Download Human Papillomavirus (HPV)

HumanPapillomavirus(HPV)
By:TriBui
Etiologicagent
TheetiologicalagentisHumanpapillomavirus,whichisasmall,double-strandedcircularDNA
virusthatinfectstheepithelium[1][2].ItcomesfromthegenusPEapillomaviruswhichcause
papillomasorbenigntumorsorwartsthatarisefromtheskin,mucousmembranes,or
glandularducts[2][3].Morethan120typesofHPVareknowntoinfecthumansandanimals
anddependingonthestrandthatsequencestheoutercapsidproteinL1;somemaybe
carcinogenic,40ofwhichusuallyinfectthemucosalepithelium[1][2].Thisisespeciallythecase
inwomen’shealth,i.e.cervicalcancer.
Transmission
HPVtransmissionincludesbutisnotlimitedtovaginal,anal,ororalsexwithsomeonewhohas
thevirus.Thesearethecommonwaysthatthevirusisspreadthroughsexualcontact[4].Any
skintoskincontactmayspreadHPV,butsomeresearchin2014atBrighamYoungUniversity
sayitispossibletotransmitHPVthroughindirectmeanssuchasamedicalinstrumentthatmay
beconsideredsterile[5].Anothermayincludemothertoinfantatthetimeofbirth,although
thisisofrareoccurrence[1].Regardlessoftransmission,symptomsmaynotalwaysshowto
alertpeoplethattheyorsomeonetheyknowhavethevirus.Thiscanleadtoeasier
transmissionforthosewhoarenotawareofhavingthevirus.
Reservoirs
TheonlynaturalreservoirforHPVishumans.Othermeansarethroughsyntheticmeasures[1].
Theskinisitsnaturalreservoironhumanssincetheyinfectepithelialcells,whichcanpromote
warts.ThemucosaisalsoaprevalentareaforHPV,especiallyinthecasesoforalandvaginal
mucosa.OralHPVinfectionsometimesiseasilyseenbythegrowthofwartsandiscommon,
butinfectionofthevaginalmucosacanleadtocervicalcancer.Thoughhumansarethemain
reservoirforHPVparticles,studiesshowthatitispossibleforthoseparticlestoliveon
inorganicobjectsand,downtheline,transmitthevirus.Butlikeothermicroorganismsthat
requirehosts,theygenerallydonotsurviveoutsidethehumanbody[5].
GeneralcharacteristicsofHPV
HPVisavirusthataffectstheepitheliallayerofspecificallyhumans(henceHuman
Papillomavirus),mostcommonlyassociatedwithsexuallytransmitteddiseaseorinfection
(STD/STI).AcureforHPVdoesnotyetexist.TreatmentisforthesymptomsofHPV[6].
Inabroadereffect,thevirusproduceswartsontheskin,wherevertheinfectedarea[2].This
includesnonsexualcontact,butmostcasesoftransmissionareduetosexualcontact.TheHPV
spreadthroughnonsexualcontactaregenerallydifferentstrainsofHPVandarenotthe
commonHPVstrainsassociatedwithsex[6].HPVspreadthroughsexualcontactinfectsgenital
areassuchasthevagina,thevulvaincludinglabia,penis,rectum,andanus.
Symptomaticresponsesaregenitalwarts.Thesewartsrangefrom“cauliflower-likegrowths”
thatareeasilyseento“hardandrough”or“softandfleshy”;theyaregenerallypainlessbut
mayeasilybleedoritch.Wartsaregenerallysmall,beinglessthanaquarterinch,butcangrow
intolargewarts,beingmorethananinch[6].
Keytestsfordiagnosisandidentification
Doctorsperformvisualexamination,sometimesbymagnifyingglass.Thisisforbothsexes[6].
Papsmearshelpwomendeterminepre-cancerouschangescausedbyHPV.Somenewtestsfor
HPVitselfmayhelpdeterminehowtotreatwomenwithPapsmearanomalies[1][2][6].But,
thesetestsarenotrecommendedforhealthyindividuals,forone,duetosilentHPVinfection
thatnevercausehealthproblems,and,fortwo,falsenegativeresults[6].Thesesecondtests
areusuallyforthosewhohaveshownabnormalitiesintheirpapsmears,whichmayindicate
highriskHPVtypesandcancer[1].
Inalaboratory,HPVDNAidentifiedwilldetermineifaninfectionisduetoHPV.Assayshave
differentsensitivitiestospecificityofHPVDNA.TheFDAhasapprovedmanytestsforhigh-risk
HPVtypeinordertodeterminecervicalcancer.However,thesetestsarenotapprovedformen
[1].
Polymerasechainreaction(PCR)assayshelpgeneratetype-specificresults.Epidemiologic
studiestargettheL1proteingene.Themostusedassaysarevirus-likeparticle(VLP)-based
enzymeimmunoassays.However,thesetestsarenotstandardizedforconsistentpositive
results[1].
Signsandsymptomsofthedisease:
HPVinfectionsareoftenasymptomaticwithnodisease.Thisisthecaseofmanyofthe100
kindsofHPV,whichcausenohealthproblems.Signsandsymptomswhensymptomsare
present“includeanogenitalwarts,recurrentrespiratorypapillomatosis,cervicalcancer
precursors(cervicalintraepithelialneoplasia),andcancers,includingcervical,anal,vaginal,
vulvar,penile,andoropharyngealcancer”[1].Mostlow-riskinfectionswillonlyhavewartsand
symptomsmostlikelygoawayontheirown.Usuallywartsappearwithinafewweeksupto3
monthsaftercatchingHPV[6].Everyonedevelopsdifferentsignsandsymptomsandso
appearanceofwartsdoesn’tnecessarilymeantheywererecentlyinfected.Thesewartscan
lookdifferentlikecauliflower,besmooth,orberough.Theyalsorangefromaquarterinchin
sizetoaninchormore[6].
Historicalinformation
Duringthe1800sandbefore,cervicalcancerwasthoughttobecausedbyasexually
transmitteddisease[7].However,ItalianphysicianRigoni-Sternin1842,sawarelationof
cervicalcancerinmarriedwomen,widows,andprostitutes,andrareinvirginsornuns.Andso
studiesbegan.Bytheendofthe1960s,thefirstnotionthatthecauseofcervicalcancerwas
attributedtoHerpessimplexvirus(HSV),butitwasdiscoverednottobethecase.Once
electronmicroscopyarose,theHPVgenomewasdelvedintomoredeeply.
Inthe1980s,agroupoftheGermanCancerResearchCenterfoundtypesofHPVincervical
tumors[7].ZurHausenwasoneofthescientistswhohadthistheory[8].Otherscientists,
supportedbytheNationalCancerInstitute(NCI)begantoexplorehowHPVcausedcancer,now
theyhadgreatsupportthatitcouldcausecancer[7].HPV16and18wereisolatedandfurther
epidemiologicalstudiesconfirmedit.Othercancerssubsequentlysuchasanogenitaland
oropharyngealcancerswereattributedtoHPVafterfurtherresearch.In2008,Dr.ZurHausen
wasawardedtheNobelPrizeforthediscoveryofinfectionetiologyofcervicalcancer[8].
Intheearly1990sDr.LowyandDr.SchilleralongwithalaboratorysupportedbyNCI,
discoveredtheproteinsthatshellHPVcouldformacloseresemblanceoftheoriginalvirusto
promotetheprotectiveantibodies,butaresafeduetothelackofviralgenes.TheseVLPs
helpedcreateGardasilandCervarix,FDAapprovedin2006and2009[7].
Virulencefactors
HPVvirionsinfectthroughmicro-abrasions.Theyhavereceptorslikethealphaintegrinsand
laminins,whichhelpvirionsenterbasalepithelialcellsbyclathrin-mediatedendocytosisand/or
caveolin-mediatedendocytosis.Additionally,viraloncogenes,E6andE7helpmodifythecell
cycle.Thiskeepsthehostinastatethatfavorsamplificationofviralgenomereplication,
importanttolatentgeneexpression[9].
TheE6oncogeneassociatedproteinhasubiquitinligaseactivity,leadingtop53proteosomal
degradation.E7actasprimarytransformingproteinsandcompeteforretinoblastomaprotein
(pRb)bindingsites.ThisfreesupthetranscriptionfactorE2Fto“trans-activateitstargets,”
helpingpushthecellcycleforward[9].
ThemostcommonmanifestationofgenitalHPVinfectioniscervicalintraepithelialneoplasia,or
CIN.LowgradeCINinfectionmaydevelop,butoftenresolvesitself[1].HighergradeCIN(CIN2
or3)presentsahigherriskofprogressionofcancerandareconsideredprecursors.Sometimes
theycanalsoregress,butifleftuntreated,cervicalcancercandevelop[1].
Control/Treatment
HPVinfectioncurrentlyhasnosolutionfortreatment.Mostrecoursesareonlymanagementof
symptomsthatpresentitselfsuchasthegenitalwarts.Somehaveimmunesystemsthatcan
fightoffthevirusontheirown,topreventfurtherinfectionoftheepitheliallayer.Signsmay
notpresentitselfformanyyears,sothepresenceofsymptomsmaynotindicaterecent
exposuretoHPV.
Forgenitalwartscanbetreatedwithtopicalcreams,immuneresponsemodifiers(imiquimod
andinterferonalfa).Fornon-genitalwarts,anti-proliferativedrugs(podofilox,podophyllin,and
otherchemo-destructiveorkerotolyticagents)canbeused[10]
Therearealsosurgicaloptions,generallyforlargerinfectedareasandcases.Cryosurgery,
electrosurgery,andsimplesurgicalexcisionareoptions.OftenforhighriskHPV,othersurgeries
include,carbondioxidelaserablation,cavitronultrasonicsurgicalaspiration(CUSA)orMohs
surgery,inwhichthinlayersofthecancercontainingskinareprogressivelyremoveduntilonly
cancer-freetissueremains[10][11].
Prevention/Vaccineinfo,newtrials
AbstinenceisthemosteffectivewaytopreventcontractionofHPV.Butformanypeoplethat
aresexuallyactive,condomsmayreducetheriskofcontractingHPV.Riskfactorsthatincrease
thechanceofobtainingthediseasealsoincludeunsafesexpractices,whichcanbelinkedto
multiplesexualpartners,presenceofotherSTDs,poorhygiene,nutrition,andotherconditions
thatmightsuppresstheimmunesystem.
Pre-vaccinationassessmentssuchasPaptestsorscreeningforHPVcanhelppreventHPVfrom
infectingsomeone.IdeallyvaccinesforHPVshouldbeadministeredbeforebeingexposed.
Thosewhohavebeenexposedarerecommendedtogetthevaccinationandwillgainsome
benefitsofthevaccine[1].
ThreeHPVvaccinesareavailableintheUS.Thesearenon-infectionssubunitvaccines.The
antigenistheL1majorcapsidprotein,whichhelpsmimicthestructureoftheHPVvirus,
promotingantibodiestobecreatedandreleasedtocounterit.However,itdoesnotcontain
viralgenessothereisnochanceforinfectionofHPV[1].
QuadrivalentHPVvaccinewasapprovedinJune2006andisknownasGardasil.Thisis
recommendedforpeoplefromage9through26orthosewhohavenothadHPVvirusorany
othervaccine.Thisisadministeredin3doses.Thishasabouta99%efficacy[1].
Merckisanotheroneapprovedin2014,a9valentvaccine,similartoGardasil[1].
BivalentHPVvaccineknownasCervarix,wasapprovedinOctober2009.Thisisavaccine
gearedtowardsfemalesage9through25.Thisisalsoadministeredina3doseseries.Thisis
notrecommendedformales.Thishasaboutan88%efficacy[1].
Localcasesoroutbreaks(withincidencefigures)
HPVisthemostcommonSTIintheUS.
Approximately79millionpeoplebetween15and59yearsofagehaveHPVintheUS[12].
14millionnewcasesarediagnosedeachyear[12].
Roughly340,000to360,000womenandmenwereaffectedbygenitalwartscausedbyHPV,
beforevaccineswereintroduced[13].
About1in100sexuallyactiveadultshavegenitalwartsatanygiventime[13].
Morethan11,000womengetcervicalcancereachyear[13].
Globalcasesoroutbreaks(withincidencefigures)
In2008,therewerejustover500,000newcasesandabout275,000deathsduetocervical
cancer[14].About70%ofcervicalcancercasesaredirectlyassociatedwithHPV,butvirtually
99%havealinktoHPV[14].
Morethan85%ofcervicalcancerdeathsareindevelopingcountries,whereitaccountsfor13%
ofallfemalecancers[14].
REFERENCES
[1]CenterforDiseaseControlandPrevention,Dr.LauriMarkowitzandElizabethUnger;Human
Papillomavirus;updated2014orlater;
http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hpv.pdf;accessedon05/09/2016.
[2]TheFreeDictionarybyFarlex;Papillomavirus;updated2012;http://medicaldictionary.thefreedictionary.com/papillomavirus;accessedon05/09/2016.
[3]MerckSource,Dorland’sMedicalDictionaryforHealthcareConsumers;Papilloma;updated
2007;
http://web.archive.org/web/20100914065344/http://www.mercksource.com/pp/us/cns/cns_h
l_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/six/000077986.htm;accessed
on05/09/2016.
[4]TheFoodDrugAdministration;HPV(humanpapillomavirus);updated09/28/2015;
http://www.fda.gov/ForConsumers/ByAudience/ForWomen/ucm118530.htm;accessedon
05/09/2016.
[5]UPI:JournalofAntimicrobialChemotherapy;HPVcanbetransmittednon-sexually;updated
Feb12,2014;http://www.upi.com/Health_News/2014/02/12/HPV-can-be-transmitted-nonsexually/11001392256174/;accessedon05/09/2016.
[6]ThePrideCenteratEqualityPark;HumanPapillomaVirus(HPV);noupdated
date;http://www.pridecenterflorida.org/resources/safer-sex/human-papilloma-virushpv/;
accessedon05/09/2016.
[7]NationalCancerInstitute;PreventingCervicalCancer:TheDevelopmentofHPVVaccines;
updatedApril3,2014;http://www.cancer.gov/research/progress/discovery/hpv-vaccines;
accessedon05/09/2016.
[8]InternationalJournalofCancerResearchandDiagnosis:EminaMalisic;Human
papillomavirus:fromdiscoverytovaccine;updatedNovember28,2013;
http://nucleionline.org/human-papillomaviruses-from-discovery-to-vaccine/;accessedon
05/09/2016.
[9]SharingInHealth.CA;HumanPapillomaVirus;updatedatleastafter2010;
http://www.sharinginhealth.ca/pathogens/viruses/hpv.html;accessedon05/09/2016.
[10]PeterAGearhart,MD;ChiefEditor;PranatharthiHaranChandrasekar,MBBS,MD;Human
Papillomavirus;updatedJan08,2016;http://emedicine.medscape.com/article/219110overview;accessedon05/09/2016.
[11]MayoClinic,MayoClinicStaff;MohsSurgery;copyright2016;
http://www.mayoclinic.org/tests-procedures/mohs-surgery/basics/definition/prc-20014261;
accessedon05/09/2016.
[12]CDC:JudyNg,PhD1,2;FayeYe,MS1;LindseyRoth,MPP1;KatherineSobel1;SepheenByron,
MHS1;MaryBarton,MD1;MeganLindley,MPH3;ShannonStokley,MPH3;Human
Papillomavirus,VaccinationCoverageAmongFemaleAdolescentsinManagedCarePlans–
UnitedStates,2013;updatedOctober30,2015;
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6442a1.htm?s_cid=mm6442a1_w;
accessedon05/09/2016.
[13]CDC;GenitalHPVInfection–FactSheet;updatedApril25,2016;
http://www.cdc.gov/std/hpv/stdfact-hpv.htm;accessedon05/09/2016.
[14]TheWorldHealthOrganization(WHO);Humanpapillomavirus(HPV);updatedSeptember
3,2016http://www.who.int/immunization/topics/hpv/en/;accessedon05/09/2016.