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HPVTesting

LouiseFarrell
PerthWesternAustralia

Aimforthispresentation

KnowledgeofwhatisHPVtesting
CurrentuseofHPVtestinginAustraliansetting
Use&limitationsofHPVtesting
CurrentuseofHPVtestinginothercountries
PossibleroleforHPVtestinginfuture

HPVtypes
Therearemorethan40typesofHPVthataffect
thefemalegenitaltract
Ofthese15havebeenidentifiedincervical
cancers 16,18,45,31,33,52,58,35,59,56,51,
39,68,73,82
Theseviruseshavebeencalledhighriskor
oncogenic
Oftheoncogenicstrains,2strainsareparticularly
important 16&18astheyaccountfor>70%of
allcancers

Schematicrepresentationof
HPVgenome

Adapted from Mnger et al, 2004

HPVinfection
Isalsoassociatedwithcancersinothersites
Anus
90%
Penis
40%
Vulvar
40%
Oropharynx
12%
3%
Mouth

Parkin,DM.IntJCancer2006;118:30303044

HPVinfection
Upto80%ofpopulationhaveoneorother
strainatsomepointintheirlife13
ThehighestprevalenceofHPVcarriageoccurs
inyoungwomen
Usuallycarriageistransient
Itispersistenceofthiscommonvirusthat
causescervicalprecancersandcancersto
develop
1.Baseman&Koutsky,JClinVirology2005;32S:S1624; 2.Brownetal,J
InfectDis2005;191:18292;3.Hoetal,NEJM1998;338(7):4238.

HPVAgePrevalence
35
30
25
20
HPV Prevalence %

15
10

Adapted from Burk RD


et al. J Infect Dis 1996;
23(4) 333-341

5
0
<25

25-29

30-34

35-39

40-44

45-50

Most of those infected will clear the virus within 2 years


Average time to clearance:
6 months non-oncogenic
8 months oncogenic

In a small number HPV persists- 3-10%

RelationshipofAgetoHPVPrevalenceandIncidenceofCervicalCancer
25

20

18

20

16
14

15

12
10

10

HPV

CvCx Cases/100,000

HPV Prevalence (%)

Cervical Cancer

4
2

0
15-19

20-24

25-29 30-34

35-39 40-44 45-49 50-54

55-59 60-64

>65

Age (years)
Sources: NCI SEER Data, 1990-94;

Melkert et al., 1993. Int J Canc 53:919.

TheCornerstoneofpreventingcervical
cancerbydetectingprecursors

Technique described by George Papanicolaou 1930s

Cervical screening - less effective in reducing


adenocarcinoma than squamous cell carcinoma rates in
Australia
Incidenceofcervicalcancer,bytype,womenaged2069years

12

Squamous
Adenocarcinoma
Adenosquamous
Other

10
8
6
4
2

20
05

20
04

20
03

20
02

20
01

20
00

19
99

19
98

19
97

19
96

19
95

19
94

19
93

19
92

0
19
91

Incidence per 100,000 women

14

Note:Ratesareexpressedper100,000women,agestandardisedto Australian2001population
Source:CervicalScreeninginAustralia20062007.AIHW,Canberra

Currentcervicalscreeningstrategy
AUSTRALIA
Normal
Ifwomanis30+yrs,
&nonegcytolin
prev23yrs,option
ofimmediatecolpor
repeatsmearin6mo

Conventional
Cytology
LSILor
?LSIL
Repeatcytology12
months
Normal
Repeat12
months

HSIL
?HSIL
Abnormal

Normalor
LSIL

Colposcopy
&Biopsy

HSIL

Normal
Returnin2years
forrepeatPap
smear.Continue
untilage70

Treatment

Surrogatemarkersoncytology

HPVTesting
Viruscantbeculturedinvivo.
Noserologicalorproteintestavailablein
routinepracticeeventhoughserologywas
usedforVaccinetrials(howeverpoor
sensitivity&reliability)
Currentlyuseddetectionassaysrelyon
detectionofviralnucleicacids(DNA,RNA)
Principle:hybridisationwithcomplementarysequences

Principlesmostcommonlyused
(hr)HPVDNAdetectionassays
Hybridisationfollowedbysignalamplification
Hybrid capture2:RNAprobecocktail(HC2;Qiagen)
Invadertechnology:ThirdwaveinvaderHPVtest(Cervista)

Insituhybridisation(ISH)
UsedforyearsforresearchintoHPV.(VentanaInformthe

onlycommerciallyavailable&recommendedforhistological
materialonly)

BroadspectrumPCR
DNAamplificationwithconsensusprimersormultiplex
format(SomelabshaveinhousePCRs;Abbott Realtime
HPVtest,AmplicorHPV&LinearArrayHPVGenotyping)

HC2/Digene

MainHPVtestsinAustralia
Digene usedinALTStrial,lackofinternalcontrolforinput
DNA&crossreactivitywithlowrisktypes.Willnotidentify
specificHPVtypes
InhousePCR.Mostsensitivetechnique&allowstestingon
sampleswithfewercells.Contaminationanissue.Cando
typedistinction.Noexternalvalidation.
Cervista(Hologic)FDAapproved(invadertechnology).
Internalcontrol.CandistinguishHPV16&18fromother
highrisktypes
AbbottRealtimeHPVtest(PCR).Mostaccuratetype
specificmeasureofviralload
RocheCobas4800HPVtest Athenatrial.Internalcontrol
&canidentifyHPV16&18infections

HPVtestinginAustralia
UnderthecurrentNH&MRCguidelinestheonly
indicationforHPVtestingisastestofcure forwomen
whohavepreviouslyundergonetreatmentforahigh
gradeabnormalityofthecervix.
AwomantreatedforHSILrequiresacolposcopy&
cervicalcytologyat46monthsaftertreatment.Cervical
cytology&highriskHPVDNAtestingat12monthsafter
treatment&thenevery12monthsuntilthewomanhas
testednegativeforbothtestsontwoconsecutive
occasions.
Womenwhoareundergoingannualcytologyforapast
historyoftreatmentforHSILarealsoeligiblefora
MedicarerebateforHPVtestsothattheymayreturnto
tothe2yearlyprogramifthetestsarenegative

RationaleforHPVtestingafter
treatment
InAustraliaapprox15,000womentreatedeach
yearforHSIL
PriortonewNH&MRCrecommendations,these
womenwererequiredtohaveannualcytology
forremainderoftheirlife
HSILonlyarisesinrelationtopersistenceofHPV
infection
IfHPVcarriagehascleared,thentheriskof
furtherabnormalityissameasnormalpopulation
returntoroutinescreeningprogram

HPVDNApersistenceaftertreatment
Approx20%ofwomenwillstillhaveHPVDNA
at12monthsfollowingtreatment
Overthenext12monthsapprox1/3will
becomenegative
Onlyabout15%womentreatedforHSILwill
havepersistentHPVcarriage
Notallthesewomenwillgetrecurrenceof
HSIL

HPVtestingversusPapsmear
HPVtestingmoresensitivebutatcostofless
specificity
Specificityimprovesinwomen>30yrs
CostofHPVtestinghigherthancytology
HPVtestingcapableofautomation.Results
reproducible
At5yearsanegHPVtesthaslowerincidenceof
CIN3+(0.25%)thannegPapsmear(0.83%).
EffectofnegHPVlaststwiceaslongasnegPap
smear longerscreeningintervals

NTCC study

HPV63%moresensitivethancytology
SpecificityHPV93.3%inwomen>35yrsversus
97.1%forcytology
TherelativePPVvaluebetweenHPVtesting&
cytolwas0.67
ARBYN META-ANALYSIS

RepeatingHPVtestinginASCUSsmearsrather
thanrepeatingcytologymoresensitive&more
specificthanrepeatingcytology

HPVtestidentifyinghighriskHPVtype

TheJournaloftheNationalCancerInstitute2005TheElevated10YearRiskofCervicalPrecancerandCancerinWomenWith
HumanPapillomavirus(HPV)Type16or18andthePossibleUtilityofTypeSpecificHPVTestinginClinicalPractice,
demonstratedthatHPV16and18 screeningmayidentifywomenatgreatestriskforcervicalcancer(CIN3)1.

ImprovingHPVspecificity
Measuringviralload
Genotyping
TestingRNAofE6&E7.Levelsincreasewith
lesionseverity
OverexpressionofP16.InNTCCifreferred
onlywomenwithoverexpressionofP16
therewasnoincreaseinreferralfor
Colposcopy,butstillgaveanimproved
sensitivityof1.53overcytology

HPVvaccinationprogram
IntroducedinAustraliain2006
Gov.fundedprogramforfreevaccinationof
schoolgirls&youngwomenageupto26yrsof
quadrivalentvaccinecovering6,11,16&18
Programforyoungwomenotherthanthe
ongoinggroupof1213yrsfinishedin2009
Bothquadrivalent&bivalent(16,18)vaccine
availabletoothergroupscoveredbythe
licenceonprivatescript

HPVvaccinationera
RapiddropofHSILcytologyexpected&this
shouldhappenfromthisyear
Performanceofcytologyinpredictivevalue
expectedtodecline
Alreadydifficulttorecruitcytologists
?Newapproachrequired

Highgradeabnormalities
~80%ofwomenwithhighgradeabnormalitiesare<40
yearsold1

AIHW,2009.

EffectofHPVvaccinationoncytology
screeningprogram
CurrentlytheaveragesensitivityPapsmearfor
detectinghighgradeabnormalitiesisapprox53%(30
70%)withapprox97%specificity1
Thereisevidencetoshowthatinlowprevalence
populationsthesensitivityofPapsmearreduces.2 HPV
vaccinationwillbereducetheprevalenceofcytol
abnormalities
ThusitmaybeexpectedthatthesensitivityofPap
smearwillfurtherdecline
Attractionforcytologyasacareerdeclining
1. Cuzick et al Int J Cancer 2006;119: 1095-105
2000;9(9):945-51

2. Ratnam S, Franco EL, Ferenzy A Cancer Epidemiol Biomarkers

THREAT

?Screeningin
thefuture

HPVTest

Negativ
e
Routine
screening
Repeat5
years

Positive

Cytology
Negative
Negative

RepeatHPV
test

Positive
Positive
Negativ
eorLSIL

Colposcopy
&Biopsy
Positive

Treatment

Liquidbasedcytology
Reducesunsatisfactoryrate
NotmoreeffectiveinAustraliansetting
Commonestmodalityofcytologyinrestof
world
Primebenefit allowsreflexHPVtesting&
othermarkersthatmaybedeveloped
InsteadofHPVDNAdetectionalonequestfor
markersofpersistenceorHPVintegration

RenewalProcessinCervicalScreening

AgeofCommencement
Screeninginterval
Liquidbasedcytology
HPVtesting

HPVtesting

WhatisHPVtesting
CurrentuseofHPVtestinginAustraliansetting
Use&limitationsofHPVtesting
CurrentuseofHPVtestinginothercountries
PossibleroleforHPVtestinginfuture

CASE PRESENTATION
USINGTRANSPONDERS

HOW TO USE THE KEYPADS


During this presentation you
will be
asked to use interactive
keypads
to respond to questions.
Please note:
All responses are
ANONYMOUS
Simply press the button that corresponds to the
answer you wish to select.

HOW TO USE THE KEYPADS


1. Chooseyourresponsefromthe
keypadbuttons.
2. ThelightwillgoGREEN toconfirm
yourresponsehasbeenreceived.
3. Youcanchangeyouranswer by
simplykeyinginyournewchoice.
(Thesystemwillonlycountthelast
vote)
NOTE:
Please DO NOT press the GO button,
this is a functionality for break-out
sessions only.

Wheredoyounormallyreside?
12%

No
n

m
et
ro

12%

Da
rw
in

12%

Pe
rt
h

12%

Da
rw
in

Br
is

12%

Ho
ba
rt

12%

ba
ne

12%

ou
rn
e

12%

M
el
b

Sydney
Melbourne
Brisbane
Hobart
Darwin
Perth
Darwin
Nonmetro
Other

Sy
dn
ey

1.
2.
3.
4.
5.
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7.
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9.

Whatbestdescribesyou
12%

12%

12%

12%

12%

12%

O
th
er

12%

N
ur
se

12%

ra
ct
i si
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m
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i si
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r..
.
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in
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ee
ai
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Se
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xu
er
al
h
ea
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lth
m
..
ily
.
P
la
nn
in
...

PractisingmetroGP
PractisingruralGP
GPtrainee
Traineeother
SexualhealthPhysician
FamilyPlanningDoctor
Nurse
Other

1.
2.
3.
4.
5.
6.
7.
8.

Scenario1
22y.o.WomanwithPapsmearLSILcytology
12monthsagohasanotherPapsmear
showingLSIL
Management?

Management?

0 of 30

re

20%

U
ns
u

te
st
R
ef
er
fo
rC
ol
...

20% 20% 20%

H
PV

R
ep
ea
tP
a

p
sm
...

20%

O
th
er

1. RepeatPapsmear12
months
2. HPVtest
3. ReferforColposcopy
4. Other
5. Unsure

Case13

ManagementofbiopsyprovenCIN2
1. Treatmentwithlaserablation
2. Treatmentwithwireloop
excision
3. ConservativeManagement
withreviewin6months
4. Conservativemanagement
withreviewin12months
5. Other

0 of 30

er
O
th

e
m
...
tiv

...
tiv

C
on
se
rv
a

e
M

...
ith
w

C
on
se
rv
a

re
at
m
en
t

re
at

m
en
tw

ith

...

20% 20% 20% 20% 20%

Rateofandrisksforregressionofcervicalintraepithelial
neoplasia2inadolescentsandyoungwomen.
MoscickiAB,MaY,WibbelsmanC,DarraghTM,PowersA,Farhat
S,ShiboskiS. ObstetGynecol. 2010Dec;116(6):137380

OBJECTIVE:
Todescribethenaturalhistoryofcervicalintraepithelialneoplasia(CIN)2inaprospectivestudyofadolescents
andyoungwomen,andtoexaminethebehavioralandbiologicfactorsassociatedwithregressionand
progression.
METHODS:
Adolescentsandwomenaged13to24yearswho werereferredforabnormalcytologyandwerefoundtohave
CIN2onhistologywereevaluatedat4monthintervals.Risksforregressionweredefinedasthreeconsecutive
negativecytologyandhistologyvisits,andprogressiontoCIN3 wasestimatedusingCoxproportionalhazards
regressionmodels.
RESULTS:
Ninetyfivepatientswithameanageof20.4years(2.3)wereenteredintotheanalysis.Thirtyeightpercent
resolvedbyyear1,63%resolvedbyyear2,and68%resolvedbyyear3.Multivariableanalysisfoundthatrecent
Neisseriagonorrhoeaeinfection(hazardratio25.27;95%confidenceinterval[CI]3.11205.42)and
medroxyprogesteroneacetateuse(permonth)(hazardratio1.02;95%CI1.0031.04)wereassociatedwith
regression.Factorsassociatedwithnonregressionincludedcombinedhormonalcontraceptionuse(permonth)
(hazardratio0.85;95%CI0.750.97)andpersistenceofhumanpapillomavirus(HPV)ofanytype(hazardratio
0.40;95%CI0.220.72).Fifteenpercentofpatientsshowedprogressionbyyear3. HPV16/18persistence(hazard
ratio25.27;95%CI2.65241.2;P=.005)andHPV16/18statusatlastvisit(hazardratio7.25;95%CI1.0749.36;
P<.05)wereassociatedwithprogressionBecauseofthesmallsamplesize,othercovariateswerenotexamined.
CONCLUSION:

ThehighregressionrateofCIN2supportsclinicalobservation
ofthislesioninadolescentsandyoungwomen.

TimetoclearanceofCIN2
.

TimetoprogressionofCIN2toCIN3

TimetoclearanceofCIN2byHPV
16/18status

Obstetricoutcomesafterconservativetreatmentforintraepithelialorearlyinvasivecervical
lesions:systematicreviewandmetaanalysis.
KyrgiouM,KoliopoulosG,MartinHirschP,ArbynM,PrendivilleW,ParaskevaidisE.
Lancet. 2006Feb11;367(9509):48998.

LaserTreatmentfollowup
SeenGynaecologistat6monthsforcolposcopy
&cytology
Colposcopy inconclusiveasTZisendocervical.
PappossibleLSIL
ReferrredbacktoGPforcytology&hrHPVtest

Whatisyouropinion?
1. Idontfeelcomfortablewith
havingtomanageanywomen
postRxforHSIL
2. Whenthe1st PapafterRxis
abnormaltheSpecialistshould
continuefollowup
3. Ifeelcomfortableinadvising
womenwhomayhaveafurther
abnormalityafterRx
4. Noneofabove
I

do
n
tf

ee
lc

.. .
W
he
n
th
e
1s
tP
...
I
fe
el
co
m
fo
rt
...
N
on
e
of
ab
ov
e

25% 25% 25% 25%

0 of 30

ResultsofPap
PapsmearPossibleHSIL
Digenepositive

Whatnextforthisyoungwoman

0 of 30

ae
co
l
e
Gy
n

O
th
er

og
...

e.
..
sh
Th

dv
ise

Y
ou
a

dv
ise
a

Y
ou
a

re
pe
at
P

...

r..
.

20% 20% 20% 20% 20%

G
P
to

1. GPtorepeatPap&hrHPV
test
2. YouadvisearepeatRxwith
laser
3. Youadviseshewillrequire
anexcisionalRx
4. TheGynaecologistmay
electtomanage
conservatively
5. Other

Whatnow?
1. Coldknifecone
biopsy
2. LaserConebiopsy
3. LLETZ
4. Expectant
management
5. Other

0 of 30

er
O
th

an
tm
an
a

...

Z
ET

pe
ct

LL
Ex

o.
..
eb
i

se
rC
on

La

C
ol

d
k

ni
fe
co

n.
..

20% 20% 20% 20% 20%

Thankyou
Ihopethishashelpedinunderstandingthe
currentmanagementofapatientwith
recurringCIN2
Alsogivenyouanawarenessimplicationsfor
pregnancyoftreatment

Doyouthinktheobjectivesofthe
presentationhavebeenmet?

0 of 30

25%

25%

U
ns
ur
e

25%

P
ar
tly

25%

N
o

Yes
No
Partly
Unsure

Y
es

1.
2.
3.
4.

Thank You

QUESTIONS???

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