1. Prospects for a Prophylactic HPV Vaccine and Future Implications for Cervical Cancer Screening Dr. Fuat Demirkıran İ.Ü Cerrahpaşa Tıp Fak. Kadın Hast. ve Doğum ABD, Jinekolojik Onkoloji Bilim Dalı Antalya,2011

2. Prevalence of cervical cancer in the world

3. World population prospects for women >15 years. case increase 50-55% case increase 6-23%

4. Secondary prevention Primary prevention

5. Faz III Etkinlik Sonuçları Cervarix (15 aylık takip Paavonen Lancet 2007) N=18,644 Gardasil (3 yıllık takip Koutsky et al. NEJM 2007 N=12,167 Garland et al. NEJM 2007 N=5,455) CIN 2/3+ HPV 16/18’e bağlı %90 (%97.9 GA: 53-99) P/V: 21/2 olay, TVC %100 (%97.9 GA: 74-100) P/V: 20/0 olay, PPR %95 (%95 GA: 85-99) P/V: 62/3 olay, USP %98 (%95 GA: 86-100) P/V: 42/1 olay, PPSP CIN 1+ HPV 16’ya bağlı HPV 18’e bağlı %94 (%97.9 GA: 54-100) P/V: 17/1 olay, PPR %100 (%97.9 GA: 34-100) P/V: 9/0 olay, PPR %100 ((%95 GA: 93-100) P/V: 53/0 olay, USP %95 ((%95 GA: 72-100) P/V: 22/1 olay, USP İlk doz sonrası Kadınlar: 0. günde aşıya özgü HPV tipleri için negatif

6. American Cancer Society (ACS) Recommendations for Human Papillomavirus (HPV) Vaccine Use to Prevent Cervical Cancer and Its Precursors 2007

7. CDC

8. March 2009

9. The Countries that are made reimbursement

10. Screening for cervical pathology should be go on after vaccination Efficacy of HPV vaccines Barriers to HPV vaccine and covarage rate New HPV infection in advanced ages Based on statistical analysis of HPV type distributions in populations, it appears unlikely that reducing the frequency of specific HPV types in a population through vaccination would lead to an increase in the frequency of other HPV types Based on statistical analysis of HPV type distributions in populations, it appears unlikely that reducing the frequency of specific HPV types in a population through vaccination would lead to an increase in the frequency of other HPV types

11. 1. Munoz N. Against which human papillomavirus types shall we vaccinate and screen? The international perspective Int J Cancer 2004; 111: 278–85. Cancer cases associated with most frequent HPV genotypes (%) Worldwide distribution of HPV types in cervical cancer

12. Efficacy Against HPV 6/11/16/18 Related CIN 2/3 or Worse and AIS (Protocols 005, 007, 013, and 015) GardasilPlacebo Day 1 StatusN No. cases IncidenceN No. of cases Incidence Efficacy 95% CI MITT-39831 122 0.79896 201 0.9 39.0% (23.3, 51.7%) PCR (-) Sero (-) 9342 1 0.69400 81 0.4 98.8% (92.9, 100.0%) PCR (-) Sero (+) 853 0 0.0910 4 0.2 100% (-63.6, 100.0%) PCR (+) Sero (-) 661 42 3.2626 57 4.6 31.2% (-4.5, 54.9%) PCR (+) Sero (+) 473 79 [121] * 9.1499 69 [130] * 7.3 -25.8% (-76.4, 10.1%) * Total number of cases in subjects who were sero+ and/or PCR+ at baseline for the relevant HPV type which was associated with disease. Source: Table 1-1, Additional efficacy analysis requested by CBER

13. In fact, in the total vaccinated cohort, efficacy against any CIN II/III irrespective of HPV type was 30.4% at 39 months after the first vaccination and is expected to increase with longer follow-up. Gynecologic Oncology 115 (2009) S15–S23

14. Worldwide female population and a speculative anticipation on the initial introduction of HPV vaccines.

15. Expanded Program of Immunization 1980–2005 DTP3 coverage by level of development Covarage Rate

16. HPV Vaccination Coverage by dose number, age in years as at mid 2007 and place of vaccination, as notified for the National HPV Vaccination Program catch up cohorts (Avustralia Women vaccinated between April 2007-December 2009) Place of VaccinationSchool ProgramSchool Catch Up GP/community Age (in years as at mid 2007) 12-1314-1516-1718-1920-26 Population (as at mid 2007) 275,597277,689282,408281,0651,031,500 Total No of Doses Notified 649,310652,014624,410433,8561,278,678 Coverage rate as at 21 Mar 2011 Dose 183%84%81%64%52% Dose 280%79%75%53%42% Dose 373%72%66%38%30%

17. Prevalence of HPV infection, precancerous lesions and cervical cancer by age of women at least 5% 35 %

18. in different regions of the world have shown that each year between approximately 5% and 15% of sexually active mid-adult women acquire a new infection with an oncogenic HPV type Age-specific incidence of oncogenic HPV infections in Ontario, Canada, Adapted from Sellors et al.

19. Approximately 5–15% of sexually active midadult women acquire a new infection with an oncogenic HPV type each year and in approximately 1–2% of these women, the responsible oncogenic HPV types will be HPV-16 or -18 Approximately 5–15% of sexually active midadult women acquire a new infection with an oncogenic HPV type each year and in approximately 1–2% of these women, the responsible oncogenic HPV types will be HPV-16 or -18 Gynecologic Oncology 115 (2009) S15–S23

20. ≥ CIN3 HPV18+ HPV16+ HC2+ HC2- Cumulative incidence of cervical intraepithelial neoplasia grade 3 and cancer ( ≥ CIN3) over a 10-year period in 20 514 women according to oncogenic human papillomavirus (HPV) status at enrollment. HPV status is defi ned hierarchically as: positive for HPV 16 ( closed circles ), else positive for HPV18 ( open circles ), else positive for the non-HPV16/18 oncogenic types in Hybrid Capture 2 ( closed triangles ), else oncogenic HPV negative ( open triangles Cumulative incidence of cervical intraepithelial neoplasia grade 3 and cancer ( ≥ CIN3) over a 10-year period in 12 976 women 30 years old and older with negative cytology at enrollment, according to oncogenic human papillomavirus (HPV) status at enrollment. HPV status is defi ned hierarchically as: positive for HPV 16 ( closed circles ), else positive for HPV18 ( open circles ), else positive for the non-HPV16/18 oncogenic types in Hybrid Capture 2 (HC2) ( closed triangles ), else oncogenic HPV negative ( open triangles ).

21. It is unclear whether new acquisition or reactivation of a latent infection is responsible for the higher detection rates observed in older women. It has been proposed that what we call incident infections at higher ages may be due to new infections as well as reactivation of latent persistent infections it is unclear whether a prophylactic vaccine can be efficacious in preventing reactivation of latent infection.

22. Any suggested screening program….

23. Implementation of a prophylactic HPV vaccination program would have important implications for cervical cancer screening. During the initial period following the introduction of a vaccine program, the population will include both vaccinated women at low risk for cervical neoplasia and women who have not been vaccinated who will be at greater risk.

24. TEN MOST FREQUENT HPV TYPES AMONG HIGH GRADE CERVICAL LESIONS WORLDWIDE WORLDDEVELOPING REGIONS DEVELOPED REGIONS Data source: IARC Infection and Cancer Epidemiology Group. Clifford et al Br J Cancer 2003, Smith et al Int J Cancer 2007 Available at: HPV Information Centre. Human Papillomavirus and Related Cancers in World. Summary Report 2009. [Accessed: 27 May 2010]. Available at www. who. int/ hpvcentre

25. TEN MOST FREQUENT HPV TYPES AMONG LOW GRADE CERVICAL LESIONS WORLDWIDE WORLDDEVELOPING REGIONS DEVELOPED REGIONS Data source: IARC Infection and Cancer Epidemiology Group. Clifford et al CEBP 2005 Available at: HPV Information Centre. Human Papillomavirus and Related Cancers in World. Summary Report 2009. [Accessed: 27 May 2010]. Available at www. who. int/ hpvcentre

26. Vaccination of adolescents reduction in rates of HPV infection low-grade SIL High-grade SIL- Cancer

27. With Vaccination program, over time The SILs remaining in the population would be related increasingly to HPV types that are less likely to persist and to progress to cancer. Consequently, there would be fewer SILs in the population, and the SILs remaining would be more likely to spontaneously regress without treatment.

28. In general population, the lifetime risk for developing carcinoma in women with low-grade SIL ….….1%. In vaccinated population, this risk ………….1/500-1000 In general population, the lifetime risk for developing carcinoma in women with low-grade SIL ….….1%. In vaccinated population, this risk ………….1/500-1000 Would LSIL require treatment ? focus on the detection of high-grade SIL. After post-vaccination program

29. Increase incidence of low risk lesions following vaccination Many problems related to screening program after Broad-Spectrum Vaccination Decrease the alertness of the cytology screeners, decrease the positive predictive value of cytological screening.

31. Long term impact of vaccination As time goes on, more women will receive the HPV vaccine before the onset of sexual activity. This will result in a fall in positive predictive value of the Pap test. Modifications to the screening Program. a change in the age of commencement of screening, a change to the screening interval, the addition of HPV DNA tests.

32. Cost-efective cancer prevention in HPV-vaccinated population…. probably require targeted screening with HPV testing a few times during entire lifetime secondary screening with cytology

33. Combining vaccination with screening still will be the most effective way to reduce the lifetime risk of cervical cancer in next years..

34. Forward looking views on cervical cancer prevention strategies

35. Widespread implementation of an HPV vaccine program is unlikely to occur until the next century, and its impact would not be fully appreciated for decades. Dramatic changes in screening program of cervical cancer has not been seen reasonable for next few decades. Dramatic changes in screening program of cervical cancer has not been seen reasonable for next few decades.

36. A clear message is that the vaccine is not a substitute for screening tests Modifications to the screening program will be necessary in the long term.