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HPV Vaccination - the end of the road for cervical cancer? Alison Fiander Wales College of Medicine Cardiff University
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HPV prophylactic vaccination Why - the burden of disease worldwide/Wales The role of the human papillomavirus (HPV) Prophylactic HPV vaccines Issues for HPV vaccination HPV information & public education needs Where do we go from here?
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Why important? 40 women die daily of cacx in Europe Second most common ca death in young women in Europe Global problem: 83,000/yr developed cf > 400,000 developing world > 80% occurs in developing world Second most common ca in women worldwide
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<3.9<7.9<14.0 <23.8 <55.6 Cancer of the cervix (mortality/100,000) Mortality falling developed world Mortality rising in developing world
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Cervical cancer – the size of the problem in England & Wales Without screening (Peto et al 2004) Epidemic of cervical cancer Estimated incidence in 2030 = 11,000 cases cxca per year Estimated mortality = 5,500 deaths per year
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Cervical cancer – the size of the problem in England & Wales With screening (CRUK 2000) Actual incidence of cxca = 2,590 Mortality of cxca = 998 Cost of screening E&W £150m/yr Cost per woman saved = £36,000
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The role of the Human Papillomavirus (HPV) Central aetiological role in cervical neoplasia Cervical intraepithelial neoplasia (CIN) & cx cancer Found in 99.7% of cervical cancers ‘Necessary’, if not sufficient, cause of cervical cancer Also important role in other anogenital neoplasia eg vulval and anal neoplasia Terminology: Low grade = borderline or mild dyskaryosis & CIN1 High grade = moderate or severe dyskaryosis or CIN2-3
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Which Human Papillomaviruses to target? ? > 100 types of HPV 20 Anogenital types Low Risk6, 11, 40, 42, 43, 44, 54, 61 Anogenital warts High risk16, 18 45, 31, 33, 52, 58, 35, 59, 56, 39, 51, 73, 68, 66 Cervical neoplasia 6,11, 16,18, 90% warts 70% cervical cancer
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The size of the problem in Wales Cervical Screening Wales (CSW) All Wales Cervical Screening Programme Population of Wales 2.93m (1.5m women)
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CSW - work load 2004/5 Female population 1.5m Screening 20-64yrs Routine recall 3 yearly Coverage 20-24yr 50% Coverage 25-64yr 79%
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CSW – work load 2004/5 208,000 smears 92.3% negative 7.7% abnormal: 3.5% BL, 2.3% mild, 0.8% moderate 0.7% ‘positive’ (severe or worse)
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CSW – work load 2004/5 Referral to colposcopy: 1x moderate/severe dyskaryosis 2x mild dyskaryosis 3x borderline 7300 new referrals 41 cancers, 3218 HG disease 22,000 colposcopy clinic visits
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Age of first screen? Screening 20-24y in Wales Small numbers of cancers Incidence & mortality 50% reduction since 1988 Prevents 1 ca & 2 microinvasive ca/yr 20-24y Prevents 8 ca 25-29y Costs £82,500 per ca But 22,000 smears, 450 LLETZ & risks of screening Could be prevented by prophylactic vaccination?
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Prophylactic HPV vaccines Prevent initial infection by HPV Current vaccines cover HR types 16 & 18 accounting for 70% cacx Encouraging phase III trials High [NA], 100% efficacy @ 4yrs Ongoing trials for missing data 300 euros for 3 IM doses
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Recombinant L1 structural protein Self-assemble into Virus Like Particles Resemble intact viruses - no DNA Non infectious L1 protein Prophylactic vaccines - Virus Like Particles (VLPs) Immunogenic - Neutralizing Antibodies
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Current candidate VLP Vaccines Vaccines in late stage clinical development: GSK bivalent vaccine HPV 16/18 + novel adjuvant Sanofi Pasteur MSD quadrivalent vaccine HPV 16/18/6/11 + Alum No head to head comparisons
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HPV 16 VLP Vaccine Merck 1533 women 16 – 23 years old HPV negative at enrollment Median FU 17.4 months Koutsky 2002
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HPV 16 VLP Vaccine Vaccine group n=768 Placebo group n=765 Persistent HPV16 infection 041 HPV16 related CIN l9 100% efficacy against HPV16 persistent infection & CIN
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GSK vaccine HPV 16/18 VLP + AS04 adjuvant 1113 women (15-25y) RCT, double blind 27 month FU Brazil and North America Harper 2004
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HPV 16/18 VLP Vaccine Vaccine group n=366 Placebo group n=355 Persistent HPV16 infection 07 Persistent HPV18 infection 00 HPV16/18 related CIN 06 100% efficacy against HPV16/18 persistent infection & CIN
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HPV 16/18 VLP Vaccine Cross protection due to adjuvant HPV31, 52, 45 Efficacy ~75-80%
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Future II study Quadrivalent vaccine HPV6/11/16/18 Protects against 70% HGCIN, 35% LGCIN, 90% genital warts Phase III, over 10,000 subjects 15-26 years Interim analysis at 17 months 21 cases of CIN2/3 with placebo cf no cases HPV16/18 related CIN with vaccine
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Future I study Quadrivalent vaccine HPV6/11/16/18 5455 women (16-23years) Looked at cervical neoplasia and external genital lesions 2 years follow-up
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Future I study Vaccine group n=2240 Placebo group n=2258 CIN or worse037 Genital warts, VIN or VAIN 040
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However… Neutralising antibodies type specific Cross protection against other HPV types? Polyvalent vaccines? 5-6 HPV types for 80-90% coverage
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Number of Types HPV Type Cummulative % 1HPV 1659 2HPV 1874 3HPV 4580 4HPV 3184 5HPV 3388 6HPV 5890 7HPV 5293 8HPV 3595 Potential for coverage by type
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However… When to vaccinate? Pre-puberty? Cultural issues?
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However… How often? How long does protection last? Are HPV infections in older women due to new infection or reactivation previous infection?
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However… Vaccinate males? Need for herd immunity? However… is he cost effective?
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However… Developing countries
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However… Consequences for cervical screening? Cost effectiveness screening and vaccination? Public education required
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Key questions remaining: Acceptability and uptake Booster requirements? Cross protection? Efficacy in older women? Effective in men? Long term efficacy of screening v. vaccination strategies?
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Combination HPV vaccination & screening - potential health gain Reduction of abnormal cytology & preinvasive disease (CIN2/3) Reduction in colposcopy workload Reduction in incidence, morbidity & mortality of cervical cancer Reduction in morbidity of screening
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Vaccine Acceptability 74 % (male = female) Factors affecting acceptance Parents’ feelings Universal recommendation Safety Low cost Viral STD Vaccine Acceptability Among College Students Boehner et al 2003 Sex Transm Dis
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HPV information needs Is there a problem? If so, does it need fixing? What? How? Role of the Health professional?
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What is known about HPV infection? Serious knowledge gap Lack of awareness of HPV as a common STI 2% males, 4.6% females Baer et al 2000 Negative emotion to testing HPV positive Ramirez et al 1997
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What is known about HPV infection? Adolescents vulnerable to HPV infection Adolescent knowledge of HPV poor 87% secondary school pupils never heard of HPV 28% thought HPV causes AIDS Dell et al 2000
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What is known about HPV infection in UK? Well women clinic: 30% heard of HPV Waller et al 2003 Welsh Colposcopy & GUM clinics: 23% heard of HPV, 15% knew link with cervical cancer 77% would have HPV test Tristram & Fiander 2003 Older female work force: good understanding of cervical screening but only 30% heard of HPV Pitts & Clarke 2002
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What is known about HPV infection? General public - not much! Healthcare professionals - not enough!
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What don’t they know? Dominant themes Unaware of how common HPV infection is Unaware of different types, LR vs HR Unsure of how acquired and spread Concern about impact upon partner
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Healthcare professionals’ HPV knowledge Many healthcare professionals trained prior to link between HPV and neoplasia established Norway GPs - 60% feel knowledge inadequate Havnegjerde Current medical students good knowledge
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The HPV knowledge gap Will affect prophylactic vaccine uptake? Could impede effective HPV-based screening Prevents risk reduction and changes in health behaviour Works against sexual health Needs urgent attention
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How? School SRE World wide web Responsible media/popular press Cervical Screening Literature Healthcare providers
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What to do in Wales? RCT : GSK v MSD vaccine or Implementation study using one vaccine (pick the best) Both strategies require monitoring of uptake of vaccine, effect upon screening, costs & health gain
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