Effectiveness of HPV interventions in Finland

Effectiveness of HPV interventions in Finland Matti Lehtinen, University of Tampere, Finland Matti Lehtinen has received grants for his HPV vaccination studies through his employer University of Tampere, Finland from Merck & Co., Inc., and GlaxoSmithKline Biologicals Mortality from cervical cancer in the EU (Arbyn et al. 27) 1

Occurrence of HPV6/11&16 and cervical cancer in Finns at 2-29 & 3-39 yrs of age (JGV 23, IJC 211 www.cancer.fi) HPV seroprevalence (%) 25 2 15 1 HPV16 (p<.7) HPV6/11 5 1982-1985- 1988-1991- 1994-1997- 2-23- ICC incidence / 1 12 1 8 6 4 Predicted Observed 2 85-88- 91-94- 97- - 3-6- 9- Coverage of the cervical cancer screening programme in Finland (FCR 25) 25 3 Age group targeted 35 4 45 5 55 6 2 4 6 8 1 C overage, % of the fem ale population V is its In v ita tio n s 2

Coverage/Trial participation ( ) Marginalization UK 84% destroys (impact of) Australia 73% public health policy Finland >5% N-lands, Germany 4% USA <3% WHICH STRATEGY? Modelled effectiveness of HPV vaccination (Barnabas et al 26, French et al. 27) cases per year 18 16 14 12 1 8 6 4 2 Incidence over time in ages 15-19 in all vaccination scenarios 25 21 215 22 225 year none F1% F1%M1% F3% F3%M3% F5% F5%M5% F7% F7%M7% F9% F9%M9% 3

Power of community-randomized trials* to assess significant HPV16/18 prevalence reduction among adolescents in 7 yrs assuming 7% coverage by coefficient of variation (CV) in background prevalence (Future Medicine 28) comparison between arms power to with different (CV.5) show reduced coefficients of (CV.2) HPV prevalence variation ( CV ) (CV.1) & vs. HBV 73% 1% 1% vs. HBV 55% 99% 1% & vs. 13% 34% 51% *8 communities/arm, p =.5 4

HPV16/18 seroprevalence in primiparous Finnish females <23 years of age Community-randomized phase IV trial on the effectiveness of different HPV vaccination strategies 33 communities (11 communities/arm): A-arm: HPV16/18 vaccinated boys&girls B-arm: HPV16/18 girls, boys HBV C-arm: HBV vaccinated boys&girls End-points: Reduction of HPV prevalence in 18.5-yr old girls (overall effectiveness) Reduction of HPV prevalence in unvaccinated girls (herd immunity) 5

Phase IV (HPV-4 Study) Study design Communities randomized (11:11:11) Arm A 9% HPV-16/18 L1 VLP AS4 vaccine (males and females) [HPV] Hepatitis B vaccine (males and females) [HBV] 9% Arm B Arm B HPV-16/18 L1 VLP AS4 vaccine (females) [HPV] Hepatitis B vaccine (males and females) [HBV] 1% Arm C Arm C Hepatitis B vaccine (males and females) [HBV] Immunization phase Effectiveness evaluation phase Safety surveillance Vaccination Follow-up visits 12 15 years 18.5 years - 1 month 18.5 years Visit 1 Day Visit 2 Month 1 Visit 3 Month 6 Visit 4/ Phone contact Month 7 Phone contact Month 12 Invitation Letter Visit 5 BS 1* US 1** US 2** US 3** BS 2* BS 3* US 4 # Study Conclusion HDLS 1 *** CS CLS*** Community-randomized phase IV trial on the effectiveness of different HPV vaccination strategies 33 communities (11 communities/arm): A-arm: HPV16/18 vaccinated boys&girls B-arm: HPV16/18 girls, boys HBV C-arm: HBV vaccinated boys&girls End-points: Reduction of HPV prevalence in 18.5-yr old girls (overall effectiveness) Reduction of HPV prevalence in unvaccinated girls (herd immunity) Birth-cohorts invited: 1992/93 in 27/8 1994/95 in 28/9(1) total eligible 8 early adolescents 6

7 6 5 4 3 2 1 1 A communities 7 HPV16/18 coverage 48% & 2% 6 427 (7/8) (8/9) 4434 5 Volunteers Vaccinees 3 6 9 12 15 18 21 24 27 3 33 36 3 6 9 12 15 18 21 24 27 3 33 36 39 42 7 B communities 5872 7 HPV16/18 coverage 5538 6 46% 6 5 HBV cover. 32% 5 (7/8) (8/9) 4 Volunteers 4 3 Vaccinees 3 2 2 3 6 9 12 15 18 21 24 27 3 33 36 3 6 9 12 15 18 21 24 27 3 33 36 39 42 C communities 7 7 4742 HBV coverage 5162 6 48% & 31% 6 (7/8) (8/9) 5 5 4 3 2 1 3 6 9 12 15 18 21 24 27 3 33 36 Volunteers Vaccinees 4 3 2 1 1 4 3 2 1 3 6 9 12 15 18 21 24 27 3 33 36 39 42 Community-randomized phase IV trial on the effectiveness of different HPV vaccination strategies 33 communities (11 communities/arm): A-arm: HPV16/18 vaccinated boys&girls B-arm: HPV16/18 girls, boys HBV C-arm: HBV vaccinated boys&girls End-points: Reduction of HPV prevalence in 18.5-yr old girls (overall effectiveness) Reduction of HPV prevalence in unvaccinated girls (herd immunity) Birth-cohorts invited: 1992/93 in 27/8 1994/95 in 28/9(1) total eligible 8 early adolescents Enrolled: vaccinated/ volunteers 1992/93 born 16 / 17 1994/95 born 16 2 / 18 total 32 2 / 35 7

Number of communities/arm required for the demonstration of significant differences in the reduction of hrhpv prevalence by coverage&strategy (with 2% effect variation) assuming VE 7%, and 1 eligible invitees and 13% co-efficient of variation /community (power 9%, p<.5) Vaccine coverage Strategies to be compared Communities/Arm 5% Arm A ( & ) vs. Arm C (HBV) 4.1 (3.3-6.) Arm B ( ) vs. Arm C (HBV) 6. (4.-13.3) 45% Arm A ( & ) vs. Arm C (HBV) 4.7 (3.5-7.5) Arm B ( ) vs. Arm C (HBV) 7.1 (4.2-19.2) 4% Arm A ( & ) vs. Arm C (HBV) 5.3 (3.7-1.) Arm B ( ) vs. Arm C (HBV) 8.4 (4.5-31.) 35% Arm A ( & ) vs. Arm C (HBV) 6.3 (4.-14.7) Arm B ( ) vs. Arm C (HBV) 1.4 (4.9-6.4) Participants*/community for assessing overall effectiveness of vaccination by vaccine efficacy (VE) assuming a 13% baseline HPV16/18 prevalence in C communities and 1% co-efficient of variation (power 9%, p=.5) VE Comparison Effectiveness Participants*/Community 9 % A vs. C 53.6 % 44 B vs. C 44.1 % 79 8 % A vs. C 49.4 % 55 B vs. C 4.3 % 16 7 % A vs. C 44.9 % 74 B vs. C 36.3 % 158 *vaccinated and unvaccinated 8

Number Number of adolescents per cluster per community in follow up 5 45 4 35 3 25 2 15 1 5 HPV16/18 prevalence in control communities 2% ( CV.1; 1- Control β=8%, α=.5) prevalence 11 communities 2%; CV per.1; arm One sided.5 HPV significance vaccination will 8% directly power; protect 11 vaccinated clusters girls per and arm indirectly protect unvaccinated girls. Thus, follow up of vaccinated girls and unvaccinated girls combined will estimate overall effectiveness and follow up of unvaccinated girls alone will estimate effect of herd immunity. Vaccinated&Unvaccinated Sample size for overall effectiveness Vaccinated Sample size Unvaccinated Conservative sample size Unvaccinated Desired sample size for herd immunity Unvaccinated Minimal sample size 1% 3% 5% 7% 9% Effect size Sample sizes for overall effectiveness: 45% of vaccinated girls followed up (2 girls/community), 15-4% of unvaccinated girls followed up (6-16 girls/community) Sample size for 25% effect of herd immunity: 25% of unvaccinated girls followed up (1 girls/community) Participants*/community for assessing indirect effectiveness of vaccination (herd immunity) by assuming a 13% baseline HPV16/18 prevalence in C communities and 1% coefficient of variation (power 8%, p=.5) Comparison Effectiveness Participants*/Community A vs. C 3 % 86 25 % 136 2 % 246 B vs. C 3 % 113 *non HPV-16/18 vaccinated 25 % 181 2 % 344 1

Cumulative numbers of cytological/pcr samples obtained:1992 born participants at 18.5 yrs of age N 3 25 2 F-U eventually results in 4 vaccinated sampled/ community (Dec 3, 211) 15 Liquid Paps (unv) Liquid Paps (vac) 1 5 Nov 26 Jan 21 March 11 Apr 28 Jun 17 Aug 26 Oct 14 Dec 2 F-U eventually results in 1 unvaccinated sampled/ community Main data sources for pharmacovigilance with SIRs Statistics Finland * Longitudinal Census files 195 197 1975 198 1985 199 1995 : occupation, education, SES, place of residence * causes of death 1971+ Population Register Center (VRK) 1967+ * complete ID * place of birth * residencial history * living coordinates * living conditions * parent-child links * PIDs of children * immigration/emigration * date of death Hospital laboratories * diagnostic biopsies Natl Agency of Medicines * prescribed drugs&vaccines Finnish Cancer Registry * cancer incidence 1953+ * cancer screening 1963+ National Research and Development Centre for Welfare & Health, THL) in-&outpatient ICD dg:s 1995+ pregnancy&birth data 1987+ malformations 1987+ Whole population Population sample Phase III/IV HPV Vaccine Trials register of 24 HPV vaccin/ unvaccinated young women (phase III 23/5) register of 35 HPV / HBV vaccinated adolescents (phase IV 27/9) Natl Inst for Health & Welfare (THL) * survey data (Mini Finland 1967, FinRisk 1972+, Adult Population Health Survey 1978+): life habits (smoking, alcohol, diet, BMI, physical exercise etc) Biobank, Finnish Maternity Cohort 1983+ 11

Table Incidence (/1 5 person years) of common, new onset autoimmune diseases in baseline 12-15 year old HPV16/18 or HBV vaccinated Finnish adolescents during 22 and 29 years of registry-based follow-up in 28-21 Category HPV16/18 or HBV vaccinated Number Incidence (95%CI) Standardized incidence rate ratio (SIR, 95% CI) Artritis 35 68.6 (45.9-91.4)/1 not available Coeliac disease (CD) 2 39.2 (22.-56.4)/1 1.2 (.7-1.8) Inflammatory Bowel Diseases (IBD) 43 84.3 (59.1-11)/1 1.2 (.9-1.6) Juvenile diabetes (IDDM) 25 49. (29.8-62.4)/1 1. (.7-1.4) SIR = standardized incidence rate ratio, CD incidence 34/1, IBD incidence 73/1, IDDM incidence 5/1 (Virta L, et al. 211, Lehtinen P, et al. 21, Harjutsalo V, et al. 28) Integration of HPV vaccination and screening is being modelled (Baussano 211) 12

Evaluating integration of HPV vaccination&screening programmes in two subsequent randomized trials Interventions: Arm 1: HPV screening of 7 HPV vaccinated women* with 4-yr interval at the ages of 18/22/26/3 yrs (*18 years of age) Arm 2: HPV screening of 7 vaccinated adolescents* with 4-yr interval at the ages of 18/22/26/3 yrs (*12-15 years of age) Arm 3: Once in a life-time HPV screening of 7 vaccinated adolescents* at the age of 3 yrs (*12-15 years of age) Study objectives: 1. To show that CIN3+ incidence in Arm 3 equals that of Arm 2 2. To show that CIN3+ incidences in Arms 3 is lower than in Arm 1 3. To verify absence of type-replacement between 18 to 22 years of age 4. To show that HPV disease burden is lowest in Arm 3 5. To show that quality of life is the highest in Arm 3 End-points: 1.& 2. CIN3+ incidence rate ratios by arms 3. hrhpv incidence rate ratios by arms 4. Cost-effectiveness comparisons between the different arms 5. Standardized incidence ratios of health registered adverse effects Most cost-effective integrated vac&screen strategy to be identified while implemented Deliverables In 214 effectiveness data on different vaccination strategies from a community-randomized phase IV study Population-based, quantitative pharmacovigilance (standardized incidence rate ratio) data for sizeable cohorts of vaccinated/ un-vaccinated individuals (altogether 6 ) from 212 onwards A population-based, randomized study on the impact of different combinations of HPV vaccination & screening on HPV disease burden launched in 214 13

Acknowledgements Dan Apter (FFF) Eliav Barr, Kathrin Tiina Eriksson, Kari Natunen (UTa) Jansen, Pekka Pekka Nieminen,Jorma Paavonen (UH) Koskinen, Heather Sings (Merck) Ahti Anttila, Eero Pukkala (FCR) Gary Dubin, David P.Koskela, P.Leinikki, M.Merikukka, Jenkins, Markku H-M.Surcel (THL) Pulkkinen, Maaria Jukka Partanen (FRC) Soila (GSK) Christian Malm, Robert Zilliacus (YTHS) J.Dillner (KI), I.Baussano, G.Garnett (ICL), L.Gissmann (DKFZ), E.Franco (McGill), A.Schneider (Charite), M.Stanley (Cambridge) Academy of Finland, Finnish Cancer Organizations, NCU, EU FP5/6/7 (CCPRB & PREHDICT-networks) Sample sizes for a community-randomized trial on the effecttiveness of HPV vacccination (IJSA 23) 14