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OCTOBER
2006: VOLUME
1, NUMBER 1
ANTIVIRALS
FOR INFLUENZA
Welcome...
The
Johns Hopkins University School of Medicine and The Institute for Johns
Hopkins Nursing are pleased to welcome you to this premier issue of eInfluenza
Review. Over the course of this series, we will be exploring and
reporting on key aspects of preventing and treating influenza.
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In this issue...
The
mortality and morbidity numbers surrounding influenza are striking.
According to the CDC, with some substantial seasonal variations, the
average number of deaths per year in the United States attributed to
the disease is 36,000. About 90% of those deaths are in persons over
65 years, with most occurring in the “elderly elderly” (over 85 years).
Further, the number of influenza-related excess hospitalizations is
about 226,000 per year. While vaccination is the preferred method of
prevention, antiviral agents can be used for both prophylaxis and treatment;
it is therefore critical for all practitioners to understand their
correct use.
In this issue, we review
the current knowledge-base regarding pharmacology, efficacy, resistance,
patient types and recommended dosages, side effects, and expected outcomes
for the use of antiviral therapies during this influenza season. |
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COMMENTARY |
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There
are four drugs in two classes for the treatment and prevention of influenza.
The adamantanes (amantadine and ramantadine) now have resistance rates
of over 90% for clinical isolates in the US for the 2005-06 season,
and, as reported by Smith et al, the CDC warns against their use. The
neuraminidase inhibitors – zanamivir and oseltamivir – appear to be
equally effective for prophylaxis and treatment, but, as discussed
in Moscona’s 2005 NEJM article, are completely different in terms of
method of delivery, pharmacology and side effects. Oseltamivir is a
capsule, distributed systemically and may cause GI side effects. Zanamivir
is inhaled, nearly all is in the respiratory tract, and it can cause
pulmonary side effects including bronchospasm.
For
treatment, both drugs must be given within 48 hours of the onset
of symptoms to show benefit; this correlates with the time of maximum
influenza virus replication. Perhaps the most important observation,
as reported by Kawai et al in their Japanese multi-center study, is
the fact that within this 48 hour window of opportunity, the benefit
is substantially greater when the drug is given early. This means there
should be no time delay in the decision to treat.
In terms of treatment
benefits, there is a modest reduction in duration of fever (the
endpoint of the trials). In addition, as Smith reports, there are also
benefits in terms of earlier return to work or school, prevention of
hospitalization, etc. The greatest medical benefit is in persons at
greatest risk for complications of influenza. This is a well-described
group who are also the highest priority for influenza vaccine – primarily
the elderly, and those with chronic diseases, especially lung, cardiovascular,
and neurologic syndromes.
Diagnosis: Early
treatment of influenza presumes an ability to make a rapid diagnosis.
For clinicians, the standard practice of making this “clinical diagnosis” is
usually based on fever, malaise and cough in the midst of an influenza
epidemic. As the Smith review points out, this would result in an over-treatment
and undertreatment rate of about 30%. The point-of-care diagnostics
(POC) may help here since results are available within 30 minutes.
As Poehling et al report, POC diagnostics will still miss about 20-30%
of cases, but if positive, the patient nearly always has influenza
by culture.
For prophylaxis,
both zanamivir and oseltamivir are 80-90% effective in prevention.
However, it needs to be emphasized that influenza vaccine is the preferred
method to prevent influenza. The highest priority for antiviral therapy
would be for those who are prioritized for the vaccine, but did not
receive it for some reason; it might also be used when there is a mismatch
between the vaccine and the epidemic strain. The antivirals may also
be used to reduce viral shedding in unvaccinated hospitalized patients
with influenza as a method of infection control, or given to healthcare
workers in the midst of an epidemic to protect both them and their
patients. The duration of prophylaxis is usually ten days at half the
treatment dose, which should provide time for the influenza vaccine
to “kick in”. For persons who have continuing exposure and cannot take
the vaccine or benefit from it, antiviral prophylaxis should continue
for the duration of risk. |
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Smith
NM, Bresee JS, Shay DK et al. Prevention and Control
of Influenza. MMWR 2006;55 (R10):1-42.
(For non-journal subscribers, an additional fee may apply
for full text articles.) |
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The
authors represent the Advisory Committee on Immunization Practices
for the CDC. This text draws on a large number of studies and provides
a timely and authoritative review of influenza by healthcare professionals
who are true experts. Although most of the document deals with immunization
practices (the focus of an upcoming issue of eInfluenza Review),
their report provides important information on the use of antivirals
for prophylaxis. Key highlights of the publication include:
Susceptible
Hosts: Those at high risk of severe influenza and its complications
are children under two years old, pregnant women, persons >65
years, patients with concurrent conditions including chronic lung
and heart disease (including asthma but not hypertension), diabetes,
renal failure, hemoglobinopathies, immunodeficiency, residents of
chronic care facilities, and those with conditions that compromise
lung function or who are predisposed to aspiration (cognitive dysfunction,
cord entries, seizure disorders etc.).
Diagnosis: Most
clinicians make a diagnosis on the basis of characteristic clinical
features (cough, fever and malaise) during an influenza epidemic.
Multiple
studies(1-3) show the sensitivity of this is 63-78% and
the specificity is 55-71%. This means that of 100 cases, clinicians
get it right about 70% of the time; in the context of antivirals,
that means we under-use and over-use them in about 30% of cases.
Rapid tests are now available for office use, can give results in
30 minutes, and have a sensitivity and specificity of 70% and 99%
respectively(4-6). Therefore, while these tests miss
as many cases as we do, a positive is much more specific.
Antivirals
for Prophylaxis: Vaccination is the preferred method for
prevention, but oseltamivir and zanamivir are considered “critical
adjuncts in preventing and controlling influenza”. The assessment
for prevention is based on large clinical trials which show effectiveness
in preventing laboratory-confirmed influenza illness in 84% with
zanamivir and 82% with oseltamivir(8,10). Both drugs
have been shown effective in preventing influenza in household members
of a diagnosed case, in institutional settings, in persons with
chronic medical conditions, and in nursing homes(11,12).
References
| 1. |
Nicholson
KG. Clinical
features of influenza. Semin Respir Infect 1992;7:26. |
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| 2. |
Boivin
G, Hardy I, Tellier G. Predicting
influenza infections during epidemics with use of a clinical
case definition. Clin Infect Dis 2000;31:166. |
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| 3. |
Monto
AS, Gravenstein S., Elliott M et al. Clinical
signs and symptoms. Arch Intern Med 2000;160:3243. |
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| 4. |
Storch
GA. Rapid
diagnostic tests for influenza. Curr Opinion Pediatr 2003;15:77. |
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| 5. |
Uyeki
TM. Influenza
diagnosis and treatment in children. Pediatri Infect Dis
J 2003;22:164. |
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| 6. |
Cox
N. Subbarao K Influenza.
Lancet 1999;354:1277. |
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| 7. |
Monto
AS, Fleming DM, Henry D et al. Efficacy
and safety of the neuraminidase inhibitor zanamivir in the treatment
of influenza A and B virus infections. J Infect Dis 1999;180:254. |
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| 8. |
Cooper
NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG. Effectiveness
of neuraminidase inhibitors in treatment and prevention of influenza
A and B: systematic review and meta-analyses of randomized controlled
trials. BMJ 2003;326:1235. |
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| 9. |
Kaiser
L, Wat C, Mills T et al. Impact
of oseltamivir treatment on influenza-related lower respiratory
tract complications and hospitalizations. Arch Intern Med
2003;163:1667. |
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| 10. |
Hayden
FG, Atmar Rl, Schilling M et al. Use
of the selective oral neuraminidase inhibitor oseltamivir to
prevent influenza. N Engl J Med 1999; 341:1336. |
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| 11. |
Hayden
FG, Gubareva LV, Monto AS et al. Inhaled
zanamivir for the prevention of influenza in families. N
Engl J Med 2000;343:1282. |
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| 12. |
Peters
PH, Gravenstein S, Norwood P et al. Long-term
use of oseltamivir for the prophylaxis of influenza in a vaccinated
frail older population. J. Am Geriatr Soc 2001;49:1025. |
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NEURAMINIDASE
INHIBITORS FOR INFLUENZA |
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Moscona
A. Neuraminidase inhibitors for influenza. N Engl
J Med 2005; 353:1363.
(For non-journal subscribers, an additional fee may apply for
full text articles.) |
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Moscona’s
2005 NEJM article draws on a number of studies to provide a comprehensive
summary on neuraminidase inhibitors for influenza. Key highlights include:
Viral
Kinetics: Viral replication peaks at 24-72 hours after onset
of illness and neuraminidase inhibitors (NI) need to be given as early
as possible.
Pharmacology: Zanaminivir
is inhaled and highly concentrated in the respiratory tract — most
is in the oropharynx, 10-20% reaches the lung, and 5-15% is absorbed.
Oseltamivir is a capsule with good oral bioavailability, it is widely
distributed in the body, the half life is 6-10 hours, and it is eliminated
primarily by renal mechanisms. Clinicians are cautioned on the need
to reduce oseltamivir to half dose in patients with a creatinine clearance <30
mL/min.
Efficacy
for Treatment: A large pivotal study(1) showed oseltamivir
treatment given within 36 hours of onset of symptoms compared to placebo
reduced the median duration of illness by about 30% (4.3 to 3 days)
and the severity of illness by about 40%. Similar results have been
achieved with zanaminivir(2) .
Treatment: Neuriminidase
inhibitors given within 48 hours of onset of symptoms can reduce the
duration of influenza by about one day(2,3). Data are limited
on the efficacy of these drugs in preventing the complications of influenza,
but a metaanalysis of 10 trials showed a 50% reduction in rates of
pneumonia and a 50% reduction in rates of hospitalization(4).
Efficacy
for Prophylaxis: Both drugs are 70-90% effective in preventing
the disease when used for prophylaxis either before or after exposure
for both influenza A and influenza B.
Side
Effects: The main side effect of zanamivir has been cough, bronchospasm,
and a reversible decrease in lung function in a small subset of patients.
There is convincing evidence that there are no long term consequences
to lung function. The current recommendation is that patients with
pulmonary dysfunction given zanamivir should have a rapid-acting bronchodialator
available, and discontinue the drug if this side effect occurs. The
main side effect with oseltamivir has been transient nausea, vomiting
and abdominal pain, noted in 5-10% of patients.
Resistance: There
is minimal emergence of resistance during treatment, with a reported
rate of 0-0.4% among treated adults. It is higher in children, with
one report of 4%(5). In general, mutations that confer resistance
to neuraminidase inhibitors cause a substantial reduction in fitness
of the virus, making it less pathogenic and less easily transmitted(6,7).
The clinical relevance of these observations in the mammalian model
is unclear.
Practical
Application: The following table summarizes relevant information
for the use of zanamivir and oseltamivir for treatment and prophylaxis
of influenza:
 References
| 1. |
Treanor
JJ, Hayden FG, Vrooman PS. Efficacy
and safety of the oral neuraminidase inhibitor oseltamivir in treating
acute influenza: a Neuraminidase Study Group. JAMA 2000;283:1016-24 |
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| 2. |
Cooper
NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG. Effectiveness
of neuraminidase inhibitors in treatment and prevention of influenza
A and B: systematic review and meta-analyses of randomized controlled
trials. BMJ 2003;326:1235. |
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| 3. |
Monto
AS, Fleming DM, Henry D et al. Efficacy
and safety of the neuraminidase inhibitor zanamivir in the treatment
of influenza A and B virus infections. J Infect Dis 1999;180:254. |
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| 4. |
Kaiser
L, Wat C, Mills T et al. Impact
of oseltamivir treatment on influenza-related lower respiratory
tract complications and hospitalizations. Arch Intern Med 2003;163:1667. |
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| 5. |
Whitley
RJ, Hayden FG, Reisinger KS, Young N et al. Oral
oseltamivir treatment of influenza in children. Pediatr Infect
Dis J. 2001;20(4):421. |
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| 6. |
Moscona
A. Oseltamivir-resistant
influenza? Lancet 2004;364:759-65. |
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| 7. |
Herlocher
ML, Truscon R, Elias S et al. Influenza
viruses resistant to the antiviral drug oseltamivir: transmission
studies in ferrets. J Infect Dis 2004;190:1627-30. |
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EFFECTIVENESS
OF OSELTAMIVIR |
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Kawai
N., Ikematsu H, Iwaki N et al. A comparison of the effectiveness
of oseltamivir for the treatment of influenza A and influenza B:
a Japanese multi-center study of the 2003-2004 and 2004-2005 influenza
seasons. Clin Infect Dis 2006;43:439-44.
(For non-journal subscribers, an additional fee may apply for
full text articles.) |
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The
authors compared the effectiveness of oseltamivir for the treatment
of influenza A and influenza B and also examined the utility of early
treatment. The method was to make a presumptive diagnosis on the basis
of the rapid flu test in patients who presented with typical symptoms
of influenza, and then randomly assign treatment for those stratified
for influenza A or influenza B. The major outcome parameter was the
duration of fever and virus eradication by cultures at 4-6 days after
treatment. The analysis of fever duration was divided into four subgroups
based on the time from onset of symptoms to first dose.
The results of the study
showed efficacy was substantially better for influenza A antiviral
activity vs influenza B on the basis of the duration of fever after
treatment and the frequency of viral isolation at 4-6 days. The rate
of positive cultures was 52% for those with influenza B compared to
16% for those with influenza A (P < 0.001). With regard to the time
of treatment, the breakdown for the 3,351 participants showed a direct
correlation between reductions in fever duration and earlier treatment.
These data are summarized
as follows:
 The
investigators also performed an analysis by age category, ranging from
0-6 years to those over 64 years, and found no important differences
based on age and outcome.
Among the authors’ conclusions are that oseltamivir is more effective
against influenza A than influenza B, better results are achieved when
the drug is given soon after the onset of symptoms, and the benefit
in terms of duration of fever appears similar across all age strata. |
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Poehling
KA, Zhu Y, Tang WY, Edwards K. Accuracy and Impact of a
point-of-care rapid influenza test in young children with respiratory
illnesses. Arch Pediatr Adolesc Med 2006;160:713-8.
(For non-journal subscribers, an additional fee may apply for
full text articles.) |
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Using
the QuickVue Influenza Test (Quidel), Poehling et al at Vanderbilt
University designed a study to determine the impact and accuracy of
point-of-care diagnostic testing for influenza in a pediatric emergency
department. The analysis included a comparison of results of the rapid
test with viral culture and the impact of test results on test ordering
and antibiotic prescribing. The results were based on observations
in 468 children, including 88 (19%) who had cultured-confirmed influenza
infection — of these 205 were in the rapid test group and 51 had influenza
infection.
The results showed the following:
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The
rapid influenza test was 82% sensitive and 99% specific |
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There
was a significant decrease in diagnostic testing in the group that
had a positive rapid test (39% vs. 51%, P=0.03) |
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There
was no decrease in antibiotic prescribing |
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The
use of antiviral agents was low |
This
study confirms the reported experience with the rapid test in terms
of sensitivity. While the investigators anticipated that this information
would translate into fewer diagnostic tests, fewer antibacterials,
and more antivirals for influenza, their results showed limited benefits
in these variables. |
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CME/CNE/CPE
INFORMATION |
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nursing education by the American Nursing Credentialing Center's
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