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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
beassociatedwithincreasedratesofspontaneouspregnancylossoradversefetaloutcomes
(289,291,292).
Despitetheevidenceonvaccinesafety,misinformationandvaccinehesitancyhashada
material effect on uptake in some countries. The WHO GACVS published a report on
communicationofvaccinesafetyin2019,afterexaminingseveralcountry-levelcasestudies.
They found that “Misinformation, occasional coincidental deaths and stress-related
reactions have led to controversy about the safety of HPV vaccines. Although these
vaccines could control a major public health problemand despite robust evidence of
theirsafety,theiruptakehasremainedlow,especiallyinmanyhigh-incomecountries”
(293).The report examined successful strategiesfor countering vaccine hesitancy crisesin
Denmark, Ireland, and the United Kingdom, noting that “coordination and engagement
amonghealth departments, immunizationprograms, stakeholders, influentialpublic leaders
andthemediaareessentialformitigatingsuchcrises.”However,unfortunatelytheeffectofa
vaccinecrisisoncoveragecontinuesinJapan(294).
VaccineDeployment
The greatest public health benefit is achieved by vaccination of individuals prior to
sexualinitiation,asthevaccinesareprophylactic(295).TheU.S.AdvisoryCommitteeon
ImmunizationPractices(ACIP)originallyrecommendedroutinevaccinationofall11-to12year-oldgirls,and “catch-up”vaccination ofall13-to26-year-oldgirls andwomen(296).
Overtime,therecommendationshavebeenupdatedtoincorporatevaccinationofmales,the
inclusionofnextgenerationvaccine,andatwo-dosescheduleforyoungeradolescents.The
2019 guidance recommends routine vaccination of adolescents at ages 11 to 12 years
(vaccination can be given starting at age 9 years), with catch-up vaccination for all
persons through age 26 years. For adults aged 27 through 45 years, ACIP states that
althoughthe publichealth benefitof HPVvaccinationinthis agerange isminimal, shared
clinical decision making is recommended because some persons who are not adequately
vaccinatedmightbenefit(297).
Vaccinationofyoungsexuallyactivewomenmaystillprovidesomeprotection.Routine
cytologyorHPVDNAtestingpriortovaccinationisnotcurrentlyrecommended,although
suchscreeningmaybeappropriateforsexuallyactivewomenaspart ofcervical screening
practices. At the present time, cervical cancer screening should continue for the
immunizedpopulation,toscreenforresidualdiseasecausedbynonvaccineHPVtypes,
and to screen HPV-infected women; however, the potential for less intensive screening
approachesinyoungercohortsvaccinatedwithnextgenerationvaccinesisanactiveareaof
research(298,299).
In2016,theU.S.AdvisoryCommitteeonImmunizationPractices(ACIP)providedupdated
guidance,withuseof a2-doseschedule forgirlsand boyswhoinitiate the vaccination
series at ages 9 through 14 years and a 3-dose schedule for persons who initiate the
vaccinationseriesatages15through26yearsandforimmunocompromisedpersons(300).
Most studies examining the cost effectiveness of vaccination of preadolescentfemales
have found that vaccinating 12-year-old girls is cost effective, even in the context of
cervical screening (251). Cost savings are achieved by reducing abnormal Pap smears,
colposcopic referrals, cervical biopsies, treatment procedures and cancer-related treatment
costs,aswellasreducingthecostsofdiagnosisandtreatmentofgenitalwarts.Reductionsin
these outcomes also increase quality of life, measured in cost-effectiveness analyses as
Quality-Adjusted Life-Years Saved (QALYS). Vaccination will potentially also reduce the
costsandmorbidityassociatedwiththecomplicationsoftreatmentproceduresamongyoung
women (301,302), although the association between cervical treatment and obstetric
complicationshasnotbeenconfirmedinallstudies(303).Studiesofthecost-effectiveness
ofsecond-generationvaccinescomparedtofirst-generationvaccineshavebeendoneand
thesehavehelpedtodefinetheincrementalpricerequiredforsecond-generationvaccinesto
becost-effective(272,304,305).MaleHPVvaccinationmaynotrepresentthebest“value
for money” compared to vaccinating more females or making other investments in
health.Thisdeterminationinaparticularsettingwill dependonvaccineprice,coveragein
females, achievable coverage in males, rates of HPV-related disease in males and other
factors.
HPVVaccineExperience
Coverage rates achieved for vaccination of young females vary widely between countries.
Thehighestcoveragerateshavebeenachievedwherenationalpubliclyfundedschoolbasedvaccinationprogramshavebeenintroduced.Initialrateswere80%inEngland,
90% in Scotland, and 73% in Australia (251). By contrast, coverage rates in countries
whichimplementedpractitioner-basedvaccinationprogramshavebeenlower.IntheUnited
Statesin2018,only51.1%ofadolescentsaged13to17yearswereconsidered“uptodate”
withtheirHPVvaccination(306).
AustraliawasthefirstcountrytointroduceanationalHPVvaccinationprogramandit
initially achieved relatively high coverage rates in adolescent girls (307). A 2-year
vaccination catch-up was performed to age 26 years and the recommended age of first
screeningwas18to20yearsinsexuallyactivewomen.Thisoverlapbetweenvaccinatedand
screenedgroupsled toearlyeffectson thenumberof high-gradelesionsidentified through
screening.Anearlypostvaccinationecologicanalysisidentifiedadecreasingincidenceof
high-gradediseaseinwomenlessthan18years(308)anddecreasingratesofhigh-grade
cervical precancerous abnormalities have since been documented in women in their
earlyandlate20s.
Australia initially used the quadrivalent vaccine and several studies have documented
substantial decreases in anogenital warts in Australia in cohorts of females who were
eligible for HPV vaccination. Early studies also documented lesser, but still substantial,
reductionsinanogenitalwartsinheterosexualmalesinthesameagegroup,presumablyasa
resultofherdimmunityfromfemalevaccination(309,310).
Routinemalevaccinationcommencedin2013andby 2015–2016,3-dosecoverage rates
wereabout80%infemalesand74%inmales(311).In2018,Australiatransitionedto2-
doses with the next generation nonavalent vaccine. As a result of the changing
environment induced by vaccination, Australia transitioned to 5-yearly primary HPV
screeningin2017. Thischangewas supported byinitial trial findings(312) andmodeling
(313),bothofwhichdemonstratedgreaterefficacyofHPVscreeningcomparedtocytologybased screening in the vaccinated population. Because of the combined effect of these
changes, Australia is predicted to be the first country in the world to achieve
eliminationofcervicalcancerasapublichealthissuebymeansofactiveintervention
(9).
TheWHOInitiativefortheEliminationofCervicalCanceras
aPublicHealthProblem
Inlowresourcesettings,theGlobalAllianceforVaccinesandImmunization(GAVI)has
madetheHPVvaccineavailabletofemalesinGAVI-eligiblecountriesforunder$5per
dose, yet to date, coverage rates in LMICs have been low (314). In 2018, the Director-
GeneraloftheWHOannouncedacall-to-actiontowardtheeliminationofcervicalcancer.In
January 2019, the Executive Board of the WHO requested a draft strategic plan be
preparedfordiscussionattheWorldHealthAssemblyinMay2020.Thus,majorefforts
are being made to define scaled-up targets for interventions, the elimination threshold for
cervical cancer, and to evaluate vaccine, screening and treatment technologic supply
pipelines,andmechanismsforeffectivedeliveryoftheseinterventionsinLMIC(315).
Inthedraftstrategicplan,WHOhasdefinedglobal“90/70/90”targetsasfollows—by
2030,90%ofyoungadolescentswillbevaccinated,70%ofwomenwillbescreenedwith
HPVatleasttwiceintheirlifetime,and90%ofwomenrequiringitwillbeeffectively
treatedfor precancer orcancer, with effective palliation also a priority for women with
advancedcervicalcancer.Thedraftthresholdforconsideringcervicalcancereliminated
asapublichealthissueis4per100,000womenperannum.Modelinghaspredictedthat
achieving high levels of scaled-up vaccination, combined with cervical screening, has the
potentialtoavert up to 12·5 to 13·4 millioncervicalcancer cases in the next half century
(317). Ongoing comparative modeling work by the WHO Cervical Cancer Elimination
Modelling Consortium (CCEMC) is supporting the development of the strategic plan by
characterizingthebenefitsintermsofcervicalcancercasesanddeathsaverted,aswellasthe
cost-effectivenessofscalingupvaccination,screening,andprecancertreatment.
ScreeningforCervicalNeoplasia
Incidence and mortality rates for cervical cancer in the United States have steadily
decreasedsincethe1950s(317,318). Although theoverall incidence ofcervical cancer in
Westerncountrieswasbeginningtodeclinebeforetheintroductionofscreeningefforts,the
significantdecreases incervical cancerincidence andmortality canbelargelyattributed to
thesuccessofwidespreadscreening(7,319–321).
AsinglePapsmearhaslimitedsensitivityforthedetectionofcervicalcancerandprecancer.
Strategies used in the past to compensate for this have included repeat screening at short
intervals(such asannual Papsmears)and alowthreshold forrepeat smearsorreferral for
colposcopy(Fig.8.17).This approachis costlyandgenerates manyunnecessary follow-up
examinationsandtests.
The2001BethesdaSystem
The Bethesda System for reporting cervical/vaginal cytologic diagnoses was originally
developed in 1988 at a U.S. National Cancer Institute (Bethesda, MD) workshop (35). In
1991,asecondNCI-sponsoredworkshopreviewedandmodifiedtheBethesdaSystembased
onlaboratoryandclinicalexperience(36).
A cervical-vaginal smear report using the revised 1991 Bethesda system had three
components: (i) a description of smear adequacy; (ii) a general categorization (i.e.,
“withinnormallimits”or“notwithinnormallimits”);and(iii)descriptionofthecytologic
abnormality, specifying whether squamous or glandular.Abnormal morphology that may
represent preinvasive squamous disease fell into three descriptive categories: ASC-US,
LSIL,andHSIL.
With the increased utilization of new cervical cancer screening technologies and in
responseto researchfindings,in2001,theNCIsponsoreda furthermultidisciplinary
workshoptoreevaluateandupdatetheBethesdaSystem(TBS)(37).Thiscreatedstandard
reporting terms and criteria for each category of smear report, which has improved
communicationbetweenpathologistsandclinicians.TBSwasdesignedtobeconsistentwith
updated knowledge of HPV-associated disease and has enabled development of clinical
managementguidelineslinkedtostandardizedterminology.
Figure8.17 Sensitivityandspecificityofscreeningtestasreciprocalratios.
AgeatStartofScreening
In recent years there has been a shift toward considering a later age to start cervical
screening.In 2006, the IARC recommended that cervical screening should start at 25
years (7). Population-based audit data have shown limited effectiveness of cytology in
womenyoungerthan25yearsinpreventinginvasivecervicalcancerbefore30years(322).
HPVvaccinationisexpectedtobeafurtherfactordrivingalaterageforstartingscreening.
Severalcountrieshaveraised,orareconsideringraising,theageofstartingscreeningto
25 years. England implemented this change from 2004 and Wales from 2013; the
CanadianTaskForcerecommended in2012 thatscreeningnot startuntil age 25years and
Scotlandwillimplementthechange from2015.In2012,revisedguidelinesintheUnited
States recommended that screening should not start until age 21 years (323–325). In
2017,Australiaraiseditsstartingageofscreeningto25yearsinthecontextofintroducing
primaryHPVscreening(326).
CervicalScreeningInterval
The IARC recommended that cervical screening with cytology should occur every 3
yearsinwomenaged25to39years,andevery5yearsinwomenaged50to65years(7).
Thisisunderpinnedbystudiesdesignedtoassesstheoptimalintervalateachage(327)and
analysis of trends in various countries which show similar outcomes in countries
implementing 3-yearly screening recommendations compared to those with more frequent
screening (328,329). Evidence suggests that HPV-based primary screening can be safely
performedatintervalsof5years(330),andthishasbeenintroducedorisunderconsideration
inseveralcountries.
PrimaryHPVScreening
UnderstandingthecentralroleofHPVinthedevelopmentofcervicalcancerhasledtotwo
effectivepreventive strategies in addition to Pap tests—primary prevention by vaccination
andenhancedsecondaryprevention(screening)withtheuseofHPV-basedmolecularassays
(331).SeveralclinicallypositionedHPVtestsystemsallowlarge-scaleautomationand
partialgenotypingforHPV16/18.Thisprovidesthepotentialforfurtherriskstratification
ofHPV16/18positivewomencomparedtowomenpositiveforotheroncogenictypes.This
hasbeenused,forexample,intheprimaryHPV-basedscreeningprograminAustralia(326).
BecauseHPV testingismore sensitiveandmore reproduciblethancytology, itallows
forsafeextensionofthescreeningintervaltoatleast5yearsatallages(330,332).HPV
testinghasbeenendorsedforseveralyearsasaprimarycervicalscreeningmethodbyIARC
(7).Comparedtocytology,HPVtestinggenerallyresultsinincreaseddetectionofCIN2+in
theinitialroundofscreening,butreducedratesofhigh-gradediseaseinthefollow-upround
of screening. Lower rates of invasive cervical cancer have also been demonstrated
following HPV screening (333,334). A pooled analysis of longitudinal data on 175,000
women from European trials (335) has shown similar ability of HPV and cytology to
protectagainstdevelopinginvasivecervicalcancerover2yearsorless,buta60–70%
increasedprotectioninHPV-screenedwomenforintervalsupto5years.Longitudinal
analyseshavereportedlowerratesof CIN3 orinvasivecancer(CIN3+)overtimein
HPVnegativecomparedto cytologicallynegative women, andhigherratesofCIN 3+
over time in HPV 16–positive women compared to other HPV types (51,52,81,336).
Because vaccination does not affect the clearance of existing HPV infections (281), HPV
testingcan risk-stratifywomen irrespectiveof whethertheyhavebeenofferedvaccination,
and if so, whether they were effectively vaccinated. The latter depends in part on dose
completion (284–286,337), and for catch-up vaccination cohorts, on whether individuals
were already exposed to HPV at the time of vaccination. Primary HPV testing as a
standalone test should in future allow for the simplification of screening
recommendationsinthepostvaccinationera.However,intheU.S.context,HPVscreening
andcytologymaybeusedforco-testingaswellasforprimaryHPVtesting(338).
RenewedAustralianNationalCancerScreeningProgram(NCSP)
In 2014 the Australian Medical Services Advisory Committee (MSAC) recommended that
theNationalCervicalScreeningProgram(NCSP)adoptHPVtestingforcervicalscreeningat
5-yearly intervals. Australia was the first country in the world to introduce high-risk
HPV-DNA testing as the national screening test for cervical neoplasia following the
successful introduction and implementation of a national HPV vaccination program.
ThenewGuidelinesforcervicalscreeningandmanagementofscreen-detectedabnormalities
fortheUnited States will be releasedin2020. It is likely that theU.S.Guidelineswill be
informedinpartbytheAustralianexperience.
In2017,theCancerCouncilAustraliaCervicalCancerScreeningGuidelinesWorkingParty,
released Guidelines for the implementation of the Renewed NCSP, including clinical
Consensus-BasedRecommendations,PracticePointsandFlowChartswhicharereproduced
withpermissionbelow.Theextensivereviewofthesupportingevidenceisavailableonline;
https://wiki.cancer.org.au/australiawiki/index.php?oldid=207530,cite2019Nov17.Available
at https://wiki.cancer.org.au/australia/Guidelines:Cervical_cancer/Screening. Much of the
followingdiscussionquotesdirectlyfromthenewAustralianguidelines.
The Medical Services Advisory committee supported public funding for the following
program,whichwasintroducednationallyinDecember2017:
Five-yearly cervical screening using a primary HPV test with partial HPV
genotypingandreflexliquid-based cytology (LBC) triage, forHPV-vaccinated and
unvaccinatedwomenaged 25 to 69 years, with exit testingofwomenupto age 74
years.
Self-collection of an HPVsample for an underscreened or never screened woman,
facilitatedbyamedicalpractitioner,nursepractitioner,orotherhealthcareprofessionalon
behalfofamedicalpractitionerwhoalsooffersmainstreamcervicalscreening.
Asystemofinvitationsandreminderstobesenttowomenaged25 to69years, and
exitcommunicationstobesenttowomenaged70to74years.
Women who have a positive oncogenic HPV (16/18) test result are referred
immediatelytocolposcopy,withreflexLBCresultsavailabletoinformthecolposcopic
examination.
ForwomenwithapositiveoncogenicHPV(not16/18)testresult,LBCisusedasa
triage to determine whether they are referred for colposcopy, or for repeat HPV
testingin12months.
The pre-renewal National Cervical Screening Program was based on 2-yearly screening
usingconventionalcytology(thePaptest)insexuallyactivewomenbetweentheagesof18–
20and69years.ThemodelingforHPVprimaryscreeningwithpartialgenotypingfor
HPV16/18indicatedan expected reductionin cancerincidence andmortalityof over
20%(ifwomenwerescreeneduntilage70years).Subsequentmodelinghaspredictedthat
a31–36% reductioninincidence andmortality may beachievable inunvaccinatedcohorts
anda24–29%reductionmaybeachievableincohortsofferedvaccination.
CervicalScreeningPathwayforPrimaryOncogenicHPVTesting
OncogenicHPVTypesnotDetectedatRoutineScreening
Women in whom oncogenic HPV types are not detected are at very low risk of cervical
intraepithelial neoplasia grade 3 (CIN 3) and cervical cancer for at least 5 years and will
continue5-yearlyscreening.
WomenwithaPositiveHPV(16/18)TestResult
Women with a positive oncogenic HPV (16/18) test result should be referred directly for
colposcopicassessment,whichwillbeinformedbytheresultofreflexliquid-basedcytology
(LBC).
Women who have a positive oncogenic HPV (16/18) test result with an LBC report of
invasive cancer (squamous, glandular, or other) should be referred to a gynecologic
oncologistforurgentevaluation,ideallywithin2weeks.
Women with a positive oncogenic HPV (16/18) test result and reflex LBC prediction of
possible (p)HSIL/HSIL should be referred for colposcopic assessment at the earliest
opportunity,ideallywithin8weeks.
ThereferralofwomenwithapositiveoncogenicHPV(16/18)testresultforcolposcopy,
regardlessof the LBC prediction, is a major change to clinical practice and requires
appropriateeducationandimplementation.
PositiveOncogenicHPV(not16/18)TestResultatRoutineScreening
Women with a positive oncogenic HPV (not 16/18) test result, with an LBC report of
negativeorpredictionofpLSIL/LSIL,shouldhavearepeatHPVtestin12months.
ReferralofWomenwithaPositiveOncogenicHPV(not16/18)TestResultand
LBCPredictionofpHSIL,HSIL,oranyGlandularAbnormality
WomenwithapositiveoncogenicHPV(not 16/18) test result, with an LBC prediction of
pHSIL/HSILoranyglandularabnormality,shouldbereferredforcolposcopicassessmentat
theearliestopportunity,ideallywithin8weeks.
ReferraltoGynecologicOncologistforLBCPredictionofInvasiveDisease
Womenwho havea positiveoncogenicHPV(not16/18) testresult withanLBC reportof
invasive cancer (squamous, glandular or other) should be referred to a gynecologic
oncologistforurgentevaluation,ideallywithin2weeks.
Figure8.18 CervicalscreeningpathwayforprimaryoncogenicHPVtesting.(Reproduced
withpermissionfromCancerCouncilAustralia©2020.)
ManagementAfterRepeatHPVTestat12Months,FollowingInitialPositive
OncogenicHPV(not16/18)TestResult
AtrepeatHPVtesting12monthsafterapositiveoncogenicHPV(not16/18)testresultwith
reflexLBCnegativeorpLSIL/LSIL:
if a woman has a positive oncogenic HPV (any type) test result, reflex LBC will be
performed,andsheshouldbereferredforcolposcopicassessment
ifoncogenic HPV is notdetected,the woman should be advisedtoreturnto routine 5yearlyscreening.
Colposcopicassessmentandmanagementwillbemorechallengingthanbefore,because
therewillbea higherproportionofwomen withapositive oncogenicHPVtestresult
who will have minimal or no cytologic changes. In particular, women with persistent
infectionswith oncogenic HPV(not 16/18)will be referredtocolposcopy after12months
anda largeproportion of thesewillrepresent productive HPVinfection withoutneoplastic
potential.ThecervicalscreeningpathwayforprimaryoncogenicHPVtestingissummarized
inFigure8.18.
Self-CollectedVaginalSamples
The MSAC systematic review made the following conclusions regarding self-collected
samples:
The accuracy of HPV testing using self-collected samples varies between different
typesofsamplingdevicesandHPVtests.
HPV tests using self-collected samples have moderate to high sensitivity and
comparablyhighspecificityfordetectingCIN2+,comparedwithclinicHPVtestingin
9of10studiesidentified,witharelativesensitivityof0.62to1.00andrelativespecificity
of0.93to1.00.
Highratesofadherencetoscreeningfollow-uphavebeenreportedamongpreviously
unscreenedwomenwithapositiveHPVtestresultfromaself-collectedsample.
A recent modeled analysis found that undergoing even one round of screening could
substantially reduce an unscreened woman’s risk of cervical cancer over her lifetime, by
around41%ifthisoccurredatage30or40(601).
OncogenicHPVTypesnotDetectedinSelf-CollectedSample
WomenwhohaveundergoneHPVtestingonaself-collectedsampleandinwhomoncogenic
HPVisnotdetectedshouldbeinvitedtore-screenwithanHPVtestin5yearsandshouldbe
advisedtohaveaclinician-collectedsample.
ReferralofWomenwithPositiveOncogenicHPV(16/18)TestResult(SelfCollectedSample)
Women who have undergone HPV testing on a self-collected sample and have a positive
oncogenicHPV(16/18)testresultshouldbereferreddirectlyforcolposcopicassessment.A
cervicalsample for LBC shouldbeobtained at the timeof colposcopy and isnotrequired
priortoreferral.
WomenwithaPositiveOncogenicHPV(not16/18)TestResult(Self-Collected
Sample)
WomenwhohaveundergoneHPVtestingonaself-collectedsampleandwhohaveapositive
oncogenic HPV (not 16/18) test result should be advised to visit their GP or healthcare
professionaltoobtainacervicalsampleforLBC:
IftheLBCtestresultisnegativeorpLSIL/LSIL,HPVtestingshouldberepeatedin12
months,preferablybyahealthcareprofessional.
IftheLBCtestresultispHSIL/HSILoranyglandularabnormality,thewomanshouldbe
referredforcolposcopyattheearliestopportunity,ideallywithin8weeks.
Managementof12-MonthRepeatHPVTestResultAfterInitialPositive
OncogenicHPV(not16/18)TestResultonaSelf-CollectedSample
At12-monthrepeatHPVtesting:
Women in whom oncogenic HPV is not detected should return to routine 5-yearly
screeningandshouldbeadvisedtohaveaclinician-collectedsampleatthattime.
Women with a positive oncogenic HPV (any type) test result should be referred for