demicheli et al_2000_prevention and early treatment of influenza in healthy adults

7/31/2019 Demicheli Et Al_2000_Prevention and Early Treatment of Influenza in Healthy Adults

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Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959

1.1. Prevention and early treatment of inuenza. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959

1.1.1. Inuenza vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959

1.1.2. Ion channel inhibitor antivirals (Amantadine and Rimantadine) . . . . . . . . . . 961

1.1.3. Neuraminidase inhibitor antivirals (NIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . 962

1.2. Rationale for the economic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962

2. Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9632.1. Methods for the reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963

2.1.1. Objectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963

2.1.2. Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963

2.1.3. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963

2.1.4. Methods for the economic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966

3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967

3.1. Results of the reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967

3.1.1. Description of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967

3.1.2. Methodological quality of included studies . . . . . . . . . . . . . . . . . . . . . . . . . 970

3.2. Eects of inuenza vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 971

3.2.1. Eect of vaccination on clinical cases of inuenza . . . . . . . . . . . . . . . . . . . . 971

3.2.2. Eect of vaccination on serologically conrmed cases of inuenza . . . . . . . . 971

3.2.3. Eect of vaccination on other outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . 971

3.2.4. Recommended vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972

3.2.5. Vaccine matching the circulating strain . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972

3.3. Eects of amantadine and rimantadine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972

3.3.1. Comparison A oral amantadine compared to placebo in inuenza

prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974

3.3.2. Comparison B oral rimantadine compared to placebo in inuenza

prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974

3.3.3. Comparison C oral amantadine compared to oral rimantadine in inuenza

prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 975

3.3.4. Comparison D oral amantadine compared to placebo in inuenza

treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 975

3.3.5. Comparison E oral rimantadine compared to placebo in inuenza

treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9763.3.6. Comparison F oral amantadine compared to oral rimantadine in inuenza

treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976

3.3.7. Comparison G oral amantadine compared to oral aspirin in inuenza

treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977

3.3.8. Comparison H inhaled amantadine compared to placebo in inuenza

treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977

3.4. Eects of NIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977

3.5. Results of the economic evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979

4.1. Inuenza vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979

4.2. Amantadine and rimantadine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981

4.3. Neuraminidase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982

4.4. Overall comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9824.5. Economic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982

Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983

Appendix A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984

Appendix B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985

Appendix C. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1030

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1. Introduction

Inuenza is an acute respiratory infection caused

by a virus, of which three serotypes are known (A, B

and C). Inuenza causes an acute febrile illness with

myalgia, headache and cough. Although the median

duration of the acute illness is three days (duration

can vary between serotypes and subtypes), cough andmalaise can persist for weeks. Complications of inu-

enza include otitis media, pneumonia, secondary bac-

terial pneumonia, exacerbations of chronic respiratory

disease and bronchiolitis in children. Additionally,

inuenza can cause a range of non-respiratory com-

plications including febrile convulsions, Reye's syn-

drome and myocarditis [1].

The inuenza virus is composed of a lipid mem-

brane surrounding a protein shell and a core consist-

ing of several RNA complexes. On the lipid

membrane are two viral glycoproteins which act as

powerful antigens: neuraminidase (N antigen) andhemagglutinin (H antigen). Hemagglutinin facilitates

the entry of the virus into cells of the respiratory epi-

thelium, while neuraminidase facilitates the release of

newly produced viral particles (so-called virions) from

infected cells. The inuenza virus has a marked pro-

pensity to mutate its external antigenic composition

to escape the hosts' immune defences. Given this

extreme mutability, the World Health Organisation

(WHO) has introduced a classication of each viral

subtype based on H and N typing. Additionally,

strains are classied on the basis of antigenic type of

the nucleoprotein core (A, B or C), geographical lo-cation of rst isolation, strain serial number and year

of isolation. Every item is separated by a slash mark

(e.g. A/Wuhan/359/95 [H3N2]).

In this century there have been four pandemics

caused by so-called antigenic shift (a major change

in H conguration with or without a concomitant

change in N and perhaps viral alteration of tissue

tropism) leading to the appearance of a new sub-

type against which there is little circulating natural

immunity. Pandemics are thought to originate in

Southern China where ducks (the animal reservoir

and breeding ground for new strains), pigs (whichare thought to be the biological intermediate host

or `mixing vessel') and humans live in very close

proximity [2]. Minor changes in viral antigenic

congurations, known as `drift', cause local or

more circumscribed epidemics. The recently isolated

Hong Kong avian inuenza (A/HK/156/97 [H5N1]

virus appears to be an example of a zoonotic

infection with direct spread of the avian virus to

humans [35]. Pandemics by denition cause a

very high morbidity and mortality burden [6]. The

191819 pandemic is estimated to have caused up

to 40 million deaths world-wide.

1.1. Prevention and early treatment of inuenza

Eorts to prevent or treat inuenza have had their

mainstay in two separate approaches: vaccines and

antivirals (ion channel inhibitors and neuraminidase

inhibitors).

1.1.1. Inuenza vaccines

Current inuenza vaccines are of four types:

1. whole virion vaccines which consist of complete

viruses which have been `killed'; or inactivated, so

that they are not infectious but retain their strain-

specic antigenic properties.

2. subunit virion vaccines which are made of surface

antigens (H and N) only.

3. split virion vaccines in which the viral structure is

broken up by a disrupting agent.4. live vaccines (as yet unlicensed).

The rst three types of vaccines contain the two sur-

face antigens; whole virion and split vaccines also con-

tain antigens which are thought to contribute to a

higher rate of vaccine reactions compared to subunit

vaccines.

Appendix A shows a list of inuenza vaccine produ-

cers and products world-wide, compiled by WHO in

1996 [7].

Periodic antigenic drifts and shifts pose problems

for vaccine production and procurement, as a new

vaccine closely matching circulating antigenic con-guration must be produced and procured for the

beginning of each new inuenza `season'. To achieve

this, WHO has established a world-wide surveillance

system allowing identication and isolation of viral

strains circulating in the dierent parts of the globe.

Sentinel practices recover viral particles from the

naso-pharynx of patients with inuenza-like symp-

toms and the samples are swiftly sent to the labora-

tories of the national inuenza centres (110

laboratories in 79 countries). When new strains are

detected the samples are sent to one of the four

WHO reference centres (London, Atlanta, Tokyo andMelbourne) for antigenic analysis. Information on cir-

culating strains is then sent to WHO, who in

February of each year recommends, through a com-

mittee, the strains to be included in the vaccine for

the forthcoming `season'. Individual governments may

or may not follow WHO recommendations.

Australia, New Zealand and more recently South

Africa follow their own recommendations for vaccine

content.

Surveillance and early identication thus play a cen-

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tral part in the composition of the vaccine.

Traditionally, inuenza vaccines have been targeted to

the elderly and those at serious risk of complications.

Despite clear theoretical advantages in the use of vac-

cines, their uptake has been patchy. Studies in family

practices suggest that 20% is a reasonable estimate of

inuenza vaccine utilisation in the Canadian popu-

lation [810]. The current low level of inuenza vac-

cine uptake in targeted populations may reect

uncertainty on the part of primary care and public

health practitioners and health policy decision-makers

regarding vaccine eectiveness.

One possible reason may be the diversity of regu-

lations for the nancing and reimbursement of the

vaccines. Other reasons may include perceived low

ecacy due to the mutable viral conguration, the

perceived commonality of the disease, which may

breed contempt and, strangely, a misperception of the

burden imposed by the disease on society. Nowhere

is this more marked than in the case of healthy

adults in employment, a population which would

most benet from protection against inuenza.

Epidemics in settings such as schools, barracks, pris-

ons, oces, hospitals and industrial complexes cause

great losses, but are seldom prevented by vaccination

of sta.

Despite the publication over a period of more than

ve decades of a large number of reports of con-

trolled clinical trials, there remains substantial uncer-

tainty about the clinical eectiveness of inuenza

vaccine. This uncertainty is manifested in widely vary-

ing estimates of vaccine eectiveness in the current

health care literature. For example MMWR states:

`The eectiveness of inuenza vaccine in preventing

or attenuating illness varies, depending primarily on

the age and immunocompetence of the vaccine recipi-

ent and the degree of similarity between the virus

strains included in the vaccine and those that circu-

late during the inuenza season. When a good match

exists between vaccine and circulating viruses, inu-

enza vaccine has been shown to prevent illness in ap-

proximately 7090% of healthy persons aged


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be expected when purely clinical outcome measures

are used. This is particularly true when the incidence

of inuenza is low, when the period of observation

extends beyond the usual four to 12 week annual

period of inuenza activity, or when the denition of

illness is imprecise (e.g. respiratory illness). To the

extent that inuenza vaccine modies illness which it

does not prevent, protection might be greater for out-

comes which reect complications of inuenza (e.g.hospitalisation with respiratory illness) rather than

primary infection (e.g. acute respiratory illness). Con-

ventionally, serological diagnosis is based on a four-

fold or greater increase in antibody titre to one or

more virus antigens. There is evidence that vaccinated

individuals are less likely than non-vaccinated persons

to mount an antibody rise following infection with an

inuenza virus antigenically related to strains con-

tained in the vaccine. This phenomenon is thought to

be based, at least in part, on higher pre-infection

antibody titres which result from vaccination. Serolo-

gical methods will therefore `miss' cases of inuenzaamong vaccinated subjects and could be expected to

produce a spuriously high observed protective eect.

Hobson has suggested (without citing supportive evi-

dence) that virus isolation results may be similarly

biased. He proposes that vaccines which fail to pro-

tect against clinical illness may reduce the amount

and duration of virus shedding [15].

Other study design features which might inuence

observed vaccine eectiveness include method of al-

location, extent of blinding and type of virus chal-

lenge (natural or articial). Variability would be

expected to be greater in studies with small samplesizes.

The deciencies of most current and past reviews of

inuenza vaccine eectiveness can be summarised as

follows:

1. lack of comprehensiveness in the identication of

primary studies

2. lack of methodological assessment of primary stu-

dies

3. failure to satisfactorily account for (or in some

cases, to acknowledge) the marked variability in

vaccine eectiveness among controlled studies

4. failure to provide estimates of vaccine eectiveness

under conditions of imperfect antigenic matching

between vaccines and prevalent viruses (that is,

when vaccines contain either a dierent strain or a

dierent subtype of inuenza virus than the preva-

lent virus)

5. lack of credible estimates of vaccine eectiveness in

specic populations currently targeted for inuenza

vaccination (for example, institutionalised elderly,

community-dwelling elderly and persons with under-

lying medical conditions associated with a high risk

of complications [16,17].

These deciencies help to explain discrepancies in

reported vaccine eectiveness in the existing literature.

Moreover, they can be expected to give rise to uncer-

tainty among clinicians and policy-makers regarding

the expected eectiveness of inuenza vaccine in the

population groups for which annual inuenza vacci-nation is currently recommended. In this scenario a

systematic review of the eects of vaccines against

naturally occurring inuenza is necessary to enable de-

cision-makers to devise strategies to deal with inuenza

based on evidence.

1.1.2. Ion channel inhibitor antivirals (Amantadine and

Rimantadine)

The main antiviral compounds used against inu-

enza are amantadine hydrochloride and rimantadine

hydrochloride (amantadine and rimantadine for

short). Amantadine (an anti-Parkinsonism) was intro-duced in the 1950s and found to have antiviral ac-

tivity in 1965. In the USA, amantadine was licensed

for the treatment and prophylaxis of inuenza A/

H2N2 infections by the FDA in 1966 and for pro-

phylaxis and treatment of all inuenza A infections

in 1976. Rimantadine was licenced in 1993 [18]. In

the USA, while amantadine is licensed for treatment

and prophylaxis of adults and children over the age

of one, rimantadine is licensed only for prophylaxis

in children as well as for treatment and prophylaxis

in adults [18]. In the UK amantadine only is licensed

and is administered orally at a recommended does of100 mg a day in healthy adults for ve days (treat-

ment role) or 100 mg a day as long as the risk of

infection lasts (prophylaxis role).

Both compounds interfere with the replication cycle

of type A (but not type B) viruses [19] and are thought

to be ecacious and, given their virus-specic action,

relatively free of adverse eect. Drug resistant H3N2

subtype inuenza A viruses have been isolated during

treatment with amantadine and rimantadine, especially

in institutions, but their clinical signicance is unclear

[20].

Given both drugs' apparent ecacy in both pro-phylactic and therapeutic roles (if administration is

started in time), their relatively scarce use is surpris-

ing [1]. Explanations for this nding include lack of

awareness of the drugs and their properties by medi-

cal practitioners, lack of a rapid diagnostic capability

and concern over their adverse eects, which include

epilepsy. Even more surprising is the list of indi-

cations for use of both drugs. While subjects at high

risk (i.e. subjects with underlying debilitating pathol-

ogies and the elderly) are included, healthy adults, es-



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pecially those working in institutions (such as health-

care workers, nursing home attendants and the mili-

tary) are not. These groups are likely to greatly

benet from the use of the drugs, which could have a

direct impact on length of sickness absence and

diminish considerably the burden of inuenza epi-

demics to society. Additionally a non-systematic

review of the evidence of the ecacy of rimantadine

identied ve small double-blind placebo-controlled

trials of both drugs in a prophylaxis role and nine

trials in a treatment role [21]. The largest study con-

tained 378 individuals, indicating the need to attempt

pooling data to derive more precise estimates of eect

and safety for the compounds. This systematic review

of the eects of amantadine and rimantadine in

healthy adults excludes children, the elderly and indi-

viduals with pre-existing pathologies. However, given

the impact of inuenza in these populations, systema-

tic reviews of the eects of amantadine and rimanta-

dine in children, elderly and at-risk groups should

also be carried out in the future.

1.1.3. Neuraminidase inhibitor antivirals (NIs)

In recent years a new generation of antiviral com-

pounds has been developed and is currently in pre-

registration phase III trials. These compounds, known

collectively as neuraminidase inhibitors (NIs), are:

. Nebulised Zanamivir developed by GlaxoWellcome

PLC (UK).

. Oral Oseltamivir (formerly known as Ro 64-0796

or GS 4104) co-developed by Gilead Sciences Inc.

(Foster City, CA, USA) and Homann-La RocheLtd (Basle, CH). Gilead Sciences Inc. still retains

the intellectual property rights to Oseltamivir.

Zanamivir is a so-called second-generation NI, whereas

Oseltamivir represents the third generation of such

compounds [22]. NIs act by inhibiting the entry of

viral particles into the target cell and subsequent

release of virions from the infected cell, neuraminidase

being essential for both functions. Both Oseltamivir

and Zanamivir appear to be eective against Inuenza

A and B, while amantadine is eective only against

inuenza A.

NIs could be used in both a preventive role and todiminish the severity of the illness [23], to:

. treat infected individuals

. supplement protection against infection in individ-

uals not fully protected by vaccination

. provide protection for individuals unable to receive

vaccine (e.g. individuals allergic to eggs)

. provide short term prophylaxis in family settings

. supplement vaccination during pandemics when vac-

cine stocks may be limited

. control outbreaks in institutions such as nursing

homes or prisons

. control outbreaks in settings such as factories,

oces or the military

. generally interrupt viral transmission.

Homann-La Roche and GlaxoWellcome are target-

ing the registration and marketing of their com-

pounds to the year 2000 inuenza season [24]. AsNIs are likely, if proved eective and safe, to become

a major form of prophylaxis and treatment of inu-

enza, reviewing and updating the available evidence is

necessary to provide an accurate assessment of their

eects.

1.2. Rationale for the economic evaluation

J95, the British Army's ICD-based surveillance sys-

tem, indicated that in soldiers respiratory disease is the

second highest cause of morbidity and sixth highestcause of productivity losses (measured in working days

lost, or WDL) both on world-wide military operations

and when in barracks [25]. Further work carried out

by the Department of Public Health of the University

of Glasgow [26] shows that within the `respiratory dis-

ease' code block approximately 40% of the morbidity

in the 19961997 season was caused by clinical inu-

enza. In some Army subpopulations (such as recruits

undergoing training) the burden of respiratory disease

is much higher (37 attendances per 1000 personnel per

month in Training Establishment compared to 13 at-

tendances per 1000 personnel per month in the rest ofthe Army). Inuenza, then, is an important recurring

public health problem for the British Army, as it

threatens the health and hence eciency of its work-

force, the most important resource that any organis-

ation has at its disposal.

Before embarking in a major expenditure pro-

gramme to purchase large quantities of these inter-

ventions (given that clinical inuenza is a disease of

such high incidence among the military) the Ministry

of Defence of the United Kingdom wanted to make

sure that resources used in the prevention programme

would be recouped by its benets. This provided therationale for an economic evaluation comparing the

costs and eects of each course of action. However,

preliminary work prior to undertaking the evaluation

indicated that there were considerable uncertainties as

to the eectiveness and safety of vaccines, antivirals

and NIs. This provided the main reason for the com-

missioning of three Cochrane reviews [2729] prior to

carrying out the economic evaluation. The evaluation

has been conducted and reported according to the

BMJ guidelines for economic submissions [30].



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2. Methods

2.1. Methods for the reviews

2.1.1. Objectives

In comparisons between groups intended for the

interventions and control/placebo groups the following

hypotheses were tested:

2.1.1.1. Cases. There is no dierence in the number of

cases of inuenza and their severity.

2.1.1.2. Adverse eects. There is no dierence in the

number and severity of adverse eects (both systemic

and localised).

2.1.2. Selection criteria

See Table 1.

2.1.3. Search strategy

. A MEDLINE search was carried out using the

extended search strategy of the Cochrane Acute

Respiratory Infections (ARI) Group [31] with the

following search terms or combined sets from 1966

to the end of 1997 in any language: inuenza; route

(oral) OR route (parenteral); vaccine; amantadine;

rimantadine; neuraminidase inhibitors; Oseltamivir ;

GS 4104; Ro 64-0796; Zanamivir

. The bibliography of retrieved articles was examined

in order to identify further trials

. A search was carried out of the Cochrane

Controlled Trials Register (CCTR) and ofEMBASE (199097 for Inuenza Vaccines and for

NIs; 1985 to 1997 for Amantadine and

Rimantadine)

. The journal Vaccine was handsearched from its rst

issue to the end of 1997 [32,33]

. The manufacturers, rst or corresponding authors

of evaluated studies and researchers active in the

eld were contacted in order to locate unpublished

trials.

2.1.3.1. Trial quality assessment. Two reviewers read

all trials retrieved in the search and applied inclusion

criteria. Trials fullling these criteria were assessed for

quality and results analysed by the same authors. Dis-

agreements on trial quality were arbitrated by a third

author. Assessment of trial quality were made accord-

ing to the following criteria:

1. generation of allocation schedule (dened as the

methods of generation of the sequence which

ensures random allocation).

2. measure(s) taken to conceal treatment allocation

(dened as methods to prevent selection bias, i.e. to

ensure that all participants have the same chance of

being assigned to one of the arms of the trial. This

protects the allocation sequence before and during

allocation)

3. number of drop-outs of allocated healthcare worker

participants from the analysis of the trial (dened as

the exclusion of any participants for whatever

reason deviation from protocol, loss to follow-

up, withdrawal, discovery of ineligibility; while the

unbiased approach analyses all randomised partici-

pants in the originally assigned groups regardless of

compliance with protocol, known as intention to

treat analysis)

4. measures taken to implement double blinding (a

double-blind study is one in which observer(s) and/

or subjects are kept ignorant of the group to which

the subjects are assigned, as in an experiment, or of

the population from which the subjects come, as in

a non-experimental situation. Unlike allocation con-cealment, double blinding seeks to prevent ascer-

tainment bias and protects the sequence after

allocation)

For criteria 2, 3 and 4 there is empirical evidence that

low quality in their implementation is associated with

exaggerated trial results [34] and it is reasonable to

infer a quality link between all four items. The four

criteria were assessed by answering a questionnaire; see

Appendix B.

2.1.3.2. Data collection. The following data were

extracted, checked and recorded:

. Characteristics of trials: date; location; setting; case

denitions used (clinical, serological, virological);

surveillance system; type and length of epidemic

(denition used, characteristics of circulating virus);

sponsor (specied, known or unknown); publication

status

. Characteristics of participants: number of partici-

pants; age; gender; ethnic group; risk category; occu-

pation

. Characteristics of interventions: type of intervention;

type of placebo; dose; treatment or prophylaxisschedule; length of follow-up (in days); route of ad-

ministration

. Characteristics of outcome measures:* Numbers and seriousness of inuenza cases (how-

ever dened) occurring in vaccine and placebo

groups. Other outcome measures used to assess

eects included cases of inuenza clinically

dened; cases of inuenza clinically dened on

the basis of a specic list of symptoms and/or

signs; cases of inuenza conrmed by laboratory



8/74

Table1

Selectioncriteriaappliedtoretrievedstudiestodetermineinclusioninsystemat

icreview

Review

Study

criteria

Participants

Interventions

Clinicaloutcomes

Adverseeects

Selectioncriteriacommon

toall

Rando

mised/quasi-

randomiseda

studiesinhumans

compa

redtoplacebo,

controls,

nointervention;orcomparing

types,

doses/schedulesof

intervention

Apparentlyhealthy,r75%

aged14to60

Interventionirrespectiveo

f

viralantigenicconguration

Numbersand/orseverityof

inuenzacases(however

dened)occurringin

interventionandplacebo

groups

Numberandseriousnessof

ad

verseeects

Inuenzavaccines

Protec

tiveeectofinuenza

vaccin

efromexposureto

natura

llyoccurringinuenza

Inuenzaimmunestatus

irrelevant

Attenuated,

killedorlive

vaccinesorfractionsthereof

administeredbyanyroute

Nootherspeciccriteria

Sy

stemiceectsincludeof

malaise,nausea,

fever,

arthralgias,rash,

headacheand

moregeneralisedandserious

sig

ns.Localeectsinclude

induration,

sorenessand

rednessatinoculationsite

(in

jectedvaccines)andrhinitis

an

dsorethroat(inhaled

va

ccines)

Amantadineand

rimantadine

forinuenza

Protec

tionortreatmentof

amant

adineand/or

rimantadinefromexposureto

natura

llyoccurringinuenza

Nootherspeci

ccriteria

Amantadineand/or

rimantadineasprophylaxis

and/ortreatmentforinu

enza

Nootherspeciccriteria

GI(diarrhoea,

vomiting,

dy

spepsia,

nausea,

co

nstipation);increasedCNS

ac

tivity(light-headedness,

co

ncentrationproblems,

insomnia,

restlessness,

ne

rvousness);decreasedCNS

ac

tivity(malaise,depression,

fatigue,vertigo,

feelingdrunk);

sk

in(urticariaandrash)

NIsforinuenza

Protec

tive/treatmenteectof

oralO

seltamivirand/or

Zanam

ivirinnaturallyor

articiallyoccurringinuenza

Nootherspeci

ccriteria

Oseltamivirand/orZanam

ivir

asprophylaxisand/or

treatmentforinuenza

Alsotemporaldistributionof

cases,andotheroutcomese.g.

distributionofsymptoms

underthecurve;timeto

improvement

Localandsystemicadverse

e

ects

a

Astudyisrandomisedwhenit

appearsthattheindividuals(orotherexp

erimentalunits)followedinthestudyweredenitelyorpossiblyassignedprospectiv

elytooneoftwo(ormore)

alternativeformsofhealthcareusin

grandomallocation.

Astudyisquasi-randomisedwhenitappearsthattheindividua

ls(orotherexperimentalunits)followedinthestudyweredenitelyor

possiblyassignedprospectivelytoo

neoftwo(ormore)alternativeformsofh

ealthcareusingsomequasi-randommethodofallocation(suchasalternation,

date

ofbirthorcaserecordnum-

ber).



9/74

tests; hospital admissions; complications; working

day lost in episodes of sickness absence regardless

of cause* Adverse eects: presence and type, with local

symptoms presented in the analysis separately

from systemic symptoms; number of withdrawals

due to adverse eects. Individual adverse eects

have been considered in the analysis, as well asa combined endpoint (any or highest symptom).

2.1.3.3. Denitions

Epidemic period. Four dierent denitions of èpi-

demic period' were found:

. the interval between the rst and the last virus iso-

lation in the community

. the interval during which inuenza virus was recov-

ered from more than a stated percentage of ill subjects

. the period during which an increase of respiratory

illness more than a stated percentage was recorded

. the winter period taken as a proxy for epidemic

period.

The data were included regardless of the denition of

epidemic period used in the primary study. When data

were presented for the epidemic period and the entire

follow-up period, those occurring during the former

were considered.

Clinically dened case. A clinically dened case was

assumed as any case denition based on symptoms

without further specication. The specic denitionwas assumed as:

. ù-like illness' according to a predened list of

symptoms (including the CDC case denition for

surveillance)

. ùpper respiratory illness' according to a predened

list of symptoms.

When more than one denition was given for the same

trial, data related to the more specic denition were

included.

Laboratory conrmation of cases. The laboratory

conrmation of cases found were:

. virus isolation from culture

. four-fold antibody increase (HI) in acute or conva-

lescent phase sera

. four-fold antibody increase (HI) in post-vaccination

or post-epidemic phase sera.

When more than one denition was given for the same

trial, data related to the more sensitive denition (sero-

conversion) were included.

Hospital admission rates. Hospital admission rates

were calculated as the proportion of cases hospitalised

for respiratory causes.

Complications. Complications were considered as the

proportion of cases complicated by bronchitis, pneu-

monia or otitis.

2.1.3.4. Data synthesis. The relative risks of events

(cases of inuenza, deaths, and adverse eects) com-paring treatment and placebo/control groups from

the individual trials were combined using Mantel-

Haenszel meta-analytical techniques. We did not com-

bine estimates from treatment and prophylactic trials

as these were conducted to answer dierent study

questions. Between-trial variability in results was

examined and incorporated into the estimates of

uncertainty of treatment eect using random eects

models where appropriate. In treatment trials the

choice of methods for combining the estimates of

severity of inuenza depended on the format in

which the data was presented. Where possible, com-parisons were made between the mean duration of

symptoms in the two groups, and methods for com-

bining dierences in means were used. Specically,

where the data were presented as the number of sub-

jects with duration of symptoms beyond a cut-o

time period these were presented as `Cases with fever

at 48 h'. The bewildering array of outcomes used in

the treatment trials (see Results section) prevented us

from using more than the `cases with fever' outcome.

Included trials did not contain sucient information

to enable us to assess the number of cases with no

documented fever at entry into the trial.For the vaccine trials, separate analyses were per-

formed for live aerosol vaccines, inactivated parent-

eral vaccines and inactivated aerosol vaccines.

Clinical inuenza outcomes were specied according

to whether specic criteria were or were not used, for

which estimates were produced separately, and com-

bined (where trials reported both denitions, only the

wider denition was retained for analysis). Vaccine

ecacy was estimated by calculating the common

relative risk, using the Mantel-Haenszel method (xed

eect model) when the trial results were consistent, or

the DerSimonian and Laird method (random eectsmodel) when signicant heterogeneity was evident

between the study results. Between-study heterogen-

eity is to be expected in vaccine trials as there are

unpredictable systematic dierences between trials in

circulating strains and levels of local immunity. Once

the relative risk (RR) had been obtained, vaccine e-

cacy (VE) was calculated as VE=1-RR. Similar ana-

lyses were also undertaken for other events, such as

complications, hospital admissions and adverse

eects.



10/74

In addition to the traditional estimate of vaccine e-

cacy, the eect of vaccination on the number of clini-

cal cases was estimated by averaging the risk

dierences (inuenza rate in vaccinated group minus

inuenza rate in control group). Where the total num-

ber of clinical inuenza cases depends more on the

number of other inuenza-like illnesses than true inu-

enza A illnesses, it is more likely that an intervention

will appear to reduce the total number of cases by an

absolute amount (i.e. a constant risk dierence) than

by a relative amount (i.e. a constant relative eect).

As the data on average time o work was reported

as a continuous measurement, these results were

expressed as dierences in means, and combined using

the weighted mean dierence method. Caution should

be exercised in interpreting these results as the data are

very skewed.

Several trials included more than one active vaccine

arm. Where several active arms from the same trial

were included in the same analysis, the placebo group

was split equally between the dierent arms, so thatthe total number of subjects in any one analysis did

not exceed the actual number in the trials.

2.1.4. Methods for the economic evaluation

2.1.4.1. Evidence-based alternative interventions to mini-

mise the burden of inuenza. While the three Cochrane

reviews were underway, we assumed a hypothetical

scenario in which all available means had a preventive

and treatment impact on inuenza. We also considered

it likely that such means would produce adverse eects

and have clinical outcomes not homogeneous for qual-ity of life. In this case, the alternatives to be explored

would be:

. which is the best single alternative

. which is the best combination of alternatives

. which is the best combination of alternatives

depending on the outcome measure considered

(avoided cases, quality weighted avoided cases,

severity of avoided cases, hospital admissions

avoided and working days lost (WDL)).

We aimed to compare these alternatives with the cur-

rent Army policy on inuenza prevention (do-noth-ing).

Once the reviews had been completed, the results led

us to introduce considerable changes to our compara-

tors. The changes (with the reasons in brackets) are

summarised in Table 2.

For our evaluation we chose the viewpoint of the

funder, the MOD (UK). We thus focused on the

eects of preventing inuenza in MOD/Army person-

nel although we believe that our methods are equally

applicable to populations of employed healthy adults,

especially in an epidemic situation. These would

include emergency services and employees of compa-

nies producing essential goods and services.

We were able to test the eect of this assumption by

setting our results in the context of a distribution of

similar variables derived from our widely known and

recently updated systematic review of the economics of

inuenza [6,35,36].

We attempted to incorporate into our evaluation

individual soldier preferences for the possible preven-

tive means. One of the eects of adopting the view-

point and decision-making perspective of the MOD/

Army was the possibility of incorporating the inu-

enza preventive campaign into existing immunisation

and routine procedures at no incremental administra-

tive cost. However, in the sensitivity analysis we have

used administration costs derived from the ratio `vac-

cine cost/total administration cost' calculated from

our systematic review of the economics of inuenza

[6,35,36].

Final selection of alternatives. Our nal criteria forthe choice of alternatives were:

. evidence of ecacy;

. evidence of safety;

. practicality of organisational implementation in the

setting of the British Army.

On the basis of the rst criterion all remaining

alternatives in the third column of Table 2 are prac-

ticable and acceptable. However applying the other

two criteria and assuming an average inuenza epi-

demic period of 46 days (as in the trials included in

the reviews) the alternatives of oral amantadine, oralrimantadine and oral Oseltamivir are no longer prac-

ticable. It is very unlikely that whole bodies of sol-

diers would comply with the requirement of

protracted daily oral drug schedules. This assumption

was further conrmed by the nding of our prefer-

ence time trade-o exercise (Table 4) in which sol-

diers preferred the risk of contracting inuenza to

that of experiencing adverse eects such as nausea or

gastrointestinal disturbances.

Two other factors contribute to making the preven-

tion of inuenza with antimicrobials and NIs proble-

matic. Firstly it is doubtful whether the protractedlogistical eort involved in maintaining the chemopro-

phylaxis campaign for 46 days is feasible. Secondly the

level and timeliness of the information required to

determine with any certainty the `beginning' and the

`end' of the inuenza epidemic is unlikely to be avail-

able, especially when the Army is deployed in dierent

areas of the UK and abroad.

Description of alternatives. Whereas before the

Cochrane review results our provisional decision tree

was very complicated, comprising preventive and treat-



11/74

ment alternatives, the nal tree consists only of the

three preventive arms each with inuenza cases with or

without adverse eects.

Form of the economic model. On the basis of the

above considerations we dened an economic model

based on the cost per avoided case to dene the best

preventive strategy, and the cost per avoided case

weighted by individual preference to dene the choiceof the best combination of interventions. The cost

per avoided case was calculated by dividing the total

costs of the interventions by the number of cases

avoided.

Data collection and assumptions made. We based our

model on a set of assumptions, which are summarised

in Table 3.

The variables and the ranges across which we car-

ried out our sensitivity analysis together with the

rationale are summarised in Table 4.

3. Results

3.1. Results of the reviews

3.1.1. Description of studies

Identied trials are listed and described in the table

of included studies using the name of the rst author

and the publication year; see Appendix C. A list and

description of excluded studies (with reason for exclu-

sion) is available from the authors.

3.1.1.1. Inuenza vaccines. The tables of comparisons

were constructed according to the following criteria

(Fig. 1):

1. Inuenza vaccine versus placebo* All studies comparing any inuenza vaccine

against a placebo (inert substances or non

Table 2

Possible alternatives to prevent and treat inuenza, before and after reviews of the evidence

Items Before Cochrane reviews After Cochrane reviews

Which is the best single alternative for

prevention

Oral vaccines Parenteral vaccines

Aerosol vaccines Oral Amantadine

Parenteral vaccines Oral Rimantadine

Oral Amantadine Oral Oseltamivir

Oral Rimantadine (aerosol/oral vaccines are less eective, or dierences are

minimal and do not currently represent a real alternative.

Zanamivir trials only apparently included laboratory

conrmed outcomes)

Inhaled Zanamivir

Oral Oseltamivir

Which is the best single alternative for

treatment

Oral Amantadine None (all compounds shortened duration of illness by 0.5

days)

Oral Rimantadine

Inhaled Zanamivir

Oral Oseltamivir

Which is the best combination of

alternatives

Prevention only Prevention only

Treatment only

Prevention treatment

Outcome measure Laboratory cases Laboratory cases

Clinical cases Clinical cases

WDL (the prevention of clinical cases is the only public health

target. Not enough outcome data were presented in the trials

to include any other outcomes)

Hospital admissions

Deaths

Complications

Length of epidemics (i.e. required

duration of antiviral & NI preventive

treatment)

84 days (SD=33.6) according to

Communicable Disease Reports

`Inuenza Surveillance England

and Wales' (199197)

62 days (SD=27) (according to inuenza vaccines trials

included in the Cochrane review [27])



12/74

inuenza vaccines) were included in this

group* Subgroup analysis were carried out for live aero-

sol vaccine, inactivated parenteral vaccine, and

inactivated aerosol vaccine* The parenteral route comprised both intramuscu-

lar and subcutaneous route* Dierent dosages and schedules of the vaccine

and the presence of dierent adjuvants were not

compared; and data from arms of trials compar-

ing only vaccine composition or dosage were

pooled in the analysis.

2. At least one vaccine strain recommended for that

year (as an indicator of goodness of serological t)

versus placebo or other vaccines:* All trials in which the studied vaccine contained

at least one of the A strains recommended for

that year by WHO or single governments (WHO

recommendations were published since 1973 only)

were included, independently from substances

used in the control arm* Subgroup analysis was carried out according to

control group for the recommended vaccine

against placebo, against inuenza B vaccine, and

against other non recommended A strains* Vaccines containing only a B recommended strain

were excluded from this comparison since a num-

ber of authors used monovalent B vaccine as pla-

cebo in the control arm which may generate

confusion* The compliance of the study vaccine with the o-

cial recommendations was checked by reviewing

WHO records when possible. In case of ambigu-

ity (in the oldest trials), the opinion stated by

authors was taken into account* The compliance of a live attenuated vaccine with

the recommendation has been decided according

to the antigenic comparability to the wild strains

3. Vaccine matching circulating strain versus placebo

or other vaccines:* All trials in which the studied vaccine contained

the strain matching the circulating virus (or at

least one of several circulating viruses) were

included in this group of comparison, indepen-

dently from substances used in the control arm* Subgroup analysis was carried out according to

the control group; matching vaccine against pla-cebo, against inuenza B vaccine, and against

other non recommended A strains* In cases of an incomplete match or ambiguity of

wording, the opinion stated by authors was also

taken into account. Minor viral drift clearly sta-

ted was assumed as non-matching.

Twenty papers describing 39 trials of sub-trials were

identied. Some of them had more than two arms,

comparing dierent vaccines, routes of administration,

Table 3

Basic assumptions of the model

Variable Assumption Source/Rationale

Population Army eectives as at 1 August 1998 Defense Analytical Services Agency (DASA)

Gender and age dierences Only incidence dierences will be tested in

sensitivity analysis

DASA

Incidence of inuenza Sickness rates for inuenza in 1997 DASA

Eectiveness Meta-analysis estimate of RCTs using inuenza

clinical outcomes

Cochrane Reviews [2729]

Adverse eects Frequent symptom reported in RCTs included

in Cochrane reviews comparable across range of

preventive interventions


Individual preferences Mean score of preferences expressed as

combination of category rating and time-trade-

o

Study on a sample of 40 soldiers

Preventive intervention costs Acquisition costs Defense Medical Supply Agency and authors'

assumption (NI)

Duration of treatment for antivirals and NIs Mean duration of inuenza epidemics from

vaccines RCTs

Cochrane Review [27]

Preventive intervention administration costs Nil Interviews with medical commanders

Productivity losses due to inuenza Nil Preventive interventions do not have dierent

eects under this perspective

Productivity loss from adverse intervention

events

Nil Diculties in valuation



13/74

schedules or dosages. These trials were split into sub-

studies. Some trials took in account the history of pre-

vious vaccine immunisations.

Included trials assessed three kinds of vaccine: live

attenuated aerosol, inactivated aerosol and inactivated

parenteral. Four trials of live attenuated vaccine were

included, all placebo controlled. These involved 26,369

subjects. The mean treatment size was 2028 individuals

(median 999, 25th percentile 508, 75th percentile 1071),

and the mean placebo arm size was 1739 (median 508,

25th percentile 289, 75th percentile 547 individuals).

Two studies which assessed inactivated vaccine aerosol

were included. Both were placebo controlled and

involved 1506 subjects. The mean treatment size was

335 individuals (median 333, 25th percentile 195, 75th

percentile 473), and the mean placebo arm size was 42

(median 42, 25th percentile 24, 75th percentile 59 indi-

viduals).

Most studies assessed ecacy of inactivated parent-

eral vaccines against placebo or other inuenza vac-

Table 4

Assumptions tested in the sensitivity analysis

Variable Assumption Source/Rationale

Incidence of i n uenza Range of values from basic Army rate to training

regiment rate

DASA, J97 & Glasgow University study [25,26]

Eectiveness Range of estimate from meta-analysis of RCTs using

inuenza clinical outcomes case denition and from

meta-analysis of RCTs using laboratory-based

inuenza case denition


Eectiveness Range of 95% Condence intervals around eect on

outcome (clinical case denition)


Adverse eects Range of incidence estimates with arbitrary variation Authors' assumption

Individual preferences 25th and 75th percentiles scores of preferences

expressed as a combination of category rating and

time-trade-o

Study on a sample of 40 soldiers

Duration of treatment for antivirals and

NIs

Minimum and maximum duration of inuenza

epidemics from vaccines RCTs

Distribution of duration is symmetrical.

Cochrane Review [27]

Vaccines administration costs Ratio of administration to vaccine costs derived from

economic studies on vaccines

Systematic review of economic studies [6,36]

Antivirals and NIs administration costs Arbitrary ratio of administration to drug costs Authors' assumptions

Fig. 1. Summary of inuenza vaccines in healthy adults (95%CI=95% Condence intervals).



14/74

cines (some of them used a monovalent inuenza B

vaccine as placebo). They involved 23,628 subjects.

The mean treatment size was 550 individuals (median

432, 25th percentile 161, 75th percentile 920), and the

mean placebo arm size was 358 (median 311, 25th per-

centile 66, 75th percentile 518 individuals).

Surveillance methods were prospective or retrospec-

tive, active (by phone interview or questionnaire com-

pilation) or passive (ill subjects spontaneously

presenting). Mean length of follow up was 87 days

(median 79 days, 25th percentile 61 days, 75th percen-

tile 119 days).

The duration of the epidemic was specied by 17

trials. Mean length of the epidemic period was 62 days

(median 63 days, 25th percentile 42 days, 75th percen-

tile 77 days).

3.1.1.2. Amantadine and Rimantadine

Preventive trials. Seventeen preventive trials met the

inclusion criteria. No unpublished trials were ident-

ied, despite receiving nine letters and three electroniccommunications from manufacturers, authors and

researchers.

The mean amantadine arm size was 494 individuals

(median 151, 25th percentile 97, 75th percentile 348),

the mean rimantadine arm size was 107 (median 108,

25th percentile 92, 75th percentile 122 individuals) and

the mean placebo arm size was 373 individuals (me-

dian 140, 25th percentile 99, 75th percentile 269). The

mean total population was 596 individuals (median

308, 25th percentile 225, 75th percentile 536). The

mean length of follow up was 28 days (median 30

days, 25th percentile 18 days, 75th percentile 42 days).Treatment trials. Ten published treatment trials were

identied. No unpublished trials were identied. The

mean amantadine arm size was 91 individuals (median

72, 25th percentile 15, 75th percentile 110), the mean

rimantadine arm size was 61 (median 56, 25th percen-

tile 15, 75th percentile 104 individuals) and the mean

placebo arm size was 77 individuals (median 76, 25th

percentile 14, 75th percentile 99). The mean total

population was 161 individuals (median 153, 25th per-

centile 30, 75th percentile 225). Mean length of follow

up was 25 days (median 25.5 days, 25th percentile 16

days, 75th percentile 33 days).

3.1.1.3. Neuraminidase inhibitors

Preventive trials. As at 1 January 1999 four accessi-

ble preventive trials met our inclusion criteria. A

further two preventive trials of Zanamivir in abstract

format were identied (Calfee H68 and Monto).

Further data was requested from the manufacturers,

GlaxoWellcome, to allow the inclusion of data from

the trials in the review. GlaxoWellcome provided the

data as requested. The mean Zanamivir arm size was

136 individuals (median 34, 25th percentile 25, 75th

percentile 61), the mean Oseltamivir arm size was 1040

(median, 25th percentile and 75th percentile 1040 indi-

viduals) and the mean placebo arm size was 189 indi-

viduals (median 21, 25th percentile 9, 75th percentile

397). The mean total population was 475 individuals

(median 68, 25th percentile 36, 75th percentile 853).

Mean length of follow up was 11 days.

Treatment trials. As at 1 January 1999 three accessi-ble treatment trials were identied which fullled the

inclusion criteria. A further two treatment trials of

Zanamivir in abstract format were also identied.

Despite a request to the manufacturers, GlaxoWell-

come did not release more detailed data in time for in-

clusion in the review.

The mean Zanamivir arm size was 80 individuals

(median 43, 25th percentile 25, 75th percentile 43), the

mean Oseltamivir arm size was 920 (median 1040, 25th

percentile 920, 75th percentile 1040 individuals) and

the mean placebo arm size was 107 individuals (me-

dian 85, 25th percentile 22, 75th percentile 151). Themean total population was 315 individuals (median

243, 25th percentile 65, 75th percentile 449). Mean

length of follow up was ve days.

Preventive and treatment trials. Only one trial was

identied containing both preventive and treatment

interventions.

3.1.2. Methodological quality of included studies

Two reviewers assessed allocation method, allo-

cation concealment, blinding and completeness of fol-

low-up.

3.1.2.1. Inuenza vaccines. There were 20 trials in all,

13 of which were placebo controlled. Three trials used

an inuenza B vaccine in the control arm, considering

it as a placebo. Four trials compared two or more

inuenza vaccines but did not use a control arm.

Thirteen trials reported data on adverse eects, but

only seven were included in the analysis: one did not

have sucient reporting and ve trials did not have a

placebo arm. The overall quality of the trials was

good.

Assessed allocation concealment was adequate in 12

of the trials, inadequate in six and unclear in two.Fifteen trials were properly randomised, four stated

that the allocation method was quasi-random, and one

trial did not report information about randomisation.

Assessment was double blinded in 14 trials. Two trials

were single blinded and four did not mention blinding.

Two studies were eld trials.

3.1.2.2. Amantadine and Rimantadine. There were 27

trials in all, 26 of which considered either amantadine

and/or rimantadine ecacy and one which considered



15/74

adverse eects only. Eleven preventive trials and seven

treatment trials reported sucient data on adverse

eects. The quality of preventive and treatment trials

is discussed separately.

Preventive trials. The quality of the preventive trials

was relatively good, considering the age of the trials.

Among the 17 preventive trials, 15 stated that the al-

location method was randomisation, although only

four mentioned a particular method and two did not

mention random allocation at all. These two trials

have therefore been classied as controlled clinical

trials (CCTs) rather than RCTs. All preventive trials

were stated to be double blind with the exception of

Payler which was open and had no placebo group

(the comparison group was no intervention other

than inuenza vaccine at the beginning of the sea-

son).

Treatment trials. Among the 10 treatment trials, nine

stated that the allocation method was randomisation;

no trials mentioned a particular method; and one(Hornick) did not mention random allocation at all.

Major aws in the reporting of trials lay in the follow-

ing:

. Lack of information on the completeness of follow-

up. In many trials there was a large dierence

between the number randomised and the number

who actually participated

. Lack of detailed description of methods to conceal

allocation, with many trials just describing a `double

blind' procedure

. Frequent inconsistencies in the reporting of numer-

ators and denominators in various arms of trials

. In the treatment trials, the use of a bewildering

variety of outcomes, such as severity scores, of

which none are alike. This makes the task of

meta-analysis impossible and leads to a great loss of

information.

3.1.2.3. Neuraminidase inhibitors. Overall methodologi-

cal quality appeared good, in keeping with the mainly

early report nature of the results of the clinical trials

of such potentially important compounds. However,

detailed descriptions of methods and steps taken to

ensure allocation concealment were not specic, lead-

ing us to grade this aspect of the trials `unclear'. This

is potentially a very important point when dealing

with cases of self-limiting upper respiratory tract infec-

tions with or without systemic symptoms, in which the

potential for a placebo eect is great. Additionally as

some trials (the WV series for instance) relied on clini-

cal case denitions the potential for bias (and overesti-

mation of eect) is even greater.

3.2. Eects of inuenza vaccines

3.2.1. Eect of vaccination on clinical cases of inuenza

Trial data for the two denitions of inuenza (no

case denition and specic case denition) are pre-

sented separately for each of the three types of vaccine:

live aerosol, inactivated parenteral and inactivated

aerosol. Signicant heterogeneity was detected between

trial results for most comparisons, and the gures

quoted are estimated from random eects models.

The live aerosol vaccines were not eective for cases

of either denition. A combined analysis of data from

the two trials estimated the vaccine ecacy to be 2%

(95%CI: 58%).

The inactivated vaccines did oer signicant protec-

tion. Taking the data from the 10 trials together,

regardless of case denition, the parenteral vaccine

reduced the number of cases by 29% (95%CI: 12

42%). The ecacy of the inactivated aerosol vaccine

was higher for the unspecied case denition

(VE=31%, 95%CI: 551%) but not the specic inu-enza case denition (VE=26%, 95%CI: 145%).

The estimates of ecacy were more consistent when

the treatment eect was expressed as a risk dierence

rather than a relative eect. Estimation as risk dier-

ences suggest that 5% (95%CI: 28%) and 9%

(95%CI: 316%) fewer participants experienced inu-

enza like illnesses who received inactivated parenteral

vaccine and inactivated aerosol vaccine respectively.

3.2.2. Eect of vaccination on serologically conrmed

cases of inuenza

Data from two studies showed that aerosol live vac-cines reduced the number of serologically conrmed

cases of inuenza by 79% (95%CI: 4492%). Six stu-

dies provided data for inactivated parenteral vaccines,

showing a similar ecacy of 65% (95%CI: 4479%).

No studies of inactivated aerosol vaccine reported

numbers of serological conrmed cases.

3.2.3. Eect of vaccination on other outcomes

Three trials of parenteral inactivated vaccine evalu-

ated time o work, estimating that vaccination saved

on average around 0.4 working days. This result was

nearly statistically signicant. Hospital admissionswere also lower, but not statistically signicant. There

was little dierence in complication rates between vac-

cinated and unvaccinated groups.

3.2.3.1. Adverse eects aerosol live vaccines. Whilst

signicantly more recipients experienced sore throats

after vaccine administration than placebo adminis-

tration (relative rate=2.5, 95%CI: 1.54.2), the overall

number of local adverse eects was not signicantly

dierent between vaccine and placebo groups. There



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was also no signicant increase in systemic side eects,

although rates of fever and myalgia were higher in vac-

cine than placebo groups. Overall 26% of vaccine reci-

pients reported the combined endpoint for local

reactions, whilst only 8% reported the combined end-

point for systemic eects.

3.2.3.2. Adverse eects inactivated vaccines. Local

tenderness and soreness was more than twice as com-mon among parenteral vaccine recipients than those in

the placebo group (relative rate=2.1, 95%CI: 1.43.4).

There were also increases in erythema (non-signicant),

but not in duration of or arm stiness. The combined

local eects endpoint was signicantly higher for those

receiving the vaccine (relative rate=2.6, 95%CI: 1.6

4.2), with 69% reporting some eect.

None of the systemic eects were individually more

common in parenteral vaccine recipients than placebo

recipients. However the combined endpoint was

increased, and nearly statistically signicant, with 26%

vaccine recipients reporting some side eect than pla-cebo recipients (95%CI: 059%). Overall 30% of

those receiving the vaccine reported possible systemic

eects, although many of these equally could be attrib-

uted to inuenza-like illnesses.

None of the trials on inactivated aerosol vaccines

reported side-eects that could be included in the

analysis. The two studies which evaluated these vac-

cines included parenteral components using an inu-

enza B control group so that the side-eects of the

oral vaccine could not be estimated separately.

3.2.4. Recommended vaccinesSixteen trials evaluated the eect of the vaccines rec-

ommended (by WHO or single governments) on clini-

cal cases of inuenza. Nine of these trials were placebo

controlled, ve made comparisons with inuenza B

vaccine, and two compared recommended inuenza A

vaccines with non-recommended inuenza A and B

vaccines. An additional trial (Tannock) only reported

serologically conrmed cases.

Live aerosol, inactivated parenteral and inactivated

aerosol all had similar vaccine ecacies, although the

estimate for inactivated aerosol vaccines was only

based on the results of one trial. Live aerosols had avaccine ecacy of 13% (95%CI: 520%), inactivated

parenterals an ecacy of 24% (95%CI: 1532%), and

inactivated aerosols an ecacy of 40% (95%CI: 13

59%). Combining the data from all three vaccine types

from the placebo controlled trials, the overall estimate

of vaccine ecacy was 24% (95%CI: 1433%). The

estimate decreased to 22% when the non-placebo con-

trolled trials were included (Fig. 2).

Again, the individual study results were more con-

sistent when expressed as risk dierences than relative

eects. Overall the percentage of participants experien-

cing clinical inuenza decreased by 5% (95%CI: 3

7%) using data from the placebo controlled trials. The

reductions were 3%, 5% and 9% for the live aerosol,

inactivated parenteral and inactivated aerosol vaccines

respectively, the rst gure not being statistically sig-

nicant.

There were signicant reductions in serologically

conrmed cases of inuenza for live aerosol and inacti-

vated parenteral preparations. There was no data for

inactivated aerosol vaccines. Vaccine ecacy was esti-

mated as 48% (95%CI: 2464%) for live aerosol vac-

cines, and 68% (95%CI: 4979%) for inactivated

parenteral vaccines.

3.2.5. Vaccine matching the circulating strain

The highest estimates of vaccine ecacy come from

the analyses of vaccines which were shown to match

the circulating vaccine strain. Twelve trials were

included in these analyses, and seven were placebo

controlled. Since several studies had more than two

arms, the ecacy of the vaccines containing the match-

ing strain was compared against non-matching A or B

inuenza vaccines. None of the live aerosol vaccines

used in the trials matched circulating strains.

Estimates of the ecacy of both parenteral and

aerosol inactivated vaccines in reducing cases of clini-

cal inuenza were similar. Overall the vaccine ecacy

based on results of the placebo controlled trials was

37% (95%CI: 1852%). The estimate declined to 31%

when the non-placebo controlled trials were included.

Expressing the ecacy as a risk dierence, on average

7% (95%CI: 410%) fewer participants who receivedmatched vaccine suered inuenza like illnesses com-

pared to placebo recipients.

The eect of the matched vaccine on serologically

conrmed cases was also larger than in any other

analysis. Overall the results of seven trials reporting

serologically conrmed cases estimated the vaccine e-

cacy to be 72% (95%CI: 5483%).

3.3. Eects of amantadine and rimantadine

All trials tested the eects of amantadine and riman-

tadine on a wide variety of inuenza A viruses. None

tested the eects on inuenza B, on which the mol-

ecules are known to be ineective. Also, no trial tested

the role of the compounds on workplace outbreak con-

trol, which is a pity considering the trial settings (pris-

ons, factories, schools, barracks).

Some trials are likely to have included individuals

who took aspirin to relive symptoms (especially in the



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Fig. 2. At least one vaccine recommended for that year compared to placebo or other vaccine in in uenza cases clinically dened

(Expt=experimental arm, ctrl=control arm; 95%CI=95% Condence intervals).



18/74

treatment trials). However the eects of this potential

confounder should have been eliminated by the process

of randomisation.

All trials commenced administration of the com-

pounds within a reasonable time lapse. When the

results of surveillance made it reasonable to do so,

treatment started at the latest 48 h after positive identi-

cation of the rst case in the population and preven-

tion.

Six main comparisons were carried out:

1. Comparison A oral amantadine compared to

placebo in inuenza prevention

2. Comparison B oral rimantadine compared to


3. Comparison C oral amantadine compared to

oral rimantadine in inuenza prevention

4. Comparison D oral amantadine compared to

placebo in inuenza treatment

5. Comparison E oral rimantadine compared to

placebo in inuenza treatment6. Comparison F oral amantadine compared to

oral rimantadine in inuenza treatment

Two minor comparisons, G and H, were also carried

out, each based on the results of a single trial.

For comparisons A, B and C the eects on `cases'

were analysed, stratied either on the basis of clinical-

laboratory criteria (a dened set of signs and symp-

toms backed up by serological conrmation and/or

isolation of inuenza virus from nasal uids) or clini-

cal criteria alone. The eects of amantadine/rimanta-

dine administration on asymptomatic cases (dened

only by serology or viral isolation) were not assessed,as these are of little public health interest.

Comparisons were stratied on the basis of whether

participants had received vaccination or not.

Finally, the adverse eects in the comparisons were

assessed. The `all adverse eects' category includes all

types and was derived from those trials which either

did not report sucient information to allow a more

detailed classication or that presented aggregate data.

Adverse eects incidence is reported in the meta-analy-

sis as event per person, thus the incidence should not

be added as more than one adverse event is likely to

have taken place in the same individual during thetrial. The dierence in incidence of adverse eects is of

importance, rather than the estimated incidence itself,

as the adverse eects reported with these drugs are

very similar to the clinical manifestations of inuenza

infection.

Apart from these caveats the analysis shows that all

types of adverse events were signicantly more likely

to happen when individuals were given amantadine

rather than placebo (with the exception of the `other'

category) but none were signicantly more likely to

take place in the rimantadine or placebo arms. Overall

both drugs appear to be eective and well tolerated,

although the evaluation of the eects of rimantadine

was carried out on a very small study population.

In all comparisons duration of action and protection

appeared directly related to duration of prophylaxis or

treatment with amantadine and rimantadine. This nd-

ing is in keeping both with the half-life of the com-

pounds which are excreted by the kidneys (at the rate

of 6.4 ml/min/kg for amantadine and 1.2 ml/min/kg

for rimantadine [37]) and the self-limiting duration of

the illness. No trials assessed onset of resistance to the

drugs although this is known to be of relatively short

induction time (1027% of patients secrete drug-resist-

ant virus within 45 days of commencing treatment

[37]).

3.3.1. Comparison A oral amantadine compared to


3.3.1.1. Ecacy. Amantadine: 61% (95%CI: 5169%)

ecacious (RR 0.39 95%CI: 0.310.49) in prevent-

ing clinically and laboratory dened inuenza cases;

23% (95%CI: 1134%) ecacious (RR 0.77 95%CI:

0.660.89) in preventing clinically dened inuenza

cases (Fig. 3). There was a signicant variation in the

trial results for the second outcome.

3.3.1.2. Adverse events. All categories of adverse eects

were signicantly more common in participants who

received amantadine than placebo, except for dermato-

logical changes. Nearly twice as many amantadine reci-

pients experienced both increased or decreased CNS

eects, and more than twice as many withdrew from

the trials due to adverse eects (Table 5).

3.3.2. Comparison B oral rimantadine compared to


3.3.2.1. Ecacy. Rimantadine: 72% (95%CI: 8

92%) ecacious (RR 0.28 95%CI: 0.081.08) in

preventing clinically and laboratory dened inuenza

cases; 35% (95%CI: 2065%) ecacious (RR 0.65

95%CI: 0.351.20) in preventing clinically inuenzacases (Fig. 4). The signicance of these ndings

depends on whether a xed or random eect model is

used.

3.3.2.2. Adverse events. Rimantadine recipients were

also more likely to experience adverse eects than pla-

cebo recipients. However, there was no evidence of an

increase in CNS-related eects with rimantadine and

withdrawal rates were similar in both groups (Table

6).



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3.3.3. Comparison C oral amantadine compared to

oral rimantadine in inuenza prevention

3.3.3.1. Ecacy. There was no evidence of a dierence

in ecacy between amantadine and rimantadine,

although the condence interval is quite wide (RR

amantadine vs rimantadine 0.88. 95%CI: 0.481.63).In some cases (Plesnik) data on cases of inuenza

have been included both under clinically and serologi-

cally dened, so the two outcomes should not be

added.

3.3.3.2. Adverse events. CNS adverse eects and with-

drawal from trials was more signicantly common

among amantadine recipients than rimantadine recipi-

ents (CNS eects; RR 2.58, 95%CI: 1.544.33; with-

drawals RR 2.30, 95%CI: 1.234.30).

Thus rimantadine appears no less ecacious but

safer than amantadine in preventing cases of inuenza

in healthy adults, although the study sizes of the safety

trials of rimantadine are considerably smaller than

those of amantadine.

3.3.4. Comparison D oral amantadine compared to


3.3.4.1. Ecacy. Amantadine signicantly shortened

duration of fever compared to placebo (by 1.00 days

95%CI: 0.731.29). The meta-analysis is based on

506 subjects (230 in the amantadine and 276 in the

placebo arm). Where time to fever clearance data were

not available (van Voris and Wingeld), a dichoto-

mous outcome was used (cases with fever at 48 h).

Fig. 3. Oral amantadine compared to placebo in inuenza prevention: inuenza cases clinically dened (Expt=experimental arm, ctrl=control

arm; 95%CI=95% Condence intervals).

Table 5

Comparison A: Incidence of adverse eects expressed as a percentage of participants

Amantadine (%) Placebo (%) No. of trials N Signicant

All adverse eects 14.7 10.4 6 4274 Yes

GI eects 5.1 2.4 5 3336 Yes

Increased CNS activity (excitation) 7.5 4.7 9 5002 Yes

Decreased CNS activity (depression) 8.6 7.1 6 3782 Yes

Skin 1.1 6.8 4 918 No



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Amantadine was shown to be signicantly better than

placebo (Peto relative risk 0.21 95%CI: 0.070.66).

3.3.4.2. Adverse events. In contrast to the increased

adverse eect rates for prevention, there was no evi-

dence that amantadine recipients had increased adverse

eect rates to placebo recipients. The incidence of

adverse eects by comparison expressed as a percen-

tage of participants is shown in Table 7.

3.3.5. Comparison E oral rimantadine compared to


3.3.5.1. Ecacy. Rimantadine also signicantly shor-

tened duration of fever compared to placebo (by 1.27

days 95%CI: 0.771.77). There was a signicantly

higher number of afebrile cases 48 h after commencing

rimantadine treatment (RR=0.17; 95%CI: 0.040.74).

3.3.5.2. Adverse events. There were very little data

available for the assessment of adverse eects of

rimantadine for treatment (45 participants) (Table 8).

3.3.6. Comparison F oral amantadine compared to

oral rimantadine in inuenza treatment

3.3.6.1. Ecacy. The little data available directly

comparing amantadine and rimantadine for treat-

ment showed that the ecacy of the two drugs was

comparable, although condence intervals are verywide.

3.3.6.2. Adverse events. There were very little data

available for the assessment of adverse eects of the

direct comparison between amantadine and rimanta-

dine (33 participants).

A meta-analysis of the symptoms outcome data was

considered to further inform the assessment of the

eects of amantadine and rimantadine in a treatment

Fig. 4. Oral rimantadine compared to placebo in inuenza prevention: inuenza cases clinically dened (Expt=experimental arm, ctrl=control

arm; 95%CI=95% Condence intervals)

Table 6

Comparison B: Incidence of adverse eects expressed as a percentage of participants

Rimantadine (%) Placebo (%) No of trials N Signicant

All adverse eects 18.6 10.8 3 558 No

GI eects 9.0 2.2 2 357 Yes

Increased CNS activity (excitation) 6.5 4.3 3 652 No

Decreased CNS activity (depression) 9.6 1.0 1 228 No

Skin 0 0



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role. When the outcome typology was tabulated it was

discovered that such a meta-analysis would be imposs-

ible (Table 9).

We resorted to using duration of fever (dened as a

temperature greater than 378C) as the only common

outcome. One drawback of this approach is the poss-

ible confounding eect of the presence of fever for a

variable length of time prior to and after entry to the

study (and hence at the moment of commencement of

treatment). However if random allocation had beenproperly carried out, this eect should disappear.

3.3.7. Comparison G oral amantadine compared to

oral aspirin in inuenza treatment

In Comparison G, based on Younkin, aspirin was

signicantly more eective than amantadine in redu-

cing the length of fever (by 0.47 days 95%CI: 0.17

0.76). This observation is based on 29 individuals.

Aspirin is well known for being a very eective anti-

pyretic and anti-inammatory drug, however it does

not inhibit viral replication and as such remains a

symptomatic remedy.

3.3.8. Comparison H inhaled amantadine compared

to placebo in inuenza treatment

In comparison H (based on Hayden's 1980 trial)

inhaled amantadine was no more ecacious than pla-

cebo in bringing down the respiratory or constitutional

symptom score (Weighted Mean Dierence 1.0

95%CI: 3.641.64 and 2.0 95%CI: 16.912.9 re-

spectively). This comparison also is based on small

numbers of participants (20). Not surprisingly, aman-

tadine caused signicantly more nasal irritation (RR

6.11 95%CI: 0.8643.3). Inhaled amantadine does

not appear to be particularly eective but has a high

incidence of local adverse eects which would make

compliance dicult.

The interpretation of Comparisons G and H is

made dicult by the small numbers involved and the

presence of single trials.

3.4. Eects of NIs

When compared to placebo, NIs are 55% (95%CIs:

2971%) eective in preventing naturally occurring

cases of laboratory conrmed inuenza and 67% eec-

tive (95%CIs: 908%) in experimental inuenza when

given intravenously. Overall NIs are 60% eective

(95%CIs: 7633%) (Fig. 5).

When the outcome is dened as cases of serologi-

cally conrmed inuenza, NIs are 74% eective

(95%CIs: 5087%) in preventing naturally occurring

inuenza and 86% eective (95%CIs: 1298%) in pre-

venting experimentally induced inuenza. Overall they

are 76% eective (95%CIs: 5587%) in preventingcases of laboratory conrmed inuenza. Both com-

pounds appear safe, but as yet no direct comparisons

have been carried out, so there can be no comment

upon their relative eects.

The adverse event prole (local nasal irritation) of

Zanamivir appears little dierent to placebo (OR 1.19

95%CIs: 0.393.62). However this may be due to

the relatively small denominator (112 individuals).

Oseltamivir appears to have a signicantly higher inci-

dence of systemic adverse eects than placebo (OR

1.68 95%CIs: 1.142.49).

Table 7

Comparison D: Incidence of adverse eects expressed as a percentage of participants

Amantadine (%) Placebo (%) No. of trials N Signicant

GI eects 13.8 13.4 3 494 No


Decreased CNS activity (depression) 56.4 65.2 3 491 Yes

Skin 0.9 0.4 2 465 No

Table 8

Comparison E: Incidence of adverse eects expressed as a percentage of participants

Rimantadine (%) Placebo (%) No of trials N Signicant

GI eects 0 0


Decreased CNS activity (depression) 0 8.3 1 31 No

Skin 0 0



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demicheli et al_2000_prevention and early treatment of influenza in healthy adults

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