who rapid ai treatment

8/8/2019 WHO Rapid AI Treatment

1/136

WHO/PSM/PAR/2006.6

WHO Rapid Advice Guidelineson pharmacological

management of humansinfected with avian influenza A

(H5N1) virus


2/136

World Health Organization 2006

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press,World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264;fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce ortranslate WHO publications whether for sale or for noncommercial distribution should be

addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail:[email protected]).

The designations employed and the presentation of the material in this publication do not imply theexpression of any opinion whatsoever on the part of the World Health Organization concerning thelegal status of any country, territory, city or area or of its authorities, or concerning thedelimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border linesfor which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers products does not imply that theyare endorsed or recommended by the World Health Organization in preference to others of a

similar nature that are not mentioned. Errors and omissions excepted, the names of proprietaryproducts are distinguished by initial capital letters.

All reasonable precautions have been taken by the World Health Organization to verify theinformation contained in this publication. However, the published material is being distributedwithout warranty of any kind, either expressed or implied. The responsibility for the interpretationand use of the material lies with the reader. In no event shall the World Health Organization beliable for damages arising from its use.


3/136

Contents

Executive summary i

Summary of clinical recommendations vii

1 Background 1

2 Scope 3

3 Methods 5

4 Case description

Assessment of possible casesCase description/clinical features

9

99

5 Treatment of H5N1 patients

OseltamivirZanamivirAmantadineRimantadine

Combination treatment

11

11141620

22

6 Chemoprophylaxis of H5N1 infection

OseltamivirZanamivirAmantadineRimantadine

25

26293235

7 Co-interventions for the management of H5N1patients

Prophylactic antibiotics

Steroids and other immunosuppressantsImmunoglobulinRibavirin

39

39

404141

8 Antiviral drug supply 43

9 Priorities for revision of the guidelines 45

10 Priorities for research 47

ANNEXES


4/136


5/136

Executive summary

i

Executive summary

The recent geographical spread of highly pathogenic avian influenza A (H5N1) virus inpoultry and wild waterfowl has increased opportunities for transmission of the virus tohumans. Outbreaks in poultry have now been accompanied by human cases in ninecountries.Todate,human caseshave remained rareand sporadic,but thedisease isverysevereand thecase fatality ishigh.With theH5N1virusnowconfirmed inbirds inmorethan 50 countries, additional sporadic human cases should be anticipated. AlthoughinternationalexpertsagreethatantiviraldrugsshouldbeconsideredfortreatmentofH5N1patientsandalsoforchemoprophylaxis,theefficacyandeffectivenessofthesemanagementoptionshavenotbeensystematicallyassessed.Guidanceontheiruseisneededworldwide.

From2829March2006,theWorldHealthOrganization(WHO)assembledaninternationalpanelofcliniciansexperiencedinthetreatmentofH5N1patients,infectiousdiseaseexperts,publichealthofficersandmethodologists todevelop rapidadvice for thepharmacologicalmanagement of patients with H5N1 infection. To develop evidencebased guidelines, thepanelusedatransparentmethodologicalguidelineprocess,basedontheGRADEapproach,that included evaluation of existing systematic reviews, literature searches and expertconsultation.The resultingguidelines separate strong fromweak recommendations fororagainsta specificactionandassign four categoriesofqualityofevidence (high,moderate,lowandverylow).

The panel considered several different specific patient and exposure groups and made anumberof strong recommendations fororagainstspecificactions regarding the treatmentand chemoprophylaxis of H5N1 virus infection. All recommendations are specific to thecurrentprepandemic situation.Recommendationswerebasedon careful considerationofthebenefits, harms,burdens and cost of interventions. Risk categorizations for exposurewere developed to assist countries in prioritizing the use of antiviral drugs where theiravailability is limited. Overall, the quality of the underlying evidence for allrecommendationswasverylow.NodatafromcontrolledclinicaltrialsofH5N1infectionareavailable.TheexistingevidenceisbasedonsmallobservationalcaseseriesofH5N1patients,

results from invitroandanimalmodelstudiesofH5N1,or theextrapolationofdata fromhighqualitystudiesconductedtoevaluate thetreatmentandchemoprophylaxisofnormal,orseasonal, influenza.Theseshortcomingshighlight theneedforfurtherresearch.Whilethequalityoftheevidenceforsomeofthecriticaloutcomeswasmoderateorlow,theoverallqualityofevidenceonwhich tobaseasummaryassessmentwasvery low forallantiviraldrugs.Differencesexistinthequalityofevidenceforindividualcriticaloutcomesamongthevariousantiviraldrugs(seeannex3forgradingsandratings).1

1 Based on the GRADE approach to grading the quality of evidence, the critical outcome with the lowestquality of evidence determines the overall quality assessment.


6/136

WHO Rapid Advice Guidelines on pharmacological management of humans infected

with avian influenza A (H5N1) virus

ii

Brief summary of recommendations

This advice pertains only to influenza A (H5N1) infections in the current prepandemicsituation. Recommendations willbe updated as new informationbecomes available or ifthere is evidence for sustained humantohuman transmission of H5N1 or another novelavian influenza virus emerges. Whenever feasible, sequential clinical data collection andvirological sampling (for analysis at WHOdesignated laboratories) shouldbe performedduringtreatmentorshouldapparentfailuresofchemoprophylaxisoccur.

Selfmedicationintheabsenceofappropriateclinicalorpublichealthadviceisdiscouraged.When considering chemoprophylaxis for H5N1 infection, priority should be given tostandard infection control practices. This includes protection of health care workers andindividuals involved in eradication of animals infected with H5N1 virus as well ashouseholdcontactsofH5N1patients.

Asstatedabove,thequalityoftheevidenceforthefollowingrecommendationsisverylowand this ismainly theresultoftheavailabilityofonlyvery indirectdatafromhighqualitystudiesinseasonalinfluenza.Fortreatmentofpatientswithconfirmedorstronglysuspectedhuman infection with the H5N1 virus, where neuraminidase inhibitors are available fortherapy:

Clinicians should administer oseltamivir treatment (strong recommendation);zanamivirmightbeusedasanalternative (weak recommendation).Thequalityofevidenceifconsideredonacontinuumratherthaninfourcategoriesislowerfortheuseofzanamivircomparedtooseltamivir.

In thesepatients,cliniciansshouldnotadministeramantadineorrimantadinealoneasafirstlinetreatment(strongrecommendation).

Cliniciansmightadministeracombinationofaneuraminidase inhibitorandanM2inhibitoriflocalsurveillancedatashowthattheH5N1virusisknownorlikelytobesusceptible (weak recommendation),but thisshouldonlybedone in the contextofprospectivedatacollection.

For treatment of patients with confirmed or strongly suspected H5N1 infection, where

neuraminidase

inhibitors

are

not

available

for

therapy:

Clinicians might administer amantadine or rimantadine as a firstline treatment iflocalsurveillancedatashowthattheH5N1virusisknownorlikelytobesusceptibletothesedrugs(weakrecommendation).

In general, decisions to initiate antiviral chemoprophylaxis shouldbe guidedby the riskstratificationdescribedbelow.StratificationisbasedonobservationaldataforreportedcasesofhumanH5N1infectionandonhighqualitydatafromstudiesofseasonalinfluenza.


7/136

Executive summary

iii

Highriskexposuregroupsarecurrentlydefinedas:

Household or close family contacts1 of a strongly suspected or confirmed H5N1patient,becauseofpotentialexposuretoacommonenvironmentalorpoultrysourceaswellasexposuretotheindexcase.

Moderateriskexposuregroupsarecurrentlydefinedas:

Personnel involved in handling sick animals or decontaminating affectedenvironments(includinganimaldisposal) ifpersonalprotectiveequipmentmaynothavebeenusedproperly.

Individualswithunprotectedandveryclosedirectexposure2tosickordeadanimalsinfectedwiththeH5N1virusortoparticularbirdsthathavebeendirectlyimplicatedinhumancases.

Health carepersonnel in close contactwith strongly suspectedor confirmedH5N1patients, for example during intubation or performing tracheal suctioning, ordelivering nebulised drugs, or handling inadequately screened/sealedbody fluidswithout any or with insufficient personal protective equipment. This group alsoincludes laboratory personnel who might have an unprotected exposure to viruscontainingsamples.3

Lowriskexposuregroupsarecurrentlydefinedas:

Health care workers not in close contact (distance greater than 1 metre) with astrongly suspected or confirmed H5N1 patient and having no direct contact withinfectiousmaterialfromthatpatient.

Health care workers who used appropriate personal protective equipment duringexposuretoH5N1patients.

Personnelinvolvedincullingnoninfectedorlikelynoninfectedanimalpopulationsasacontrolmeasure.

Personnel involved in handling sick animals or decontaminating affectedenvironments (including animal disposal), who used proper personal protectiveequipment.

1 A close contact may be defined as an individual sharing a household with, or remaining unprotectedwhilst within speaking distance (< 1 metre) of, or in the care of, a patient with confirmed or strongly suspectedH5N1 infection.

2 Examples of high risk exposure based on confirmed transmission to humans include: unprotectedexposure to infected animal products such as consumption of blood from H5N1 infected ducks; preparation offood or other products from infected animals (e.g. plucking feathers); or prolonged exposure to infected birds ina confined space, such as playing with pets.

3 This definition of moderate risk is based on very few cases recognized under these situations to date. Ascircumstances may change rapidly, it would be reasonable to consider the moderate and high risk groupstogether for prophylaxis decisions. If a particular patient has been implicated in possible human-to-humantransmission, then these examples of exposures could be defined as high risk.


8/136



iv

Whereneuraminidaseinhibitorsareavailable:

In high risk exposure groups, including pregnant women, oseltamivir shouldbeadministeredaschemoprophylaxis,continuing for710daysafter the lastexposure(strong recommendation); zanamivir could be used in the same way (strongrecommendation)asanalternative.

Inmoderateriskexposuregroups,includingpregnantwomen,oseltamivirmightbeadministeredaschemoprophylaxis,continuing for710daysafter the lastexposure(weak recommendation); zanamivir might be used in the same way (weakrecommendation).

In low risk exposure groups oseltamivir or zanamivir should probably not beadministeredforchemoprophylaxis(weakrecommendation).Pregnantwomeninthelow risk group should not receive oseltamivir or zanamivir for chemoprophylaxis(strongrecommendation).

Amantadineorrimantadineshouldnotbeadministeredaschemoprophylaxis(strongrecommendation).

Whereneuraminidaseinhibitorsarenotavailable:

In high or moderate risk exposure groups, amantadine or rimantadine mightbeadministered for chemoprophylaxis if local surveillancedata show that thevirus isknownorlikelytobesusceptibletothesedrugs(weakrecommendation).

In low risk exposure groups, amantadine and rimantadine should not beadministeredforchemoprophylaxis(weakrecommendation).

In

pregnant

women,

amantadine

and

rimantadine

should

not

be

administered

for

chemoprophylaxis(strongrecommendation).

In the elderly, people with impaired renal function and individuals receivingneuropsychiatric medication or with neuropsychiatric or seizure disorders,amantadine should not be administered for chemoprophylaxis (strongrecommendation).

The panel also considered the question of antibiotic use in H5N1 patients and made thefollowinggeneralrecommendations:

In patients with severe communityacquired pneumonia regardless of thegeographical location, clinicians should follow appropriate clinical practiceguidelines(strongrecommendation).

Inpatientswith confirmedor strongly suspectedH5N1 infectionwhodonotneedmechanicalventilationandhavenootherindicationforantibiotics,cliniciansshouldnotadministerprophylacticantibiotics(strongrecommendation).

In patients with confirmed or strongly suspected H5N1 infection who needmechanical ventilation, clinicians should follow clinical practice guidelines for theprevention or treatment of ventilatorassociated or hospitalacquired pneumonia

(strongrecommendation).


9/136

Executive summary

v

Other cointerventions considered were: routine use of corticosteroids, use ofimmunoglobulin and interferon, and also of ribavirin. There was no basis to make arecommendationforuseofanyofthesemedicinesoutsidethecontextofarandomizedtrial,butribavirinparticularlyshouldnotbeusedinpregnantwomen(strongrecommendation).

Generally, the recommendations havebeen developed tobe as specific and detailed aspossiblewithout losing sightof theuserfriendlinessof thisdocument and the individualrecommendations. The panel encourages feedback on all aspects of these guidelines,includingtheirapplicabilityinindividualcountries.

Thepaneldevelopedanumberof clinicalandbasic research recommendations that couldhelp augment the currently sparse direct evidence. Emergence of new influenza A viralsubtypes or a change in the pathogenicity or transmissibility of the H5N1 virus, thedevelopmentofnewpharmacologicalagentsortheavailabilityofimportantclinicalresearchdatawillnecessitateanupdateoftheseguidelines.


10/136



vi


11/136

Summary of clinical recommendations

vii


Briefdescriptionofmethodologyusedforgradingthequalityofevidenceandstrengthof

recommendations(seethesectiononmethods)

TheevidencewasassessedaccordingtothemethodologydescribedbytheGRADEworkinggroup. Briefly, in this system the quality of evidence is classified as high, moderate,loworverylowbasedonmethodologicalcharacteristicsoftheavailableevidenceforaspecifichealthcareproblem.Thedefinitionofeachisprovidedbelow.

High:Furtherresearchisveryunlikelytochangeconfidenceintheestimateofeffect.

Moderate:Furtherresearchislikelytohaveanimportantimpactonconfidenceintheestimateofeffectandmaychangetheestimate. Low:Furtherresearchisverylikelytohaveanimportantimpactonconfidenceinthe

estimateofeffectandislikelytochangetheestimate. Verylow:Anyestimateofeffectisveryuncertain.

Recommendationsareclassifiedasstrongorweak recommendations,asdelineated intheGRADEmethodology.Strongrecommendationscanbeinterpretedas:

Mostindividualsshouldreceivetheintervention.

Mostwell informed individualswouldwant the recommended courseofactionandonlyasmallproportionwouldnot. Therecommendationcouldunequivocallybeusedforpolicymaking.

Weakrecommendationscanbeinterpretedas:

Themajorityofwellinformedindividualswouldwantthesuggestedcourseofaction,butanappreciableproportionwouldnot.

Valuesandpreferencesvarywidely. Policymakingwillrequireextensivedebatesandinvolvementofmanystakeholders.

Whilethequalityoftheevidenceforsomeofthecriticaloutcomeswasmoderateorlow,theoverallqualityof evidenceonwhich tobase a summary assessmentwasvery low forallantiviraldrugs.Differences in thequalityofevidenceexist for individualcriticaloutcomesamongthevariousantiviraldrugs(seeannex3forgradingsandratings).1



12/136



viii

Recommendations

Self-medication in the absence of appropriate clinical or public health advice is

discouraged.

Context: Treatment of patients with confirmed or strongly suspected infection with avian

influenza A (H5N1) virus in a non-pandemic situation where neuraminidase inhibitors areavailable for therapy.

Rec 01: In patients with confirmed or strongly suspected H5N1 infection, cliniciansshould administer oseltamivir treatment as soon as possible (strongrecommendation, very low quality evidence).

Remarks:Thisrecommendationplacesahighvalueonthepreventionofdeathinanillnesswithahighcasefatality.Itplacesrelativelylowvaluesonadversereactions,thedevelopmentofresistanceandcostsoftreatment.DespitethelackofcontrolledtreatmentdataforH5N1,thisisastrongrecommendation,inpart,becausethereisa

lackofknowneffectivealternativepharmacological interventionsat this time.Therecommendationapplies toadults, includingpregnantwomenandchildren.Untilfurtherinformationbecomesavailable,thecurrenttreatmentregimenforH5N1isasrecommended forearly treatmentofadults,specialpatientgroups (e.g. thosewithrenalinsufficiency)andchildrenwithseasonalinfluenza.

Rec 02: In patients with confirmed or strongly suspected infection with avian influenza A(H5N1) virus, clinicians might administer zanamivir (weak recommendation,very low quality evidence).

Remarks:Thisrecommendationplacesahighvalueonthepreventionofdeathinan

illness

with

high

case

fatality.

It

places

a

relatively

low

value

on

adverse

effects

(includingbronchospasm), the potential development of resistance and costs oftreatment.Thebioavailabilityofzanamiviroutsideoftherespiratory tractislowerthan that of oseltamivir. Zanamivir may be active against some strains ofoseltamivirresistantH5N1virus.Therecommendationappliestoadults,includingpregnantwomenandchildren.Useofzanamivir requires thatpatientsareable touse thediskhalerdevice.Until further informationbecomesavailable, the currenttreatment regimen for (H5N1) infection is the same as recommended for earlytreatmentofadultsandchildrenwithseasonalinfluenza.

Although

the

quality

of

evidence

when

considered

on

a

continuum

is

lower

for

the

useofzanamivircomparedtooseltamivir,theoverallqualityofevidenceinthefourcategorygradingsystemisverylowforbothinterventions.

Rec 03: If neuraminidase inhibitors are available, clinicians should not administeramantadine alone as a first-line treatment to patients with confirmed or stronglysuspected human infection with avian influenza H5N1 (strong recommendation,very low quality evidence).

Remarks: Although recognizing that the illness is severe, this recommendationplacesahighvalueonthepotentialdevelopmentofresistanceandavoidingadverseeffects.Thisisastrongrecommendationinpart,becauseoftheavailabilityofother

optionsfortreatmentthatmaybemoreeffective.


13/136


ix

Rec 04: If neuraminidase inhibitors are not available and especially if the virus is knownor likely to be susceptible, clinicians might administer amantadine as a first-linetreatment to patients with confirmed or strongly suspected infection with avianinfluenza A (H5N1) virus (weak recommendation, very low quality evidence).


illnesswithahighcase fatality. Itplacesa relatively lowvalueonadverseeffectsand the development of resistance in a situation without alternativepharmacologicaltreatment.Untilfurtherinformationbecomesavailable,thecurrenttreatment regimen for (H5N1) infection is the same as recommended for earlytreatment of adults and childrenwith seasonal influenza.Theuse of amantadineshould be guided by knowledge about local resistance patterns, and specialconsideration of thebenefits and harms in patients at higher risk for adverseoutcomes(e.g.pregnantpatients).

Rec 05: If neuraminidase inhibitors are available, clinicians should not administerrimantadine alone as a first-line treatment to patients with confirmed or

strongly suspected infection with avian influenza A (H5N1) virus (strongrecommendation, very low quality evidence).

Remarks: Although recognizing that the illness is severe, this recommendationplacesahighvalueonthepotentialdevelopmentofresistanceandavoidingadverseeffects.Thisisastrongrecommendationinpart,becauseoftheavailabilityofotheroptionsfortreatmentthatmaybemoreeffective.

Rec 06: If neuraminidase inhibitors are not available and especially if the virus is knownor likely to be susceptible, clinicians might administer rimantadine as a first-linetreatment to patients with confirmed or strongly suspected infection with avianinfluenza A (H5N1) virus (weak recommendation, very low quality evidence).

Remarks:Thisrecommendationplacesahighvalueonthepreventionofdeathinanillnesswithahigh case fatality. Itplacesa relatively lowvalueonadverseeffectsand the development of resistance. The use of rimantadine shouldbe guidedbyknowledgeaboutlocalantiviralresistancepatterns,andspecialconsiderationofthebenefits,harms,burdensand cost inpatientsathigher risk foradverseoutcomes.Rimantadinehasgenerallyamorefavorablesideeffectprofilethanamantadine.

Rec 07: If neuraminidase inhibitors are available and especially if the virus is known orlikely to be susceptible, clinicians might administer a combination ofneuraminidase inhibitor and M2 inhibitor to patients with confirmed or strongly

suspected infection with avian influenza A (H5N1) virus (weak recommendation,very low quality evidence). This should only be done in the context ofprospective data collection.

Remarks:Thisrecommendationplacesahighvalueonthepreventionofdeathinanillnesswithahighcasefatality. Itplacesarelatively lowvalueonadverseeffects,thepotentialdevelopmentofresistanceandcostsassociatedwiththerapy.Theuseof combination therapy should be guided by knowledge about local antiviralresistancepatternsunder special consideration for thebenefits anddownsides inpatientsofhigherrisk foradverseoutcomes.Combination therapyshouldonlybecarriedoutifdetailedandstandardizedclinicalandvirologicaldatacollectionisin

placeatthestartoftherapy(prospectivedatacollection).Cliniciansshouldcarefullydetermine which patients (e.g. severely ill patients) could receive combinationtherapy.


14/136



x

Chemoprophylaxis

Antiviral chemoprophylaxis should generally be considered according to the riskstratificationdescribedbelow.ItisbasedonobservationaldataforreportedcasesofhumanH5N1infectionandonhighqualitydatafromstudiesofseasonalinfluenza.

Highriskexposuregroupsarecurrentlydefinedas:

Household or close family contacts1 of a strongly suspected or confirmed H5N1patient,becauseofpotentialexposuretoacommonenvironmentalorpoultrysourceaswellasexposuretotheindexcase.

Moderateriskexposuregroupsarecurrentlydefinedas:

Personnel involved in handling sick animals or decontaminating affectedenvironments(includinganimaldisposal) ifpersonalprotectiveequipmentmaynot

have

been

used

properly.

Individualswithunprotectedandveryclosedirectexposure2tosickordeadanimalsinfectedwiththeH5N1virusortoparticularbirdsthathavebeendirectlyimplicatedinhumancases.

Health carepersonnel in close contactwith strongly suspectedor confirmedH5N1patients, for example during intubation or performing tracheal suctioning, ordelivering nebulised drugs, or handling inadequately screened/sealedbody fluidswithout any or with insufficient personal protective equipment. This group alsoincludes laboratory personnel who might have an unprotected exposure to viruscontainingsamples.3

Lowriskexposuregroupsarecurrentlydefinedas:

Health care workers not in close contact (distance greater than 1 metre) with astrongly suspected or confirmed H5N1 patient and having no direct contact withinfectiousmaterialfromthatpatient.

Health care workers who used appropriate personal protective equipment duringexposuretoH5N1patients.

Personnelinvolvedincullingnoninfectedorlikelynoninfectedanimalpopulations

as

a

control

measure.

Personnel involved in handling sick animals or decontaminating affectedenvironments (including animal disposal), who used proper personal protectiveequipment.

1 A close contact may be defined as an individual sharing a household with, or remaining unprotectedwhilst within speaking distance (< 1 metre) of, or in the care of, a patient with confirmed or strongly suspectedH5N1 infection.

2 Examples of high risk exposure based on confirmed transmission to humans include: unprotectedexposure to infected animal products such as consumption of blood from H5N1 infected ducks; preparation offood or other products from infected animals (e.g. plucking feathers); or prolonged exposure to infected birds ina confined space, such as playing with pets.

3 This definition of moderate risk is based on very few cases recognized under these situations to date. Ascircumstances may change rapidly, it would be reasonable to consider the moderate and high risk groupstogether for prophylaxis decisions. If a particular patient has been implicated in possible human-to-humantransmission, then these examples of exposures could be defined as high risk.


15/136


xi

Inthepresentabsenceofsustainedhumantohumantransmission,thegeneralpopulationisnotconsideredatrisk.

Rec 08: In high risk exposure groups oseltamivir should be administered aschemoprophylaxis continuing for 7-10 days after the last known exposure(strong recommendation, very low quality evidence).

Remarks:This recommendationplacesahighvalueonpreventingan illnesswithhighcasefatality.Itplacesarelativelylowvalueonadverseeffects,developmentofresistanceand cost.Administrationof chemoprophylaxis shouldbegin as soonaspossibleafterexposurestatus isknownandbeusedcontinuouslyfor7 to10daysafter last known exposure.Oseltamivirhasbeenused for as long as 8weeks forchemoprophylaxis of seasonal influenza. The dose of oseltamivir for H5N1chemoprophylaxisshouldbethatusedinseasonalinfluenza.Thisrecommendationalsoappliestopregnantwomeninthehighriskexposuregroup.

Rec 09: In moderate risk exposure groups oseltamivir might be administered aschemoprophylaxis, continuing for 7-10 days after the last known exposure(weak recommendation, very low quality evidence).

Remarks:This recommendationplacesahighvalueonpreventingan illnesswithhighcasefatality.Itplacesarelativelylowvalueonadverseeffects,developmentofresistanceand cost.Administrationof chemoprophylaxis shouldbegin as soonaspossibleafterexposurestatus isknownandbeusedcontinuouslyfor7 to10daysafter last known exposure.Oseltamivirhasbeenused for as long as 8weeks forchemoprophylaxis of seasonal influenza. The dose of oseltamivir for H5N1chemoprophylaxisshouldbethatusedinseasonalinfluenza.Thisrecommendation

appliestopregnantwomeninthemoderateriskexposuregroup.Rec 10: In low risk exposure groups oseltamivir should probably not be administered for

chemoprophylaxis (weak recommendation, very low quality of evidence).

Remarks: This recommendation places a high value on avoiding adverse effects,potentialdevelopmentofresistanceandcost.ItplacesalowervalueonpreventingthelowriskofH5N1disease.

Rec 11: Pregnant women in the low exposure risk groups should not receive oseltamivirfor chemoprophylaxis (strong recommendation, very low quality of evidence).

Remarks: This recommendation places a high value on avoiding possible but

uncertainharmassociatedwithoseltamivirchemoprophylaxisduringpregnancy.ItplacesalowervalueonpreventingthelowriskofH5N1disease.

Rec 12: In high risk exposure groups zanamivir should be administered aschemoprophylaxis, continuing for 7-10 days after the last known exposure(strong recommendation, very low quality evidence).

Remarks:This recommendationplacesahighvalueonpreventingan illnesswithhighcasefatality.Itplacesarelativelylowvalueonadverseeffects,developmentofresistanceand cost.Administrationof chemoprophylaxis shouldbegin as soonas

possibleafterexposurestatus isknownandbeusedcontinuouslyfor7 to10daysafterlastknownexposure.Thedoseofzanamivirshouldbe thatusedforseasonalinfluenza chemoprophylaxis. The bioavailability of zanamivir outside of the


16/136



xii

respiratorytractislowerthanthatofoseltamivir.Zanamivirmaybeactiveagainstsome strains of oseltamivirresistant H5N1 virus. Consequently, it might be areasonable choice for health care workers with a highrisk exposure to anoseltamivirtreated H5N1 patient. This recommendation also applies to pregnantwomenwhohavehighriskexposure.

Rec 13: In moderate risk exposure groups, zanamivir might be administered aschemoprophylaxis, continuing for 7-10 days after the last known exposure(weak recommendation, very low quality evidence).

Remarks:This recommendationplacesahighvalueonpreventingan illnesswithhighcasefatality.Itplacesarelativelylowvalueonadverseeffects,developmentofresistanceand cost.Administrationof chemoprophylaxis shouldbegin as soonaspossible after exposure status is known and continued for 7 to 10days after lastknownexposure.Thebioavailabilityofzanamiviroutsideoftherespiratorytractislower than that of oseltamivir. Zanamivir maybe active against some strains of

oseltamivir resistant H5N1 virus. This recommendation also applies to pregnantwomeninthemoderateriskexposuregroup.

Rec 14: In low risk exposure groups zanamivir should probably not be administered forchemoprophylaxis (weak recommendation, very low quality of evidence).

Remarks: This recommendation places a high value on avoiding adverse effects,possibledevelopmentofresistanceandcost.Itplacesa lowervalueonpreventingthelowriskofH5N1disease.

Rec 15: Pregnant women in the low risk exposure group should not receive zanamivir forchemoprophylaxis (strong recommendation, very low quality of evidence).

Remarks: This recommendation places a high value on avoiding possible butuncertainharmassociatedwithzanamivirduringpregnancy.ItplacesalowervalueonpreventingthelowriskofH5N1disease.

Rec 16: If the virus is known or likely to be an M2 inhibitor resistant H5N1 virus,amantadine should not be administered as chemoprophylaxis against humaninfection with avian influenza A (H5N1) virus (strong recommendation, very lowquality evidence).

Remarks:Thisrecommendationplacesahighvalueonavoidingadverseeffectsina

situationwhennodrugefficacywouldbeexpected.

Rec 17: If neuraminidase inhibitors are not available and especially if the virus is knownor likely to be susceptible, amantadine might be administered aschemoprophylaxis against human infection with avian influenza A (H5N1) virusin high or moderate risk exposure groups (weak recommendation, very lowquality evidence).

Remarks: This recommendation does not apply to pregnant women, the elderly,people with impaired renal function and individuals receiving neuropsychiatricmedicationorwithneuropsychiatricorseizuredisorders.Itplacesahighvalueonpreventing an illness with high case fatality. It places a relatively low value on

adverse effects, development of resistance and cost. Administration ofchemoprophylaxisshouldbeginassoonaspossibleafterexposurestatusisknownfor710daysafterthelastknownexposure.Amantadinehasbeenusedforaslong


17/136


xiii

as 6 weeks for chemoprophylaxis of seasonal influenza A. This recommendationapplieswhenneuraminidaseinhibitorsarenotavailableorhavelimitedavailability.

Rec 18: If neuraminidase inhibitors are not available and even if the virus is known orlikely to be susceptible, amantadine should probably not be administered aschemoprophylaxis against human infection with avian influenza A (H5N1) virus

in low risk exposure groups (weak recommendation, very low quality evidence).

Remarks: This recommendation places a high value on avoiding adverse events,developmentofresistance,andcost.Itplacesalowervalueonpreventingthe lowriskofH5N1disease.

Rec 19: In pregnant women, the elderly, people with impaired renal function andindividuals receiving neuropsychiatric medication or with neuropsychiatric orseizure disorders amantadine should not be administered as chemoprophylaxisagainst human infection with avian influenza A (H5N1) virus (strongrecommendation, very low quality of evidence).

Rec 20: If the virus is known or likely to be M2 inhibitor resistant H5N1 virus,rimantadine should not be administered as chemoprophylaxis against humaninfection with avian influenza A (H5N1) virus (strong recommendation, very lowquality evidence).

Remarks:Thisrecommendationplacesahighvalueonavoidingadverseeffectsinasituationwhennodrugefficacywouldbeexpected.

Rec 21: If neuraminidase inhibitors are not available and especially if the virus is knownor likely to be susceptible, rimantadine might be administered aschemoprophylaxis against human infection with avian influenza A (H5N1) virusin high or moderate risk exposure groups (weak recommendation, very lowquality evidence).

Remarks:This recommendationplacesahighvalueonpreventingan illnesswithhighcasefatality.Itplacesarelativelylowvalueonadverseeffects,developmentofresistanceand cost.Administrationof chemoprophylaxis shouldbegin as soonaspossibleafterexposure status isknownand continued for710daysafter the lastknown exposure. Rimantadine has been used for as long as 7 weeks forchemoprophylaxis of seasonal influenza A. This recommendation applies whenneuraminidase inhibitors are not available or have limited availability. Thisrecommendationdoesnotapplytopregnantwomen.

Rec 22: If neuraminidase inhibitors are not available and even if the virus is known orlikely to be susceptible, rimantadine should probably not be administered as

chemoprophylaxis against human infection with avian influenza A (H5N1) virusin low risk exposure groups (weak recommendation, very low quality evidence).

Remarks: This recommendation places a high value on avoiding adverse events,developmentofresistance,andcost.Itplacesalowervalueonpreventingthe lowriskofH5N1disease.

Rec 23: In pregnant women rimantadine should not be administered forchemoprophylaxis of human infection with avian influenza A (H5N1) virus(strong recommendation, very low quality of evidence).


18/136



xiv

Rec 24: In patients with severe community acquired pneumonia regardless of thegeographical location, clinicians should follow appropriate clinical practiceguidelines (strong recommendation, the panel has not judged the quality of theevidence for this recommendation).

Remarks:Thechoiceofantibioticsshouldbebasedonknowledgeoflocalpathogens,

other comorbidities and resistance patterns. Hospitals should havelocal antimicrobial surveillance data that can be used to inform the choice.Further advice about monitoring antimicrobial resistance is available intheWHO Global Strategy for Containment of Antimicrobial Resistance,at http://www.who.int/drugresistance/WHO_Global_Strategy_English.pdf. Localstandardtreatmentguidelinesshouldbeupdatedregularly.

Rec 25: In patients with confirmed or strongly suspected infection with avian influenza A(H5N1) virus who do not need mechanical ventilation and have no otherindication for antibiotics, clinicians should not administer prophylacticantibiotics (strong recommendation, the panel has not judged the quality of the

evidence for this recommendation).

Remarks:ThisisastrongrecommendationinpartbecausethereisnoevidencethatantibioticchemoprophylaxisreducestheriskofbacterialsuperinfectioninH5N1orseasonal influenza, whether or not the patients require mechanical ventilation.Antibioticsarelikelytoselectforresistantbacteria,ifsuperinfectionoccurs.Thus,atpresent there are no known clinical net benefits from chemoprophylaxis withantibiotics.

Rec 26: In patients with confirmed or strongly suspected infection with avian influenza A(H5N1) virus who need mechanical ventilation, clinicians should follow clinicalpractice guidelines for the prevention or treatment of ventilator associated or

hospital acquired pneumonia (strong recommendation, the panel has not judgedthe quality of the evidence for this recommendation).

Remarks:As the risk forbacterial infection inmechanically ventilatedpatients isincreased, this recommendationplaces ahigh valueon avoiding consequencesofproven or suspectedbacterial infection and a low value on adverse effects ofantibiotics, the development of resistance, and cost. Appropriatebroad spectrumantibiotic therapy shouldbe institutedwith a commitment to tailor antibiotics assoonaspossibleonthebasisofserialclinicalandantimicrobiologicdata.

Rec 27: In pregnant patients with confirmed or strongly suspected infection with avian

influenza A (H5N1) virus, clinicians should not administer ribavirin as treatmentor chemoprophylaxis (strong recommendation, very low quality evidence).

Remarks: This recommendationplaces ahigh value on avoiding thehigh risk ofteratogeniceffectsofribavirinduringpregnancy.


19/136

Background

1

1. Background

HumancasesofinfectionwiththeH5N1avianinfluenzaviruswerefirstreportedinHongKongSAR in1997(18cases)andagain in2003(2cases).Inthepresentoutbreakofhumancases,whichbegan inDecember2003,more than200 caseshavebeen reported fromninecountries inAsia,Europe,northernAfrica,and theMiddleEast.Humancasesaredirectlylinked to the presence of the virus in birds, and this geographical presence is nowconsiderable.Anupdatedrecordofcasesandtheiroutcomesandofaffectedcountriescanbefoundathttp://www.who.int/csr/disease/avian_influenza/country/en/.

Of all influenza A viruses that circulate inbirds, the H5N1 virus is of greatest present

concernforhumanhealthfortwomainreasons.First,theH5N1virushascausedbyfarthegreatestnumberofhumancasesofveryseverediseaseandthegreatestnumberofdeaths.Asecondimplicationforhumanhealth,offargreaterconcern,istheriskthattheH5N1virusifgivenenoughopportunitiescoulddevelopthecharacteristics tostartanother influenzapandemic.Thevirushasmetallprerequisitesforthestartofapandemicsaveone:anabilitytospreadefficientlyandsustainablyamonghumans.WhileH5N1ispresentlytheinfluenzaAvirusofgreatest concern, thepossibility thatotheravian influenzaAviruses,known toinfecthumans,mightcauseapandemiccannotberuledout.

At present, infection with influenza A(H5N1) virus is primarily a disease ofbirds. The

speciesbarrierissubstantial:thevirusdoesnoteasilyinfecthumans.Nonetheless,withthevirusnow reported indomesticorwildbirds inmore than50 countries, sporadichumancaseswillalmostcertainlycontinuetooccur.Fewguidelinesfortheclinicalmanagementofsuch patients havebeen published. In February 2004, WHO published interim clinicalguidelines. These guidelines were updated in September 2005 (WHO Writing Committee2005) followingan expert consultation.Thepurposeof thepresentdocument is to reviewand update recommendations on clinical case management of patients infected with theH5N1virusaswellastoreviewandupdaterecommendationsontheuseofantiviraldrugsaschemoprophylaxis.Theguidelinesapplytothecurrentsituationinwhichnoefficientorsustainedhumantohumantransmissionofthevirusisknowntobeoccurring.

The document is addressed primarily to clinicians managing H5N1 cases or advising onmanagementofspecificpopulationspotentiallyatriskofthedisease.Itislikelythatitwillbeusedbyhealthcaremanagersandpolicymakers.Ithasbeenpreparedasarapidadvicedocument, and therefore has a defined scope,based on clinical questions that havebeenraised by health care teams managing H5N1 patients. While it does not cover allinterventions that maybe relevant, it willbe updated and expanded as experience andevidenceaccumulatefromreportedcasesandfromformalclinicaltrialsoranimalresearch.Inaddition,thecurrentpicturecouldchangegiventhepropensityofallinfluenzaAvirusestomutaterapidlyandunpredictably.Suchachangewouldalsonecessitateupdatingofthe

guidelines.


20/136



2

A fundamental firstline approach to the clinical management of patients withH5N1 avian influenza is to ensure that appropriate infection control proceduresare in place in health care systems and are used by all involved in managinganimal or human disease or suspected cases. Specific guidelines for infectioncontrol procedures are described in a parallel document: Influenza A (H5N1):

WHO Interim Infection Control Guidelines for Health Care Facilities, 2004)(http://www.who.int/csr/disease/avian_influenza/guidelines/Guidelines_for_health_care_facilities.pdf)andare thereforenot includedhere.However, itshouldbeassumed that forallrecommendations about pharmacological treatments that are described here, therecommendationson infection controlprocedureandpracticeapplyandarecritical to themanagementofH5N1patients.


21/136

Scope

3

2. Scope

The target audience of these guidelines is primarily health care professionals managingH5N1patientsoradvisingonmanagementofspecificpopulationspotentiallyatriskofthedisease,buthealthcarepolicymakersandpublichealthofficershavealsobeenconsidered.Nationalprogrammesandtreatmentguidelinegroupsmayalsowishtousethedocumentasthebasis for implementationordevelopmentof locally adaptedguidelines (seeannex1Adaptationofguidelines).

The clinical questions covered by this document were developed in consultation withclinicians fromavarietyofcountries involved in themanagementofH5N1patients.They

canbesummarizedbrieflyas:

ShouldcliniciansusetheantiviraldrugsthatarecurrentlyavailableforthetreatmentofH5N1patients?Whatarethebenefits,harms,burdensandcostofeachcurrentlyavailablealternative?Canallpatientgroupsbetreatedinthesameway?Whatdoseofthemedicineshouldbeusedandforhowlong?

Should clinicians use the antiviral drugs that are currently available forchemoprophylaxisinpersonswhomaybeatriskofcontractingavianinfluenza?Inthe context of prevention,what are thebenefits,harms,burdens and cost of eachcurrently available alternative?Are thereparticularpopulation groupswho are atgreateror lesser riskof thedisease, and if so, should theuseof themedicinesbemodified?

Ifthereislimitedavailabilityofantiviraldrugs,shouldtheuseofthesemedicinesbeprioritizedandshouldothermedicinesbeused?

WhatadditionalpharmacologicaltreatmentsmightbeofbenefitinthetreatmentofH5N1 patients? Should antibioticsbe used prophylactically? What is the role ofcorticosteroids,immunoglobulinandinterferon?Whatistheroleofribavirin?

Thesequestionshavebeen considered in the contextof the current situation inwhichno

efficient or sustained humantohuman transmission of the H5N1 virus is known tobeoccurring,andnoevidenceindicatesthatapandemicisimminent.Achangeinthissituationwould require modification of the recommendations. The recommendations in thisdocumentdonotapplytotreatmentorchemoprophylaxisofseasonalinfluenza.

These guidelines do not provide recommendations on use of ventilators, isolationprocedures, vaccination and other public health interventions, although these will beincludedinlaterversions.However,recommendationsontheuseofparticulartherapiesthatare covered in the document mustbe considered together with infection control, whichremainsaprimarystrategyforthecontrolofoutbreaks.


22/136



4


23/136

Methods

5

3. Methods

This document was prepared according to a modification of the WHO Guidelines forGuidelines (WHO 2003), as a rapid adviceguidelinedocument, taking into account theneed foradvice tobeprovidedurgently.Completedetailsof themethodsareprovided inannex2;abriefsummaryisprovidedbelow.

The clinical questions and scope of these guidelines were defined in consultation withcliniciansmanagingH5N1patients.WHOcommissionedanindependentacademiccentretocompile summaries of evidence, based on systematic reviews and health technologyassessments (see annex 3) according to the GRADE methodology described in the WHO

GuidelinesforGuidelines.Publishedanimalandinvitrostudieswerealsosummarized.Thesummariesofevidencewerethenpeerreviewedandcorrectionsandcommentsincorporatedbytheexpertpanel.Ifnorelevantsystematicreviewswerefoundforspecificinterventions,evidence summaries could not be completed in the time available. In such cases,recommendationswhichgradedthequalityoftheevidencecouldnotbemade(antibiotics,othercointerventions).A guideline panel comprising international scientists and experts in clinical treatment ofavian and seasonal influenza, guideline methodology, basic research, policy making,pharmacologyandvirologywas convened from2829March2006 (seeannex4 for listof

participantsandannex5forconflictofinterestdeclarations).Thepanelwasaskedtoidentifycriticalclinicaloutcomesasabasisformakingtherecommendations.Mortality,durationofhospitalization, incidenceof lowerrespiratory tractcomplications,antiviraldrugresistanceand seriousadverseeffectswere ratedas criticaloutcomes in theassessmentof treatmentinterventions forH5N1patients.For chemoprophylaxis, influenza cases,outbreak control,drug resistanceand seriousadverse effectswere ratedas criticaloutcomes.The impactofchemoprophylaxisontheseoutcomesformedthebasisofconsiderationsusedwhenreachingconclusions. All outcomes reported in the clinical trials are summarized in the evidenceprofilessetoutinannex3.

The evidence was assessed according to the methodology described in GRADE (GRADEWorkingGroup2004)Inthissystemevidenceisclassifiedashigh,moderate,loworverylow.Definitionsareasfollows:

High:Furtherresearchisveryunlikelytochangeconfidenceintheestimateofeffect.

Moderate:Furtherresearchislikelytohaveanimportantimpactonconfidenceintheestimateofeffectandmaychangetheestimate.

Low:Furtherresearchisverylikelytohaveanimportantimpactonconfidenceintheestimateofeffectandislikelytochangetheestimate.

Verylow:Anyestimateofeffectisveryuncertain.


24/136



6

Factors considered when classifying evidence are the study design and rigour of itsexecution, the consistencyof results,howwell the evidence canbedirectly applied to thepatients, the interventions, the outcomes, the comparator, whether the data are sparse orimpreciseandwhetherapotentialforreportingbiasexists.Nocontrolledclinical trialsarepresentlyavailableforH5N1patients.Inadditionitisuncertainwhethertheevidencethatis

available forseasonal influenzacanbedirectlyapplied topatients infectedwith theH5N1virus, as thebiology of this disease appears tobe different from infection with seasonalinfluenzavirus.ThedataavailablefrompreclinicalstudiesofH5N1infectionwereusedtoinformthisconsideration.Itisimportanttonotethatagroupoftrialsmayconstitutehighquality evidence foronequestion,butbecauseofuncertainty about their applicabilityordirectness,canberegardedasverylowqualityevidenceforadifferentquestion.Whilethequalityof theevidence forsomeof thecriticaloutcomeswasmoderateor low, theoverallqualityofevidenceonwhich tobaseasummaryassessmentwasvery low forallantiviraldrugs.Differencesexistinthequalityofevidenceforindividualcriticaloutcomesamongthevariousantiviraldrugs(seeannex3forgradingsandratings).1

The panel reviewed the evidence summaries and the draft guidelines and maderecommendations. Consensus was reached on nearly all recommendations, but onerecommendation required voting about the strength of the recommendation (weak asopposed tostrong)andone requiredvotingaboutwhetheraweakrecommendationornorecommendationshouldbemade.

Formulatingtherecommendationsincludedexplicitconsiderationofthequalityofevidence,benefits,harms,burdens,costsandvaluesandpreferences,describedin theRemarksforeachrecommendation.Valuesarethedesirabilityorpreferencethatindividualsexhibitfor

aparticularhealthstate.Individualsusuallyassignlessvaluetoandhavelesspreferenceformore impaired health states (e.g. death or dependency after a stroke) compared to otherhealthstates(e.g.fullhealthorhavingaverymildstrokewithoutserioussequelae).Inthisdocument, the termvaluesrefers to therelativeworthor importanceofahealthstateorconsequences(benefits,harms,burdensandcosts)ofadecision.

VerylittleinformationaboutcostsoftreatmentorchemoprophylaxisofH5N1wasavailableto thepanel.For thisguideline themaincostconsiderationwas theacquisitioncostof theantiviraldrugs.Estimatesofcurrentacquisitioncostsaresetoutinsection8ondrugsupply.

Recommendationsareclassifiedasstrongorweakrecommendations,asrecommendedintheGRADEmethodology.Strongrecommendationscanbeinterpretedas:

Most individuals should receive the intervention, assuming that they havebeeninformedaboutandunderstanditsbenefits,harmsandburdens.

Most individualswouldwant the recommendedcourseofactionandonlya smallproportionwouldnot.

Therecommendationcouldunequivocallybeusedforpolicymaking.



25/136

Methods

7

Weakrecommendationscanbeinterpretedas:

The majority of individuals would want the suggested course of action,but anappreciableproportionwouldnot.

Values

and

preferences

vary

widely.

Policymakingwillrequireextensivedebatesandinvolvementofmanystakeholders.

Specific recommendations about antiviral drugs are presented in two sections:recommendations for treatment of H5N1 patients and recommendations forchemoprophylaxisofH5N1infection.Forrecommendationspertainingtochemoprophylaxis,an exposurebased assessment of risk was developed, based on observational data forreported cases of H5N1 infection and corresponding information on viral transmission.Generalrecommendationsabouttheuseofcointerventionsaregiveninaseparatesection.Fulldetailsofthemethodsaresetoutinannex2.

Rapidly changing information about this disease may require frequent updating of theguidelines.Thefirstrevisionmayoccurinnotmorethan12monthsfollowingpublicationofthisdocument.Themainfactorsthatwillinfluencethetimingoftheupdateinclude:whethersignificant new scientific evidence becomes available, the availability of new antiviralmedicinesorachangeinthepathogenicityortransmissibilityofH5N1viruses,includingtheemergenceofapandemicvirus.


26/136



8


27/136

Case description

9

4. Case description

Assessment of possible cases1

InvestigationsofmostlaboratoryconfirmedcasesofhumanH5N1infectionhaveidentifieddirect contact with infectedbirds as the most likely source of exposure. When assessingpossible cases, the level of clinical suspicion shouldbe heightened for persons showinginfluenzalikeillness,especiallywithfeverandsymptomsinthelowerrespiratorytract,whohave a history of direct contact with poultry or wild birds (generally sick or deadunvaccinated poultry) in an area where confirmed outbreaks of highly pathogenic H5N1avianinfluenzaareoccurring.

Case description/clinical features

Likemostemergingdiseases,H5N1avian influenzavirus infections inhumansarepoorlyunderstood.ClinicaldatafromH5N1casesin1997andthecurrentoutbreakarebeginningtoprovideapictureoftheclinicalfeaturesofdisease,butmuchremainstobelearned.Inmanypatients, the disease causedby the H5N1 virus follows an unusually aggressive clinicalcourse,withrapiddeteriorationandhighfatality.

The incubationperiod forH5N1 inpeoplemaybe longer than that forseasonal influenza,

whichisaroundtwotothreedays.CurrentdataforH5N1virusinfectionsuggestasimilarincubationperiodbutranginguptoeightdaysandrarelylonger(periodsaslongas17dayshavebeen reported). However, the possibility of multiple exposures to the H5N1 virusmakesitdifficulttodefinetheincubationperiodprecisely.WHOcurrentlyrecommendsthatanH5N1incubationperiodofsevendaysbeusedforfieldinvestigationsandthemonitoringofpatientcontacts.

Initial symptoms include ahigh fever,usuallywith a temperaturehigher than 38C, andinfluenzalike symptoms. Diarrhoea, vomiting, abdominal pain, chest pain, andbleedingfrom the nose and gums have alsobeen reported as early symptoms in some patients.

Waterydiarrhoea withoutblood appears tobe more commonwith H5N1 virus infectionthaninseasonalinfluenza.

However,inmanypatientstherapiddevelopmentoflowerrespiratorytractsymptomsisacommonfeaturethatcauses them tofirstseektreatment.Onpresentevidence,difficulty inbreathingdevelops around fivedays following the first symptoms.Respiratorydistress,ahoarse voice, and a crackling sound when inhaling are commonly reported. Sputumproduction isvariableandsometimesbloody.Recently,bloodtintedrespiratorysecretionshavebeenobserved inTurkey.AlmostallH5N1patientsdeveloppneumonia.During the1997HongKongSARoutbreak,allseverelyillpatientshadprimaryviralpneumonia,which

1 Adapted from the WHO Fact sheet on Avian Influenzahttp://www.who.int/mediacentre/factsheets/avian_influenza/en/index.html


28/136



10

didnot respond toantibiotics.Limiteddataonpatients in the currentoutbreak suggestaprimary viral pneumonia with H5N1 virus infection, usually without microbiologicalevidence ofbacterial superinfection at presentation. Turkish clinicians have also reportedpneumonia as a consistent feature in severe cases; as elsewhere, these patients did notrespondtotreatmentwithantibiotics.

Thespectrumofclinicalsymptomsmay,however,bebroader,andnotallconfirmedH5N1patientshavepresentedwithrespiratorysymptoms.IntwopatientsfromsouthernVietNam,theclinicaldiagnosiswasacuteencephalopathy;neitherpatienthadrespiratorysymptomsat presentation. In another case, from Thailand, the patient presented with fever anddiarrhoea,butnorespiratorysymptoms.However,allpatientshadradiographicevidenceoflowerrespiratorytractdiseaseandarecenthistoryofdirectexposuretoinfectedpoultry.

InpatientsinfectedwiththeH5N1virus,clinicaldeteriorationisrapid.InThailand,thetimebetweenonsetofillnesstothedevelopmentofacuterespiratorydistresswasaroundsixdays,

with a range of four to 13 days. In severe cases in Turkey, clinicians have observedrespiratory failure three to five days after symptom onset. Another common feature ismultiorgan dysfunction. Common laboratory abnormalities include leukopenia (mainlylymphopenia),mildtomoderate thrombocytopenia, elevatedaminotransferases, and someinstancesofdisseminatedintravascularcoagulation.

AccordingtoreportsfromVietNam,ThailandandTurkey,chestradiograph(CXR)findingshavebeen consistently abnormal on admission. Chest radiographs have typically shownconsolidation, often bilateral and multifocal. In addition, patchy lobar and interstitialinfiltrateshavebeendescribedamedianof7daysafteronsetofsymptoms(range317days)

(Chotpitayasunondh2005;HienandFarrar,personalcommunication).Pleuraleffusionshavebeen less commonly reported with cavitation, in the absence of superinfection,being anoccasionalfindinginVietnamesepatients.


29/136

Treatment of H5N1 patients:

recommendations for use of antiviral drugs

11

5. Treatment of H5N1 patients:


ThefollowingrecommendationsforuseofantiviraldrugsforthetreatmentofH5N1patientsapply to the current situation definedby the absence of efficient or sustained humantohumantransmission.

At present, no controlled clinical trials have evaluated treatment or chemoprophylaxis ofH5N1patients. The evidence on which the recommendations arebased ispredominantlyderivedfromstudiesofinfectionwithhumaninfluenzavirusesduringseasonalepidemics,and is thus indirect. In addition, themajorityof these studies focuson early treatmentof

uncomplicated human influenza in otherwise healthy adults in which infection hasbeenacquired following humantohuman transmission. So far, most patients with H5N1infectionhavepresentedlateinthecourseofillnessandwerehospitalizedaftertheonsetofseveredisease.ManyofthoseinfectedwiththeH5N1virushavebeenchildren.Thispatientprofile increases uncertainty about the generalizability of the evidence to H5N1 patients.SummariesofevidenceusedtomaketherecommendationsaresetoutinAnnex3.WhereaGRADEevaluationoftheavailableliteraturehasbeenpossible,thisisdisplayedinevidenceprofilesandacorrespondingsummaryoffindings.

Thepanel ratedmortality,durationofhospitalization, incidenceof lower respiratory tract

complications,resistanceandseriousadverseeffectsascriticaloutcomesfortheassessmentof treatment interventions for H5N1patients. While the quality of the evidence for somecriticaloutcomeswasmoderateor low, theoverallqualityofevidenceonwhich tobaseasummary assessment was very low for all antiviral drugs. Differences in the quality ofevidence exist for individual critical outcomesbetween the various antiviral drugs (seeannex3forgradingsandratings).1

Selfmedicationwith antivirals, in the absence of appropriate clinical or public health

advice,isdiscouraged.

5.1 Should H5N1 patients receive treatment with oseltamivir?

Summaryoffindings

NoclinicaltrialhasevaluatedoseltamivirinthetreatmentofH5N1patients.

Foursystematicreviewsandhealthtechnologyassessments(HTA)reporting5studiesoftheuse of oseltamivir in seasonal influenza were identified (see annex 3). These studiesexaminedtheuseofoseltamivirinotherwisehealthyadults,highriskadultsorchildrenfortreatmentofseasonal influenza. In these trials,oseltamivir treatmentwasgenerallystarted



30/136



12

earlyinthedisease(within48hoursofsymptomonset).Childrenupto1yearofagewerenot included.Thedurationof treatmentwasup to5days.Thestudieswere conducted inseveral countries in the northern and southern hemispheres,but resourcepoor countrieswerenotrepresented.

Thereare three published case series describing H5N1 patients treated with oseltamivir(Beigel2005,Hien2004,Chotpitayasunondh2005).1

Therearemany invitroandanimalstudiesoftheeffectsofoseltamivirontheH5N1virus(seeannex3).

Benefits

TherearetoofeweventsinthereportedstudiestoprovideevidenceofbenefitofoseltamivironmortalityordurationofhospitalizationineitherseasonalinfluenzaorH5N1infection.Inseasonal influenza lower respiratory tract complications (including pneumonia) werereduced(RR0.15,95%CI0.03to0.69)inaseriesof5similarlydesignedtrials(n=1644)thataddressed this outcome in otherwisehealthy adultswith seasonal influenza (Kaiser et al,2003),buttherewereonly11events.Thissameanalysisalsoreportedasignificantreduction(RR 0.40, 95%CI 0.18 to 0.88) in allcausehospitalizationswithin 30daysofdiagnosis inoseltamivirrecipientscomparedtoplacebo,butthisfindingwasbasedonatotalof27events(18 out of 1063 patients treated with placebo compared with 9 out of 1350 treated withoseltamivir).2The most recent case series describes 37 H5N1 patients, of whom 25 weretreatedwithoseltamivir(19deaths)and12describedasnotbeingtreatedwithoseltamivir(9deaths)(Beigel2005).Treatmentregimensdifferedacrossthesepatientsbeginningbetweenday4to22ofillness.

Harms

Serious adverse events and drug resistance were generally not reported in systematicreviews of oseltamivir use in adults with seasonal influenza. There havebeen 2 trials inpaediatricpopulationsthatreportedveryfewadverseevents(RR2.00,95%CI0.61to6.61).However,reportingofharmsisoftencomplicatedbywithdrawalsofpatientsfromtrialsdueto adverse events that arenot fullydescribed in published reports.Data from regulatorytrials submittedby the manufacturer to the US Food and Drug Administration includednauseaandvomitingasthemostfrequentadverseevent inbothchildrenandadults(FDA

label

information,

Dutkowski

2003).

Rare

cases

of

anaphylaxis

and

serious

skin

reactions

werealsoreportedduringpostmarketingexperiencewithoseltamivir.Spontaneousreportsto WHO of adverse reactions listed 644 reports of adverse reactions, but there is noassessment of causality or severity of these events in relation to oseltamivir. The mostcommonly reported adverse event was nausea (n = 110 cases). There were 86 reports ofexposure to oseltamivir in pregnancy (maternal exposure) recorded on the Roche DrugSafetydatabaseasat31March2005.Twentyfiveofthesewomenwereeitherlosttofollowuportheoutcomeofthepregnancywasunknown.For33women,thepregnancywasstill

1 There has been an additional published fatal case report of a pregnant woman with human infection ofavian influenza H5N1, who did not receive antiviral therapy (Shu 2006).

2 A recent report of 8 cases (6 of these had complete data) described that 3 H5N1 patients who hadcleared pharyngeal viral RNA by the end of 5 days treatment with oseltamivir survived. Three patients whosepharyngeal samples remained positive despite therapy died, two of whom had emergence of osletamivir-resistant variants (de Jong NEJM 2005).


31/136



13

ongoing. Among the remainder there were 2 reports of birth defects and 4 cases ofspontaneousabortion.ThreecasesofresistancetooseltamivirdevelopingaftertreatmentofH5N1patientshavebeenpublished(Le2005,DeJong2005).

Treatmentconsiderations

Available formulations:

Oseltamivirphosphateisavailableasacapsulecontaining75mgoseltamivirfororaluse,intheformofoseltamivirphosphate,andasapowderfororalsuspension.

Treatmentregimen:

Patientswith renal impairment, i.e.acreatinineclearancebetween10and30ml/min,whoarebeingconsideredforoseltamivirtreatmentrequiredosereduction.Basedonunpublishedpharmacokineticdata from themanufacturer,adoseof75mgoncedailycouldbeused inthese patients. There is no recommendation for dose reduction in patients with hepatic

disease.

Patients

with

severe

gastrointestinal

symptoms

may

have

reduced

oral

absorption

of

oseltamivirbutthishasnotbeenstudied.Thereiscurrentlynoempiricalevidencetosuggesttheuseofaloadingdoseorhigherdosesofoseltamivirinpatientswithseverediseasebutincreaseddosesanddurationof treatmenthavebeensuggestedasastrategy toreduce therisk fordevelopmentofdrug resistance.Patientswhovomitwithinonehourof ingestionmightbegivenanadditionaldoseof75mg,butthisisbasedonphysiologicalconsiderations.There are no documented differences in the metabolism of the drug for different ethnicgroups.

Therecommendeddoseforseasonalinfluenzais75mgtwicedailyinadultsorthefollowing

weight

adjusted

doses

in

children

for

5

days

(CDC

2006a,

CDC

2006b

and

appropriate

FDA

label).

Children1yearofageorolder:weightadjusteddoses

30mgtwicedailyfor 15kg

45mgtwicedailyfor>15to23kg

60mgtwicedailyfor>23to40kg

75mgtwicedailyfor>40kg

Currentlythereisasinglepublishedobservationalstudythatreporteduseofoseltamivirin47childrenunderoneyearofageandshowednosignificantadverseeffects(Tamura2005).

OtherresearchandbasicresearchfindingsforH5N1patients

One studyhas evaluated the effect of oseltamivir on neuraminidase and viral replicationusingH5N1isolatesfromhumans.TwoadditionalstudiesusingH5N1isolatedfromducksevaluatedtheeffectofoseltamivironviralreplication(seeannex3). Consistentanimaldatafromthreestudiesinmiceindicatethathighdoseoseltamivirtreatmentincreasedsurvivalinthisanimalmodel.


32/136



14

Conclusion

OseltamivirtreatmentmaybeofnetclinicalbenefitinH5N1patients.However,therearenoclinical trials directly dealing with human H5N1 infection;based on the GRADE qualitycriteria,theevidenceisofverylowquality.Thisassessmentofpossiblenetbenefitisbasedon extrapolation from studies performed in populations with seasonal influenza andconsiderationofotherresearchdata.

Clinicalrecommendation1

Rec 01: In patients with confirmed or strongly suspected H5N1 infection, cliniciansshould administer oseltamivir treatment as soon as possible (strongrecommendation, very low quality evidence).

Remarks:Thisrecommendationplacesahighvalueonthepreventionofdeathinanillnesswithahighcasefatality.Itplacesrelativelylowvaluesonadversereactions,

thedevelopmentofresistanceandcostsoftreatment.DespitethelackofcontrolledtreatmentdataforH5N1,thisisastrongrecommendation,inpart,becausethereisalackofknowneffectivealternativepharmacological interventionsat this time.Therecommendationapplies toadults, includingpregnantwomenandchildren.Untilfurtherinformationbecomesavailable,thecurrenttreatmentregimenforH5N1isasrecommended forearly treatmentofadults,specialpatientgroups (e.g. thosewithrenalinsufficiency)andchildrenwithseasonalinfluenza.

5.2. Should H5N1 patients receive treatment with zanamivir?

Summaryoffindings

NoclinicaltrialorcasestudyhasevaluatedzanamivirinthetreatmentofH5N1patients.

Therewere4systematicreviewsandHTAs(annex3)thatexaminedtheuseofzanamivirinotherwisehealthy adults,high risk adults or children for treatmentof seasonal influenza.The doses of inhaled zanamivir in the studies were 10 mg twice and four times daily inadults and children for up to 5 days. There were 3 studies evaluatingboth inhaled andintranasalzanamivirincombination;howevertheintranasalformulationisnotavailableforclinicaluse.Thestudieswereconducted inseveralcountries in thenorthernandsouthern

hemispheres.

Thereareveryfewstudiesdescribinganimalandinvitrodataabouttheeffectsofzanamiviron the H5N1 virus. Zanamivir is active in vitro and in vivo against oseltamivirresistantH5N1virusthatcontainstheH274Ymutation(Le2005).

1 The panel voted on whether this recommendation should be strong or weak and there was oneabstention and one dissenting vote out of thirteen.


33/136



15

Benefits

Therearetoofeweventsinthereportedstudiestoprovideevidenceofabenefitofzanamivirtreatmentonmortalityordurationofhospitalization ineither seasonal influenzaofH5N1infection.Lowerrespiratorytractcomplications(pneumonia)werenotsignificantlyreduced(OR0.83,95%CI0.24to2.26)in3trials(n=2299patientswith46events)thatdescribedthisoutcome inotherwisehealthy adultswith seasonal influenza (Jefferson 2006,Monto 1999,Puhakka2003,MIST1998).

Harms

The identifiedsystematicreviewsdidnotprovide informativeevidenceonseriousadverseevents. Data submittedby the manufacturer to the US Food and Drug Administrationreported headache and nausea as the most frequent adverse events inboth children andadults. This report also included warnings regarding an increased incidence of

bronchospasm;

patients

with

airway

disease

appear

to

be

at

increased

risk

for

this

severe

adversereaction(FDAnote.JAMASept132003).SpontaneousreportingofadversereactionstotheWHOlisted253casesofadversereactions,butthereisnoassessmentofcausalityorseverityof theseevents inrelation tozanamivir.Headachewasoneof themostfrequentlyreportedbiologicallyplausibleadversereactions(n=22).Therearefourcasereportsofuseofzanamivirduringpregnancy thatreport threespontaneousabortionsandonedeathbutthere was no assessment of causality. No information on resistance of H5N1 viruses tozanamivirexists.



Zanamivirisavailablefororalinhalationonly,usingadiskhalerdevice.

Zanamivirhasbeen approvedby theUSFood andDrugAdministration for treatmentofinfluenza in individuals aged 7 years. Nodose adjustment for patientswithhepatic orrenalimpairmentisrecommended.

Therecommendedtreatmentdoseforinhaledzanamivirinseasonalinfluenzais10mgtwicedailyfor5days,inadultsandchildren 7years(CDC2006a,CDC2006b).

The ability to deliver inhaled zanamivir to sites of viral replication in the context ofpneumonia or serious lower respiratory tract disease is uncertain. It is also unknownwhether inhaled zanamivir achieves sufficient blood and tissue levels to inhibit virusreplicationoutside the respiratory tract.Thebioavailabilityof inhaledzanamivir inadultsrangesfrom4%to17%,comparedtoanaverageof2%afteringestion(GlaxoWellcome2001,FDAapproved label). Inhaledzanamivirmightbeappropriate in thosepatientsunable totakeoralmedications,includingoseltamivir.

Otherresearchandbasicresearchfindings

Two studieshave evaluated theeffectofzanamivironneuraminidase inhibitionandviralreplicationusingH5N1virusisolatefromhumans.AnadditionalstudyusingH5N1virusesisolated from ducks evaluated the effect of zanamivir on viral replication (see annex 3).


34/136



16

Consistent animal data from three studies in mice indicate that zanamivir treatmentincreased survival in this animal model. Zanamivir is active in vitro and in vivo againstoseltamivirresistantH5N1virusthatcontainstheH274Ymutation.Inhaledzanamivirmayhavelowerbioavailabilityinorgansystemsotherthantherespiratorytract(WongandYuen2006).

Conclusion

Nodirectdataareavailableon theuseofzanamivir to treatH5N1patients.While there isevidenceofnetclinicalbenefitofinhaledzanamivirinpatientswithseasonalinfluenza,thequality of evidence when considered on a continuum is lower for the use of zanamivircomparedtooseltamivir.However,basedonthefourcategoryGRADEapproach,theoverallqualityofevidenceisverylowforbothinterventions.

Clinicalrecommendations

Rec 02: In patients with confirmed or strongly suspected infection with avian influenza A(H5N1) virus, clinicians might administer zanamivir (weak recommendation,very low quality evidence).

Remarks:Thisrecommendationplacesahighvalueonthepreventionofdeathinanillness with high case fatality. It places a relatively low value on adverse effects(includingbronchospasm), the potential development of resistance and costs oftreatment.Thebioavailabilityofzanamiviroutsideoftherespiratory tractislowerthan that of oseltamivir. Zanamivir may be active against some strains ofoseltamivirresistantH5N1virus.Therecommendationappliestoadults,includingpregnantwomenandchildren.Useofzanamivir requires thatpatientsareable to

use thediskhalerdevice.Until further informationbecomesavailable, the currenttreatment regimen for (H5N1) infection is the same as recommended for earlytreatmentofadultsandchildrenwithseasonalinfluenza.

Althoughthequalityofevidencewhenconsideredonacontinuumislowerfortheuseofzanamivircomparedtooseltamivir,theoverallqualityofevidenceinthefourcategorygradingsystemisverylowforbothinterventions.

5.3 Should H5N1 patients receive treatment with amantadine?

Summaryoffindings

NocontrolledclinicaltrialhasevaluatedamantadineforthetreatmentofH5N1infection.

Therewere3systematicreviewsandHTAs(annex3)thatexaminedtheuseofamantadineinotherwisehealthyadults,highriskadultsorchildrenfortreatmentofseasonalinfluenzaA.Thedosesofamantadineinthestudieswere100mgoncedailyand100mgtwicedailyinadults forup to10days.The studieswere conducted in several countries in thenorthernhemisphere,butresourcepoorcountrieswerenotrepresented.


35/136



17

Therearecasestudydatafor10patientsinwhomamantadinewasusedforthetreatmentofH5N1infection(Beigel2005).Allfourofthepatientswhoreceivedamantadinewithin5daysof symptomonset survived, and twoof the sixpatientswhowere treatedafter5daysofillness survived. Six of the eight patients who did not receive amantadine survived. Noconclusionscanbereachedfromtheseuncontrolledclinicaldata.

Two studies reported clade 1 H5N1 viruses isolated from humans in Thailand and frombirds in Southeast Asia carrying M2 inhibitor resistance mutations. Few in vitro studieswere found thatdescribed theeffectsofamantadineonH5N1virusandnoanimalstudiesabouttheeffectsofamantadineonH5N1viruswereidentified.

Benefits

ThereisinsufficientevidenceinthereportedstudiestoevaluatethebenefitofamantadineonmortalityordurationofhospitalizationineitherseasonalinfluenzaorH5N1infection.Dataobtainedfrom3smalltrialsofindividualswithseasonalinfluenzaAsuggestnoreductionininfluenzaAviralsheddingassociatedwithamantadine treatment (RR0.96,95%CI0.72 to1.27).

Harms

There are limited data on serious adverse events described in the systematic reviewshighlighting the limitations of systematic reviews and published randomized controlledtrials in reporting adverse events. The Cochrane review of amantadine treatment andchemoprophylaxis in seasonal influenza reportsno significantdifference in thenumberofmildadverseeffects(gastrointestinalandcentralnervoussystem)betweenthetreatmentand

placebo

groups

but

it

focused

on

randomized

controlled

trials.

The

data

submitted

by

the

manufacturer to the US Food and Drug Administration reported nausea, dizziness(lightheadedness)and insomniaas themost frequentadverse events inboth childrenandadults. Observational studies and case reports have documented increased frequencies ofmoderate to severe central nervous system side effects, including hallucinosis, delirium,psychosis, alteredmentation, and coma in elderly subjects, thosewith renal insufficiency,and those receiving concurrent psychoactive medications, as well as increased seizureactivity in those patients with preexisting disorders. Spontaneous reporting to WHO ofadverse reactions listed 1863 reports of adverse reactions,but there is no assessment ofcausalityorseverityoftheseeventsinrelationtoamantadine.Themostcommonlyreported

adverse

event

was

hallucinations

(n

=

389

cases).

There

are

two

case

reports

of

use

of

amantadineduringpregnancy.Inoneofthesecasesspontaneousabortionoccurredalthoughthemotherwasalsoreceivingtwootheradditionalmedications;noassessmentofcausalitywascarriedout.

Thedevelopmentofresistanceisafrequentproblemwithamantadine.


36/136



18



Amantadineisavailableintablet100mg,capsuleandsyrupform.

The recommended treatmentdoseofamantadine in seasonal influenzaA is100mg twicedailyinadultsandchildrenbetween10and65yearsofage,for5days(CDC2006a).Intheelderlyover65andinotherpopulationsinsomejurisdictions,aoncedailydoseof100mgisrecommended.1

Inchildrenunder10(CDC2006a(table1))

19years:5mg/kg/day(nottoexceed150mgperday,in2divideddoses) 1012years:100mgtwicedaily

Inpatientswithrenalimpairment(SeeFDAapprovedlabel):

Creatinineclearance(ml/min/1.73m2) Dose 3050 200mg1stdayand100mgeachdaythereafter 1529 200mg1stdayand100mgonalternatedays 10yrs of age.


37/136



19

Conclusion

Amantadine appears not tobe of greater net clinicalbenefit as a firstline agent in thetreatment of H5N1 infection compared to the neuraminidase inhibitors where thesemedicines are available.Drug resistance is amajor limitation.However, amantadinemayhave net clinicalbenefit as a firstline agent in the treatment of H5N1 infection whenneuraminidase inhibitors are not available and the H5N1 virus is known or likely tobesusceptibletoamantadine.TherearenoclinicaltrialsdealingwithamantadinetreatmentinH5N1patients.Thisassessmentofpossiblenetbenefitundercertaincircumstancesisbasedon extrapolations from studies performed in populations with seasonal influenza A andincludes considerationof likelydevelopmentofdrug resistanceand the incidenceof toxiceffects.


Rec 03: If neuraminidase inhibitors are available, clinicians should not administeramantadine alone as a first-line treatment to patients with confirmed or stronglysuspected human infection with avian influenza H5N1 (strong recommendation,

very low quality evidence).

Remarks: Although recognizing that the illness is severe, this recommendationplacesahighvalueonthepotentialdevelopmentofresistanceandavoidingadverseeffects.Thisisastrongrecommendationinpartbecauseoftheavailabilityofotheroptionsfortreatmentthatmaybemoreeffective.

Rec 04: If neuraminidase inhibitors are not available and especially if the virus is knownor likely to be susceptible, clinicians might administer amantadine as a first-line

treatment to patients with confirmed or strongly suspected infection with avianinfluenza A (H5N1) virus (weak recommendation, very low quality evidence).

Remarks:Thisrecommendationplacesahighvalueonthepreventionofdeathinanillnesswithahighcase fatality. Itplacesa relatively lowvalueonadverseeffectsand the development of resistance in a situation without alternativepharmacologicaltreatment.Untilfurtherinformationbecomesavailable,thecurrenttreatment regimen for H5N1 infection is the same as recommended for earlytreatment of adults and childrenwith seasonal influenza.Theuse of amantadineshould be guided by knowledge about local resistance patterns, and special

consideration

of

the

benefits

and

harms

in

patients

at

higher

risk

for

adverse

outcomes(e.g.pregnantpatients).


38/136



20

5.4 Should H5N1 patients receive treatment with rimantadine?

Summaryoffindings

NoclinicaltrialorcasestudyhasevaluatedrimantadinetreatmentofH5N1infection.

Twosystematicreviews(annex3)wereidentifiedthatexaminedtheuseofrimantadineforthe treatment of seasonal influenza A in otherwise healthy adults, high risk adults orchildren.Thedosesofrimantadineinthestudieswere200mgoncedailyand150mgtwicedailyinadultsforupto10days.ThestudieswereconductedintheUSA.

Two studies reported clade 1 H5N1 viruses isolated from humans in Thailand and frombirds inSoutheastAsiacarryingM2 inhibitor resistancemutations.Thereare few invitrostudiesabouttheeffectsofrimantadineonH5N1virusandnoanimalstudiesdescribingthe

effects of rimantadine on H5N1 virus. Animal and in vitro studies have shown thedevelopmentofcrossresistance to theM2 inhibitors inhuman influenzaAvirusgrown inthepresenceofthesecompounds(Abed2005,Hay1996,Hayden1996).

Benefits

There isinsufficientevidence inthereportedstudiestoevaluatethebenefitofrimantadineon mortality or duration of hospitalization in either seasonal influenza A or H5N1infection. Datafrom3smalltrialsofindividualswithseasonalinfluenzaAsuggestthereisnoevidenceofastatisticallysignificantreduction in influenzaAviralsheddingassociatedwithrimantadinetreatment(RR0.67,95%CI0.22to2.07).

Harms

Similarly to thedescriptionofadverse eventswith amantidineuse, there arevery limiteddataonseriousadverseeventsdescribedinthesystematicreviews.TheCochranereviewofrimantadineuse in influenzaA showsno significantdifference in thenumber of adverseeffects (gastrointestinaland centralnervous system)occurring in the treatmentorplacebogroupsbut thedatafromrandomized trialsare limited.Inaddition, thereviewshowednosignificantdifferenceinthenumberofadverseeffectswhenrimantadinewascomparedwithamantadine. The data submitted by the manufacturer to the US Food and DrugAdministration reported nausea, vomiting, dizziness and insomnia as the most frequentadverseevents.SpontaneousreportingtoWHOofadversereactionsincludes182reportsofadverse reactions,but there is no assessment of causality or severity of these events inrelationtorimantadine.Themostcommonlyreportedadverseeventwasconvulsions(n=21),withafurther17reportedwithgrandmalconvulsions.However,observationalstudieshaveshown that the incidence of adverse central nervous system effects was significantly lesswith rimantadine than with amantadine (Dolin 1982). No case reports on the use ofrimantadineduringpregnancyexist.


39/136



21



Rimantadineisavailableintabletandsyrupform.

TherecommendedtreatmentdoseofrimantadineinseasonalinfluenzaAis100mgtwiceadayforadultsandchildrenover12yearsofage(CDC2006a,CDC2006b).Inpatientswithsevere hepatic dysfunction, renal failure (creatinine clearance of 10 ml/min) and elderlynursing home patients, a dose reduction to 100 mg daily is recommended. There arecurrently no data available regarding the safety of rimantadine in patients with renal orhepaticimpairment(seeFDAapprovedlabel)

Otherresearchandbasicresearchfindings

OnestudyevaluatedtheeffectofrimantadineonviralreplicationusingH5N1isolatesfrom

humans,anddemonstratednoeffect.OneadditionalstudyusingmultiplestrainsofH5N1virusalso evaluated the effectof rimantadineonviral replication.Highlevel resistance isreadily selectedby growth ofhuman influenzaA virus in thepresence of amantadine invitroandinvivoandconferscrossresistancetootherM2inhibitors.NodatawereavailablefromanimalstudiesofH5N1virusandrimantadine.

Conclusion

Although therearenocomparativeclinical trials, rimantadineappearsnot tobeofgreaternet clinical benefit as a firstline agent in the treatment of H5N1 infection than theneuraminidaseinhibitors,whenthesedrugsareavailable.However,rimantadinemaybeof

net clinical benefit as a firstline agent in the treatment of H5N1 infection whenneuraminidaseinhibitorsarenotavailableandthe virus is known or likely to be susceptible.In this situation theuseof rimantadinemaybepreferable toamantadine,given themorefavourable sideeffect profile (Dolin 1982). There are no clinical trials dealing withrimantadinetreatmentinH5N1patients.Thisassessmentofpossiblenetbenefitisbasedonextrapolations from studies performed in populations with seasonal influenza A andincludes considerationof likelydevelopmentofdrug resistanceand the incidenceof toxiceffects.


Rec 05: If neuraminidase inhibitors are available, clinicians should not administerrimantadine alone as a first-line treatment to patients with confirmed orstrongly suspected infection with avian influenza A (H5N1) virus (strongrecommendation, very low quality evidence).

Remarks: Although recognizing that the illness is severe, this recommendationplacesahighvalueonthepotentialdevelopmentofresistanceandavoidingadverseeffects.Thisisastrongrecommendationinpartbecauseoftheavailabilityofotheroptionsfortreatmentthatmaybemoreeffective.


40/136



22

Rec 06: If neuraminidase inhibitors are not available and especially if the virus is knownor likely to be susceptible, clinicians might administer rimantadine as a first-linetreatment to patients with confirmed or strongly suspected infection with avianinfluenza A (H5N1) virus (weak recommendation, very low quality evidence).


illnesswithahigh case fatality. Itplacesa relatively lowvalueonadverseeffectsand the development of resistance. The use of rimantadine shouldbe guidedbyknowledgeaboutlocalantiviralresistancepatterns,andspecialconsiderationofthebenefits,harms,burdensand cost inpatientsathigher risk foradverseoutcomes.Rimantadinehasgenerallyamorefavorablesideeffectprofilethanamantadine.

5.5 Should H5N1 patients receive combination treatment of M2inhibitors and neuraminidase inhibitors?

Summaryoffindings

No clinical trial or case study has evaluated the combination of M2 inhibitors andneuraminidaseinhibitorsinthetreatmentofH5N1infection.

No systematic reviewhas examined the combinationofM2 inhibitors andneuraminidaseinhibitors in the treatmentofH5N1 infection.Thereview identifiedonesmallrandomizedcontrolledtrialthatcomparednebulizedzanamivir(16mgfourtimesdaily)andrimantadine(100mgonceortwicedailyadministeredtohospitalizedpatientswithseasonalinfluenzaAonly)torimantadineandplacebointheUSA.Thestudywasterminatedafterenrollmentof41patientsandapproximately40percentofpatientswere lost to followup (9of20 in the

combined

treatment

group

and

7

of

21

in

the

rimantadine

group)

(Ison

2003,

Madren

1995,

Leneva2000,Govorkova2004).Nebulizedzanamivirisnotcurrentlyavailable.

Few animal and in vitro studies describe the effects of combination treatment of H5N1infection. Oral administration of oseltamivir, in combination with rimantadine in miceinfectedwithavian influenzaA (H9N2)virus reduced thenumberofdeaths. Invitroandanimal model studies with human influenza A (H1N1 and H3N2) viruses suggest thatcombiningneuraminidaseinhibitorsandrimantadineexertsanadditiveorsynergisticantiinfluenzaeffectforvirusesthataresuscepti

who rapid ai treatment

Documents