1. Global HPV Burden in the Era of 21st Century Prevention Tools Marc Steben, MD STI unit, INSPQ Chair of the Canadian HPV prevention network, School of public health, Université de Montréal Medical director, Clinique A rue McGill

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3. 3 Let me share my vision of HPV We will have eradicated HPV related cancers within the next century Only if we bring those incredible new preventive tools, screening and vaccines, to those who need it the most…

4. 4 Objectives At the end of the presentation we will have reviewed The HPV burden The disease states The available prevention technologies The international political scene The way forward Some final comments

5. The burden of disease

6. 6 Projections of mortality and burden of disease, 2004-2030. World Health Organization website. www.who.int/healthinfo/global_burden_disease/ projections/en/index.html. Accessed November 23, 2010.

7. 7 7 Cx Ca is second to only breast cancer as the leading cause of cancer in women worldwide. 1 –Global prevalence: ~2.3 million –Global incidence: ~500,000 GLOBOCAN about cx ca deaths in developing countries –2002 = >80% of cx ca deaths –2008 = 88% –And by 2030 = >98% Nearly every minute of every day a woman is diagnosed with cx ca Cervical cancer claims younger lives than most cancers 1. Ferlay J, Bray F, Pisani P, Parkin DM. Lyon, France: IARC Press; 2004.

8. 8 Cx Ca: No country has better cancer treatments or palliative care than their screening program. This means not only that most women of LMIC cannot prevent this cancer but they will die an inhumane death because they cannot get the surgery, the treatments and end of life palliative care

9. 9 9 The number of life years lost to cx ca represents a hidden productivity loss in developing countries Women in developing countries contribute substantially more to the household economy than their male counterparts. Almost 75 percent of food production each year is a direct result of women's labor. Cervical cancer claims more years of women lives 1 –than any other cause in Latin America and the Caribbean Breast, lung or stomach cancers AIDS Tuberculosis Maternal Conditions –Than any other cancer in SubSaharan Africa and South-Central Asia Cause-specific total years of life lost among women aged 25–64 years for developing countries, in 2000. 1 1. Yang BH, Bray D, D. Parkin M, Sellors JW, Zhang Z-F. Int. J. Cancer: 109, 418–424 (2004)

10. 10 166,485 YLL 977,633 YLL 1,240,208 YLL

11. The disease states

12. 12 Infections causing cancers 5.2% of all cancers are caused by HPV –2.2% in developed countries –7.7% in developing countries The link between HPV and cervical cancer is 7X stronger than the link between tobacco smoking and lung cancer

13. DiseaseHPV typeTransmissionCervical cancer risk Cervical cancer HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 59, 68, 73 Sexual High Cancer of vulva, vagina, anal canal, penis HPV 16 and othersSexual Anogenital wartsHPV 6, 11Sexual Low Juvenile-onset RRPHPV 6, 11Mother-child, at birth Adult-onset RRPHPV 6, 11Unclear Cutaneous warts HPV 1, 2, 3, 4, 10 and others Non-sexual contact None Focal epithelial hyperplasia of the oral cavity HPV 13, 32Non-sexual contact Armstrong D, Cohen J. Infectious Diseases. Mosby, London, 1999. Cox JT. Baillieres Clin Obstet Gynaecol 1995; 9(1):1-37. Hiller T, Iftnet T. In: Prendiville W, Davies P (eds.). The Health Professional’s HPV Handbook. Volume 1. Human Papillomavirus and Cervical Cancer. Taylor & Francis, London/New York, 2004, pp. 11-26. Munoz N, et al. N Engl J Med 2003; 348(6):518-27. zur Hausen H. Nat Rev Cancer 2002; 2(5):342-50. Major Clinical Associations of HPV Infections

14. 14 Natural Course of Genital HPV Infection First Lesion Immune Response Incubation (1-6 Mo.) Active Growth (3-6 Mo.) Host Containment (3-6 Mo.) Late Stage Sustained clinical remission Persistent or recurrent disease Infection Seroconversion Average time 9mo Immune containmnent= no viral shedding but viral persistance Recurrent disease in immune tolerance/deficiency/senescence 4 out of 5 will have been infected by One HPV genotype/lifetime

15. Serum antibody levels after natural HPV infection when detectable are low 1 40-50% of women develop no measurable antibody response after HPV natural infection 2-5 Natural immunity does not reliably protect against subsequent infection Infection with an HPV does not provide protection against infection with a different type, a phylogenetically- related type, or either with the same type. Natural immunity 1 Viscidi et al. Cancer Epidemiol Biomarkers Prev. 2004. 2 Nonnenmacher et al. J Infect Dis 1995. 3 Park et al. Gynecol Oncol 1998. 4 Heim et al. Am J Obstet Gynecol 2002. 5 Skjeldestad et al. Acta Obstet Gynecol Scand 2008.

16. The Clinical Spectrum of HPV-related Disease in Females Genital warts 1 Recurrent respiratory papillomatosis Vulvar intraepithelial neoplasia (VIN) and carcinoma Anal intraepithelial neoplasia (AIN) and carcinoma Some oropharyngeal cancers (tongue, tonsillar, throat, and soft palate) 1,4

17. The Clinical Spectrum of HPV-related Disease in Males Genital warts 1 Recurrent respiratory papillomatosis Penile intraepithelial neoplasia (PIN) and carcinoma 1,2 Anal intraepithelial neoplasia (AIN) and carcinoma 1,3 Some oropharyngeal cancers (tongue, tonsillar, throat, and soft palate) 1,4 1. Giuliano AR, et al. Vaccine 2008; 26(suppl 10):K17-K28. 2. Gross G, et al. Med Microbiol Immunol 2004; 193(1):35-44. 3. Frisch M, et al. N Engl J Med 1997; 337(19):1350-8. 4. Gillison ML, et al. J Natl Cancer Inst 2000; 92(9):709-20.

18. Regional Distribution of HPV Type Prevalence in Cervical Cancer Pagliusi SR, et al. Vaccine 2004; 23:569-78. 16 18 45 31 33 58 52 35 others North America 54.9 22.1 South America 51.7 10.6 Asia 43.4 15.3 Europe 56.0 17.2 Africa 50.2 14.1 HPV types:

19. 020406080100 HPV 16 + HPV 18 + HPV 45 + HPV 31 + HPV 33 + HPV 52 + HPV 58 Cumulative contribution (%) HPV 16HPV 18 HPV 45HPV 31HPV 33HPV 52HPV 58 70 % 90 % Based on de Sanjose et al. Lancet Oncol. 11:1048-56 (2010) Relative contribution of HPV types to cervical cancers, worldwide

20. Khan MJ, et al. J Natl Cancer Inst 2005; 97(14):1072-9. Cumulative incidence rate of ≥ CIN3 (%) 0 5 10 15 20 25 04.515.039.051.063.075.087.099.0111.0 Follow-up time (months) 119.5 27.0 Incidence of ≥ CIN3 Over Ten Years HPV16+ HPV18+ HPV+/HPV16-/18- HPV- 12,976 women aged ≥ 30 years with negative cytology at enrollment Oncogenic HPV status at enrollment:

21. Genital Warts Diagnosis Has an Emotional Impact: Canadian Survey Steben M et al. J Low Genit Tract Dis Respondents (%) 0 20 40 60 80 I would worry I would not be able to get rid of the warts 60.6% I would worry my family and friends would judge me 44.0% My self-esteem would dramatically decrease 53.0% I would be ashamed 54.3% Only 43% of respondents said they would stop having sex until the spots were gone, and 25% believed they were not at risk of genital warts if they used a condom 2012 Oct;16(4):409-15

22. SECOND CANCER SITE Cervix uteri AnusVulvaVaginaPharynxLarynxTongueTonsil FIRST CANCER SITE Cervix uteri 0.61 2.93 4.72 16.08 2.39 2.93 - 3.34 Anus - 7.27 7.45 8.42 -- 3.43 6.12 Vulva - 10.12 12.74 8.04 - 3.74 3.38 - Vagina -- 11.89 ---- Pharynx ---- 9.54 2.78 25.11 9.88 Larynx ---- 6.12 1.79 8.40 7.01 Tongue - -- 4.98 18.88 5.34 27.1723.36 Tonsil - 4.06 -- 16.16 6.28 39.7715.06 RISK OF SUBSEQUENT PRIMARY CANCERS BY SITE OF PRIMARY (significant associations) SEER program – 1973-2004

23. Available prevention technologies

24. Limits of primary prevention Primary prevention = protection before exposure = to limit acquisition of infection –Abstinence protects…while it lasts –Most human being will become sexualy active –Many with marriage –Condoms are good but far from perfect Most Canadian mother think their daughter will come forward before initiating sex life –Overestimate coitarche by 1 year = too late for maximizing benefits of HPV vaccine!

25. FUTURE I STUDY = 100% protection against all vulvar, vaginal, cervical lesions and warts!

26. AAHS 225μg AAHS 500μg 6 20μg 11 40μg “ORIGINAL TYPES” “NEW TYPES” ADJUVANT 4HPV 9HPV 16 40μg 18 20μg 6 30μg 11 40μg 16 60μg 18 40μg 31 20μg 33 20μg 45 20μg 52 20μg 58 20μg V503 Composition: 9-Valent HPV vaccine ACIP meeting October 24, 2013

27. Relative contribution of HPV types in 9vHPV vaccine to cervical diseases, worldwide Type of lesion 6/11/16/18 Contribution 31,33, 45,52,58 Contribution Total 9 Types Cervical cancer* 71%20%90 % CIN2/3**50%30%75-85 % CIN1**30-35%25%50-60 % * Based on SanJose et al 2010 ** Based on placebo cohort in the HPV 6/11/16/18 clinical program and several meta-analyses. Presented at ACIP meeting. Oct 24 2013.

28. Efficacy of a novel 9-valent HPV vaccine in 16-26 year old women Joura E. Abstract SS 8-4 Eurogin Florence Nov 3-6, 2013 Endpoint 9vHPV vaccine No cases/n qHPV Vaccine No of cases/n Efficacy (95%CI) High grade HPV31/33/45/52/58 cervical/vulvar/vaginal disease 1/6016 30/6017 96.7 % (80.9-99.8) Any grade HPV31/33/45/52/58 cervical/vulvar/vaginal disease 3/6016103/6017 97.1 % (91.8-99.2) HPV31/33/45/52/58 6 months related persistent infection 35/5939810/5953 96.0 % (94.4-97.2) Per protocol population

29. Endpoint 9vHPV Vaccine No. of cases/n qHPV Vaccine No. of cases/n Risk Reduction (95% CI) Biopsy7 / 6016222 / 6017 96.9% (93.6, 98.6) External Genital Biopsy 2 / 600922 / 6012 90.9% (65.7, 98.5) Cervical Biopsy 6 / 6012208 / 6014 97.2% (93.9, 98.8) Definitive Therapy (Cervical, Non- ablative) 4 / 601232 / 6014 87.5% (65.7, 96.0) Anti-HPV 31/33/45/52/58 Efficacy Per Protocol Efficacy Population Luxembourg A. ACIP meeting Feb 27 2014

30. OTTAWA, Dec. 9, 2015 /CNW/ - After reviewing Canadian and international information regarding the safety of the HPV vaccine, Gardasil, Health Canada is informing Canadians that the benefits of using this vaccine continue to outweigh the risks. The overall evidence continues to demonstrate that this vaccine can be safely used and that there are no new safety risks associated with its use. Gardasil is authorized in 133 countries around the world and is used to protect against four types of Human Papilloma Virus (HPV types 6, 11, 16, and 18), which cause 70% of cervical cancers, 90% of genital warts, and 80-90% of anal cancers. Vaccines are authorized for sale by Health Canada only after undergoing rigorous reviews to ensure their safety, efficacy and quality. Once on the Canadian market, Health Canada and the Public Health Agency of Canada continue to monitor the safety of all vaccines. A review of the safety of Gardasil by Health Canada was triggered by media reports of autoimmune and cardiovascular diseases. The safety review by Health Canada concluded that there is no evidence of an increased risk of autoimmune or cardiovascular diseases. Recent international reports are in line with Health Canada's findings. Since its authorization in 2006, nearly 2 million Canadians, and more than 63 million people worldwide, have been vaccinated with Gardasil. Approximately 1800 people in Canada, which represents approximately 1 out of 1,000 Canadians, reported side effects following vaccination with Gardasil. These include light-headedness, dizziness, nausea, headache, fever, and pain, swelling or redness at the injection site. The side effects are known and described in the Canadian labelling information. The benefits of using the vaccine outweigh the risks and potential side effects http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/gardasil- eng.phphttp://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/gardasil- eng.php

31. Safety

32. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2015/11/WC500196762.pdf Safety

35. OutcomeAustraliaCanadaNew Zealand United StatesSwedenGermanyBelgiumDenmark HPV type prevalence Tabrizi et al S JID. 2012Markowitz et al. JID 2013 Powell et al. Vaccine 2012 Delere et al. BMC Infect Dis. 2014 Genital warts Sexual Health Clinic Fairley et al. Sex Transm Infect. 2009 Read et al. STI. 2011 Kliewer et al. IPV 2012* Oliphant et al. NZMJ 2012 Genital warts Other Ecological Donovan et al. Lancet Infect. 2010 Ali H et al. BMJ. 2013 Liu B Sex Transm Infect. 2014 Kliwer E (IPV 2012) * Steben et al IPV 2014 Bauer H et al. Am Journal Public Health Wikstrom A et al. Eurogin 2012 SS12-1 Mikolajczyk R et al. STD 2013 Van tielen Eurogin 2012 Baandrup et al. STD 2012 Genital warts Population Based Leval et al. JID 2012 Herweijer E JAMA 2014 Blomberg etal. CID 2013 LSIL/HSIL Cervical registry Ecological Brotherton et al. Lance2011 Ogilvie et al IPV 2014 Mahmud et al JCO 2014* Niccolai et al Cancer Epidem Biomarkers Prev 2013. LSIL/HSIL Population wide Registry linked with vaccination status. Gertig, BMC 2013 Crowe E. BMJ 2014 BaldurFelskov B,JNCI 2014 Baldur Felskov B. Cancer Causes Control 2014 Countries With Reported Effectiveness Data With qHPV Vaccine *Assessment was done in girls or women who received the vaccine in the private market.

36. HPV Vaccination program impact on genital warts in Quebec Adapted from Steben M. et al. Poster presented at IPV, Seattle, USA, August 21-25, 2014 Results: GWs incidence rate by age and gender, 2006 and 2012

37. Prevalence of genital HPV infection in women aged 18-29, in the post vaccination period, Quebec, Canada VaccinatedAny HPV HPV 16HPV 6/11/16/18 HPV 31/33/45 17-19 yYES (n=594)32%0.3%0.3%**1.5% 17-19 yNO (n=52)32.7%1.9%7.7%5.8% 20-22 yYES (n=374)39.6%1.6%** 4.8% 20-22 yNO (n=150)48%6.7%9.3%4.7% 23-29 yYES (n=86)45.4%7%10.5% 23-29 yNO (n=320)48.6%7.6%11.6%6.1% 17-29 yYES (n=1054)35.8%*1.3%*1.6%*3.4% 17-29 yNO (n=531)46.9%6.8%10.6%5.7% HPV prevalence by age group and vaccine status (sexually active women only) *Statistically significant p ˂ 0.05 ** Statistically significant p ˂ 0.017 Adapted from Goggin P et al. Poster presented at EUROGIN, Sevilla, Spain, February 4-7, 2015

38. Limits of secondary prevention Secondary prevention = post exposure prevention = to limit consequences of acquisition –No screening test for HPV –No sexual contact treatment –Nor post exposition prophylaxis No test of cure Pap test is screening for complications of persistent high risk HPV Most infected are asymptomatic

39. Limits of screening with cytology 39 2/3 sampling 1/3 detection 50-60 % 20-25 % 8-15 %

40. Institut Català d’Oncologia ICO Hospitalet. Cancer Epidemiology Research Program (CERP) Accuracy of HPV screening vs. cytology Screening testNSensitivity (95% CI)Specificity (95% CI) Detection of CIN2+ Cytology (ASC-US+)2570.0% (62.5–77.6%)91.9% (90.3–93.6%) HC23190.4% (88.0–92.8%)88.5% (87.0–90.0%) Co-testing*1394.2% (90.8–97.6%)87.7% (85.0–90.3%) Detection of CIN3+ Cytology (ASC-US+)2174.6% (65.6–83.6%)91.8% (90.0–93.7%) HC22295.3% (93.3–97.3%)89.0% (87.2–90.8%) Co-testing*1296.7% (93.7–99.7%)82.9% (77.1–88.6%) Updated meta-analysis data from Arbyn et al. 21,22 In Bosch FX et al. Nature reviews Clinical oncology 2015 * Cytology (ASC-US+) and HC2

41. 41 Feasability by comparison Primary prevention Vaccines are safe No repeat Highly effective Cheaper / QALY* Infrastructure exists in most countries And are lighter Secondary prevention Screening is safe Repeated q 5-8 years? High NPV if done by HPV DNA More expensive / QALY Infrastructure does not exist in most LMIC And are more complex *QALY = quality adjusted life year

42. 42 Synergistic not competitive HPV preventive strategies We have to remember that the bulk of disease will remain for a few years in the middle aged women that may require some protection. Adopting screening techniques that are more sensitive, specific and allow for extension of time between two screenings may permit resources to be allocated to vaccination programs

43. The political scene

45. 45 WHO position statement on HPV vaccines HPV vaccination should be included in national immunization programs, provided that: prevention of HPV-related diseases constitutes a public health priority vaccine introduction is programmatically feasible sustainable financing can be secured cost effectiveness of vaccination strategies is considered The primary target population is likely to be girls within the age range of 9-10 through to 13 HPV WHO position paper, WER 10Apr, No. 15, 2009, 84, 117-132

46. 46 United Nations high-level meeting on noncommunicable disease prevention and control To shape the international agenda –19-20 September 2011, NY, USA –NCDs – like cancers account for over 63% of deaths in the world today. –NCDs kill 9 million/yr people under 60. –Socio-economic impact is staggering. –This is only the second time in the history of the UN that the General Assembly meets on a health issue the first issue was AIDS

47. 47 Possible linkages between non-communicable diseases and some communicable diseases, such as HIV/AIDS, call for the integration Loss of productivity that threatens the economies of Member States may have a direct impact on the achievement of the internationally agreed development goals, including the Millennium Development Goals Recognize the importance of strengthening local, provincial, national and regional capacities to address and effectively combat non-communicable diseases Promote increased access to cost-effective vaccinations to prevent infections associated with cancers, as part of national immunization schedules; Promote increased access to cost-effective cancer screening programmes, as determined by national situations; Promote the inclusion of non-communicable disease prevention and control within sexual and reproductive health and maternal and child health programmes, especially at the primary health-care level, as well as other programmes, as appropriate

48. 48 GAVI offers new support for vaccines against cervical cancer 57 poorest countries are invited to apply for support to introduce human papillomavirus Geneva, 5 April 2012 Source : GAVI alliance Demonstrate feasability Demonstrate sustainability

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50. Recommend to delete this slide, as the vaccine launches in the private sector do not assure vaccine access for the majority of the eligible cohort 57 GAVI Eligible Countries http://www.gavialliance.org/support/who/eligible/index.php Afghanistan Bangladesh Benin Burkina Faso Burundi Cambodia Cameron Central African Republic Chad Comoros Congo, Dem Republic of Côte d'Ivoire Cuba Djibouti Eritria Ethiopia Ghana Guinea Guinea-Bissau Haiti India Kenya Korea, DPR Kyrgyz Republic Lao PDR Lesotho Liberia Madagascar Haiti Malawi Mali Mauritania Mozambique Myanmar Nepal Nicaragua Niger Nigeria Pakistan Papua New Guinea Rwanda São Tomé e Príncipe Senegal Sierra Leone Solomon Islands Somalia North Sudan South Sudan Tajikistan Tanzania Togo Uganda Uzbekistan Viet Nam Yemen Zambia Zimbabwe GARDASIL Approved Cervarix Approved GARDASIL Launched Cervarix Launched 24 7 18 4 GAVI Classification: Countries with a Gross National Income (GNI) per capita below US$1,520 in 2009

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55. Going forward

56. 3 North America: USA Canada Mexico 9 South America: Brazil Bolivia ArgentinaUruguay PeruEcuador ColombiaChile Paraguay 35 Middle East & Africa: GabonNamibia IsraelC.A.R. MoroccoMauritius KenyaKuwait MauritaniaUAE Guinea Eq.Ethiopia UgandaTogo MalawiCongo Brazzaville JordanEgypt Cote d’IvoireBurkina Faso ChadBahrainBotswana LebanonTanzaniaZambia South AfricaCameroonNigeria PakistanTunisiaMali Guinea ConakrySaudi ArabiaRwanda 22 Asia Pacific & Japan: Kyrgyzstan Uzbekistan Kazakhstan Australia Indonesia Korea Taiwan Hong Kong Singapore New Zealand Macau Malaysia Philippines Thailand India Vietnam Fiji Bhutan Georgia JAPAN Sri Lanka Brunei 42 Europe: GermanyCyprusIreland France Czech RepublicLatvia UK DenmarkLithuania Spain EstoniaLuxembourg Italy FinlandMalta AustriaGreeceNetherlands BelgiumHungaryNorway BulgariaIcelandPoland PortugalRomaniaSlovakia SloveniaSwedenSerbia MontenegroSwitzerlandLiechtenstein BosniaRussiaBelarus CroatiaTurkeyUkraine HerzogovinaMacedoniaAlbania Caribbean & Central America: Costa Rica Trinidad/Tobago Puerto RicoEl Salvador GuatemalaHonduras Curaçao Nicaragua BermudaPanama BahamasCayman Islands BarbadosAruba JamaicaDominican Republic 16 Gardasil / Silgard Approvals GARDASIL approved in 127 countries (includes 24 GAVI-eligible) GAVI – Eligible Registration Approvals (24): Burkina Faso, Cameroon, Central African Republic, Chad, Congo (DR), Cote d’Ivoire, Ethiopia, Guinea (Conakry), India, Kenya, Kyrgyzstan, Malawi, Mali, Mauritania, Nicaragua, Nigeria, Pakistan, Rwanda, Tanzania, Togo, Uganda, Uzbekistan, Vietnam, Zambia

57. 57 HPV Recommendations by National Expert Advisory Bodies on Immunization – For Female: 44 Countries – For Males: 3 countries National Funding: For Females: 40 Countries – For Males: 2 countries Update: September 7, 2012 Cayman Is. 3 North America USA* Canada* Mexico 5 South America Argentina Peru Guyana Colombia Trinidad & Tobago 3 Middle East & Africa Kuwait UAE Lesotho 7 Asia Pacific Australia* New Zealand Malaysia Brunei India Singapore Japan 24 Europe Austria Belgium Bulgaria Czech Republic Denmark Finland France Germany Greece Iceland Ireland Italy Latvia Luxemburg Macedonia Netherlands Norway Portugal Romania Slovenia Spain Sweden Switzerland United Kingdom Caribbean & Central America Puerto Rico Panama 2 FUNDING GARDASIL only Bivalent Only Both vaccines No funding * Male Recommendation for HPV Vaccination

58. Global Progress in HPV vaccine introduction August 2015 http://www.cervicalcanceraction.org/comments/comments.php

59. 59 General challenges to all new vaccines intro in LMICS Taking into consideration what has been learned and accomplished to date –Competing health challenges, including several new vaccines (PCV, rotavirus, HPV) –However, non-GAVI-eligible LMICs may lack dedicated funding sources and ability to implement (vaccine & delivery costs) and sustain the introduction of these new vaccines –Variable country capacity with respect to education, advocacy, & institutional capacity (including national immunization technical advisory groups, BOD studies, capacity to evaluate vaccine cost effectiveness, procurement & delivery capacity, etc). –Uneven political will in some countries

60. 60 Challenges specific to the introduction of HPV vaccine Continued need for education and advocacy for HPV prevention Build political will for HPV disease prevention Need for countries to develop well-suited national comprehensive strategies for CxCa prevention that take into consideration individual country capacity and resources Further optimize HPV vaccine delivery approaches that take into consideration existing health infrastructure, resources –Identify the most cost-effective delivery strategy Respect any cultural sensitivities about a vaccine program that targets adolescent females only

61. 61 Financing vaccines Various bilateral assistance programs exist The GAVI Alliance will begin offering HPV vaccine at a subsidized rate for the poorest countries in the world –as low as US $0.20 vaccine per dose co-pay for a fixed period The PAHO EPI Revolving Fund also has negotiated low prices for its member countries.

62. Global Progress in Visual Inspection (VIA) for Cervical Cancer Screening August 2015 http://www.cervicalcanceraction.org /comments/comments.php

63. Institut Català d’Oncologia ICO Hospitalet. Cancer Epidemiology Research Program (CERP) Accuracy of HPV screening vs. cytology Screening testNSensitivity (95% CI)Specificity (95% CI) Detection of CIN2+ Cytology (ASC-US+)2570.0% (62.5–77.6%)91.9% (90.3–93.6%) HC23190.4% (88.0–92.8%)88.5% (87.0–90.0%) Co-testing*1394.2% (90.8–97.6%)87.7% (85.0–90.3%) Detection of CIN3+ Cytology (ASC-US+)2174.6% (65.6–83.6%)91.8% (90.0–93.7%) HC22295.3% (93.3–97.3%)89.0% (87.2–90.8%) Co-testing*1296.7% (93.7–99.7%)82.9% (77.1–88.6%) Updated meta-analysis data from Arbyn et al. 21,22 In Bosch FX et al. Nature reviews Clinical oncology 2015 * Cytology (ASC-US+) and HC2 HPV testing = Amenable to self-sampling

64. Global Progress in HPV DNA testing August 2015 http://www.cervicalcanceraction.org /comments/comments.php

65. De Sanjosé S et al. Lancet Infect Dis.2007; 453-9 0 5 10 15 20 25 30 < 2525-3435-4445-54> 54 Age group (years) Africa CS. America Asia N. America Europe Second peak of HPV infection prevalence occurs among women ≥45 years of age Age Specific HPV prevalence (%)

66. Institut Català d’Oncologia ICO Hospitalet. Cancer Epidemiology Research Program (CERP) HPV vaccine efficacy in mid-adult women Outcome4vHPV (to age 45)2vHPV (to age 55) ‘per-protocol’/‘according-to-protocol’ ( HPV negative) 6M Persistent infection VE: 89.6% (95%CI 79.3–95.4)VE: 82.9% (95%CI 53.8–95.1) CIN2+ VE: 83.3% (95%CI −37.6–99.6)VE: 100% (95%CI −100.7–100.0) External genital lesions VE: 100% (95%CI 30.8–100.0)NR ‘intention-to-treat’/‘total-vaccinated-cohort’ (irrespective of HPV) 6M Persistent infection VE: 49.0% (95%CI 35.5–59.9) VE: 47.0% (95% CI 25.4 ‑ 62.7) ‡ CIN2+ VE: 22.4% (95% CI −42.5–58.3)VE: 29.1% (95% CI −22.5–59.6) ‡ External genital lesions VE: 8.5% (95% CI −126.6–63.4)NR Baseline seropositive but HPV-DNA-negative (previous infection) 6M persistent infection (≥ 1 dose) VE: 66.8% (95% CI 3.8 ‑ 90.5) NR 6M Persistent infection or + (3 doses) NRVE: 86.4% (30.1–99.0) Bold blue: statistically significant under trial conditions

67. 67 Integrating vaccination and screening strategies Strategies that integrate HPV or cervical cancer screening and HPV vaccination are complex and should be carefully deployed. It is essential that governments and resources are not pulled apart into two separate programs (vaccination and screening) but proper attribution of resources is of utmost importance. In young women, cervical cancer screening should not be done too early and vaccine should be prioritized early in adolescence.

68. Institut Català d’Oncologia ICO Hospitalet. Cancer Epidemiology Research Program (CERP) FX Bosch Institut Catala d’Oncologia Amsterdam April 2016 The case for adult women vaccination The HPV FASTER concept and related projects

69. Institut Català d’Oncologia ICO Hospitalet. Cancer Epidemiology Research Program (CERP) Anticipated new indications for HPV vaccination / screening (at least) in developed countries PROPHYLACTIC prevent new infections and transmission Adult women –To 26, 30, 45+… Males –To 18, 50+… Infants (EPI) HIGH RISK GROUPS HIV cohorts / MSM Transplants & immunosuppresse d Autoimmune patients STI clinics Partners of HPV+ Migrants / marginal Abused children AS PART OF THERAPY interrupt reinfections and transmission HPV + women in screening Post treatments in CIN lesions RRP HPV GW and cancer survivors Therapeutic / mixed vaccines

70. Institut Català d’Oncologia ICO Hospitalet. Cancer Epidemiology Research Program (CERP) New guidelines for cervical cancer prevention in Europe and the US 91425 65 HPV Test x 5/10 years 30 Cytology x 3 years 45 Bosch FX et al. 2015 Nat Rev Clin Oncol 1945 - EU 2006 - HPV and cytology Co-Test x 5 years USA 2006 - Cytology hpv test co- testing

71. Institut Català d’Oncologia ICO Hospitalet. Cancer Epidemiology Research Program (CERP) Current HPV vaccination and cervical cancer screening strategy in developed countries and proposed FASTER initiative 91425 65 Age (years) Cytology every 3 yrs HPV test every 5/10 yrs Routine andCatch-up / opportunistic vaccination: intervention ( x2 or x3, based on age) Cytology screening: intervention ( )HPV screening: intervention ( ) 30 HPV tetst x 2 / 3 lifetime 45 Male vaccination

72. Institut Català d’Oncologia ICO Hospitalet. Cancer Epidemiology Research Program (CERP) Ongoing studies and planned trials Frida 2 Australian & Pacific Islands HPV Faster CoheaHr Vaccine acceptability & logistics Aborigine & marginal populations Inuits & migrants Unscreened semi-rural areas Amazonian Favelas in BA Under evaluation

73. 73 Challenges to implement HPV prevention There may be challenges to implement screening or HPV immunization programming in LMIC But none of these challenges should be considered insurmountable. Many LMIC have decided with success to adopt HPV prevention agenda despite prevailing pessimism. Not acting on this issue perpetuated inequity in STI and cancer prevention.

74. 74

75. 75 Decreasing maternal mortality in developing countries. Impressive progress has been achieved Result of significant investment in evidence-based best practices Rigorous impact monitoring Driven in part by desire to achieve Millennium Development Goal 5.

76. 76 Decreasing maternal mortality in developing countries. Our success reducing maternal mortality is cause for great hope That with similar investments These same mothers having been saved during pregnancy Will be protected 10 or 20 years later in life when they face the threat of cervical cancer.

77. 77 Would HPV vaccine be the best of all preventive activity of public health yet? Cervical cancer prevention by vaccine and screening might be the most efficient way to fight the inequities about women’s health issues Our breast cancer and HIV colleagues are so jealous as they do not have such a powerful vaccine and versatile testing scheme. Moment of reflexion

78. Institut Català d’Oncologia ICO Hospitalet. Cancer Epidemiology Research Program (CERP) We can control cervical cancer within one generation –We have the science –We have the tools –We need the policy

79. 79 Final words from a wise friend "...no person should be denied access to an effective measure to prevent serious disease, simply because they were born in the wrong place..."

80. 80 http://www.gavialliance.org/library/news/press-releases/2012/gavi-recognised-hpv- vaccines-in-developing-countries/ A young girl in Burkina Faso will one day enjoy the same access to the HPV vaccine as their contemporaries in developed nations. Photo credit: UNICEF Jonathan Shadid/2011.

81. 81 My final words Failure to scale up against this lethal STI is a serious indictment of our research community and it’s leadership