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