivir show that all 3 agents are
potent inhibitors of influenza virus neuraminidases in the low
nanomolar range (table 2) [
]. In an animal model of
influenza A(H5N1) virus infection, mice receiving multiple oral
doses of oseltamivir over 5 consecutive days or peramivir
(administered as either a single intramuscular injection or as 5
intramuscular injections over 5 consecutive days), starting at
1 h after virus inoculation, were more likely to survive than
were control mice injected with saline (table 4) [
multiple-dose peramivir regimen was the only regimen that
prevented paralysis by day 15 (table 4). However, intramuscular
peramivir provided incomplete protection against
neuroinvaS8 • CID 2009:48 (Suppl 1) • Hayden
sive A(H5N1) disease in a second animal model. Among ferrets
infected with 1 of 3 different doses of influenza A(H5N1) virus,
overall survival improved with multiple doses of intramuscular
peramivir (70%–86%), compared with survival among those
given an intramuscular injection of saline (11%–43%);
encephalitis was less common among peramivir recipients (32%
[8/25]), compared with saline recipients (50% [13/26]); and
paralysis developed in 8% (2/25) of animals that received
treatment with multiple intramuscular doses of peramivir,
compared with 42% (11/26) of animals given intramuscular doses
of saline [
Peramivir has a prolonged plasma elimination half-life in
humans and also appears to bind to the enzyme for a prolonged
]—2 factors that permit infrequent dosing regimens.
In dose-ranging studies performed with healthy volunteers, the
peak plasma concentrations for intramuscular and intravenous
peramivir (10,000–20,000 ng/mL) are nearly 2 orders of
magnitude higher than those achieved with standard doses of oral
oseltamivir (∼350 ng/mL; figure 4) [
]. It remains to be
determined in clinical trials to what extent these higher levels in
blood may provide greater antiviral efficacy and perhaps
reduced frequency of resistance emergence. Future studies will
need to determine whether such high plasma NAI levels will
translate into greater clinical benefits for high-risk or
hospitalized patients with influenza. A recent report indicated that
a single 300- or 600-mg dose of intravenous peramivir was
efficacious in the treatment of uncomplicated influenza in adult
Long-acting NAIs. Biota Holdings of Australia and Sankyo
Pharmaceuticals of Japan are codeveloping long-acting inhaled
NAIs. CS-8958 (also known as R-118958) shows good activity
in murine models of influenza treatment with once weekly
]. Rennecke et al.  reported that, in healthy
male subjects, R-118958 doses of 1, 2, 5, or 10 mg administered
by inhalation did not result in the active metabolite being
detectable in plasma, although it was detected in urine for up to
144 h after administration of the 5-mg and 10-mg doses. No
serious adverse events or clinically significant changes in
laboratory tests were noted. Available data suggest that CS-8958
may permit a more convenient topical dosing regimen, and the
sponsors of a phase 2 study in Japan recently announced that
a single inhaled dose was found to be as effective as a standard
5-day course of oseltamivir in the treatment of uncomplicated
Polymerase inhibition. T-705 (Toyama Chemical) is not
only active against all 3 influenza virus types (A, B, and C) but
also has some activity against other RNA viruses, including
some of the hemorrhagic fever viruses [
undergoes ribosylation and then phosphorylation and thus functions
like a nucleoside. Its primary mechanism of action is the
inhibition of viral RNA polymerase. It appeared to show a more
favorable therapeutic index than did ribavirin in preclinical tests
of toxicity, including those done with human cells (table 5)
, and has been shown to be active in murine models of
influenza A(H5N1) virus infection (figure 5) [
]. These data
demonstrated a survival benefit as late as 48 h after virus
inoculation in a cohort given a 300-mg/kg/day dose and up to
60 h after virus inoculation in a cohort given the 600-mg/kg/
day dose. Initial unpublished data on human pharmacology
are encouraging with regard to oral absorption and tolerability,
and phase 2 efficacy studies have been ongoing in Japan during
the 2007–2008 influenza season.
Attachment inhibition. DAS181 (Fludase; NexBio) is a
fusion construct that incorporates the sialidase from Actinomyces
viscosus, a common oral bacterium linked to a human
epithelium-anchoring domain; it can be mass produced in Escherichia
]. The sialidase targets the viral attachment process, an
early event in the replication of influenza virus. When this
molecule is exposed to cells, it cleaves off the surface receptors
on respiratory epithelium that are recognized by influenza
hemagglutinin—both the a2,6-sialic acid–linked receptors to which
human viruses attach and the a2,3-sialic acid–linked receptors
to which avian viruses attach. DAS181 is inhibitory for a range
of influenza A and B viruses, with in vitro EC90 values ranging
from !1 to 56 nmol/L [
]. The epithelial tag on this molecule
increases its activity by an order of magnitude (∼5–30-fold)
]. In vitro removal of receptors by DAS181 leads to a
prolonged antiviral effect, although it is not clear whether this
effect will translate into a less-frequent dosing regimen in the
clinic. The molecule is not inhibitory for human cell growth.
Intranasal dosing has shown prophylactic and therapeutic
activity in mice and antiviral effects with reduced inflammatory
responses in ferrets [
]. Figure 6 illustrates the effect of
DAS181 when administered intranasally in a rodent model of
]. In a murine model of highly pathogenic avian
influenza using influenza A/Vietnam/1203/2004(H5N1)—a
stringent test of an antiviral agent—DAS181 was active both
prophylactically and therapeutically [
prophylactically, a DAS181 dosage of 1 mg/kg/day protected 100%
of mice from fatal disease and prevented viral dissemination
to the brain. Therapeutically, antiviral effects and increased
survival of mice exposed to an A(H5N1) virus challenge were
noted when treatment began as late as 72 h after infection [
Combination therapy is not a new concept in the management
of influenza. In fact, it initially was explored for the treatment
of influenza in preclinical assays years before it became the
standard of care in the management of HIV infection. Although
a promising strategy, little data from controlled clinical trials
of combination therapy for the treatment of influenza have
been published. Several years ago, when circulating influenza
A viruses were predictably susceptible to M2 inhibitors, the
National Institute of Allergy and Infectious Diseases
Collaborative Antiviral Study Group compared outcomes among
hospitalized adults who received either nebulized zanamivir plus
oral rimantadine or nebulized saline placebo plus oral
]. The small number of patients enrolled in this study
limited its statistical power, but some encouraging trends were
noted among patients who received combination therapy,
compared with those who received rimantadine alone. Patients
treated with zanamivir plus rimantadine demonstrated
nonsignificant trends toward fewer days of viral shedding and reduced
frequency of M2-inhibitor resistance. Patients assigned to
combination therapy also were more likely to have either no cough
or only a mild cough by the third day of treatment (15/16
[94%] vs. 11/20 [55%]; P p .01) [
]. No resistant variants
were found in patients in the group receiving combination
therapy, compared with 3 patients in the group receiving
M2 inhibitor–NAI combination therapy also has been
investigated for the treatment of A(H5N1) disease. Figure 7 shows
the effect of single drugs and combination therapy on survival
among mice inoculated with an amantadine-sensitive strain of
influenza A(H5N1) virus [
]. Although monotherapy showed
dose-related effects, the combination of amantadine and
oseltamivir at higher doses resulted in the highest level of survival
and antiviral effects in this animal model. In contrast, no greater
benefit was noted beyond the effects of oseltamivir alone when
the infecting A(H5N1) virus was resistant to M2 inhibitors.
This suggests that M2 inhibitor–NAI combination therapy is a
potential treatment option for seriously ill patients if the
influenza virus causing the infection is susceptible to M2
inhibitors. As previously noted, some A(H5N1) strains retain
susceptibility to M2 inhibitors; consequently, the possibility of
combination therapy has been suggested in recent WHO
management guidelines [
Various other antiviral combinations have been studied or
proposed, as shown in table 6 [
]. Further preclinical
studies and eventually clinical trials will be invaluable for
determining whether these new agents or suggested combinations
will offer clinically meaningful benefits beyond those attained
S10 • CID 2009:48 (Suppl 1) • Hayden
with current agents. However, until such clinical trial data are
available, physicians must make difficult treatment decisions
based on knowledge of patient characteristics and likely or
actual antiviral susceptibility patterns. The following 2 cases are
examples of such choices.
A kidney-transplant patient, aged 40 years, was admitted to
the hospital with respiratory symptoms and influenza A virus
infection in February 2007. In theory, this patient could have
been treated with oseltamivir, zanamivir, or rimantadine, alone
or in combination. Given the fact that the influenza virus
infection was most likely due to an A(H3N2) virus that was
resistant to the M2 inhibitors, there would be little point in
the use of rimantadine, since it would have increased the risk
of toxicity with little chance of improving the clinical outcome.
Combination therapy with oseltamivir and zanamivir would
have offered the benefit of providing 2 NAIs with differing
spectrums of action and sites of drug delivery. Unfortunately,
the efficacy and tolerability of orally inhaled zanamivir for
hospitalized patients or of this combination approach in relevant
animal models have not been studied adequately. High-dose
oral ribavirin [
] and intravenous ribavirin [
] are other
possibilities but are investigational for the treatment of
influenza. Thus, at that time, oral oseltamivir was the most practical
By contrast, suppose that, during the course of an
investigation into an avian influenza outbreak in Romania, a patient
with confirmed poultry exposure is admitted to the hospital
with a 5-day history of fever, cough, and now-increasing
shortness of breath. Testing reveals influenza A(H5N1) virus
infection, presumably owing to a clade 2.2 virus, and there is
radiographic evidence of pneumonia. Currently, there is no
evidence from randomized, controlled clinical trials to indicate
selection of a specific antiviral intervention in this case. The
updated WHO guidelines would recommend oseltamivir
therapy but also would suggest consideration of alternative drug
regimens, including combination treatment with an M2
inhibitor and oseltamivir, as well as doubling the oseltamivir dose
and duration of therapy. Since almost all A(H5N1) viruses from
clade 2.2 are susceptible to the M2 inhibitors, combination
treatment with oseltamivir and rimantadine would be a
reasonable approach. Given the low likelihood of survival of
someone with pneumonic A(H5N1) disease, interventions that
control replication as quickly as possible make sense. Hopefully,
in future, parenteral agents, including specific monoclonal
] or possibly convalescent plasma [
], will become
available for study in such a patient.
CURRENT TRENDS IN ANTIVIRAL DRUGS
FOR INFLUENZA TREATMENT
Numerous efforts are under way to develop new antiviral agents
for influenza treatment that possess an improved spectrum of
activity or better pharmacologic profiles, relative to current
treatments. Some of the most desirable features of future
antiviral agents for influenza treatment include greater potency
that quickly curtails viral replication, longer plasma or
pulmonary half-lives that permit fewer doses (or even a single
therapeutic dose), reduction in the risk of development of
resistant influenza virus strains, and completely new modes of
antiviral action for use in combination therapies.
Financial support. BioCryst Pharmaceuticals, Inc., provided
educational grant support to develop this article and the symposium on which
it is based, “Antiviral Therapy for Influenza: Challenging the Status Quo”
(San Diego), 4 October 2007.
Supplement sponsorship. This article was published as part of a
supplement entitled “Antiviral Therapy for Influenza: Challenging the Status
Quo,” jointly sponsored by the Institute for Medical and Nursing Education
and International Medical Press and supported by an educational grant
from BioCryst Pharmaceuticals, Inc.
Manuscript preparation. F.H. was a staff member of the World Health
Organization at the time of the symposium and during the writing of this
manuscript; the views expressed in this article are those of the author and
do not necessarily represent the decisions or the stated policy of the World
Health Organization. Margery Tamas of International Medical Press
(Atlanta) provided assistance in preparing and editing the manuscript.
Potential conflicts of interest. F.H.: no conflicts.
S12 • CID 2009:48 (Suppl 1) • Hayden
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