TreatmentandPreven,onofShingles
LesiaK.Dropulic,M.D.JeffreyI.Cohen,M.D.
TheGoalsofAn,viralTherapy
• Decreaseseverityanddura<onofpaincausedbyacuteneuri<s• Promotemorerapidhealingofskinlesions• Preventnewlesionforma<on• Decreaseviralsheddingtoreduceriskoftransmission
FDA-approvedAn,viralMedica,onsforHerpesZoster
An,viral Bioavailability DosingFrequency
CommonSideEffects
Acyclovir(Zovirax)
Poor High(800mgorally5<mesdailyfor7-10days)
Malaise
Valacyclovir(Valtrex)
Wellabsorbed,pro-drugofacyclovir
Low(1gorally3<mesdailyfor7days)
Nausea,headache
Famciclovir(Famvir)
Wellabsorbed,pro-drugofpenciclovir
Low(500mgorally3<mesdailyfor7days)
Nausea,headache
EvidenceforEfficacyofAn,viralsBasedonControlledTrials
• Hastenresolu<onoflesions• Reduceforma<onofnewlesions• Reduceviralshedding• Decreaseseverityofacutepain• Noevidenceforreduc<onofpostherpe<cneuralgia
Pa,entsMostLikelytoBenefitfromAn,viralTherapyforHerpesZoster
• Persons50yearsofageorolder• Pa<entswithmoderatetoseverepainatonsetofshingles
• Pa<entswithsevererashwithlargenumbersoflesions
• Pa<entswhosefaceoreyesareinvolvedorwhohaveothercomplica<ons
• Immunocompromisedpa<ents
An,viralTherapyforHerpesZosterinImmunocompromisedPa,ents
An,viral Dose Sideeffects
Acyclovir 10mg/kgintravenouslyevery8hoursfor7-10days
Renalinsufficiency
FoscarnetforacyclovirresistantVZV(notFDAapproved)
40mg/kgintravenouslyevery8hoursun<llesionshealed
Renalinsufficiency,electrolyteabnormali<es,nausea,vomi<ng,diarrhea,anemia,granulocytopenia,headache
Medica,onsUsedtoTreatAcutePainAssociatedwithHerpesZoster
Medica,on Examples
Non-opioidanalgesics AcetominophenNaproxen,ibuprofen(NSAIDS)
Opioidanalgesics Codeine,tramadoloxycodone
An<convulsants Gabapen<norpregabalin
An<depressants Nortryp<line,desipramine
Cor<costeroids Prednisone
Topicaltherapy Lidocainepatch(5%)
UseofGlucocor,coidswithAn,viralTherapyforHerpesZoster
• Somerandomized-controlledtrialshaveshownareduc<oninacutepain,acceleratedhealing,improvedperformanceofac<vi<esofdailyliving
• Studieshavenotshownareducedincidenceofpostherpe<cneuralgia
• UsedforthetreatmentofCNScomplica<onssuchasvasculopathyorBell’spalsy
• Avoidinpa<entswhocanexperiencecomplica<onsfromsteroids
TreatmentofPostherpe,cNeuralgiaTreatmentStrategy Medica,on Cau,onor
Contraindica,on
Tricyclican<-depressants
Nortryp<line,desipramine
Heartdisease,epilepsy,glaucoma;theelderly
An<convulsants Gabapen<n,pregabalin
Renalinsufficiency
Opioids Oxycodone Poten<alforabuseandaddic<on
Topical LidocaineCapsaicin
ApplytointactskinBurningsensa<on
VaccinesforVaricellaandHerpesZoster
• Varicellavaccine,Varivax,approvedbyFDAin1995forpreven<onofchickenpoxinpersons≥12months
• Zostervaccine,Zostavax,approvedbyFDAin2006topreventshinglesinpersons≥60
• VaricellavaccinedevelopedinJapanasalivevirusahenuatedincellculture(Okavaccine)
• Zostervaccineistheiden<calvirus,but~14-foldhigher<terthanvaricellavaccine
• In2008,CDCrecommendedrou<nevaccina<onamongpeopleaged≥60
ShinglesPreven,onStudy
• Arandomized,double-blind,placebo-controlledclinicaltrialof38,546adults60yearsofageorolder
• Hypothesis:theliveahenuatedOka/Merckvaricella-zostervirusvaccinewoulddecreasetheincidenceandseverityofherpeszosterand/orpostherpe<cneuralgia
ShinglesPreven,onStudyEligibilityCriteria
Inclusioncriteria:• >60yearold(meanwas69yr,range59-99)• Historyofvaricellaorlived>30yearsinUSExclusioncriteria:• Historyofzoster• Immunocompromised• <5yearlifeexpectancy
OxmanetalJID2008
PrimaryEndpointofZosterVaccineTrial:BurdenofIllnessScore
BOI=Areaunderthecurve
BOI=acompositeoftheincidence,severity,anddura<onofpaincausedbyHZ
SecondaryEndpoint:Postherpe,cNeuralgia
• Postherpe<cneuralgiadefinedaspainordiscomfortwithapainscore≥3/10persis<ngorappearingmorethan90daysaperonsetofherpeszosterrash
ShinglesPreven,onStudyResults
• Comparedtoplacebothezostervaccinereduced1)theburdenofillnessby61.1%(p<0.001)2)theincidenceofpostherpe<cneuralgiaby66.5%(p<001)3)theincidenceofherpeszosterby51.3%(p<0.001)• Vaccinewaswelltolerated,mildinjec<onsitereac<ons
OxmanetalJID2008
VaccineReducesBurdenofIllnessScore,butLessEffec,veinElderly
VaccineEfficacy
forZosterDeclinesinElderly
VaccineEfficacyforPostherpe,c
NeuralgiaUnchangedwith
Age Oxman et al JID 2008
PaininPersonswithZosterinVaccineandPlaceboRecipients
• Mediandura<onofpaininpersonswhodevelopedzosterwasshorterinvaccine(21days)thanplacebogroup(24days),p=0.03
• Degreeofpainwaslessinvaccinerecipientsthanplacebogroup(p=0.008)
OxmanMetal.NEnglJMed2005;352:2271-2284.
Kaplan–MeierEs,matesoftheEffectofZosterVaccineontheCumula,veIncidenceofPostherpe,cNeuralgia(PanelA)andHerpesZoster(PanelB)intheModifiedInten,on-to-Treat
Popula,on.
ZosterVaccine:Indica,ons&Contraindica,ons
Indica,ons• Allpersons>60yearsoldContraindica,onsinpersonswith• Hematologicmalignancies-canbegivenifinremissionandno
chemotherapyorradia<onfor>3months• AIDS,orHIVandCD4<200or<15%• Cellularimmunodeficiency(BMT,Tcelldeficiency)• Highdoseimmunosuppressivetherapy(e.g.>20mgof
prednisonedailyfor>2weeks),oran<-tumornecrosisfactortherapy;wait1monthaperstoppingtherapytovaccinate
• Allergytovaccinecomponents(neomycinorgela<n)
ShinglesPreven,onStudy:Summary
Zostervaccinemaintainsitsefficacyregardlessoftheageofthesubject:
– Theeffectin“younger”subjectsismediatedmostlybypreven<ngzoster
– Theeffectin“older”subjectsismediatedmostlybyahenua<ngzoster,includingPHN
WeinbergetalJID2009
ComparisonoftheVaricella-ZosterVirus-SpecificImmuneResponsestoHerpesZosterandtotheZosterVaccine
Randomized-controlledTrialforHerpesZosterVaccineinPersonsAged50-59Years• ZEST=ZostavaxEfficacyandSafetyTrial-evalua<onofsafetyandefficacyofvaccinein22,439subjectsaged50to59years
• Randomizedtoreceiveasingledoseofvaccineorplacebo
• Monitoredfortheoccurrenceofshinglesforamedianof1.3yearspost-vaccina<on
• Vaccineefficacyof69.8%• ApprovedbytheFDAbutnotrecommendedbyACIP
SchmaderKEClinInfectDis2012
Long-termPersistenceofZosterVaccineEfficacy
• AssessedvaccineefficacyinShinglesPreven<onStudyvaccinerecipients(6,867)upto11yearspostvaccina<on
• ComparedtoSPS,foryears7to11postvaccina<on,es,matedvaccineefficacydecreasedfrom– 61.1%(yr4)to37.3%(yr11)forHZburdenofillness
– 66.5%(yr4)to35.4%(yr11)forincidenceofpostherpe<cneuralgia
– 51.3%(yr4)to21.1%(yr11)forincidenceofherpeszoster
• Sta<s<callysignificantvaccineefficacyforBOIpersistedintoyear10,whereasefficacyforincidenceofzosterpersistedun<lyear8
MorrisonVAetalCID2015
BoosterDoseofShinglesVaccineAdministeredtoOlderAdults≥10YearsAiertheFirstDose
• Seconddoseofzostervaccineadministeredto200par<cipants≥70yearsoldandcomparedtoTcellimmuneresponsesinpar<cipantsvaccinatedforthefirst<me
• Forsubjects≥70yearsold,VZV-specificTcellimmunity(IFN-γandIL-2ELISPOTS)wassignificantlyhigheratbaselineandapervaccina<onintheboosterdosegroup
• Theboosterdoseimprovedcellularimmunity,buttheeffectontheincidenceofzosterwasnotevaluated.
LevinMJetal.JID2016
AdjuvantedHerpesZosterSubunitVaccineinOlderAdults≥50
• PhaseIII,randomized,placebocontrolledstudyofavaccinecontainingVZVgpEandAS01Badjuvantsystem(HZ/su)
• TwoIMdosesofvaccineorplacebo2monthsapart;meanfollow-up3.2years
• Overallvaccineefficacyagainstherpeszoster97.2%
• Vaccineefficacyinadults≥70yearsofagewassimilarto50to59and60to69agegroup
LalHetal.NEJM2015
LalHetal.NEnglJMed2015;372:2087-2096.
VaccineEfficacyagainsttheFirstorOnlyEpisodeofHerpesZosterInfec,on.
Summary:TreatmentandPreven,onofHerpesZoster
• An<viralagentsreducethedura<onoflesionsandseverityofdisease,butnottheincidenceofpostherpe<cneuralgia
• Improvedtreatmentsareneededforpostherpe<cneuralgia
• Herpeszostervaccineiseffec<ve,butuptakehasbeensubop<mal
• Newsubunitvaccinemayhaveimprovedefficacycomparedwithcurrentliveahenuatedvaccineandmaybeusedinimmunocompromisedpersons
• Theefficacyand<mingofboosterdosesofthezostervaccineneedstobedetermined
ZosterVaccine:UnansweredQues<ons
• Isthevaccineappropriateinpersons≥80yearsold?Efficacyforzoster18%,forPHN39%
• Howlongwillthevaccinebeeffec<ve(boosterdoses)?Afollow-upstudyshowedthatthereduc<oninriskforHZremainedsignificantatleastfor8yearsapervaccina<on
• Canthevaccinebeusedsafelyinimmunocompromisedpersons?Studiesongoing;preferabletogiveit2-4weeksbeforestar<ngimmunosuppressivetherapy
• Willzosterbesignificantlyreducedwhenvaricellavaccinereplaceswild-typevaricella?Vaccinestrainofzosterreac<vateslessfrequentlythanwild-type