Human papillomavirus (HPV) vaccine policy and evidence-based medicine: Are they at odds?

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1 Annals of Medicine, 2011; Early Online, Informa UK, Ltd. ISSN print/issn online DOI: / REVIEW ARTICLE Human papillomavirus (HPV) vaccine policy and evidence-based medicine: Are they at odds? Lucija Tomljenovic1 & Christopher A. Shaw 1,2 1 Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia, 828 W. 10th Ave, Vancouver, BC, V5Z 1L8, Canada and 2 Program in Experimental Medicine and the Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada All drugs are associated with some risks of adverse reactions. Because vaccines represent a special category of drugs, generally given to healthy individuals, uncertain benefits mean that only a small level of risk for adverse reactions is acceptable. Furthermore, medical ethics demand that vaccination should be carried out with the participant s full and informed consent. This necessitates an objective disclosure of the known or foreseeable vaccination benefits and risks. The way in which HPV vaccines are often promoted to women indicates that such disclosure is not always given from the basis of the best available knowledge. For example, while the world s leading medical authorities state that HPV vaccines are an important cervical cancer prevention tool, clinical trials show no evidence that HPV vaccination can protect against cervical cancer. Similarly, contrary to claims that cervical cancer is the second most common cancer in women worldwide, existing data show that this only applies to developing countries. In the Western world cervical cancer is a rare disease with mortality rates that are several times lower than the rate of reported serious adverse reactions (including deaths) from HPV vaccination. Future vaccination policies should adhere more rigorously to evidence based medicine and ethical guidelines for informed consent. Key words: Cervarix, cervical cancer, Gardasil, HPV vaccines, informed consent, vaccine adverse reactions Key messages Todate,theeffcacyofHPVvaccinesinpreventing cervicalcancerhasnotbeendemonstrated,while vaccinerisksremaintobefullyevaluated. CurrentworldwideHPVimmunizationpracticeswith eitherofthetwohpvvaccinesappeartobeneither justifiedbylong termhealthbenefitsnoreconomically viable,noristhereanyevidencethathpvvaccination (evenifproveneffectiveagainstcervicalcancer)would reducetherateofcervicalcancerbeyondwhatpap screeninghasalreadyachieved. Cumulatively,thelistofseriousadversereactions relatedtohpvvaccinationworldwideincludesdeaths, convulsions,paraesthesia,paralysis,guillain Barré syndrome(gbs),transversemyelitis,facialpalsy, chronicfatiguesyndrome,anaphylaxis,autoimmune disorders,deepveinthrombosis,pulmonaryembolisms, andcervicalcancers. BecausetheHPVvaccinationprogrammehasglobal coverage,thelong termhealthofmanywomenmaybe atriskagainststillunknownvaccinebenefits. Physiciansshouldadoptamorerigorousevidence based medicineapproach,inordertoprovideabalancedand objectiveevaluationofvaccinerisksandbenefitstotheir patients. Introduction In2002theUSFoodandDrugAdministration(FDA)statedthat vaccines represent a special category of drugs aimed mostly at healthyindividualsandforprophylaxisagainstdiseasestowhich an individual may never be exposed(1). This, according to the FDA,places significant emphasis on vaccine safety (1). In other words,contrarytoconventionaldrugtreatmentsaimedatmanagement of existing, oftentimes severe and/or advanced disease conditions,inpreventativevaccinationacompromiseineffcacy for the benefit of safety should not be seen as an unreasonable expectation. Furthermore, physicians are ethically obliged to provideanaccurateexplanationofvaccinerisksandbenefitstotheir patientsand,whereapplicable,adescriptionofalternativecourses oftreatment.thisinturnenablespatientstomakeafullyinformed decisionwithregardtovaccination.forexample,theaustralian guidelines for vaccination emphasize that for a consent to be legallyvalid,thefollowingelementmustbesatisfied: it[consent] canonlybegivenaftertherelevantvaccine(s)andtheirpotential risksandbenefitshavebeenexplainedtotheindividual (emphasis added) (2). Likewise, the United Kingdom (UK) guidelines pertainingtovaccinationpracticesstatethatsubjectsmustbegiven Correspondence: Lucija Tomljenovic, Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia, 828 W. 10th Ave, Vancouver, BC, V5Z 1L8, Canada. E mail: lucijat77@gmail.com (Received 24 May 2011; accepted 31 October 2011)

2 2L. Tomljenovic & C. A. Shaw adequateinformationonwhichtobasetheirdecisiononwhether to accept or refuse a vaccine (3). This includes having a clear explanationonvaccinerisksandside effects(3). Surprisingly,intheUnitedStates(US),therearenogovernmentalrequirementsforinformedconsentforvaccination(4).Such anomissionleavesthedooropentoafailuretoobtaininformed consent. Nonetheless, there are regulatory agencies such as the USFDAwhichareempoweredtoassurethatonlydemonstrably safe and effective vaccines reach the market.in addition, health authorities(i.e.uscentersfordiseasecontrolandprevention (CDC)) are expected to provide expert advice concerning the benefitsandrisksrelatedtoparticulardrugs,includingvaccines. Whentheseoffcialbodiesarenotabletoprovidetheirnormal regulatoryoversightand/oriffinancialintereststakeprecedence overpublichealth,significantproblemsintrueinformedconsent guidelinescanoccur. What is known about the currently licensed human papillomavirus(hpv)vaccines?whataretheirbenefits,andwhatare theirrisks?whilemedicalauthoritiesinanumberofcountries, includingtheus,stronglyadvocatetheiruse,somemembersof thepublichavebecomeincreasinglyscepticalforavarietyofreasons.thekeyquestionposedbysuchscepticsisthis:isitpossible thathpvvaccineshavebeenpromotedtowomenbasedoninaccurateinformation?thepresentarticleexaminestheevidencein ordertoanswerthiscriticalquestion. Can the currently licensed HPV vaccines prevent cervical cancer? Gardasil s manufacturer, Merck, states on their website that Gardasildoesmorethanhelppreventcervicalcancer,itprotects against other HPV diseases, too. Merck further claims that Gardasildoesnotpreventalltypesofcervicalcancer (5). Similarly,theUSCDCandtheFDAclaimthat This[Gardasil] vaccine is an important cervical cancer prevention tool thatwillpotentiallybenefitthehealthofmillionsofwomen (6)and Basedonalloftheinformationwehavetoday,CDC recommends HPV vaccination for the prevention of most typesofcervicalcancer (7).Allfourofthesestatementsareat significantvariancewiththeavailableevidenceastheyimply thatgardasilcanindeedprotectagainstsometypesofcervical cancer. At present there are no significant data showing thateither GardasilorCervarix(GlaxoSmithKline)canpreventanytypeof cervicalcancersincethetestingperiodemployedwastooshort to evaluate long termbenefits of HPV vaccination. The longest follow updatafromphaseiitrialsforgardasilandcervarixare 5and8.4years,respectively(8 10),whileinvasivecervicalcancer takesupto20 40yearstodevelopfromthetimeofacquisitionof HPVinfection(10 13).Bothvaccines,however,arehighlyeffectiveinpreventingHPV 16/18persistentinfectionsandtheassociatedcervicalintraepithelialneoplasia(CIN)2/3lesionsinyoung womenwhohadnohpvinfectionatthetimeoffirstvaccination (13 15). Nonetheless, although cervical cancer may be caused by persistent exposure to 15 out of 100 extant HPVs through sexual contact (11), even persistent HPV infections caused by high risk HPVswillusuallynotleadtoimmediateprecursorlesions,letaloneinthelongertermtocervicalcancer.Thereason forthisisthatasmuchas90%hpvinfectionsresolvespontaneouslywithin2yearsand,ofthosethatdonotresolve,onlyasmall proportion may progress to cancer over the subsequent years (10,11,16 18). Moreover, research data show that even higher degrees of atypia (such as CIN 2/3) can either resolve or stabilize over time (19). Thus, in the absence of long term follow updata,itisimpossibletoknowwhetherhpvvaccines can indeed prevent some cervical cancers or merely postpone them.inaddition,neitherofthetwovaccinesisabletoclearexistinghpv 16/18infections,norcantheypreventtheirprogression tocin2/3lesions(20,21).accordingtothefda, Itisbelieved that prevention of cervical precancerous lesions is highly likely to result in the prevention of those cancers (emphasis added) (22).ItwouldthusappearthateventheFDAacknowledgesthat thelong termbenefitsofhpvvaccinationrestonassumptions ratherthansolidresearchdata. Gardasil and Cervarix: do the benefits of vaccination outweigh the risks? Currently,governmentalhealthagenciesworldwidestatethat HPV vaccines are safe and effective and that the benefits ofhpvvaccinationoutweightherisks(6,23,24).moreover, theuscdcmaintainsthatgardasilis animportantcervicalcancerpreventiontool andtherefore recommendshpv vaccinationforthepreventionofmosttypesofcervicalcancer (6,7).However,therationalebehindthesestatementsis unclear given that the primary claim that HPV vaccination preventscervicalcancerremainsunproven.furthermore,in theus,thecurrentage standardizeddeathratefromcervicalcanceraccordingtoworldhealthorganization(who) data(1.7/100,000)(tablei),is2.5timeslowerthantherate ofseriousadversereactions(adrs)fromgardasilreported to the Vaccine Adverse Event Reporting System (VAERS) (4.3/100,000dosesdistributed)(TableII).IntheNetherlands, thereportedrateofseriousadrsfromcervarixper100,000 doses administered (5.7) (Table II) is nearly 4 fold higher than the age standardized death rate from cervical cancer (1.5/100,000)(TableI). Although it may not be entirely appropriate to compare deaths alone from cervical cancer to serious ADRs from HPV vaccines, it should be re emphasized that (in accordance with FDA guidelines) the margin of tolerance for serious ADRs for a vaccine with uncertain benefits needs to be very narrow, especiallywhensuchvaccineisadministeredtootherwisehealthy individuals (1).HPV vaccination, even if proven effective as claimed,istargeting9 12yearoldgirlstopreventapproximately 70%ofcervicalcancers,someofwhichmaycausedeathatarate of /100,000womenindevelopedcountrieswitheffective Pap smear screening programmes (Table I). For a vaccine designedtopreventadiseasewithsuchalowdeathrate,therisk to those vaccinated should be minimal. Further, according to someestimates,hpvvaccinationwoulddolittletodecreasethe alreadylowrateofcervicalcancerincountrieswithregularpap screening(10).thus,anyexpectedbenefitfromhpvvaccination will notably drop in the setting of routine Pap screening. Accordingly, the risk to benefit balance associated with HPV vaccinationwillthenalsobecomelessfavourable.ontheother hand,indevelopingcountrieswherecervicalcancerdeathsare muchhigherandpapscreeningcoveragelow(tablei),thepotentialbenefitsofhpvvaccinationaresignificantlyhamperedby highvaccinecosts(25). Itshouldbenotedthatforanyvaccinethenumberofdoses that are eventually administered is lower than the number of dosesthataredistributed.thus,calculationsbasedonthelatter tendtounder estimatetherateofvaccine associatedadrs(figure 1). Supporting this interpretation, we show in Table II and Figure1thatforanyofthetwoHPVvaccines,thereportedrateof ADRsper100,000dosesadministeredisverysimilaracrossdifferentcountriesandapproximatelyseventimeshigherthanthat

3 HPV vaccines and evidence-based medicine 3 TableI.Keydataoncervicalcancer,HPV 16/18prevalence,andcervicalcancerpreventionstrategiesin22countries.DatasourcedfromtheWorldHealth Organization(WHO)/InstitutCatalad Oncologia(ICO)InformationCentreonHPVandcervicalcancer(105). HPV 16/18 prevalencein Incidenceper Mortalityper Mortalityranking womenwithlow / 100,000women 100,000women amongallcancers high gradelesions/ HPVvaccine Country (age standardized) (age standardized) (allages) Papscreeningcoverage(%) cervicalcancer(%) introduced Australia Netherlands US France Canada Spain UKandIreland Israel Germany China VietNam Russia Brazil Thailand th 16th 15th 15th 14th 15th 16th 14th 13th 7th 4th 7th 2nd 2nd 60.6(Allwomenaged20 69y screenedevery2y) 59.0(Allwomenaged> 20y screenedevery5y) 83.3(Allwomenaged> 18y 74.9(Allwomenaged20 69y screenedevery2y 72.8(Allwomenaged18 69y screenedevery3y;annualifat highrisk) 75.6(Allwomenaged18 65y screenedevery3y 80(Allwomenaged25 64y screenedevery5y) 34.7(Allwomenaged18 69y 55.9(Womenaged20 49y screenedevery5y) 16.8(Allwomenaged18 69y 4.9(Allwomenaged18 69y 70.4(Allwomenaged18 69y 64.8(Allwomenaged18 69y 37.7(Allwomenaged15 44y 3.8/44.6/ /61.6/ /55/ /63.4/ /56.2/ /46.9/ /61.9/ /44.8/ /54.1/ /45.7/71 2.1/33.3/ /56/74 4.3/54/ /33.3/73.8 No Pakistan SouthAfrica India Cambodia Nepal Nigeria Ghana Uganda nd 2nd 1st 1st 1st 2nd 1st calculatedfromthenumberofdistributeddoses.thelattercalculationsalsoshowacomparablerangeacrossseveralcountries(figure1).giventhatgovernment offcialvaccinesurveillanceprogrammesroutinelyrelyonpassivereporting(26),therateofadrs fromhpvandothervaccinesmaybefurtherunder estimated. 1st everscreened 1.9(Allwomenaged18 69y 13.6(Allwomenaged18 69y screenedevery3y 2.6(Allwomenaged18 69y None 2.4(Allwomenaged18 69y screenedevery3y None 2.7(Allwomenaged18 69y None 6/59.3/ /58.4/62.8 6/56/ /33.3/72.6 6/59.3/ /41.3/50 4.6/41.3/50 6.7/37.9/74.1 No Accordingtosomeestimates,only1 10%oftheADRsintheUS arereportedtovaers(27). ThelackofdataonseriousADRsincountrieswhereroutine HPVvaccinationforyoungwomenisrecommendedandstrongly promoted(tableii)greatlyhampersourunderstandingaboutthe TableII.Summaryofadversereactions(ADRs)fromHPVvaccinesGardasilandCervarix.NotethattheUSFDACodeofFederalRegulationdefinesaserious adversedrugeventas anyadversedrugexperienceoccurringatanydosethatresultsinanyofthefollowingoutcomes:death,alife threateningadversedrug experience,inpatienthospitalizationorprolongationofexistinghospitalization,apersistentorsignificantdisability/incapacity,oracongenitalanomaly/birth defect (106). Vaccine Country Totaln ADRs(ref.) Dosesn(ref.) Gardasil US 18,727(7) 35,000,000 a (7) France 1,700(34) 4,000,000 a (34) Australia 1,534(39) 6,000,000 a (39) Ireland 314(33) 90,000 b (33) Cervarix Netherlands 575(32) 192,000 b (32) UK 8,798(23) 3,500,000 b (23) na= notavailable. a Dosesdistributed. b Dosesadministered. c Excluding2010data(unavailableatthetimeofwritingofthisreport). Total n ADRs/100,000 doses Total n serious ADRs(ref.) 1,498(7) na 91 c (26,28,29) na 575(32) na Total n serious ADRs/100,000doses c 5.7

4 4L. Tomljenovic & C. A. Shaw Figure 1. The rate of adverse reactions (ADRs) from Gardasil and Cervarix reported through various government official vaccine surveillance programmes. For the data source, see Table II. overallsafetyofthevarioushpvvaccinationprogrammes.nonetheless, analysis of the UK Medicines and Healthcare products RegulatoryAgency(MHRA)vaccinesafetydatashowsthatthere may be valid reasons for concern. For example, the total number of ADRs reported for Cervarix appears to be times higher than that reported for any of the other vaccines in the UKimmunizationschedule(Figure2). Off cial reports on adverse events following immunization (AEFI) in Australia also raise concerns(26). In 2008, Australia reported an annual AEFI rate of 7.3/100,000, the highest since 2003, representing an 85% increase compared with AEFI rate from2006(26).thisincreasewasalmostentirelyduetoaefis reportedfollowingthecommencementofthenationalhpvvaccinationprogrammeforfemalesaged12 26yearsinApril2007 (705 out of a total of 1538 AEFI records). Thus, nearly 50% of allaefisreportedduring2007wererelatedtothehpvvaccine. Moreover, HPV vaccine was the only suspected vaccine in 674 (96%) records, 203 (29%) had causality ratings of certain or probable,and43(6%)weredefinedas serious.themostsevere AEFIsreportedfollowingHPVvaccinationwereanaphylaxisand convulsions.notably,in2007,10outof13reportedanaphylaxis (77%) and 18 out of 35 convulsions (51%) occurred in women followinghpvvaccination(26).during2008,thehpvvaccine wasstillthenumberonevaccineonthelistofaefisinaustralia, with497records(32%ofallaefis),andaccountablefornearly 30%ofconvulsions(13outof43)(28).During2009,theAustralianreportedAEFIrateforadolescentsdecreasedbyalmost50% (from 10.4 to 5.6/100,000)(29). This decline in AEFI rates was attributedtoareductioninthenumbersofhpvvaccine related reports, following cessation of the catch up component of the HPV programme(29). Namely, the percentage of AEFIs related to HPV vaccines was only 6.4 in 2009 (29) compared to 50 in 2007(26).InspiteoftheoverallsignificantdecreaseinAEFIrate, the percentage of convulsions attributable to the HPV vaccine remainedcomparablebetween2007and2009(51%(26)and40% (29),respectively). Cumulatively,thelistofseriousADRsrelatedtoHPVvaccinationintheUS,UK,Australia,Netherlands,France,andIreland includes deaths, convulsions, syncope, paraesthesia, paralysis, Guillain Barrésyndrome(GBS),transversemyelitis,facialpalsy, chronic fatigue syndrome, anaphylaxis, autoimmune disorders, deep vein thrombosis, pulmonary embolisms, and pancreatitis (23,24,26,28 35). Itmaybethusappropriatetoaskwhetheritisworthrisking deathoradisablinglifelongneurodegenerativeconditionsuch asgbsatapreadolescentageforavaccinethathasonlyatheoreticalpotentialtopreventcervicalcancer,adiseasethatmaydevelop20 40yearsafterexposuretoHPV,when,asHarpernoted, thesamecanbepreventedwithregularpapscreening(36)? Itisalsoofnotethatinthepost licensureperiod( ), theusvaersreceived360reportsofabnormalpapsmears,112 reports of cervical cancer dysplasia, and 11 reports of cervical cancersrelatedtohpvvaccines(35).inareporttothefda(37), Merckexpressedtwo importantconcerns regardingadministration of Gardasil to girls with pre existing HPV 16/18 infection. One was the potential of Gardasil to enhance cervical disease, andtheother wastheobservationsofcin2/3orworsecasesdue tohpvtypesnotcontainedinthevaccine.accordingtomerck, ThesecasesofdiseaseduetootherHPVtypeshavethepotentialtocountertheeffcacyresultsofGardasilfortheHPVtypes containedinthevaccine. Table17inMerck sreporttothefda shows that Gardasil had an observed effcacy rate of 44.6% in subjectswhowerealreadyexposedto relevanthpvtypes (37). If,asimpliedbyMerck sownsubmission,gardasilmayexacerbate Figure 2. The rate of adverse reactions (ADRs) from Cervarix compared to that of other vaccines in the UK immunization schedule. Data sourced from the report provided by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for the Joint Committee on Vaccination and Immunisation in June 2010 (23).

5 HPV vaccines and evidence-based medicine 5 the very disease it is supposed to prevent, why do the US FDA and the CDC allow for preadolescent girls and young women to be vaccinated with Gardasil without prescreening them for HPV 16/18infections? Side-effects from HPV vaccines: are they a minor concern? Accordingtogovernmentalhealthagenciesworldwide,including theuscdc,healthcanada,theaustraliantherapeuticgoods Administration(TGA),theUKMHRA,andtheIrishMedicines Board(IMB),thevastmajorityofadversereactionsfromeither GardasilorCervarixarenon serious(6,23,24,38,39).thesesourcesfurtherstatethatmostparticipantsreportbriefsorenessatthe injectionsite,headache,nausea,fever,andfainting(6,23,24,38,39). Moreover,theUKMHRAandtheUSFDAandtheCDCmaintain that fainting is common with vaccines (especially among adolescents)andhencenotareasonforconcern(6,23).specifically,theukmhrastatesthat Psychogenicevents including vasovagal syncope, faints and panic attacks can occur with any injectionprocedure andthat sucheventscanbeassociatedwith awiderangeoftemporarysignsandsymptomsincludinglossof consciousness, vision disturbances, injury, limb jerking (often misinterpreted as a seizure/convulsion), limb numbness or tingling,diffcultyinbreathing,hyperventilationetc. (23). TheVAERSdatashowthatsince2006whenitwasfirst approved,gardasilhasbeenassociatedwith18,727adversereactionsintheusalone,8%ofwhichwereserious(1498)including 68deaths(TableII).Areporttoanypassivevaccinesurveillance systemdoesnotbyitselfprovethatthevaccinecausedanadr. Systematic,prospective,controlledtrialsareneededtoestablish orrejectcausalrelationshipswithregardtodrug relatedadverse reactionsofanytype.nevertheless,theunusuallyhighfrequency ofreportsofadrsrelatedtohpvvaccines(figure2),aswellas theirconsistentpattern(i.e.withonlyminordeviations,nervous system relateddisordersrankthehighestinfrequencyacrossdifferentcountries,followedbygeneral/administrationsiteconditionsandgastrointestinaldisorders)(figure3),indicatesthatthe risksofhpvvaccinationmaynothavebeenfullyevaluatedin clinicaltrials.indeed,intheiranalysisofadrsofpotentialautoimmuneaetiologyinalargeintegratedsafetydatabaseofaso4 adjuvantedvaccines(anoveladjuvantsystemcomposedof3 Odesacyl 4 monophosphoryllipidaandaluminumsaltsusedin Cervarix),Verstraetenetal.(40)acknowledgethat Itisimportant tonotethatnoneofthesestudiesweresetupprimarilytostudy autoimmunedisorders. Ifthepurposeofthestudywasindeedto assessadrsof potentialautoimmuneaetiology,asthetitleitself clearlystates(40),thenthestudyshouldhavebeendesignedto detectthem.alloftheeightauthorsoftheaso4safetystudy areemployeesofglaxosmithkline(gsk),themanufacturerof Cervarix(40).Theseauthorsnotedthat oursearchoftheliteraturefoundnostudiesconductedbyindependentsourcesonthis subject and Allstudiesincludedinthisanalysiswerefundedby GSKBiologicals,aswastheanalysisitself.GSKBiologicalswas involvedinthestudydesign,datacollection,interpretationand analysis,preparationofthemanuscriptanddecisiontopublish (40). Giventhatvaccinescantriggerautoimmunedisorders(41 44), a more rigorous safety assessment than that provided by the GSK sponsoredstudywouldappeartohavebeenwarranted. Figure 3. Percentages of reported ADRs associated with HPV vaccines for each system organ class. Data sourced from the Database of the Netherlands Pharmacovigilance Centre Lareb (32), the UK Medicines and Healthcare products Regulatory Agency (MHRA) (62), and the Irish Medicines Board (IMB) (24). The most commonly reported ADRs in the nervous system and psychiatric disorders class were headache, syncope, convulsions, dizziness, hypoaesthesia, paraesthesia, lethargy, migraine, tremors, somnolence, loss of consciousness, dysarthria, epilepsy, sensory disturbances, facial palsy, grand mal convulsion, dysstasia, dyskinesia, hallucination, and insomnia.

6 6L. Tomljenovic & C. A. Shaw Meanwhile, independent scientific reports have linked HPV vaccination with serious ADRs, including death (45,46), amyotrophic lateral sclerosis (ALS) (45), acute disseminated encephalomyelitis (ADEM) (47 49), multiple sclerosis (MS) (50 52),opsoclonus myoclonussyndrome(oms)(whichischaracterized by ocular ataxia and myoclonic jerks of the extremities)(53), orthostatic hypotension (54), brachial neuritis (55), visionloss(56),pancreatitis(57),anaphylaxis(58),andpostural tachycardiasyndrome(pots)(59). ADEMandMSareseriousdemyelinatingdiseasesofthecentral nervoussystemthattypicallyfollowafebrileinfectionor vaccination(49,50,60).bothdisordersarealsothoughttobetriggeredby anautoimmunemechanism(50).clinicalsymptomsincluderapid onset encephalopathy, multifocal neurologic deficits, demyelinatinglesions,opticneuritis,seizures,spinalconditions,andvariable alterationsofconsciousnessormentalstatus(47,49,60).regarding POTS,thereportedcasehadnootherrelevantfactorsoreventsprecedingthesymptomsonsetapartfromGardasilvaccination(59). POTSisdefinedasthedevelopmentoforthostaticintolerance(61). According to Blitshteyn, It is probable that some patients who developpotsafterimmunizationwithgardasilorothervaccines are simply undiagnosed or misdiagnosed, which leads to underreporting and a paucity of data on the incidence of POTS after vaccinationinliterature (59).PatientswithPOTStypicallypresent withcomplaintsofdiminishedconcentration,tremulousness,dizzinessandrecurrentfainting,exerciseintolerance,fatigue,nausea andlossofappetite(59,61).suchsymptomsmaybeincorrectlylabelledaspanicdisordersorchronicanxiety.notably,symptomsof POTSappeartobeamongthemostfrequentADRsreportedafter vaccinationwithhpvvaccines(6,23,24,39).inspiteofthis,health authoritiesworldwidedonotregardtheseoutcomesascausallyrelatedtothevaccine(6),butratheras psychogenicevents (23,39). In summary, it appears that many medical authorities may have been too quick to dismiss a possible link between HPV vaccinesandseriousadrsbyrelyingheavilyondataprovided by the vaccine manufacturers rather than from independent research.theukmhrastatesthat Thevastmajorityofsuspected ADRs reported to MHRA in association with Cervarix vaccinecontinuetoberelatedtoeitherthesignsandsymptoms of recognized side effects listed in the product information or totheinjectionprocessandnotthevaccineitself(i.e. psychogenic innaturesuchasfaints) (23).Itisinterestingtonotethat theentiregroupofsystemclassdisordersshowninfigure3is regarded as unrelated to the HPV vaccine by the MHRA. AccordingtotheAgency, ThesesuspectedADRsarenotcurrently recognisedassideeffectsofcervarixvaccineandtheavailable evidencedoesnotsuggestacausallinkwiththevaccine.th ese are isolated medical events which may have been coincidental withvaccination (23,62).However,thefactthatasimilarpattern ofsystemclassadrstothatintheukhasalsobeenobservedin atleasttwoothercountriesarguesagainstthemhraconclusion andsuggeststheopposite,namelyacausalrelationshipwiththe HPVvaccine(Figure3). Safety assessment of HPV vaccines in clinical trials: was it adequate? Adouble blinded,placebo controlledtrialisconsideredthe gold standard forclinicaltrialsasitisthoughttopreventpotentialresearchers biasesfromdistortingtheconductofatrialand/orthe interpretationoftheresults(63).biases,however,maystilloccur due to selective publication of findings from within such trials, subject selection factors (inclusion/exclusion criteria), as well as placebochoices.withregardtothelatter,accordingtothefda,a placebois aninactivepill,liquid,orpowderthathasnotreatment value (63).Itisthereforesurprisingthustonotethatnoregulations governplacebocomposition,giventhatcertainplaceboscaninfluencetrialoutcomes(64).specifically,placebocompositioncan,in principle,bemanipulatedtoproduceresultsthatarefavourableto thedrugeitherintermsofsafetyoreffcacy(64). TheclinicaltrialsforGardasilandCervarixusedanaluminumcontaining placebo (15,20,40,65 69). Both HPV vaccines, like manyothervaccines,areadjuvantedwithaluminuminspiteof well documented evidence that aluminum can be highly neurotoxic (70 72). Moreover, current research strongly implicates aluminum adjuvants in various neurological and autoimmune disordersinbothhumansandanimals(41,73 80).Itisthusbecomingincreasinglyclearthattheroutineuseofaluminumasa placeboinvaccinetrialsisnotappropriate(80,81). Notably, safety data for Gardasil presented in Merck s packageinsertandthefdaproductapprovalinformation(82)show thatcomparedtothesalineplacebo,thosewomenreceivingthe aluminum containingplaceboreportedapproximately2 5times more injectionsite ADRs. On the other end, the proportion of injectionsiteadrsreportedinthegardasiltreatmentgroupwas comparabletothatofthealuminum control group(tableiii). Thus,Merck sowndataseemtoindicatethatalargeproportion ofadrsfromthehpvvaccinewereduetotheeffectofthealuminumadjuvant. For the assessment of serious conditions, the manufacturer pooledtheresultsfromthestudyparticipantswhoreceivedthe salineplacebowiththosewhoreceivedthealuminum containing placeboandpresentedthemasone control group.theoutcome ofthisprocedurewasthatgardasilandthealuminum control group had exactly the same rate of serious conditions (2.3%) (TableIV). Inarecentmeta analysisofsafetyandeffcacyofhpvvaccines, seventrialsenrollingatotalof44,142femaleswereevaluated(83). Twomainpopulationsofwomenweredefinedinthesetrials:those who received three doses of the HPV vaccine or the aluminumcontainingplacebowithinayear(denotedastheper protocolpopulation(ppp)),andthosewhoreceivedatleastoneinjectionofthe vaccine or the placebo within the same period (intention to treat population (ITT)). While HPV vaccine effcacy was evaluated in bothpppandittcohorts,vaccinesafetywasprimarilyevaluated intheittcohort(83).althoughittanalysisis conservative for assessment of treatment benefits (since dropouts may occur), it is anti conservative forassessmentofadrs,becauseadrswilloccur Table III. Injectionsite adverse reactions (ADRs) reported in Gardasil clinical trials among 8878 female participants aged 9 26 years, 1 5 days post vaccination(82). Aluminum(AAHS) a Salineplacebo ADRtype Gardasil(n =5088)% (n =3470)% (n =320)% Gardasil/saline Gardasil/AAHS AAHS/saline Pain Swelling Erythema Pruritus Bruising a AAHSControl= amorphousaluminumhydroxyphosphatesulfate.

7 HPV vaccines and evidence-based medicine 7 Table IV. Number of girls and women aged 9 26 years who reported a condition potentially indicative of a systemic autoimmune disorder after enrolmentingardasilclinicaltrials(82). Aluminum(AAHS) Gardasil(n =10,706) a (n =9412) Condition n(%) n(%) Arthralgia/arthritis/arthropathy 120(1.1) 98(1.0) Autoimmunethyroiditis 4(0.0) 1(0.0) Coeliacdisease 10(0.1) 6(0.1) Insulin dependent 2(0.0) 4(0.0) Diabetesmelitusinsulin dependent 2(0.0) 2(0.0) Erythemanodosum 27(0.3) 21(0.2) Hyperthyroidism 35(0.3) 38(0.4) Hypothyroidism 7(0.1) 10(0.1) Inflammatoryboweldisease 2(0.0) 4(0.0) Multiplesclerosis 2(0.0) 5(0.1) Nephritis 2(0.0) 0(0.0) Opticneuritis 4(0.0) 3(0.0) Pigmentationdisorder 13(0.1) 15(0.2) Psoriasis 3(0.0) 4(0.0) Raynaud sphenomenon 6(0.1) 2(0.0) Rheumatoidarthritis 2(0.0) 1(0.0) Scleroderma/morphea 1(0.0) 0(0.0) Stevens Johnsonsyndrome 1(0.0) 3(0.0) Sytemiclupuserythematosus 3(0.0) 1(0.0) Uveitis 3(0.0) 1(0.0) Total 245(2.3) 218(2.3) lessfrequentlyiffewerdosesofthevaccineareadministered.th us, suchaselectionproceduremayexplainwhythemeta analysisfound therisk to benefitratiotobeinfavourofthehpvvaccines(83). Theseventrialsincludedinthemeta analysiswereallsponsored bythevaccinemanufacturers(14,15,20,65 69).Inalengthyreport ofpotentialconflictsofinterestsofthefutureiitrialstudygroup (15),themajorityofauthorsdeclared receivinglecturefeesfrom Merck,SanofiPasteur,andMerckSharp&Dohme.Inaddition, IndianaUniversityandMerckhaveaconfidentialagreementthatpays theuniversityonthebasisofcertainlandmarksregardingthehpv vaccine. Inthe2009JAMAeditorial(11),Haugnotedthat When weighingevidenceaboutrisksandbenefits,itisalsoappropriateto askwhotakestherisk,andwhogetsthebenefit.patientsandthe publiclogicallyexpectthatonlymedicalandscientificevidenceis putonthebalance.ifothermattersweighin,suchasprofitfora companyorfinancialorprofessionalgainsforphysiciansorgroups ofphysicians,thebalanceiseasilyskewed.thebalancewillalsotilt iftheadverseeventsarenotcalculatedcorrectly. Are there safe and effective alternatives to HPV vaccination? Although approximately 275,000 women die annually from cervicalcancerworldwide,almost88%ofthesedeathsoccurin developing countries. Such disproportion of cancer deaths may besurprisinggiventhattheprevalenceofhpv 16/18inwomen withcervicalcancerisequalinbothdevelopinganddeveloped countries(71.0%and70.8%,respectively)(tablev).furthermore, HPV 16andHPV 18arethemostoncogenicofallHPVsubtypes and increasingly dominant with increasing severity of cervical cancerlesions(tablei)(84).nonetheless,analysisofwhodata in Figure 4 shows that HPV 16/18 prevalence in women with high gradelesionsaswellascervicalcancerisnotasignificant promoterofhighcervicalcancermortalityindevelopingcountries (P = ), but rather it is the lack of or insuffcient Papscreeningcoverage(P < ).Thesedatadonotdispute that HPV 16/18 infection is a primary prerequisite for cervical cancer.however,theydopointtootherco factorsasnecessary determinantsofbothdiseaseprogressionandoutcome(85). TheeffcacyofregularPapscreeningproceduresindeveloped countriesisfurtheremphasizedbythefactthatsuchprogrammes helped to achieve a 70% reduction in the incidence of cervical cancer over the last five decades (10,12,86,87). Conversely, in Finland,whenwomenstoppedattendingPapscreens,a4 foldincreaseincervicalcanceroccurredwithin5yearsfromscreening cessation(88,89). ItshouldbeemphasizedthatHPVvaccinationdoesnotmake Papscreeningobsolete,especiallysincethecurrentHPVvaccines guardonlyagainst2outof15oncogenichpvstrains.harpernotedthatifhpv vaccinatedwomenstoppedgoingforpapsmears, the incidence rate of cervical cancer would increase (36,86). A similarconcernwasalsoraisedbyfrenchandcanadianresearcherswhosuggestedthepossibilitythatvaccinatedwomenmightbe lessinclinedtoparticipateinscreeningprogrammes(87,90).such outcomeswouldinturncompromisetimelyspecialistreferralof casesharbouringprecancerouslesions,especiallythoserelatedto HPVgenotypesotherthan16/18(90). Are HPV vaccines cost-effective? Th ecurrentlylicensedhpvvaccinesareamongthemostexpensivevaccinesonthemarket(i.e.gardasilcurrentlycostsus$400 forthethreerequireddoses)(87),makingitunlikelythatthose countries with the heaviest burden of cervical cancer mortality (i.e.uganda,nigeria,andghana)wouldeverbenefit from them.thatisundertheassumptionthatthelong termbenefits fromhpvvaccination(i.e.cancerprevention)wereproven.for example, preadolescent HPV vaccination in Thailand is costeffectiveonlywhenassuminglifelongeffcacyandacostof10 international dollars (I$, a currency that provides a means of translatingandcomparingcostsamongcountries)pervaccinated girl(approximatelyi$2/dose)orless(91).thecost effectiveness analysisofhpvvaccinationforeasternafricashowsasimilar outcome(25).incountrieswherepricingislessofanissue,such astheus,hpvvaccinationisonlycost effectivebasedonthe assumption of complete and lifelong vaccine effcacy and 75% coverageofthetargetedpreadolescentpopulation(92,93).inthe Netherlands,HPVvaccinationisnotcost effectiveundersimilar assumptions(e.g.thatthehpvvaccineprovideslifelongprotectionagainst70%ofallcervicalcancers,hasnoside effects,and isadministeredtoallwomenregardlessoftheirriskofcervical cancer)(94).notethatthereasonwhyhighcoverageisneeded for a vaccine to be cost effective in the developed countrysetting is the very low incidence of cervical cancer (due to effectivenessofpapscreeningprogrammes).forexample,toprevent asingleoutof5.7/100,000cervicalcancercases(oroneoutof 1.7/100,000cervicalcancerdeaths)intheUS,nearlyeverygirl wouldneedtobevaccinatedforthehpvvaccineprogrammeto becost effective. The increased pressure to make the HPV vaccines mandatory for all preadolescent girls makes the cost of the HPV vaccinationprogrammeasignificantissue.forexample,according toa2006reportinthe New York Times (95),tomakeGardasil mandatorywouldprobablydoublethecostoftheusvaccination programme: North Carolina, for instance, spends $11 million annuallytoprovideeverychildwithsevenvaccines.gardasilalone wouldprobablycostatleastanother$10million. UndertheassumptionthattheHPVvaccineoffersfullprotectionagainstHPV infectionfor5years,an11 year oldgirlwouldneed13booster shotsifsheweretolivetotheageof75.atacurrentcostofus $120perdose,thetotalcostforvaccinatingonegirlwouldthus exceedus$1500.accordingtosomeestimates,tovaccinateevery 11 and12 year oldgirlintheuswouldcostus$1.5billionandto