Review

Synthèse

The treatment of influenza with antiviral drugs

Grant Stiver
Abstract group of anti-influenza drugs. It has been used to treat and
prevent influenza A since the mid-to-late 1960s.2 In the
Influenza vaccination with current inactivated vaccines homol- United States, rimantadine, an agent with fewer side effects
ogous to the prevalent wild-type virus can reduce influenza ill- than amantadine is more commonly used, but has never
ness in 75%–80% of healthy adults. Vaccine is recommended been licensed in Canada. The second class of agents con-
for all individuals with chronic underlying diseases and for sists of the viral neuraminidase inhibitors (NAIs), zanamivir
those aged 65 years or older. Although influenza vaccination is
(Relenza) and oseltamivir (Tamiflu).3
still advocated for patients with blunted immunity, protection
rates are not as high, running at 40% for frail institutionalized
elderly people. The influenza antiviral agents amantadine or ri- Biology of influenza and mechanism of action
mantadine, zanamivir and oseltamivir can modify the severity of anti-influenza drugs
of illness and reduce the duration of illness by about 1.5–
2.5 days. Amantadine inhibits only influenza A. Resistant virus
may emerge in up to 33% of amantadine-treated patients in the In order to understand the action of the antiviral drugs,
first 5 days of treatment and be transmitted to susceptible close a quick overview of the influenza virus is in order. In-
contacts. Side effects are usually mild in short courses of treat- fluenza belongs to the orthomyxovirus group of RNA
ment. The neuraminidase inhibitor drugs zanamivir and os- viruses. Influenza is a relatively large virus that is essen-
eltamivir act on both influenza A and B. Treatment is most ef- tially confined to infecting cells of the upper and lower
fective when given within 30–36 hours after the onset of respiratory tract. Viremia has rarely been detected. The
illness, and the earlier the better. Influenza should be treated infection cycle of the influenza virus is depicted in Fig. 1.
with antiviral drugs in unvaccinated and vaccinated high-risk There are 2 major proteins on the surface of the influenza
patients, as well as immunosuppressed patients with influenza- virus, the hemagglutinin (HA) and the neuraminidase
like illness, in periods of confirmed influenza prevalence. (NA). The hemagglutinin mediates attachment of the
These drugs may be of great value in the event of a major viral virus particles to the respiratory epithelial cells via specific
antigenic shift that causes pandemic influenza, if an adequate receptors. Once the virus has bound to its host cell, it is
supply can be sustained.
transported into the cytoplasm in an endosome. The acid
CMAJ 2003;168(1):49-57 pH in the endosome activates or opens an ion channel
called the M2 protein, permitting hydrogen ions to enter
the virion. The resulting acidification of the virus is nec-

I
nfluenza is responsible for more morbidity and mortal- essary for viral uncoating, another essential step in viral
ity each year in North America than all other respira- replication. Amantadine inhibits the function of the M2
tory diseases combined, and it results in tremendous protein and thus stops the replication process. Amanta-
economic costs both from admissions to hospital and loss dine is only effective against influenza A, and not in-
of productivity. Influenza and its attendant complication of fluenza B, because influenza B does not have an M2 pro-
pneumonia constitute the sixth leading cause of death over- tein, but a substitute protein called NB that is not affected
all in Canada.1 Preventive strategies are the key to reducing by amantadine.4
the impact of influenza on our communities, and effective Neuraminidase is a viral enzyme that cleaves the neu-
vaccination strategies have been in place for half a century raminic acid component of sialic acid in the respiratory
and continue to be improved upon. However, for the indi- epithelial cell hemagglutinin receptors. After replication,
vidual physician faced with a severely ill patient during an in order to exit the cell and infect other cells, influenza
influenza epidemic, effective treatment is required. This virus particles bud off the host cell membrane. The viral
need has led to the development of antiviral agents that halt neuraminidase is required to release the budding virus
or impede the ability of the virus to infect respiratory ep- particles by digesting the hemagglutinin receptors hold-
ithelial cells. ing the viruses to the cell. The virus particles thus re-
Two main classes of drug interfere with influenza virus leased still have hemagglutinin receptors from the cell
infection (Table 1). The first drug to be developed was membrane coating them, and the hemagglutinins of other
amantadine, which belongs to the ion channel blocker newly released viruses bind to these causing clumping.

CMAJ • JAN. 7, 2003; 168 (1) 49

© 2003 Canadian Medical Association or its licensors

Stiver

The neuraminidase cleaves these residues, allowing the refuse vaccination, especially if they have had previous side
viruses to disperse, enhancing their ability to infect other effects, or have developed a respiratory viral infection (that
cells. The third function of the may have been caused by some
neuraminidase is to digest neu- noninfluenza respiratory virus)
raminic acid in respiratory mu- Preventive strategies are the key to reducing after receiving an influenza vac-
cus, perhaps facilitating viral the impact of influenza on our communities, cine in previous years. Influenza
spread. 5 The NAI drugs, and effective vaccination strategies have been vaccine is only 40%–60% effec-
zanamivir and oseltamivir, bind in place for half a century and continue to be tive in elderly patients,6 espe-
to the active site on the viral improved upon. However, for the individual cially nursing home residents,
neuraminidase, blocking its ac- physician faced with a severely ill patient dur- and in patients with immuno-
tivity. Thus, virus particles can- ing an influenza epidemic, effective treatment suppression caused by underly-
not exit the cells as easily, and is required. This need has led to the develop- ing disease or by the drugs they
they tend to clump and not dis- ment of antiviral agents that halt or impede the are taking, because they may
perse. This impedes their abil- ability of the virus to infect respiratory epithe- not form sufficient antibodies.6,7
lial cells.
ity to infect more cells and at- Antiviral treatment of influenza
tenuates the patient’s infection. in these types of individuals may
However, there is still subclini- attenuate the infection and re-
cal or mild infection that actively immunizes the patient duce morbidity and mortality. Strategies for the use of in-
against that strain. The NAIs are active against both in- fluenza antiviral drugs should complement the preventive
fluenza A and B. benefits of vaccination.

Why does influenza require treatment?

In what circumstances should influenza
Many people do not require treatment for influenza, antiviral drugs be used?
however, treatment may be of significant benefit to those at
high risk of complications or those who for whatever rea- These clinical indications are listed in Table 2 and range
son need to minimize their absence from work. High-risk from presumptive treatment in nursing home outbreaks to
individuals are those over the age of 65 years and those treatment in the immunocompromised patient. The cate-
with chronic underlying diseases such as chronic obstruc- gories listed may also apply to prevention of influenza with
tive pulmonary disease (COPD), asthma, chronic heart dis- antiviral agents, the effectiveness of which has been con-
ease, diabetes, chronic renal or hepatic disease, neoplastic firmed for both amantadine and the NAIs.8–12 Influenza an-
disease and chronic connective tissue disease. They may tivirals may also be used to prevent influenza in the event
have increased morbidity and mortality from influenza that the epidemic strain has undergone such a significant
virus infection, usually as a result of bacterial superinfec- change in its antigenic structure (antigenic shift or anti-
tion, the most common being pneumonia. Influenza vac- genic drift) that it is no longer covered by the current vac-
cine should be given to all such patients, but in reality this cine, as occurred in January of 1997 when the epidemic
does not always happen. Moreover, some patients may strain suddenly changed from A/Wuhan to A/Sydney.

Table 1: Drugs available in Canada for the treatment of influenza

Virus Approximate
type cost to
Drug class affected Drug Dose Route Duration, d Side effects patients, $*
Ion channel A Amantadine 100 mg bid Oral 5 0%–15% incidence jitteriness, 13
blockers (100 mg daily insomnia, nightmares, rarely
for elderly hallucinations
patients)†

Neuraminidase A and B Zanamivir 10 mg bid Inhaled 5 Possible worsening of asthma — use 45

inhibitors zanamivir with puffer in asthmatic
patients29‡
A and B Oseltamivir 75 mg bid Oral 5 8%–10% incidence nausea, 53
vomiting usually lasts 1–2 days and
is not severe
Note: bid = twice a day.
*Approximate cost in pharmacies in British Columbia.
†Serum creatinine should be determined, if possible before the influenza season.
‡However, a double-blind placebo-controlled trial in 525 patients with asthma and chronic obstructive pulmonary disease showed no adverse effect of zanamivir on airway resistance.30

50 JAMC • 7 JANV. 2003; 168 (1)

 Treatment of influenza with antiviral drugs

Clinical trials with influenza antiviral drugs tution of treatment with oseltamavir was found to be asso-
ciated with the cessation of further cases.12 However, iso-
Descriptions of comparative studies of the influenza an- lates were not tested for amantadine resistance. Because of
tiviral drugs are listed in Table 3. All but one of these stud- this concern, it has been suggested that if one is going to
ies were double-blind and placebo-controlled. The older treat the index case in a family with amantadine, other at-
trials of amantadine for the treatment of influenza demon- risk family members should receive an NAI rather than
strated a reduction in febrile influenza illness of about amantadine, for prophylaxis.
1–1.6 days compared with placebo.13–15 Interestingly, one In more recent trials of the NAIs, patients were re-
study showed no reduction in the rates of virus-positive cruited by media advertisements, as well as emergency de-
nasal culture when using amantadine compared with partments and general practice clinics. The major end
placebo over the 5 days of treatment.13 Whether a compo- points of the studies were cessation of symptoms of fever-
nent of this was related to acquired amantadine resistance ishness, cough, nasal obstruction, sore throat, myalgias,
was not tested. Another small family-based double-blind headache and fatigue. These trials showed a statistically
trial of amantadine in young adults and children with in- significant reduction in these acute symptoms of between
fluenza showed a reduction of 1.5 days of reduced activity, 1 and 2.5 days, depending on the subgroup analyzed,
2.6 days to 50% fewer symptoms and 1.6 days fewer of compared with placebo. This clinical effect was coinci-
fever. However, 33% of recipients began excreting amanta- dent with a decrease in the titre of viral shedding. Sec-
dine-resistant virus by day 5 of treatment.15 In a recent re- ondary benefits included 50%–70% fewer complications,
port of the apparent failure of amantadine prophylaxis to 30%–50% fewer courses of antibiotics compared with
curtail influenza outbreaks in Ontario nursing homes, insti- placebo and earlier return to normal activities by 1–

Hemagglutinin protein (HA) Virion clumping

Neuraminidase protein (NA)
HA receptor
Influenza virus
M2 protein
Amantadine
NA inhibitor (NAI) drugs

NAIs inhibit
release of virions
and promote clumping
Attachment

Budding virion

Internalization
and uncoating

Amantadine disables M2 Synthesis of viral proteins

protein, preventing viral
uncoating – virus
rendered inert
Myra Rudakewich

Replication of viral RNA

Fig. 1: Schematic representation of influenza virus attachment, internalization, replication and exit from the host respiratory
cell and steps inhibited by antiviral drugs. Amantadine blocks viral internalization and uncoating. Neuraminidase inhibitors pre-
vent the neuraminadase from releasing budding viruses and dispersing virions.

CMAJ • JAN. 7, 2003; 168 (1) 51

Stiver

3 days. In these trials, all patients received an anti- strated that 46% more patients in the zanamivir group
pyretic/analgesic such as acetaminophen or paracetamol were afebrile by 24 hours after the start of treatment com-
for symptomatic relief, and there was less use of these pared with placebo.21 In most of these studies, the earlier
medications in the drug-treated patients, reflecting less the antiviral was started after the onset of symptoms of
severe disease. The symptom scores in the MIST influenza-like illness (ILI), the greater the difference be-
zanamivir trial (in Australia, New Zealand and South tween drug and placebo. For example, with zanamivir, al-
Africa)16 and US trials with zanamivir,17,18 as well as the US though patients were enrolled within 48 hours of the on-
and international trials with oseltamivir,19,20 indicated that set of symptoms, the significant differences in symptom
illness in patients treated with the NAI was less severe, al- resolution were only seen in those patients treated within
lowing an earlier return to normal function. A European 30 hours of onset.17,18 There are further data from the
trial in Scandinavia and the United Kingdom demon- IMPACT trial (1428 patients treated) showing that os-

Table 2: Indications for antiviral drug treatment of influenza*

Indication Clinical circumstances Example
1. Vaccine may not be Influenza-like illness (ILI) in: A patient with chronic lymphocytic leukemia
1. immunogenic • Immunosuppressed host with hypogammaglobulinemia
• Unvaccinated household contact A patient on immunosuppressant drugs
• of immunosuppressed patient
• Elderly nursing home patient
2. Subject at high risk and has Sudden influenza epidemic with Patients with chronic heart failure, chronic
2. not been immunized ILI in patients at high risk of obstructive pulmonary disease, chronic renal
influenza or liver disease, or diabetes; elderly patients,
especially frail elderly
Complications and excess
mortality due to pneumonia
3. Vaccine is not matched with ILI in any patient who was or
3. the circulating virus strain should have been vaccinated
*Influenza antiviral drugs should be used only where prevalent ILI has been demonstrated to be influenza by public health agencies.

Table 3: Results of selected clinical trials of antiviral drug therapy for influenza
Median reduction compared
with placebo or comparative
regimen, d
Duration Relative reduction
Influenza of Time to resume in influenza
Drug Reference Study population and setting virus type symptoms normal activity complication rate, %
Amantadine/ 13–15 Naturally occurring influenza A 1.0–1.6 1.5 NR
rimantadine outbreak in prisoner volunteers
200 mg once daily and selected families
Inhaled zanamivir 16–18 Naturally occurring influenza in A and B 1.5–2.5 1.0–2.0 33–70
10 mg bid communities of previously healthy
adults
23 Naturally occurring influenza in A and B 2.5 3.0 43
high-risk patients
30 Naturally occurring influenza in A and B 1.5 NR 58*
patients with COPD and asthma
Oseltamivir 19–21 Naturally occurring influenza in A and B 1.3 1.4–2.9 50
75 mg bid orally communities of previously healthy
adults
22 Naturally occurring influenza in NR 3.1 5.3 NR
communities of previously healthy
adults — treatment within 12 h v.
48 h after onset
Note: COPD = chronic obstructive pulmonary disease, NR = not reported.
*No adverse effect of zanamivir on peak expiratory flow rates or forced expiratory volume in 1 second compared with placebo.

52 JAMC • 7 JANV. 2003; 168 (1)

 Treatment of influenza with antiviral drugs

eltamivir treatment within 12 hours of symptom onset provincial health agency Web sites as well as from televi-
further reduces the duration of illness and accelerates re- sion broadcasts. In an average influenza prevalence pe-
turn to normal activities by 3.1 days and 5.3 days respec- riod, clinical ILI has been shown to be true influenza in
tively, compared with starting treatment 48 hours after about 50%–70% of cases. Rapid enzyme-linked im-
the start of symptoms.22 In all of the trials, the viral shed- munosorbent assay (ELISA) and polymerase chain reac-
ding in nasal secretions was significantly reduced in quan- tion (PCR) diagnostic tests for influenza A and B are
tity and duration. Although not tested, this presumably available. ELISA tests are more sensitive in children than
would lessen the exposure risk for close contacts. adults (over 80% sensitive for children less than 4 years of
It is important to remember that in evaluating the spe- age versus 25% for adults over 40 years of age) and have
cific efficacy of influenza antiviral drugs, the true test of not been widely used in the office setting.24 PCR-based
the drug’s inherent potency is tests are more sensitive (over
its performance in ILI proven to 90%) for all age groups but are
be influenza. In intention-to- Treatment may be of significant benefit to indi- not widely used for primary di-
treat analyses, all patients who viduals at high risk of complications or those agnosis in commercial labora-
received at least one day of who for whatever reason need to minimize tories. In Canada, there is no
drug, whether they turned out their absence from work. High-risk individuals reimbursement made to the
to have influenza or ILI caused are those over the age of 65 years and those clinician of the cost of purchas-
by another virus, are included in with chronic underlying diseases such as ing or interpreting office-based
the analysis of efficacy. Al- chronic obstructive pulmonary disease, tests, and they take extra time.
though this may reflect the “real asthma, chronic heart disease, diabetes, On the other hand, when
life” use of antivirals, it is really chronic renal or hepatic disease, neoplastic 30%–50% of individuals with
a test of effective strategy in us- disease and chronic connective tissue disease. ILI may not have influenza and
ing the drug, not the inherent They may have increased morbidity and mor- will not benefit from the drugs,
efficacy of the drug against in- tality from influenza virus infection, usually as rapid diagnosis is cost-effective.
fluenza virus. The more intense a result of bacterial superinfection, the most A second caution is not to pre-
common being pneumonia.
the influenza epidemic is, that scribe an influenza antiviral
is, the higher the attack rate, the drug if symptoms have been
better the efficacy will be in present for longer than 36–
intention-to-treat studies, as the effect will not be as di- 48 hours, and the most benefit occurs when drug therapy
luted by noninfluenza ILI. Most of the patients entered is started earlier than 30 hours after the onset of symp-
into the phase III trials were previously healthy. We still toms, at least for the NAIs.18,22
need more data on the performance of antiviral agents for These data raise questions about the best logistics for
the treatment of influenza in high-risk patients. One such physicians to follow in prescribing influenza antivirals.
study that examined the efficacy of zanamivir in high-risk Should all patients be seen in the office first? In a severe
patients from 6 placebo-controlled trials demonstrated epidemic, this could flood the office possibly to the exclu-
that patients had 2.5 fewer days of symptoms, and re- sion of other patients. Should influenza antivirals be pre-
23
turned to their previous baseline activities 3 days earlier. scribed over the telephone after a brief history is taken?
Only one of the trials (with zanamivir) featured signifi- The chances are that if there is an ongoing influenza epi-
cantly high attack rates of influenza B,16 and more infor- demic, the latter strategy would often work well. However,
mation is required on treating this virus type in adults. there have been concerns about bacterial pneumonia being
misdiagnosed as influenza during an epidemic and treated
Diagnosing influenza and initiating treatment with an NAI, resulting in a poor outcome. Therefore, best
practice may dictate that at least in those patients at high
The first caution is not to prescribe anti-influenza drug risk of pneumonia as a complication of influenza, an exami-
therapy unless one is sure there is an influenza outbreak nation is necessary before deciding to treat with amanta-
in the community. One cannot diagnose influenza virus dine, oseltamivir or zanamivir. Guidelines such as those
infections clinically with confidence, because many respi- created for the treatment of community-acquired pneumo-
25
ratory viruses such as parainfluenza, respiratory syncytial nia should be formulated for treating influenza. A sug-
virus, adenovirus and coxsackievirus cause similar symp- gested algorithm is depicted in Fig. 2.
toms and signs. When evaluating an adult patient in a sit-
uation in which there is influenza and other respiratory Which antiviral drug is best — amantadine,
viruses causing ILI in the community, the presence of zanamivir or oseltamivir?
fever (oral temperature ≥ 37.8° C) early on in the illness
suggests influenza rather than another virus.17 Currently, The information needed to answer this question with as-
in Canada there are several influenza surveillance pro- surance is lacking. No published trials have compared these
grams operating, and updates can be obtained from most agents head to head. Any preferences therefore must be

CMAJ • JAN. 7, 2003; 168 (1) 53

 Stiver

based on each drug’s antiviral spectrum, side effects and centrations of 300 ng/mL prevent influenza infection, and
ease of administration, which might affect compliance, as in elderly patients 1.4 mg/kg daily (about 100 mg daily for
well as affordability for patients. a 70-kg person) achieves this level.27 In elderly people, re-
The side effects of amantadine have been a potential gardless of serum creatinine, and in those individuals with
limitation to its use. The most frequent reactions are nau- creatinine clearances of 30–50 mL/minute, treatment
sea, dizziness and insomnia. These have been reported to should be started with one dose of 200 mg, then reduced
occur in 5%–15% of patients taking amantadine for pro- to 100 mg daily for 4 days. An NAI would be preferable if
phylaxis over 6 weeks,8 but other studies of amantadine the serum creatinine level is greater than 200 mg/L. An-
treatment (lasting up to 10 days) have documented no dif- other drawback of amantadine for the treatment of in-
ference in side effects compared with placebo.9,10,26 The fluenza is that within 5 days of treatment up to one-third
major side effects are almost an amphetamine-like effect, of patients may begin to shed resistant virus due to a mu-
including jitteriness, anxiety, nightmares and, rarely, hal- tation in the amantadine target, the M2 protein. In family
lucinations. These effects appear to be due to an effect of settings, family members of the person being treated with
amantadine, similar to amphetamines, of stimulation of amantadine can be infected by these amantadine-resistant
the central nervous system. The symptoms usually resolve strains.28 The spectrum of amantadine, as previously men-
once the medication is stopped. For current treatment tioned, covers only influenza A, although A strains cause
courses of 5 days, these side effects are less likely to occur. most epidemics.
In patients with impaired renal function and elderly peo- The NAIs may be used to treat both A and B influenza
ple, the dose should be reduced. Amantadine plasma con- and have relatively fewer side effects. A caution that the

Patient with ILI (fever, headache, myalgia,

nasal congestion, cough) ≤ 36 hours

NO Probably not influenza –

Influenza present in community?*
treat symptomatically
YES
YES
Coughing purulent sputum? Consider bacterial pneumonia
NO

Patient < 65 years; Patient ≥ 65 years with risk factors

no immunosuppression for complications of influenza;
immunosuppressed patient of any age

Vaccinated against influenza?

YES NO Vaccinated and unvaccinated

Probably not influenza Antiviral agent

(vaccine protection likely) –
treat symptomatically Unvaccinated household contacts?
NO YES

YES Influenza is NO zanamivir, 10 mg inhaled bid for 5 days, OR

Amantadine NAI
type A? oseltamivir, 75 mg orally bid for 5 days
100 mg bid for 5 days if patient < 65 years
100 mg once daily for 5 days if patient ≥ 65 years
Myra Rudakewich

– Check serum creatinine

Fig. 2: An algorithm for the treatment of acute influenza-like illness (ILI). *Influenza virus outbreak confirmed by public health
authorities. †Influenza antiviral treatment could be considered. It could also be considered in relatively healthy unvaccinated
people aged less than 65 years to minimize absence from work.

54 JAMC • 7 JANV. 2003; 168 (1)

 Treatment of influenza with antiviral drugs

inhaled zanamivir powder may be associated with bron- especially admission to hospital.34 Most of the available
chospasm and may exacerbate asthma in some patients29 cost–benefit studies have used quality-adjusted life years
appears in the product monograph, although one double- or QALYs as the end point. The potential additional eco-
blind placebo-controlled study of zanamivir treatment of nomic benefit of the indirect cost–benefit ratio of earlier
acute influenza in patients with asthma and COPD return to work productivity has not been extensively stud-
showed no difference in airway resistance. 30 The oral ied, but it is estimated that the indirect costs of epidemic
agent oseltamivir causes mild nausea and vomiting (in influenza may be 5 to 10 times higher than direct costs.35
about 7% of cases) that is relatively short-lived (first day This should be born in mind when assessing the
or two of therapy), and in the published trials this did not cost–benefit ratio of influenza antiviral drugs.
affect compliance.19,20 Oseltamivir may be easier to admin-
ister to frail or confused elderly patients who may have Summary
trouble using the zanamivir inhalation device. Zanamivir,
however, may be better tolerated by patients with a lot Influenza is a major public health problem causing
of nausea. clinical morbidity, mortality and major economic losses
Although NAI–resistant isolates have been described, each year that there is an epidemic. Up until now, vacci-
they are at present uncommon (about 1% of treated nation strategies, which constitute the mainstay of in-
adults).31,32 Evidence suggests that the mutation in the fluenza control, have been directed at preventing morbid-
neuraminidase required for ity and mortality in
resistance to the NAIs may high-risk groups. Diligent
also make the virus less suc- Two main classes of drug interfere with influenza efforts to optimize vaccine
cessful at infecting, but this virus infection. The first drug to be developed was coverage must be main-
requires more clinical study. amantadine, which belongs to the ion channel tained and strengthened.
There have been no docu- blocker group of anti-influenza drugs. It has been Unvaccinated individuals in
mented secondary cases used to treat and prevent influenza A since the mid- critical occupations and
to-late 1960s. The second class of agents consists of
caused by the spread of an those high-risk individuals
the viral neuraminidase inhibitors, zanamivir (Re-
NAI–resistant virus in fami- who do not mount an effec-
lenza) and oseltamivir (Tamiflu), which are active
lies in which one family tive protective antibody
against both influenza A and B.
member was being treated level to influenza vaccine
with an NAI for influenza, as may develop influenza and
there have been with amanta- may benefit from one of the
dine-resistant strains during amantadine treatment. 3 available antiviral agents in Canada, amantadine,
zanamivir or oseltamivir. Limiting factors for amantadine
How much does it cost? are side effects and the need to check renal function espe-
cially in elderly patients, as well as the rapid appearance of
The cost–benefit ratio determines which drug costs are resistant virus that can be spread to close contacts. The
reimbursed by today’s provincially funded drug benefit limiting factor for the NAIs is cost. We have yet to design
programs. At a retail pharmacy in British Columbia, the the optimal logistics for effectively and efficiently using
cost to the patient of a 5-day course of amantadine, which antivirals in the face of an epidemic. “The earlier the bet-
has generic status, is about $13 including the dispensing ter” seems to be the important concept for treating each
fee. The same course of oral oseltamivir, 75 mg twice individual. Influenza antiviral drugs may be of life-saving
daily, is about $53, and 5 days of inhaled zanamivir, 10 mg importance if and when the next worldwide pandemic
twice daily, is $45. Cost–benefit analyses have been pub- hits, and supply will be a critical issue. Stockpiling in-
lished comparing treating acute influenza with NAIs to fluenza antiviral drugs of all types to deal with this latter
prevention by vaccination. If one considers vaccination of eventuality is likely to be crucial.
all individuals aged 15–65 years, representing predomi-
nantly individuals at low risk of complications, vaccination This article has been peer reviewed.
or supportive care only are more cost-effective than treat- Dr. Stiver is with the Division of Infectious Diseases, Department of Medicine,
ment with the the NAIs.33 Amantadine treatment was not University of British Columbia, Vancouver, BC.
compared. If one models the cost–benefit ratio of treating Competing interests: None declared.
high-risk patients (these data come from the high-risk pa-
tients treated in the MIST trial with zanamivir), treat-
ment becomes cost-effective, largely because of the re-
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Diseases, University of British Columbia, D-Floor, 2733 Heather
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A patient information sheet appears on page 57

56 JAMC • 7 JANV. 2003; 168 (1)

 Treatment of influenza with antiviral drugs

Questions and answers about drugs used to treat and prevent influenza
An information sheet for patients

What is “influenza”? • Zanamivir belongs to a newer group of anti-influenza

drugs and is marketed as Relenza. It can treat both
Influenza is an acute respiratory illness caused by one of the influenza A and influenza B. It comes in a device that
influenza viruses, either type A (the most common) or type B. allows the user to inhale a powdered form of the drug.
Both can pass easily from person to person, mainly through • Oseltamivir also belongs to a group of newer anti-
sneezing or coughing. Over time they change, or mutate, so influenza drugs and is marketed as Tamiflu. It can treat
that even if you have been ill and have developed resistance both influenza A and influenza B. It can also prevent
to a particular influenza virus in one year, you may not be both types of influenza. It comes in capsule form.
immune to its effects the next year. Because influenza viruses
change in this way and travel through the air easily, many Can antiviral drugs cause side effects?
people can become ill at once and a whole community can
Amantadine may cause nausea, dizziness and insomnia.
experience an outbreak of the disease.
Zanamivir may cause breathing problems and can make
asthma worse. Oseltamivir may cause nausea and vomiting.
Who is most at risk from influenza?
Severe side effects are rare.
Influenza can make elderly people and those with underlying
health problems (such as asthma, cancer, diabetes, chronic I have influenza-like symptoms. Will my doctor
obstructive pulmonary disease or chronic heart disease) prescribe an antiviral drug?
especially sick. Sometimes influenza can be followed by If there is no evidence of an influenza outbreak in your
other serious illnesses, such as pneumonia. community, your doctor is unlikely to offer you antiviral
medication. If there is evidence of an outbreak, your doctor
What role does vaccination play in preventing may prescribe an antiviral drug, but only after considering
influenza? several factors:
Because influenza can cause serious illness and can keep • Your symptoms (Do you have influenza or some other
workers from their jobs for many days, health authorities infection?)
recommend that anyone older than 65 and anyone with a • Your symptom history (Did your symptoms begin less
chronic health condition receive a vaccination to prevent than 36 hours ago?)xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
infection. Vaccination allows you to develop antibodies — • Your age (Are you older than 65 and at greater risk of
molecules that fight the influenza virus (but not other serious illness?)xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
noninfluenza viruses). However, some people who receive • Your health status (Do you have a chronic condition that
the vaccine may not develop the antibodies needed to puts you at greater risk of serious illness?)xxxxxxxxx
prevent infection. In addition, some people cannot take the • Your vaccination history (Were you vaccinated against
vaccine because of certain health concerns, and some influenza and are you likely to be protected by the vaccine?)
people choose not to take the vaccine. These people and
others may benefit from taking antiviral drugs if they become I have been in close contact with someone with influenza
ill from influenza. symptoms and I have not been vaccinated against
influenza. Will my doctor prescribe an antiviral drug?
What are “antiviral” drugs?
Again, your doctor will need to know if there is a community
Antiviral drugs are medications that can stop or slow down outbreak and when you were exposed to the virus. Your doctor
the action of viruses. To be effective, they must be taken very will also need to consider your age and your health status.
soon after exposure to a virus — preferably within 36 hours,
and earlier is even better. Some antiviral drugs can help How long does treatment last?
people in the early stage of influenza infection experience
less severe symptoms. Other antiviral drugs can help people In most cases, antiviral drugs are taken for 5 days.
in close contact with an influenza patient avoid infection.
Three antiviral influenza medications are available in
How much do antiviral drugs cost?
Canada: Zanamivir and oseltamivir are more expensive than
amantadine. For example, in British Columbia a 5-day course of
• Amantadine belongs to a group of older anti-influenza
amantadine costs about $13, a 5-day course of zanamivir costs
drugs. It can treat and prevent influenza A, but not
about $45 and a 5-day course of oseltamivir costs about $53.
influenza B. It comes in capsule or syrup form.

CMAJ • JAN. 7, 2003; 168 (1) 57