Human Papillomavirus (HPV) Vaccination and Implications for Cervical Cancer Screening

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1 Human Papillomavirus (HPV) Vaccination and Implications for Cervical Cancer Screening Vlastos Anne-Therese Departement of Obstetrics and Gynecolgy Geneva University Hospital

2 HPV, DNA virus More than 120 different type High-risk: : 68% SCC 18: 71% AdenoCx Intermediate-risk:

3 + 70% of sexually active people face the Papillomavirus during their lifetime Incidence estimated to be 6.2 million/year for genital HPV infection in U.S.

4 HPV and related diseases

5 5.2% of all cancers worldwide attributable to HPV infection (Parkin et al. Vaccine 2006) Organ Site for women % HPV Related CANCER Estimated number/year Cervical ,000 Vulva ,000 Vagina Total with vulva Anal ,000 Oral/larynx 25 3,000 Oro-pharynx ,000 TOTAL 534,000 WHO Information Center

6 HPV Burden These worldwide and U.S. estimates show: the burden of noncervical HPV-related cancers is substantial, approximately equal among men and women oropharyngeal cancers constitute a high proportion of noncervical HPVrelated cancers, particularly among men Additionally, the burden of noncervical cancers approximates that of cervical cancers in the United States such an equilibrium may be true only for developed nations with established Pap smear screening programs In developing countries without organized Pap smear screening programs, the burden of cervical cancers far exceeds that of noncervical cancers.

7 Estimated HPV burden in women in Europe: Nearly 1.4 million events/year Oncogenic types Pre-cancerous Cervical Lesions Cervical Cancer Non Oncogenic types Low Grade Cervical Lesions Genital warts Calculations 817,000 cases/yr 250,000 cases/yr 187,000 cases/yr 60,000 cases/yr 30,000 deaths/yr Simoens C, Sabbe M, Van DP et al. Introduction of HPV vaccination in Belgium, Euro.Surveill 2009; 14 Europe 25 member states plus Iceland, Norway and Switzerland.

8 Estimated HPV burden in women in Switzerland Oncogenic types Pre-cancerous Cervical Lesions Cervical Cancer Non Oncogenic types Low Grade Cervical Lesions Genital Warts Calculations?? 5,000 cases/yr 320 cases/yr Commission fédérale pour la vaccination, 2007

9 Cervical cancer and HPV Secondary prevention: Pap smear

10 Screening with the Conventional Pap Smear Widely available Inexpensive But not perfect Screening test not diagnostic 7-10% of women need further evaluation Low sensitivity need regular repeats Cervical Cytology Screening. ACOG Practice Bulletin No ; 102:

11 Incidence of cervical cancer in the Nordic countries From Hakama, 1992

12 Cervical cancer and HPV Secondary prevention: HPV testing

13 HPV Testing: Pcr test HPV testing is approved for use in two contexts: 1. As a triage test following an equivocal cytology result of ASCUS 2. Primary screening in conjunction with cervical cytology for women aged 30 years and older. Interpretation HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2. Naucler P, Ryd W, Törnberg S, et al.: Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst 101 (2): 88-99, 2009 Ronco G, Giorgi-Rossi P, Carozzi F, et al.: Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol 11 (3): , 2010.

14 Essential Traits Of HPV Screening as Compared With Standard Cytology GAIN IN SENSITIVITY 30% to 40% LOSS IN SPECIFICITY 5% to 8% HIGH REPRODUCIBILITY and AUTOMATIZATION Not benefical in young women (transient HPV infection)

15 Cervical cancer and HPV Primary prevention: vaccine

16 Current HPV Vaccines: VLP Vaccines Vaccine/ Manufacturer HPV Types Schedule Adjuvant Target Groups Quadrivalent Merck 6/11/16/18 0,1,6 mos Alum females & males Bivalent GSK 16/18 0,1,6 mos Alum and MPL (ASO4) females

17 Proportion of Potentially avoided Lesions with a quadrivalent vaccine HPV type Types 16, 18 Types 6, 11 Low Grade Cervical Lesions 34% 1 Genital Warts 90% 2, 3 Pre-cancerous Cervical Lesions 50 70% 4 7 Cervical Cancer 70% 8 HPV (types 6,11,16,18) vaccine 1. Clifford GM et al. Cancer Epidemiol Biomarkers Prev 2005;14: Wieland U and Pfister H. Papillomaviruses in human pathology: Epidemiology, pathogenesis and oncogenic role. In: Gross, Barrasso eds. Human Papilloma Virus Infection: A clinical atlas. Ullstein Mosby; p Von Krogh G. Eur J Dermatol 2001;11: Sotlar K et al. J Clin Microbiol 2004;42: Clifford GM et al. Brit J Cancer 2003;89: Liaw K-L et al. J Natl Cancer Inst 1999;91: Voglino G et al. Pathologica 2000;92: Munoz N et al. N Engl J Med 2003;348:

18 Delivering promised benefits The Australian Experience 48% Reduction of Genital Warts in all women <28 years old Maximum risk reduction for women <28 years 32% Reduction of Genital Warts in all women Vaccinating the recommended cohorts show an impact on all consulting women 18% Reduction of Genital Warts in all men Some risk reduction for men (Heterosexual Men) but not for Homosexual Men «Herd Immunity» The high vaccination coverage is the major factor of a successful implementation of vaccination program Fairley C K et al Melbourne, Australia

19 The Australian Experience: Study Results Vaccination program started July % P= , P=< P for change< % P= % P=0.34 Fairley C K et al Melbourne, Australia 2009

20 Efficacy Against HPV 6/11/16/18-related External Genital Lesions in MALES HPV Efficacy, % 95% CI, % 6/11/16/18- related All EGL Condylomas PIN Giuliano et al. Abstract 0-01, 25th Int.Pap. Conference 2009

21 Implications of HPV Vaccines Females are not protected if they have been infected with HPV prior to vaccination HPV vaccine does not protect against less common HPV types, not included in the vaccine Duration of protection, need for booster doses, not certain Routine vaccination of year old girls will take decades to show a discernable effect on the incidence of cervical cancer; screening needs to continue for other women

22 Preliminary Evaluation of the Geneva Vaccination Program

23 Estimated HPV burden in women in Geneva Oncogenic types CIN 3/in situ Cervical Cancer Non Oncogenic types Genital Warts Lower than CIN3 Calculations?? 400 cases/yr 30 cases/yr 5-10 death/y Registre Genevois des Tumeurs, 2009

24 Earlier age of sexual debut in Europe Age of sexual debut 15 40% of 15 years old girls are sexually active Year rs % GB Germany France Belgium Spain Italy 0 Median age of sexual debut (cohort born 1950) Median age of sexual debut (cohort born ) % 15 year old girls who have had intercourse (2001/02) Bozon, M. Population et Sociétés 2003; 391: Currie C, Roberts C, Morgan A, et al. Young people's health in context, Health Behaviour in School-aged Children (HSBC) study: international report from the 2001/2002 survey. Health Policy for Children and Adolescents, No. 4. p

25 Vaccination Campaign Aims & Population Resident of the Geneva canton y.o. female (1988 to 1998) Free vaccine if distributed in the organized programm «programme cantonal de vaccination» as defined in Best coverage for the best price and best expected dicrease in HPV related disease in the cervix

26 Vaccination Campaign Where to be vaccinated Service de Sante Jeunesse/ Depatement de l Instruction Publique Pediatrician/ Primary health care practitionner/ gynecologist Vaccination centers inside the Geneva University Ospital (HUG)

27 Vaccination Campaign Cohorte September 2007: potentially 22,693 candidates Plus about 2,400 candidates of 11y.o. to add each year Total for : 25,062 candidates Mailed invitation to every eligeable candidate

28 Vaccination Campaign Peliminary Analysis: 33,460 doses 90% 86%

29 Vaccination Campaign Peliminary Analysis: 33,460 doses

30 Vaccination Campaign who accually did the vaccination?

31 YTD June 2010 Cantonal Program: HPV Penetration Rate YTD June 010 (September 07 - June 010) VS VD GE JU NE FR BE BS BL SO AG ZH TG AR AI SG SH GR GL SZ ZG LU OW NW UR TI CH

32 HPV Penetration Rate YTD June 2010: Comparison F-CH D-CH I-CH CH 37.7

33 Evolution HPV Penetration Rate HPV penetration rate evolution CH TI UR NW OW LU ZG SZ GL GR SH SG YTD June 010 AI YTD Dec 09 AR YTD June 09 TG YTD Dec 08 ZH AG SO BL BS BE FR NE JU GE VD VS

34 Guideline Conclusions Fitting vaccination with existing screening strategies

35 When

36 Adherence to cervical screening in the era of human papillomavirus vaccination Mathematical model of vaccination, screening, and disease incidence For a population with opportunistic screening and 30% vaccine coverage: Screening rates in vaccinated women would have to decline by at least 80% before the incidence of cervical cancer would increase in the era since the introduction of the vaccine. In populations that have highly eff ective cervical screening programmes, incidence of cervical cancer starts to increase after smaller, but still substantial, decreases in screening. Introduction of vaccine is unlikely to lead to an increased incidence of cervical cancer as a result of diminished screening. Adherence to cervical screening in the era of human papillomavirus vaccination: how low is too low? Chris T Bauch, Meng Li, Gretchen Chapman, Alison P Galvani. Lancet Infect Dis 2010; 10:

37 Cervical Cancer Screening at the vaccine age Cervical cancer screening no change 30% of cervical cancers caused by HPV types not prevented by the quadrivalent HPV vaccine Vaccinated females could subsequently be infected with non-vaccine HPV types Coverage of the population never = 100% Sexually active females could have been infected prior to vaccination

38 Conclusions: Screening for Cervical Cancer Prevention Non vaccinated women: Vaccinated women while sexually active: Continue program / change to HPV screening HPV screening/continue program Vaccinated women while presexually active: HPV screening

39 Where

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41 Thank you! Helmut Newton

42 Cervical Cancer Screening Guidelines First screen 3 years after first intercourse or by age 21 Screen annually with regular Paps or every 2 years with liquid-based tests After three normal tests, can go to every three years Stop at years with history of negative tests Still need annual check-ups Cervical Cytology Screening. ACOG Practice Bulletin No ; 102:

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44 Suggested Cost-Effectiveness Strategies

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47 Demonstration of Immune Memory with an Antigen Challenge at Month 601 Anti-HPV HPV response (GMT Levels with 95% CI [log10 scale]) HPV 18 Anamnestic Response Antigen Challenge 0 Vaccination Period YY Months Memory B cells for recall response Long lived plasma cells for sustained antibody 1 Olsson SE et al Vaccine 25 (2007)

48 HPV test vs Cytology: summary Sensitivity CIN2 Specificity CIN2 HPV-DNA 96% 92% Cytology 53% 97%

49 Impact of Human Papillomavirus (HPV)6/11/16/18 Vaccine on All HPV-Associated Genital Diseases in Young Women Nubia Muñoz, et a. J Natl Cancer Inst 2010;102:

50 Prevalence rates of HPV infection (%) HPV infection is most prevalent in young women 25 Total mucosal PV Oncogenic PV Wart-causing PV 20% Š69 60Š64 55Š59 50Š54 45Š49 40Š44 35Š39 30Š34 24Š29 20Š24 0 Age Prevalence of mucosal PapillomaViruses in cytomorphologically normal smears in 3,305 women related to age (Netherlands ) Where PV = PapillomaVirus. 1. Koutsky. Am J Med1997;102: Jacobs et al. Int J Cancer 2000;87:

51 Cumulative Incidence of HPV Infection among Female College Students, by Time Since Sexual Debut 4 years, > 50% Winer et al. Am J Epidemiol 2003;157 38% the first 12 month!

52 Loss of screening performance due to vaccination As successive cohorts of women are vaccinated, we will achieve a significant (50% +) reduction in the prevalence of the most significant cytologic abnormalities resulting in: Decrease in positive predictive value of cytology Increase in false positive rates will lead to overdiagnosis and over-treatment Negative impact on technician training and quality assurance (largely avoided by HPV tests)

53 Vaccination Campaign Peliminary Analysis: 33,460 doses