Vaikuttavaa terveyttä - Case HPV

Transcript

1. Jorma Paavonen Naistentaudit ja synnytykset HYKS Vaikuttavaa terveyttä-Case HPV!
3. Papillomavirus phylogenetic tree Warts on hands and feet 66 56 53 30 26 29 10 28 3 57 2a 27 61 45 11 6 18 16 59 70 39 68 42 32 40 7 55 44 PCPV1 13 73 34 RhPV1 58 33 52 35 31 Anogenital warts 51 HPV 18 closely related to HPV 45 HPV 16 closely related to HPV 31, 33, 35, 52 and 58 High-risk HPV types Low-risk HPV types de Villiers EM, et al. Virology 2004; 324:17–27. 59 70 39 42 56 30
4. HPV disease burden: Cancer HPV Today Feb 2010; no.20
5. Cervical cancer incidence Globocan 2012
6. HPV types in cervical cancer 53.5% 70.7% 77.4% 80.3% 82.9% 85.2% 87.4% Munoz N et al. Int J Cancer 2004; 111: 278–85 Cancer cases attributed to the most frequent HPV genotypes (%) HPV genotype 5 most frequent types after 16/18 53.5 2.3 2.2 1.4 1.3 1.2 1.0 0.7 0.6 0.5 0.3 1.2 4.4 2.6 17.2 6.7 2.9 0 10 20 30 40 50 60 70 80 90 100 X Other 82 73 68 39 51 56 59 35 58 52 33 31 45 18 16
7. Natural history of cervical hrHPV infection Schiffman et al: Lancet 2007;370:890 Cleared Persisted Progressed
8. Prevention of cervical cancer §  Secondary prevention §  Early detection by screening – Disease burden has shifted to management of CIN §  Primary prevention §  Vaccination – Eradication of disease
9. Secondary prevention §  Pap test is >80 years old §  Cervical screening programs have reduced cervical cancer rates §  Surprisingly few countries have organised screening programs
10. After-effects of having Pap smear* *TOMBOLA trial; Cotton S, et al: Br J Gen Pract 2011;e334
11. Cervical Cancer Screening Program in Finland §  Organised program 1963 §  Women aged 30 (25)-64 (69) §  Five-year interval §  Attendance rate 72% §  Large volume of opportunistic screening outside organised screening program
12. Source: Nieminen P, 2013
13. Source: Nieminen P, 2013
14. Source: Nieminen P, 2013 500 000 Pap tests >16 000 colposcopies >3 000 cervical conizations
15. Recurrent CIN2+ posttreatment Kocken M, et al: Lancet Oncol 2011;12:441
16. Cervical procedures for treatment of CIN increase the risk for preterm delivery §  N=25,827 women, of whom 5,835 had subsequent singleton deliveries §  Risk for preterm delivery (<h.37) §  Excisional Rx OR 1.99 (95%CI 1.8-2.2)* §  Ablative Rx OR 1.60 (95%CI 1.4-1.8)* *Adjusted for maternal age, parity, and smoking; Jakobsson M, et al, Obstet Gynecol 2007;109:309 Kalliala I, Nieminen P: Duodecim 2006;122:2401
17. HPV DNA test in clinical practice §  Primary screening §  ASC-US triage §  Test of cure http://www.kaypahoito.fi/web/kh/etusivu
18. HPV DNA test by Roche: FDA approved for primary screening §  High risk HPV types §  Strong data from ATHENA trial (N=47,000) 1 §  Negative predictive value (NPV) 99,7 % 2 1 Wright TC, et al. Primary Cervical Cancer Screening with Human Papillomavirus: End of Study Results from the ATHENA study using HPV as the First-line Screening Test. Gynecol Oncol 2014 12Castle PE et al. Lancet Oncol 2011; 12(9): 880-906
19. HPV test in primary screening §  Pap smear has high specificity but low sensitivity §  HPV test has high sensitivity and high specificity §  Several randomised trials: Less cancer with HPV screeening!* Pap smear HPV test Sensitivity 55% 95% Specificity 97% 94% Sasieni and Cuzick: BMJ, 2009 *Arbyn M, et al: Vaccine 2012
20. 0.000 0.005 0.010 0.015 0.020 0.025 0.030 0.035 0.040 0.045 0.050 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Time since baseline screening (Years) Cytology & HPV negative HPV negative Cytology negative Figure 1. Study Arms Combined - Cumulative Incidence Proportion of CIN2+ by Baseline Test Result Swedescreen; Dillner J, et al: Unpublished HPV test protects against high grade precencer >6 years; Pap smear protects only for 3 years Swedescreen
21. Primary screening strategy is changing §  HPV screening is more sensitive than cytology and protects longer §  Costs of HPV tests are decreasing §  HPV screening followed by cytology §  Start with a sensitive test (HPV test) §  Continue with a specific test (Pap smear) §  Self-sampling increases participation rate §  Organised screening program necessary §  Opportunistic screening is not cost-effective
22. Prevention of cervical cancer §  Secondary prevention §  Early detection by screening – Disease burden has shifted to management of CIN §  Primary prevention §  Vaccination – Eradication of disease
24. HPV Vaccine Success Story Harald zur Hausen Lutz Gissmann
25. Global phase III efficacy trials with disease endpoints Quadrivalent vaccine (Gardasil™, Merck Co.) §  FUTURE I/II §  HPV 6/11/16/18 vaccine vs. placebo (0, 2, 6 mo) §  Alum adjuvant §  Age range 16-26 §  N=17,622 §  Study start: 2002 §  Europe, Asia-Pacific, Latin America, North America (13 countries; 90 sites) Bivalent vaccine (Cervarix™, GSK) §  PATRICIA §  HPV 16/18 vaccine vs. HAV (0, 1, 6 mo) §  Alum+MPL adjuvant (ASO4) §  Age range 15-25 §  N= 18,644 §  Study start: 2004 §  Europe, Asia-Pacific, Latin America, North America (14 countries;135 sites)
26. Efficacy of both vaccines against HPV16/18 related CIN3+ HPV naive* Vaccine Control VE (%) No./Total No./Total 95%CI §  Quadrivalent 0/4,616 34/4,680 97.2 (91.5-99.4) §  Bivalent 0/5,466 27/5,452 100 (85.5-100) Intention-to-treat (ITT)** §  Quadrivalent 100/8,562 177/8,598 43.5 (27.3-56.2) §  Bivalent 51/8,694 94/8,708 45.7 (22.9-62.2) VE=Vaccine efficacy; *HPV naive population: Subjects received at least 1 vaccination, were seroneg and DNA neg to vaccine types and DNA neg to 12 non-vaccine types and had normal Pap test; **All subjects who received at least 1 vaccination and had follow-up regardless of the presence of HPV infection or HPV-related disease at enrollment Lehtinen M, Dillner J: Nat Rev Clin Oncol 2013;10:400
27. Efficacy of both vaccines against any CIN3+ HPV naive* Vaccine Control VE (%) No./Total No./Total 95%CI §  Quadrivalent 36/4,616 64/4,680 43.0 (13.0-63.2) §  Bivalent 3/5,466 44/5,452 93.2 (78.9-98.7) Intention-to-treat (ITT)** §  Quadrivalent 237/8,562 284/8,598 16.4 (0.4-30.0) §  Bivalent 86/8,694 158/8,708 45.6 (28.8-58.7) VE=Vaccine efficacy; *HPV naive population: Subjects received at least 1 vaccination, were seroneg and DNA neg to Vaccine HPV types and DNA neg to 12 non-vaccine types and had normal Pap test; **All subjects who received at least 1 vaccination and had follow-up regardless of the presence of HPV infection or HPV-related disease at enrollment Lehtinen M, Dillner J: Nat Rev Clin Oncol 2013;10:400
28. Endpoint/HPV-naive* Vaccine Placebo VE % (95%CI) (N=4616) (N=4680) §  Genital warts** 29 169 82.8 (74.3-88.8) §  VIN2/3;VaIN2/3** 7 31 77.1 (47.1-91.5) Endpoint/ITT** Vaccine Placebo VE % (95%CI) (N=8562) (N=8598) §  Genital warts** 134 351 62.0 (53.5-69.1) §  VIN2/3;VaIN2/3** 30 61 50.7 (22.5-69.3) *Subjects received at least 1 vaccination, were seroneg and DNA neg to HPV6/11/16/18 and DNA neg to 10 non-vaccine types and had normal Pap test; ***All subjects who received at least 1 vaccination and had follow-up regardless of the presence of HPV infection or HPV-related disease at enrollment; VIN=Vulvar intraepithelial neoplasia; VaIN=Vaginal intraepithelial neoplasia; Munoz N, et al: JNCI 2010;102:325 Efficacy against external genital disease
29. Proportion of women with genital warts by age group, 2004-2011: Australia Percent Pre-vaccine period Vaccine period 92.6% 72.6%
30. 3.6 year follow-up; Lehtinen M, et al: Lancet Oncology 2012;13:89 Reduction in cytological atypias, colposcopy referrals and cervical excision procedures HPV-naive
31. Trends in histological high-grade cervical abnormalities, 2004-2010 Source: Cervical Screening in Australia 2009-2010 Courtesy of Brotherton J, Grulich A
32. Efficacy of HPV vaccines Overall vaccine efficacy Efficacy against HPV 16/18 Efficacy against non-vaccine oncogenic types = +
33. Rational for a multivalent vaccine 5 new types: HPV 31/33/45/52/58
34. 9-valent HPV vaccine: Gardasil 9 §  Additional 5 hrHPV types 31, 33, 45, 52, 58 §  Approximately 90% of cervical cancer cases worldwide could be prevented §  FDA approval Dec 10, 2014 Joura EA, et al: Cancer Epidemiol Biomarkers Prev 2014;23:1997; Joura EA, et al: NEJM 2015;372:711
35. Overall efficacy against high grade cervical, vulvar, vaginal disease and infection High grade disease 9vHPV qHPV RiskRed Related to §  HPV31/33/45/52/58 1/6016 30/6017 96.7%* Persistent infection*** Related to §  HPV31/33/45/52/58 35/5939 810/5953 96.0%** *95% CI 79.5-99.8; **94.4-97.2;***6 months Joura EA, et al: NEJM 2015;372:711
36. HPV-related disease in men: Not just a women’s issue!
37. Rationale §  HPV-associated cancers in men are on the rise §  Not to vaccinate men is unethical and unfair §  Vaccination programs should be gender neutral Stanley M; Nature Outlook 2012;488:S10
38. Phase IV HPV16/18 community randomised vaccination trial (CRT) § 33 communities (11 communities per arm): A: HPV16/18 to boys and girls B: HPV16/18 to girls, HBV to boys C: HBV to boys and girls § Birth cohorts enrolled (from Oct 2007): 1992/1993 in 2007-2008 1994/1995 in 2008-2009 § Total enrolled: 32,200 vaccinated* 35,000 volunteers not vaccinated** § End-point: Rate of hrHPV by birth-cohort by 2010- 2014 (A vs. C; B vs. C; A vs. B) *1992/1993 N=16,000; 1994/1995 N=16,200; **1992/1993 N=17,000; 1994/1995 N=18,000 Lehtinen M, et al: Unpublished
39. Incidence rate ratios of new onset autoimmune diseases among Phase IV CRT participants in Finland IRR (95% CI) Arthritis 1.57 (0.80-3.04) Coeliac disease 1.32 (0.55-3.17) IBD 1.15 (0.64-2.07) Juvenile DM 0.25 (0.08-0.63) IBD=Inflammatory bowel disease; DM=Diabetes mellitus; IRR=Incidence rate ratio= Incidence rate among HPV16/18 recipients divided by incidence rate among control vaccine recipients Lehtinen et al: Unpublished
40. Risk of miscarriage: Health registry based 4-year follow-up study from Finland Cohort Total Miscarriages IR No. No. (95% CI) HPV* 2,409 22 219 (137-331) HAV* 2,399 20 200 (122-308) Unvacc** 15,744 162 246 (210-288) Women aged 17-18 at baseline; Passive follow-up started 6 months from the last vaccination; Registry of vaccinated and unvaccinated individuals linked with Hospital Discharge Registry; *HPV=Received HPV 16/18 vaccine; HAV=Received hepatitis A vaccine; **Unvacc=Women adjusted by age and duration of the follow-up; IR=Incidence rate; Lehtinen M, et al: Unpublished
41. Finland is a paradise of biobanks and health registries… Eero Pukkala Mika Gissler Eero Pukkala Mika Gissler
42. Cancer registry based follow-up for CIN3+: Real life impact Cohort F/U CIN3+ Incidence Efficacy (yrs) (No.) (95%CI) (95%CI) § Vaccine (N=2,047) 10,235 2 18 (4-71) 84% (37-96) § Unvaccinated (N=15,719) 78,595 90 115 (93-141) *5-year passive cancer registry based follow-up; Lehtinen et al (unpublished)
43. Expert group report on prevention of HPV disease burden in Finland §  HPV vaccination program approved §  Primary target group: Girls aged 11-12 §  Catch-up vaccination: Girls aged 13-15 §  Vaccination of boys recommended §  Organised mass screening from age 25 every 5 years up to age 65 §  By cytology in young age groups §  By HPV DNA testing from age 35 §  HPV exit test at age 65 §  Less opportunistic screening outside screening program §  Integration of HPV vaccination and screening §  ”Once in a lifetime” HPV DNA test? National Institute for Health and Welfare, Finland: 28/2011; June 2011
44. Screening and vaccination: Eradication of HPV disease burden §  HPV screening and HPV vaccination are synergistic §  Vaccine efficacy high in younger age groups §  HPV screening effective in older age groups §  HPV vaccination does not replace screening §  Screening strategy will change
45. Acknowledgements §  Matti Lehtinen §  Pekka Nieminen §  Dan Apter §  Eero Pukkala §  Mika Gissler §  Ahti Anttila §  Xavier Bosch §  Harald zur Hausen §  Lutz Gissmann §  Maija Jakobsson, Annika Riska, Anna-Maija Tapper, Päivi Pakarinen, Leena Laitinen §  Gary Dubin, Frank Struyf, Jenny Andersson, Attila Mihalyi §  Heather Sings §  HPV vaccination trial Investigators ad Co- investigators Matti Lehtinen Eero Pukkala Mika Gissler Harald zur Hausen Lutz Gissmann Matti Lehtinen Pekka Nieminen
46. Back-up
47. Sasieni and Cuzick, BMJ 2009 Problem: Young women!
48. HPV vaccination coverage rates in Europe 2011 Country   Coverage  %   Financing   Delivery   Portugal   84   HA   PH   UK   80   HA   SHS   Denmark   79   HA   PH   Italy   65   HA   PH   Spain   64   HA   PH/SHS   Norway   63   HA   SHS   Netherlands   58   HA   PH   Slovenia   55   HA   SHS   Germany   30   HA   Private   France   24   65%HA   Private   HA=health authorities, PH=public health, SHS=school health system
49. Coverage Baum U, 12/2014