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

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 Estimated incidence in women born after 1950 in 2030 = 11,000 cases per yrEstimated incidence in women born after 1950 in 2030 = 11,000 cases per yr

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? ? > 100 types of HPV 20 Anogenital types mortality/100,00 mortality/100,00

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 Colp referral 82% because of abn smear, 18% clinical - 31%HGColp referral 82% because of abn smear, 18% clinical - 31%HG

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? Single screen 50% sensitiveSingle screen 50% sensitive

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)

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 This was the 1st proof of principle trial using an HPV16 VLP (Merck).This was the 1st proof of principle trial using an HPV16 VLP (Merck).

18. HPV 16 VLP Vaccine

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 Novel adjuvant containing 500ug aluminum hydroxide & 50ug MPL monophosphoryl lipid A Novel adjuvant containing 500ug aluminum hydroxide & 50ug MPL monophosphoryl lipid A

20. HPV 16/18 VLP Vaccine

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?

30. However� Developing countries

31. However� Consequences for cervical screening? Cost effectiveness screening and vaccination? Public education required to promote good sexual health to promote good sexual health

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

35. HPV information needs Is there a problem? If so, does it need fixing? What? How? Role of the Health professional? 2nd topic for discussion is one that I think is imp but it may just be my soapbox and we could perhaps discuss whether there really is a problem, whether it needs fixing and if so what info do we want or need to get across, how do we do it and what�s the role for gynaecologists here?2nd topic for discussion is one that I think is imp but it may just be my soapbox and we could perhaps discuss whether there really is a problem, whether it needs fixing and if so what info do we want or need to get across, how do we do it and what�s the role for gynaecologists here?

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 The seriousness of the knowledge gap is obvious as previous studies on other STDs, have shown that adequate knowledge is important in altering health behaviours. Baer et al looked at HPV knowledge in a group of university students in the USA and investigated gender differences. They knew little about HPV infection, how the virus is transmitted and prevalence compared to other STI. Male respondents didn�t feel well informed and expressed deep concern about STD�s and this emphasizes the need for accurate information about HPV infection for both sexes if transmission of HPV is to be reduced. The majority of women attributed negative emotion to being hypothetically tested positive for HPV. A greater neg emotion score was associated with refusing HPV testing. The seriousness of the knowledge gap is obvious as previous studies on other STDs, have shown that adequate knowledge is important in altering health behaviours. Baer et al looked at HPV knowledge in a group of university students in the USA and investigated gender differences. They knew little about HPV infection, how the virus is transmitted and prevalence compared to other STI. Male respondents didn�t feel well informed and expressed deep concern about STD�s and this emphasizes the need for accurate information about HPV infection for both sexes if transmission of HPV is to be reduced. The majority of women attributed negative emotion to being hypothetically tested positive for HPV. A greater neg emotion score was associated with refusing HPV testing.

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 Adolescents are vulnerable to HPV infection, in whom HPV is widely prevalent. Dell et al assessed knowledge of HPV among high school adolescents in Canada and found 87% had never heard of HPV. They were also unaware of their risk if sexually active and 28% incorrectly identified HPV as a cause of AIDS. Adolescents are vulnerable to HPV infection, in whom HPV is widely prevalent. Dell et al assessed knowledge of HPV among high school adolescents in Canada and found 87% had never heard of HPV. They were also unaware of their risk if sexually active and 28% incorrectly identified HPV as a cause of AIDS.

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 Dr Waller et al look at HPV awareness among women attending a well women clinic in central London. Even among those who had heard of HPV, knowledge was generally poor and fewer than half were aware of the link with cervical cancer. There was also confusion about whether condoms or oral contraceptives could protect against HPV infection. This is disappointing since the sample was generally well educated. In a local study conducted amongst patients attending Cardiff colposcopy and GUM clinics only 23% of women had heard of HPV and only 15% knew it was causally associated with cervical cancer. In another UK survey of the female work force of a UK university with a mean age of 40y only 30% had heard of HPV. 15% of those who�d heard of HPV identified a potential link between HPV and cervical cancer.Dr Waller et al look at HPV awareness among women attending a well women clinic in central London. Even among those who had heard of HPV, knowledge was generally poor and fewer than half were aware of the link with cervical cancer. There was also confusion about whether condoms or oral contraceptives could protect against HPV infection. This is disappointing since the sample was generally well educated. In a local study conducted amongst patients attending Cardiff colposcopy and GUM clinics only 23% of women had heard of HPV and only 15% knew it was causally associated with cervical cancer. In another UK survey of the female work force of a UK university with a mean age of 40y only 30% had heard of HPV. 15% of those who�d heard of HPV identified a potential link between HPV and cervical cancer.

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 A number of studies have investigated what is and isn�t known about HPV infection and what the public wish to know or have clarified. If we can understand these concerns we may be able to address areas of concern and confusion and present relevant, accurate and appropriate information to a receptive audience. An old adage in education is to start with where they�re at. Emotional support & counseling imp to reduce distress and anxiety, thereby enabling women to receive, remember and understand the information presented to them. A number of studies have investigated what is and isn�t known about HPV infection and what the public wish to know or have clarified. If we can understand these concerns we may be able to address areas of concern and confusion and present relevant, accurate and appropriate information to a receptive audience. An old adage in education is to start with where they�re at. Emotional support & counseling imp to reduce distress and anxiety, thereby enabling women to receive, remember and understand the information presented to them.

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 Many healthcare professionals currently involved with cervical screening underwent medical training prior to recognition of link between HPV infection and cervical screening. A Norwegian study showed that whilst 80% of GPs thought it important to inform women about HPV, 60% did not think their knowledge adequate and 50% didn�t know where to get the necessary information. All the medical students in our Cardiff study last year had heard of HPV and knew it could cause warts and abnormal smears. 95% of medical students knew that it caused cervical cancer. Good knowledge probably attributable to current training and possibly local interest in HPV infection.Many healthcare professionals currently involved with cervical screening underwent medical training prior to recognition of link between HPV infection and cervical screening. A Norwegian study showed that whilst 80% of GPs thought it important to inform women about HPV, 60% did not think their knowledge adequate and 50% didn�t know where to get the necessary information. All the medical students in our Cardiff study last year had heard of HPV and knew it could cause warts and abnormal smears. 95% of medical students knew that it caused cervical cancer. Good knowledge probably attributable to current training and possibly local interest in HPV infection.

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 Lack of knowledge and misunderstanding about HPV infection could greatly impede the prospects for effective cervical screening based upon HPV testing. Since adequate knowledge is imp in altering health behaviours any successful prevention or management programme for HPV infection must incorporate into its development a detailed education programme.Lack of knowledge and misunderstanding about HPV infection could greatly impede the prospects for effective cervical screening based upon HPV testing. Since adequate knowledge is imp in altering health behaviours any successful prevention or management programme for HPV infection must incorporate into its development a detailed education programme.

43. How? School SRE World wide web Responsible media/popular press Cervical Screening Literature Healthcare providers There is a large variety of information is available to both professionals and the general public and the question is how can we use this to ensure that the right messages are put across? We probably need to use multiple methods - starting by incorporating it into school SRE. Gynae = advocate for women�s health and therefore an imp part to play.There is a large variety of information is available to both professionals and the general public and the question is how can we use this to ensure that the right messages are put across? We probably need to use multiple methods - starting by incorporating it into school SRE. Gynae = advocate for women�s health and therefore an imp part to play.

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