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