HPV Vaccination - the end of the road for cervical cancer?

1. HPV Vaccination - the end of the road for cervical cancer? Alison Fiander Wales College of Medicine Cardiff University

2. 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?

3. 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

4. Cancer of the cervix (mortality/100,000) <3.9 <7.9 <14.0 <23.8 <55.6 • Mortality falling developed world • Mortality rising in developing world

5. 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

6. 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

7. 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

8. Which Human Papillomaviruses to target? ? 90% warts • > 100 types of HPV • 20 Anogenital types 6,11, • Low Risk 6, 11, 40, 42, 43, 44, 54, 61 Anogenital warts 70% cervical cancer 16,18, • High risk16, 18 45, 31, 33, 52, 58, 35, 59, 56, 39, 51, 73, 68, 66 Cervical neoplasia

9. The size of the problem in Wales • Cervical Screening Wales (CSW) • All Wales Cervical Screening Programme • Population of Wales 2.93m (1.5m women)

10. CSW - work load 2004/5 • Female population 1.5m • Screening 20-64yrs • Routine recall 3 yearly • Coverage 20-24yr 50% • Coverage 25-64yr 79%

11. 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)

12. 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

13. 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?

14. 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

15. Recombinant L1 structural protein Prophylactic vaccines - Virus Like Particles (VLPs) • Resemble intact viruses - no DNA L1 protein • Self-assemble into Virus Like Particles • Non infectious • Immunogenic - NeutralizingAntibodies

16. 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

17. HPV 16 VLP Vaccine • Merck • 1533 women • 16 – 23 years old • HPV negative at enrollment • Median FU 17.4 months Koutsky 2002

18. HPV 16 VLP Vaccine 100% efficacy against HPV16 persistent infection & CIN

19. GSK vaccine • HPV 16/18 VLP + AS04 adjuvant • 1113 women (15-25y) • RCT, double blind • 27 month FU • Brazil and North America Harper 2004

20. HPV 16/18 VLP Vaccine 100% efficacy against HPV16/18 persistent infection & CIN

21. HPV 16/18 VLP Vaccine • Cross protection due to adjuvant • HPV31, 52, 45 • Efficacy ~75-80%

22. 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

23. 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

24. Future I study

25. However… • Neutralising antibodies type specific • Cross protection against other HPV types? • Polyvalent vaccines? • 5-6 HPV types for 80-90% coverage

26. Potential for coverage by type

27. However… • When to vaccinate? • Pre-puberty? • Cultural issues?

28. However… • How often? • How long does protection last? • Are HPV infections in older women due to new infection or reactivation previous infection?

29. However… • Vaccinate males? • Need for herd immunity? However… is he cost effective?

30. However… • Developing countries

31. However… • Consequences for cervical screening? • Cost effectiveness screening and vaccination? • Public education required

32. 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?

33. 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

34. 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

35. HPV information needs • Is there a problem? • If so, does it need fixing? • What? • How? • Role of the Health professional?

36. 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

37. 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

38. 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

39. What is known about HPV infection? "HPV! How do I know I've got it?" General public - not much! • Healthcare professionals - • not enough!

40. 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

41. 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

42. 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

43. How? • School SRE • World wide web • Responsible media/popular press • Cervical Screening Literature • Healthcare providers

44. 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