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The Value and Long Term Benefits of HPV Vaccine

Explore the significance of HPV vaccination in reducing cervical cancer rates, global prevalence of HPV infection, and the burden of HPV-related diseases. Learn about prevention strategies and the value of early detection through screening programs. Discover the current statistics and mortality estimates related to HPV.

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The Value and Long Term Benefits of HPV Vaccine

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  1. The Value and Long Term Benefits of HPV Vaccine Vivien Brown MDCM, CCFP,FCFP Department of Family & Community Medicine University of Toronto October 13, 2008

  2. Learning Objectives: • Discuss the prevalence of HPV disease • Review the Guidelines and the Standard of Care • Understand the burden of disease and the changing impact of vaccination

  3. HPV Nonenveloped double-stranded DNA virus1 • >150 types identified2 • ~30–40 anogenital types2,3 ~15–20 oncogenic types*,2,3 • HPV 16 and HPV 18 types cervical cancers.4 ~15-20 nononcogenic** types HPV 6 and 11 types external anogenital warts.3 Most Common Sexually Transmitted Infection 1. Howley PM, Lowy DR. In: Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 2001:2197–2229. 2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278–285.

  4. Global HPV Prevalence The worldwide prevalence of HPV infection is estimated at 9 to 13% ~630 million infected individuals.1 13.3% 2Ontario, Canada 15.3%5Reims, France 18%*,7Shanxi Province, China 14.5%3Morelos State, Mexico 40.2%–41.6%6Harare, Zimbabwe 16.6%4Concordia, Argentina *Among women 30–45 years of age 1. World Health Organization; 2001. Available at: http://www.who.int/vaccines/en/hpvrd/shtml. Accessed July 12, 2004. 2. Sellors JW, Mahony JB, Kaczorowski J, et al. CMAJ. 2000;163:503–508. 3.Lazcano-Ponce E, Herrero R, Muñoz N, et al. Int J Cancer. 2001;91:412–420. 4. Matos E, Loria D, Amestoy GM, et al. Sex Transm Dis. 2003;30:593–599. 5.Clavel C, Masure M, Bory JP, et al. Br J Cancer. 2001;84:1616–1623. 6. Blumenthal PD, Gaffikin L, Chirenje ZM, McGrath J, Womack S, Shah K. Int J Gynecol Obstet. 2001;72:47–53. 7. Belinson J, Qiao YL, Pretorius R, et al. Gynecol Oncol. 2001;83:439–444.

  5. Cervical CancerGlobal Prevalence, Incidence and Mortality Estimates Prevalence: 2,274,000 women have cervical cancer1 Incidence: 510,000 new cases each year1 510,000 new cases/year 14,845 United States/Canada 64,928 Europe 51,266 Eastern Asia 151,297 Southcentral Asia 39,648 Southeast Asia 21,596 Central America 67,078 Africa 49,025 South America 1077 Australia/ New Zealand Mortality: Second leading cause of female cancer-related deaths (288,000 annually)1 1. World Health Organization. Geneva, Switzerland: World Health Organization; 2003:1–74. 2. Bosch FX, de Sanjosé S. J Natl Cancer Inst Monogr. 2003;31:3–13.

  6. HPV Disease Burden AIS = adenocarcinoma in situ. CIN = cervical intraepithelial neoplasia. VIN = vulvar intraepithelial neoplasia. VaIN = vaginal intraepithelial neoplasia.

  7. HPV Types of Cervical Cancer in Southern China (在中國南部城市引致子宮頸癌的 HPV 種類分佈) 香港 Lo K PREVALENCE OF HUMAN PAPILLOMAVIRUS IN CERVICAL CANCER: A MULTICENTER STUDY IN CHINA Int. J. Cancer: 100, 327–331 (2002)

  8. The Annual Burden of HPV in Canada ~510 deaths from cervical, vulvar and vaginal cancers6 ~1835 newly diagnosed cases of cervical, vulvar and vaginal cancers2,3 Up to 77,000 newly diagnosed cases of genital warts, VIN VAIN 4,5 >325,000 abnormal Pap tests1 >4 million Pap tests performed1 • 1. Akom E, Venne S. November 2002. 2. Statistics Canada. Table 103-0513. CANSIM [Canadian Cancer Registry]. • 3. Canadian Cancer Society / National Cancer Institute. Canadian Cancer Statistics 2005:88-9. 4. BC Cancer Agency, 2006. 5. Statistics Canada. Accessed at http://www.40.statcan.ca/101/cst01/demo02.htm. 6. Statistics Canada. Table 102-0522. CANSIM [Vital Statistics – Death Database].

  9. Cervical Cancer- Hong Kong (子宮頸癌 香港數據) 9th most common female cancer 3rd top cancer in 25-45 females Cumulative life time risk = 1 in 129 9th leading cause of cancer death 376 (2005) 126 (2005) (Hong Kong) Report of Cancer Expert Working Group on Cancer Prevention and Screening December 2004 http://www3.ha.org.hk/cancereg/eng/cx.pdf Crude rate = 10.6 per 100,000

  10. HPV Prevention Strategies Primary - prevention of HPV acquisition • safer sex practices - # partners, condoms • prophylactic vaccination Secondary – prevention of disease • cervical screening programs • vulvar, vaginal, anal detection • treatment of pre-invasive disease

  11. HPV Prevention Strategies Primary - prevention of HPV acquisition • safer sex practices - # partners, condoms • prophylactic vaccination Secondary – prevention of disease • cervical screening programs • vulvar, vaginal, anal detection • treatment of pre-invasive disease

  12. The Annual Burden of HPV in Canada ~510 deaths from cervical, vulvarand vaginal cancers6 ~1835 newly diagnosed cases of cervical, vulvar and vaginal cancers2,3 Up to 77,000 newly diagnosed cases of genital warts, VIN, VAIN 4,5 >325,000 abnormal Pap tests1 >4 million Pap tests performed1 • 1. Akom E, Venne S. November 2002. 2. Statistics Canada. Table 103-0513. CANSIM [Canadian Cancer Registry]. • 3. Canadian Cancer Society / National Cancer Institute. Canadian Cancer Statistics 2005:88-9. 4. BC Cancer Agency, 2006. 5. Statistics Canada. Accessed at http://www.40.statcan.ca/101/cst01/demo02.htm. 6. Statistics Canada. Table 102-0522. CANSIM [Vital Statistics – Death Database].

  13. Who Should Be Vaccinated? • Most studies have been conducted with women aged 15–26 • Clinical trials are now being conducted with mid-adults • Target population for infection • Assuming 1st sexual intercourse ≤ 15 years of age • Infection occurs soon after first intercourse • Highest prevalence for HPV infections between the ages 15-29 years of age • Primary target population for vaccination • Female adolescents • Young women

  14. Using Risk Factors to implement HPV Vaccine Strategy We conclude that targeting individuals based on either the presence or absence of risk factors does not appear to be a viable strategy for HPV catch-up vaccination of young adults. Instead, our results support the ACIP recommendations for comprehensive vaccination of all women in the eligible age range against HPV, regardless of sexual or social history Only women with high number of risk factors: • Success in reaching women at high risk for future HPV Infection. • Will fail to protect many susceptible women Only women with low number of risk factors: • Success in reaching many women who are still susceptible to HPV (6, 11, 16, 18), although these women had lower risk of future HPV infection. • Will fail to protect many women who are susceptible and higher risk of future infection. Dempsey, et al, Vaccine (2008) 26, 1111—1117

  15. Risk of HPV with First Male Partner • 244 female university students age 18-22, 2000 - 2006 • enrolled within first 3 months of first intercourse with their first male partner • excluded from trial if they had a second partner • 30% positive for HPV after 1 year • 50% positive for HPV after 3 years HPV Risk by Number of Partners; Rachel Winer et al, Univ of Washington, Jan 2008, J Inf Dis

  16. Risk of HPV with First Male Partner Winer, et al, J Infectious Disease, 2007

  17. Women Over 26 years

  18. All women are at risk of HPV infections ALL HPV HR HPV LR HPV Other HPV Chan et al.Determinants of cervical human papillomavirus infection: differences between high and low oncogenic risktypes. J Infect Dis 2002; 185: 28-35.

  19. 200 600 Males Females 500 160 400 120 Rate (/100.000) 300 Rate (/100,000) 80 200 Males Females 100 40 0 0 85+ 00-09 15-19 25-29 35-39 45-49 55-59 65-69 75-79 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Age Year Canadian Epidemiology of Genital Warts Age Specific Prevalence Rate 2000 - 2004 Age Standardised Prevalence Rate 2000 - 2004 Kliewer E et al. Twenty year trends (1985-2004) in the incidence and prevalence of anogenital warts in Manitoba. Cancer Care Manitoba, 2008.

  20. Rising Incidence of GenitalWarts in Hong Kong1 Age 13-19 1. SY Cheng Sexually Transmitted Infections in Adolescents HK J Paediatr 2002 7 76-84

  21. Genital Warts in HK • In Hong Kong, between 3 – 4 thousand patients with genital warts attended the Social Hygiene Clinic every year in the past decade, which account for about 9% of all attendances • Estimated 30,000 to 40,000 cases per year

  22. The CCDR: APublic HealthAgency of Canada Publication • The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge. • Members: Dr. M. Naus (Chairperson), Dr. S. Deeks (Executive Secretary), Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. K. Laupland, Dr. A. McGeer, Dr. S. McNeil, Dr. M.-N. Primeau, Dr. B. Tan, Dr. B.Warshawsky. • Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), E. Holmes (CNCI), Dr. B. Larke (CCMOH), Dr. B. Law (ACCA), Dr. D. Money (SOGC), Dr. P. Orr (AMMI Canada), Dr. S. Rechner (CFPC), Dr. M. Salvadori (CPS), Dr. J. Smith (CDC), Dr. J. Salzman (CATMAT), Dr. D. Scheifele (CAIRE).

  23. Health Canada Recommendations: NACI Guidelines(February 15, 2007)

  24. Recommended Use Group Recommendation Comments • Studies are ongoing • Use can be considered in individual circumstances Females Age > 26 years • No recommendation can be made Females Age < 9 years • Not recommended • No data for this age group Males • Cannot be recommended at this time • Although immunogenicity data are available, efficacy is as yet unknown Immuno-compromised persons • Can be given • Immunogenicity and efficacy not known in this population • Immune response could be weaker Pregnancy • Not recommended • Data on vaccination in pregnancy is limited • Pregnant women can complete the vaccination regimen after pregnancy • No intervention necessary if vaccine was given during pregnancy 15 February 2007Statement on human papillomavirus vaccine. Canada Communicable Disease Report. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2007;33(ACS-2):1-32.

  25. Infections with Multiple HPV Types Distribution of HPV positivity (types 6, 11, 16, 18) by serology or PCR among 3,578 North American women aged 16 to 26 years participating in the quadrivalent HPV recombinant vaccine phase II and III clinical trials • Only 1% of the study participants were positive for both oncogenic vaccine HPV types (16 and 18). • 1.1% positive for 3 or more and only 0.1% positive for all four types. 15 February 2007Statement on human papillomavirus vaccine. Canada Communicable Disease Report. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2007;33(ACS-2):1-32.

  26. HPV Vaccine Public Programs 2008/09 • Multiple Age Groups • Quebec: Grade 4 & 9, & Girls <18 yrs • British Columbia: Grade 6 & Grade 9. • Alberta: Grade 5 & Grade 9 (2009) • Saskatchewan: Grade 6,Grade 7 catch-up. • New Brunswick: Grade 7,Grade 8 catch-up. • One Age Group • Manitoba: Grade 6 • Ontario: Grade 8 • Nova Scotia: Grade 7 • Prince Edward Island: Grade 6 • Newfoundland and Labrador: Grade 6 One Age Group Yuk Multiple Age Groups NWT Nun No Public Announcement BC AB SK MB QC NF ON PEI NB NS September 2008

  27. HPV Vaccine Public Program Uptake by Province Nova Scotia ~85% Prince Edward Island ~80% Newfoundland ~75% Ontario ~53% Uptake across Ontario varies from 39% to 65% depending on the Public Health Region.

  28. What Are the Issues? • 1. Efficacy over time • 2. Duration of Protection • 3. Cross reactivity • 4. Impact of Disease • 5. Changing the Paradigm

  29. How to evaluate HPV vaccine efficacy? WHO EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION Geneva, 23 to 27 October 2006 http://www.who.int/biologicals/publications/trs/areas/vaccines/human_papillomavirus/en/index.html Correlate of protective level is unknown Measuring or comparing antibody titers is not appropriate for evaluating HPV vaccine efficacy -especially measured in different assays WHO Guidelines: Disease Endpoints (CIN 2/3, AIS or above) are primarily the objectives of HPV vaccine clinical studies.

  30. Clinical Program for Quadrivalent HPV L1 VLP Vaccine Ph III–FUTURE II CIN 2/3 (N=12,167)15- to 26-year-old women Duration of Efficacy Registry StudyNordic Region Jan2003 Jan2004 Jan2005 Jan2006 Jan2007 Jan2008 Jan2009 Jan2010 Ph II–P005 (N=2,392)Proof of Principle 16- to 23-year-old women • ~29,000 subjects enrolled • Ethnically diverse • 33 countries Ph II–P007 (N=1,158) Dose-ranging 16- to 23-year-old women Yr 5 Immune MemoryEvaluation Ph III–FUTURE I CIN/EGL (N=5,455) 16- to 24-year-old women Norwegian HPV Surveillance and Disease Burden/Population Effectiveness Study Ph III–Immunogenicity (N=4,836) 9- to 15-year-old boys and girls Efficacy in women up to 45 years old Efficacy in 16- to 26-year-old men FUTURE = Females United to Unilaterally Reduce Endo/Ectocervical Disease

  31. Bivalent HPV Vaccine 2005 2006 2007 2008 2009 LT follow-up HPV-012 (immuno 10-25y) HPV-013 (safety/immuno 10-14 yrs) LT follow-up LT follow-up HPV-014 (immuno 15-55y) HPV-010 (GSK HPV vaccine vs Gardasil 18-45 yrs) HPV-001/007 (efficacy in 15-25 yr old women) N = 1113 5.5 yrs 6.5 yrs Efficacy 4.5 yrs Immunogenicity Interim analyses virological/histopath endpoints HPV-009 (efficacy in 18-25 yr old women in Costa Rica) N = 7,462 HPV-008 (efficacy in 15-25 yr old women) N =18,665 Interim analysis CIN2+ HPV-015 (efficacy >25yrs) N=5,700 ACIP Presentation, Dubin, June 28, 2007

  32. Summary of Phase III HPV Vaccine Efficacy Trials

  33. Vaccine and Older Women: Future III Luna, IPV Nov 2007 • Multi-center, international study • Randomization (1:1 ratio) to GARDASIL or placebo (1:1 stratification to 24 to 34 or 35 to 45 year-olds) • In 3817 24- to 45-year-old women • No history of LEEP or hysterectomy • No history of biopsy-diagnosed cervical HPV disease in past 5 years • No history of genital warts • Pap testing and cervicovaginal sampling at ~6 month intervals for a total of 48 months • Colposcopy for ≥ASC-US

  34. Primary Efficacy Results Combined Incidence of HPV 6/11/16/18-Related Persistent Infection or Cervical/Vulvar/Vaginal Disease – Per Protocol Efficacy Population PYR = person years at risk; CI = confidence interval. Luna, IPV Nov 2007

  35. What Are the Issues? • 1. Efficacy over time • 2. Duration of Protection • 3. Cross reactivity • 4. Impact of Disease • 5. Changing the Paradigm

  36. 10,000 1000 100 10 0 2 3 6 7 12 18 24 30 36 54 60 61 60 + 1 Demonstration of Immune Memory With and Antigen Challenge at Month 60 with Quadrivalent HPV vaccine Olsson SE et al. Vaccine 2007; 25:4931-9.

  37. Vaccines’ Long-Term Protection: 4 Examples: Poliovirus Vaccine (Inactivated) 19551 • Recommended to give series of four doses at two, four, and 18 months, and a booster dose at 4 to 6 years1 • 18-year follow-up shows that vaccine remains effective.2 • The need for subsequent boosters has not been established.1 Hepatitis B Vaccine 1981 and 19861 • 15-year follow-up shows that vaccine remains effective.3,4 • Anamnestic response at 5-10 years even when antibodies undetectable.6,7 • To date, routine booster is not recommended.1 Hepatitis A Vaccine HPV vaccine 19951 2006 • 12-year persistence of antibodies and anamnestic response5 • To date, based on mathematical models, it is estimated that the protection could last 20+ years.1,5 • 5 year follow-up shows that vaccine remains effective 8,9 • anamnestic response for the quadrivalent HPV vaccine at 5 years10 1. Mast E, Mahoney F, Kane M, Margolis H. Hepatitis B vaccine. In: Vaccine, 4th Ed. Plotkin SA, Orenstein WA editors. Elsevier Inc. USA publisher; 2004. 2. Bottiger M. Vaccine. 1990;8:443–445. 3. McMahon BJ, Bruden DL, Petersen KM, et al. Ann Intern Med. 2005;142:333–341. 4. Ni Y-H, Chang M-H, Huang L-M, et al. Ann Intern Med. 2001;135:796–800. 5. Van Herck K, Van Damme P, Lievens M, et al. J Med Virol. 2004;72:194–196. 6. Duval, B., Gilca, V., Boulianne, N., De Waals, P., Masse, P., Trudeau, G. De Serres, G. Pediatr Inf Dis J. 2005; 24: 213-218. 7. Banatvala, J., Van Damme, P.; Oehen, S. Vaccine. 2001; 19: 877-885. 8. Villa et al British Journal of Cancer (2006) 95, 1459 – 1466 9. Harper, D. et al Lancet (2006) 367: 1247-125510. Olsson S-E et al. Vaccine. 2007; 25: 4931-4939.

  38. What Are the Issues? • 1. Efficacy over time • 2. Duration of Protection • 3. Cross reactivity • 4. Impact of Disease • 5. Changing the Paradigm

  39. Cancer-Causing HPV SpeciesHPV Phylogenetic Tree A6 Species:HPV 56-Related A9 Species:HPV 16-Related A7 Species:HPV 18-Related A5 Species:HPV 51-Related 39

  40. Cross-Protection Analysis: Quadrivalent Vaccine Endpoint: CIN 2/3 or AIS in Generally HPV-Naïve Women Abstract presented by Brown, ICAAC 2007 and Villa, Eurogin 2007

  41. Cross Protection Analysis - Bivalent Vaccine – Phase III Endpoint – 6 month persistent infection *data are % (97.9% CI) †HPV types 31,33,35,39,45,51,52,56,58,59,66 and 68. ‡HPV types 16,18,31,33,35,39,45,51,52,56,58,59,66 and 68. Paavonen et al., Lancet 2007

  42. 1. Efficacy over time • 2. Duration of Protection • 3. Cross reactivity • 4. Impact of Disease • 5. Changing the Paradigm

  43. Psychosocial Responses to HPV Diagnosis (Warts) Clarke P, Ebel C, Catotti DN, Stewart S. Int J STD AIDS. 1996;7:197-200

  44. PreliminaryAnalysisPapCohort Senecal et al. IPV 2007

  45. PreliminaryAnalysisWartCohort Senecal et al. IPV 2007

  46. Quality of Life in Cervical Cancer Survivors QOL persistently impaired: • Sexual discomfort1 • Hot flashes1 • Vaginal dryness1 • Reproductive concerns (ie, inability to bear children)1 • Fearful of future diagnostic tests and cancer recurrence1 • Cancer-specific distress1 • Sexual-life impairment2 54% between 30–49 years of age 1. Wenzel L, DeAlba I, Habbal R, et al. Gynecol Oncol. 2005;97:310–317. 2. Buković D, Strinić T, Habek M, et al. Coll Antropol. 2003;27:173–180.

  47. What Are the Issues? • 1. Efficacy over time • 2. Duration of Protection • 3. Cross reactivity • 4. Impact of Disease • 5. Changing the Paradigm

  48. And the Physical Impact? Study Design (SGO Presentation 09/08) • 18,150 16- to 26-year-old women were enrolled in 1 of 3 randomized, placebo-controlled, efficacy trials (protocol 007, FUTURE I and FUTURE II. • Pap testing occurred at Day 1 and every 6-12 months for up to 48 months. • Colposcopy referral was Pap algorithm/HPV test-based. • Mean follow-up time was ~3.3 years post-dose 1. Case counting began 1 month post-dose 1.

  49. Reduction in Any Abnormal Pap tests Regardless of Causal HPV type ↓43% ↓35% ↓23% ↓16% ASC-US HR + LSIL ASC-H HSIL Cases Placebo 359 1000 89 41 Cases Vaccine 285 864 59 24

  50. Reduction in Any Cervical Procedure Regardless of Causal HPV type ↓42% ↓22% ↓19% Colposcopy Cervical Biopsy Definitive therapy Cases Placebo 1077 950 230 Cases Vaccine 869 741 132

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