hpv vaccination - the end of the road for cervical cancer? alison fiander wales college of medicine...
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HPV Vaccination - the end of the road for cervical cancer?
Alison Fiander
Wales College of Medicine
Cardiff University
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?
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
<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
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
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
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
Which Human Papillomaviruses to target? ?
> 100 types of HPV
20 Anogenital types
Low Risk 6, 11, 40, 42, 43, 44, 54, 61
Anogenital warts
High risk 16, 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
The size of the problem in Wales
Cervical Screening Wales (CSW) All Wales Cervical Screening Programme Population of Wales 2.93m (1.5m women)
CSW - work load 2004/5
Female population 1.5m Screening 20-64yrs Routine recall 3 yearly Coverage 20-24yr 50% Coverage 25-64yr 79%
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)
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
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?
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
Recombinant L1 structural protein
Self-assemble into Virus Like Particles
Resemble intact viruses - no DNA
Non infectiousL1 protein
Prophylactic vaccines - Virus Like Particles (VLPs)
Immunogenic - Neutralizing Antibodies
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
HPV 16 VLP Vaccine
Merck
1533 women
16 – 23 years old
HPV negative at enrollment
Median FU 17.4 monthsKoutsky 2002
HPV 16 VLP Vaccine
Vaccine groupn=768
Placebo groupn=765
Persistent HPV16 infection
0 41
HPV16 related CIN
l 9
100% efficacy against HPV16 persistent infection & CIN
GSK vaccine
HPV 16/18 VLP + AS04 adjuvant 1113 women (15-25y) RCT, double blind 27 month FU Brazil and North America
Harper 2004
HPV 16/18 VLP Vaccine
Vaccine groupn=366
Placebo groupn=355
Persistent HPV16 infection
0 7
Persistent HPV18 infection
0 0
HPV16/18 related CIN
0 6
100% efficacy against HPV16/18 persistent infection & CIN
HPV 16/18 VLP Vaccine
Cross protection due to adjuvant HPV31, 52, 45 Efficacy ~75-80%
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
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
Future I study
Vaccine groupn=2240
Placebo groupn=2258
CIN or worse 0 37
Genital warts, VIN or VAIN
0 40
However…
Neutralising antibodies type specific
Cross protection against other HPV types?
Polyvalent vaccines? 5-6 HPV types for 80-90% coverage
Number of Types
HPV Type
Cummulative %
1 HPV 16 59
2 HPV 18 74
3 HPV 45 80
4 HPV 31 84
5 HPV 33 88
6 HPV 58 90
7 HPV 52 93
8 HPV 35 95
Potential for coverage by type
However…
When to vaccinate?
Pre-puberty?
Cultural issues?
However…
How often? How long does protection last? Are HPV infections in older women due to
new infection or reactivation previous infection?
However…
Vaccinate males?
Need for herd immunity?
However… is he cost effective?
However…
Developing countries
However…
•Consequences for cervical screening?
•Cost effectiveness screening and vaccination?
•Public education required
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?
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
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
HPV information needs
Is there a problem? If so, does it need fixing? What? How? Role of the Health professional?
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 positiveRamirez et al
1997
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 AIDSDell et al
2000
What is known about HPV infection in UK?
Well women clinic: 30% heard of HPVWaller 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
What is known about HPV infection?
General public -
not much!
Healthcare professionals -
not enough!
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
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
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
How?
School SRE World wide web Responsible media/popular press Cervical Screening Literature Healthcare providers
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