Human Papillomavirus and Related Diseases Report EUROPE

Human Papillomavirus and Related Diseases Report EUROPE Version posted at www.hpvcentre.net on 27 July 217

- ii - Copyright and Permissions ICO Information Centre on HPV and Cancer (HPV Information Centre), 217. All rights reserved. HPV Information Centre publications can be obtained from the HPV Information Centre Secretariat, Institut Català d Oncologia, Avda. Gran Via de l Hospitalet, 199-23 898 L Hospitalet del Llobregat (Barcelona) Spain. E-mail: hpvcentre@iconcologia.net. Requests for permission to reproduce or translate HPV Information Centre publications - whether for sale or for noncommercial distribution- should be addressed to the HPV Information Centre Secretariat, at the above address. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part the HPV Information Centre concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended the HPV Information Centre in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the HPV Information Centre to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the HPV Information Centre be liable for damages arising from its use. The development of this report has been supported by grants from the European Comission (7th Framework Programme grant HEALTH-F3-21-24261, HEALTH-F2-211-282562, HPV AHEAD). Recommended citation: Bruni L, Barrionuevo-Rosas L, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé S. ICO Information Centre on HPV and Cancer (HPV Information Centre). Human Papillomavirus and Related Diseases in Europe. Summary Report 27 July 217. [Date Accessed]

- iii - Abbreviations Abbreviation HPV PREHDICT Project Table 1: Abbreviations Full term Human papillomavirus Health economic modelling of prevention strategies for HPV-related diseases in European countries ICO Information Centre on HPV and Cervical Cancer Genital warts Recurrent respiratory papillomatosis Squamous intraepithelial lesions Low-grade cervical lesions High-grade cervical lesions Invasive cervical cancer Carcinoma in situ Cervical intraepithelial neoplasia HPV Information Centre GW RRP SIL LSIL HSIL ICC CIS CIN AIN2/3 Anal intraepithelial neoplasia of grade 2 and/or 3 VIN 2/3 Vulvar intraepithelial neoplasia of grade 2 and/or 3 VaIN 2/3 Vaginal intraepithelial neoplasia of grade 2 and/or 3 PeIN 2/3 Penile intraepithelial neoplasia of grade 2 and/or 3 95% CI 95% confidence interval N Number of cases tested HPV Prev HPV prevalence ASR Age-standardised rate MSM Men who have sex with men Non MSM Heterosexual men SCC Squamous cell carcinomas STI Sexually transmitted infections HIV/AIDS Human immunodeficiency virus/acquired immunodeficiency syndrome TS Type specific EIA Enzyme immunoassay RLBM Reverse line blotting method RFLP Restriction fragment length polymorphism RHA Reverse hybridisation assay RLH Reverse line hybridisation LiPA Line probe assay SBH Southern blot hybridisation ISH In situ hybridisation MABA Micro array-based assay LBA Line blot assay HC2 Hybrid Capture 2 SAT Suspension array technology PCR Polymerase chain reaction SPF Short primer fragment q-pcr Quantitative polymerase chain reaction RLBH Reverse line blot hybridisation RT-PCR Real-time polymerase chain reaction DBH Dot blot hybridisation HR High risk DSA Direct sequence analysis MAA Microchip array assay

- iv - Executive summary Human papillomavirus (HPV) infection is now a well-established cause of cervical cancer and there is growing evidence of HPV being a relevant factor in other anogenital cancers (anus, vulva, vagina and penis) as well as head and neck cancers. HPV types 16 and 18 are responsible for about 7% of all cervical cancer cases worldwide. HPV vaccines that prevent HPV 16 and 18 infections are now available and have the potential to reduce the incidence of cervical and other anogenital cancers. This report provides key information for Europe on: cervical cancer; other anogenital cancers, and head and neck cancers; HPV-related statistics; factors contributing to cervical cancer; cervical cancer screening practises; HPV vaccine introduction, and other relevant immunization indicators. The report is intended to strengthen the guidance for health policy implementation of primary and secondary cervical cancer prevention strategies in the region. Europe has an estimated population of 325.3 million women aged 15 years and older who are at risk of developing cervical cancer. Current estimates indicate that every year 58,373 women are diagnosed with cervical cancer and 24,44 die from the disease. Cervical cancer ranks as the sixth most frequent cancer among women in Europe. Ranking of cervical cancer incidence to other cancers among all women according to highest incidence rates (ranking 1st). Ranking is based on crude incidence rates (actual number of cervical cancer cases). Ranking using age-standardized rate (ASR) may differ. Population Table 2: Key statistics on Europe and its regions Women at risk for cervical cancer (Female population aged >=15 yrs) in millions Burden of cervical cancer Europe Eastern Europe Northern Europe Southern Europe Western Europe 325.3 131.2 43.5 67.4 83.2 Annual number of new cervical cancer cases 58,373 33,882 5,382 9,285 9,824 Standardised incidence rates per 1, population 11.4 16.3 8.7 8.5 7.3 Annual number of cervical cancer deaths 24,44 15,436 1,963 3,526 3,479 Standardised mortality rates per 1, population 3.8 6.2 2.2 2.4 1.8 Burden of cervical HPV infection Prevalence (%) of HPV 16 and/or HPV 18 among women with: Normal cytology 3.8 9.7 4.5 3.2 2.6 Low-grade cervical lesions (LSIL/CIN-1) 27.1 31.8 3.6 25.4 25.2 High-grade cervical lesions (HSIL/ CIN-2 / CIN-3 / CIS) 54.5 6.5 54.9 53.2 59.4 Cervical cancer 74. 84.7 77. 68. 78.7 LSIL, low-grade intraepithelial lesions; HSIL, high-grade intraepithelial lesions; CIN, cervical intraepithelial neoplasia; CIS, carcinoma in-situ. Please see the specific sections for more information.

LIST OF CONTENTS - v - Contents Abbreviations Executive summary iii iv 1 Introduction 1 2 Demographic and socioeconomic factors 3 3 Burden of HPV-related cancers 6 3.1 Cervical cancer.............................................. 6 3.1.1 Incidence............................................. 6 3.1.2 Mortality............................................. 23 3.1.3 Comparison of incidence and mortality........................... 35 3.2 Anogenital cancers other than the cervix.............................. 36 3.2.1 Anal cancer............................................ 38 3.2.2 Vulvar cancer........................................... 56 3.2.3 Vaginal cancer.......................................... 64 3.2.4 Penile cancer........................................... 72 3.3 Head and neck cancers......................................... 8 3.3.1 Pharyngeal cancer (excluding nasopharynx)........................ 82 4 HPV-related statistics 89 4.1 HPV burden in women with normal cervical cytology, cervical precancerous lesions or invasive cervical cancer......................................... 89 4.1.1 HPV prevalence in women with normal cervical cytology................ 9 4.1.2 HPV type distribution among women with normal cervical cytology, precancerous cervical lesions and cervical cancer.............................. 99 4.1.3 HPV type distribution among HIV+ women with normal cervical cytology...... 117 4.1.4 Terminology............................................ 118 4.2 HPV burden in anogenital cancers other than the cervix..................... 119 4.2.1 Anal cancer and precancerous anal lesions......................... 119 4.2.2 Vulvar cancer and precancerous vulvar lesions....................... 123 4.2.3 Vaginal cancer and precancerous vaginal lesions..................... 128 4.2.4 Penile cancer and precancerous penile lesions....................... 131 4.3 HPV burden in men........................................... 134 4.4 HPV burden in the head and neck.................................. 141 4.4.1 Burden of oral HPV infection in healthy population.................... 141 4.4.2 HPV burden in head and neck cancers............................ 143 5 Factors contributing to cervical cancer 157 6 Sexual behaviour and reproductive health indicators 161 7 HPV preventive strategies 172 7.1 Cervical cancer screening practices.................................. 172 7.2 HPV vaccination............................................. 175 7.2.1 HPV vaccine licensure and introduction........................... 175 8 Protective factors for cervical cancer 177 9 References 179 1 Glossary 22

LIST OF FIGURES - vi - List of Figures 1 European regions.......................................................... 1 2 Population pyramid of Europe.................................................. 4 3 Population trends in four selected age groups in Europe for 217............................. 4 4 Age-standardised incidence rates (ASR) of cervical cancer in regions of Europe (estimates for 212)........ 6 5 Age-standardised incidence rates of cervical cancer in Europe (estimates for 212).................. 7 6 Age-standardised incidence rate of cervical cancer cases attributable to HPV by country in Europe (estimates for 212)............................................................... 8 7 Ranking of cervical cancer versus other cancers among all women and women aged 15-44 years, according to incidence rates in Europe (estimates for 212)........................................ 1 8 Comparison of the ten most frequent cancers in all women in Europe and its regions (estimates for 212).... 11 9 Comparison of the ten most frequent cancers in women aged 15-44 years by Europe and its regions (estimates for 212)............................................................... 13 1 Age-specific incidence of cervical cancer in Europe and its regions (estimates for 212)................ 14 11 Annual number of new cases of cervical cancer by age group in European regions (estimates for 212)...... 15 12 Annual number of cases and age-specific incidence rates of cervical cancer in Europe and its regions (estimates for 212)............................................................... 16 13 Annual number of cases and age-specific incidence rates of cervical cancer in Europe and its regions (estimates for 212) (Continued)....................................................... 17 14 Time trends in cervical cancer incidence type in Austria (cancer registry data)..................... 19 15 Time trends in cervical cancer incidence type in Switzerland (cancer registry data).................. 19 16 Time trends in cervical cancer incidence type in Spain (cancer registry data)...................... 2 17 Time trends in cervical cancer incidence type in France (cancer registry data)..................... 2 18 Time trends in cervical cancer incidence type in the United Kingdom (cancer registry data)............. 21 19 Time trends in cervical cancer incidence type in Italy (cancer registry data)...................... 21 2 Time trends in cervical cancer incidence type in Poland (cancer registry data)..................... 22 21 Time trends in cervical cancer incidence type in the Russian Federation (cancer registry data)........... 22 22 Age-standardised mortality rates (ASR) of cervical cancer in European regions (estimates for 212)........ 23 23 Age-standardised mortality rates of cervical cancer in Europe (estimates for 212).................. 24 24 Ranking of cervical cancer versus other cancers among all women and women aged 15-44 years, according to mortality rates in Europe (estimates for 212)........................................ 26 25 Comparison of the ten most frequent cancer deaths in women aged 15-44 years in Europe and its regions (estimates for 212)........................................................... 27 26 Comparison of the ten most frequent cancer deaths in women of all ages in Europe and its regions (estimates for 212)................................................................. 29 27 Age-specific mortality of cervical cancer in Europe and its regions (estimates for 212)................ 3 28 Annual number of deaths of cervical cancer by age group in European regions (estimates for 212)........ 31 29 Annual number of deaths and age-specific mortality rates of cervical cancer in Europe and its regions (estimates for 212)............................................................... 32 3 Annual number of deaths and age-specific mortality rates of cervical cancer in Europe and its regions (estimates for 212) (Continued)....................................................... 33 31 Age-specific incidence and mortality rates of cervical cancer in Europe and its regions (estimates for 212)... 35 32 Age-standardised incidence rates of anogenital cancers other than the cervix in Europe (estimates for 212).. 36 33 Age-standardised incidence rate of other anogenital cancer cases attributable to HPV by country in Europe (estimates for 212)........................................................ 37 34 Time trends in anal cancer incidence in Austria (cancer registry data).......................... 42 35 Time trends in anal cancer incidence in Croatia (cancer registry data).......................... 43 36 Time trends in anal cancer incidence in Denmark (cancer registry data)........................ 44 37 Time trends in anal cancer incidence in Estonia (cancer registry data)......................... 45 38 Time trends in anal cancer incidence in France (cancer registry data).......................... 46 39 Time trends in anal cancer incidence in Iceland (cancer registry data).......................... 47 4 Time trends in anal cancer incidence in Italy (cancer registry data)........................... 48 41 Time trends in anal cancer incidence in the Netherlands (cancer registry data).................... 49 42 Time trends in anal cancer incidence in Poland (cancer registry data).......................... 5 43 Time trends in anal cancer incidence in the Russian Federation (cancer registry data)................ 51 44 Time trends in anal cancer incidence in Slovakia (cancer registry data)......................... 52 45 Time trends in anal cancer incidence in Spain (cancer registry data)........................... 53 46 Time trends in anal cancer incidence in Switzerland (cancer registry data)....................... 54 47 Time trends in anal cancer incidence in the United Kingdom (cancer registry data).................. 55 48 Time trends in vulvar cancer incidence in Austria (cancer registry data)........................ 59 49 Time trends in vulvar cancer incidence in Croatia (cancer registry data)........................ 59 5 Time trends in vulvar cancer incidence in Denmark (cancer registry data)....................... 59 51 Time trends in vulvar cancer incidence in Estonia (cancer registry data)........................ 6 52 Time trends in vulvar cancer incidence in France (cancer registry data)......................... 6

LIST OF FIGURES - vii - 53 Time trends in vulvar cancer incidence in Iceland (cancer registry data)........................ 6 54 Time trends in vulvar cancer incidence in Italy (cancer registry data).......................... 61 55 Time trends in vulvar cancer incidence in Netherlands (cancer registry data)..................... 61 56 Time trends in vulvar cancer incidence in Poland (cancer registry data)......................... 61 57 Time trends in vulvar cancer incidence in Russian Federation (cancer registry data)................. 62 58 Time trends in vulvar cancer incidence in Slovakia (cancer registry data)........................ 62 59 Time trends in vulvar cancer incidence in Spain (cancer registry data)......................... 62 6 Time trends in vulvar cancer incidence in Switzerland (cancer registry data)..................... 63 61 Time trends in vulvar cancer incidence in United Kingdom (cancer registry data)................... 63 62 Time trends in vaginal cancer incidence in Austria (cancer registry data)........................ 67 63 Time trends in vaginal cancer incidence in Croatia (cancer registry data)........................ 67 64 Time trends in vaginal cancer incidence in Denmark (cancer registry data)....................... 67 65 Time trends in vaginal cancer incidence in Estonia (cancer registry data)........................ 68 66 Time trends in vaginal cancer incidence in France (cancer registry data)........................ 68 67 Time trends in vaginal cancer incidence in Iceland (cancer registry data)........................ 68 68 Time trends in vaginal cancer incidence in Italy (cancer registry data)......................... 69 69 Time trends in vaginal cancer incidence in Netherlands (cancer registry data)..................... 69 7 Time trends in vaginal cancer incidence in Poland (cancer registry data)........................ 69 71 Time trends in vaginal cancer incidence in Russian Federation (cancer registry data)................ 7 72 Time trends in vaginal cancer incidence in Slovakia (cancer registry data)....................... 7 73 Time trends in vaginal cancer incidence in Spain (cancer registry data)......................... 7 74 Time trends in vaginal cancer incidence in Switzerland (cancer registry data)..................... 71 75 Time trends in vaginal cancer incidence in United Kingdom (cancer registry data).................. 71 76 Time trends in penile cancer incidence in Austria (cancer registry data)......................... 75 77 Time trends in penile cancer incidence in Croatia (cancer registry data)......................... 75 78 Time trends in penile cancer incidence in Denmark (cancer registry data)....................... 75 79 Time trends in penile cancer incidence in Estonia (cancer registry data)........................ 76 8 Time trends in penile cancer incidence in France (cancer registry data)......................... 76 81 Time trends in penile cancer incidence in Iceland (cancer registry data)......................... 76 82 Time trends in penile cancer incidence in Italy (cancer registry data).......................... 77 83 Time trends in penile cancer incidence in Netherlands (cancer registry data)..................... 77 84 Time trends in penile cancer incidence in Poland (cancer registry data)......................... 77 85 Time trends in penile cancer incidence in Russian Federation (cancer registry data)................. 78 86 Time trends in penile cancer incidence in Slovakia (cancer registry data)........................ 78 87 Time trends in penile cancer incidence in Spain (cancer registry data).......................... 78 88 Time trends in penile cancer incidence in Switzerland (cancer registry data)...................... 79 89 Time trends in penile cancer incidence in United Kingdom (cancer registry data)................... 79 9 Age-standardised incidence rates of head and neck cancer in Europe (estimates for 212).............. 8 91 Age-standardised incidence rate of head and neck cancer cases attributable to HPV by country in Europe (estimates for 212)........................................................... 81 92 Comparison of cancer incidence and mortality of pharynx (excluding nasopharynx) in males by age group in Europe and its regions. Includes ICD-1 codes: C9-1,C12-14 (estimates for 212).................. 85 93 Comparison of cancer incidence and mortality of pharynx (excluding nasopharynx) in females by age group in Europe and its regions. Includes ICD-1 codes: C9-1,C12-14 (estimates for 212).................. 87 94 Prevalence of HPV among women with normal cervical cytology in Europe....................... 9 95 Crude age-specific HPV prevalence (%) and 95% confidence interval in women with normal cervical cytology in Europe and its regions...................................................... 91 96 Prevalence of HPV among women with normal cervical cytology in Europe by country and study......... 92 97 Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued).. 94 98 Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued).. 96 99 Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued).. 98 1 Prevalence of HPV 16 among women with normal cervical cytology in Europe by country and study........ 1 11 Prevalence of HPV 16 among women with normal cervical cytology in Europe by country and study (continued) 11 12 Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study....... 12 13 Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study (continued) 13 14 Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study (continued) 14 15 Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study...... 15 16 Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study (continued) 16 17 Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study (continued) 17 18 Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study........ 18 19 Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study (continued). 19 11 Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study (continued). 11 111 Comparison of the ten most frequent HPV oncogenic types among women with and without cervical lesions in Europe and its regions...................................................... 111

LIST OF FIGURES - viii - 112 Comparison of the ten most frequent HPV oncogenic types among women with and without cervical lesions in Europe and its regions (continued)............................................... 112 113 Comparison of the ten most frequent HPV oncogenic types among women with invasive cervical cancer by histology in Europe and its regions................................................ 113 114 Comparison of the ten most frequent HPV oncogenic types among women with invasive cervical cancer by histology in Europe and its regions (continued).......................................... 114 115 Comparison of the ten most frequent HPV types in anal cancer cases in Europe and the World........... 122 116 Comparison of the ten most frequent HPV types in AIN 2/3 cases in Europe and the World............. 122 117 Comparison of the ten most frequent HPV types in cases of vulvar cancer in Europe and the World........ 126 118 Comparison of the ten most frequent HPV types in VIN 2/3 cases in Europe and the World............. 127 119 Comparison of the ten most frequent HPV types in vaginal cancer cases in Europe and the World......... 129 12 Comparison of the ten most frequent HPV types in VaIN 2/3 cases in Europe and the World............ 13 121 Comparison of the ten most frequent HPV types in penile cancer cases in Europe and the World.......... 133 122 Comparison of the ten most frequent HPV types in PeIN 2/3 cases in Europe and the World............ 133 123 Prevalence of female tobacco smoking in Europe....................................... 157 124 Total fertility rates in Europe.................................................. 158 125 Prevalence of hormonal contraceptive use in Europe.................................... 159 126 Prevalence of HIV in Europe................................................... 16 127 Percentage of 15-year-old girls who report sexual intercourse in Europe......................... 161 128 Percentage of 15-year-old boys who report sexual intercourse in Europe......................... 162 129 Status of HPV vaccination programmes in Europe...................................... 175 13 Prevalence of male circumcision in Europe.......................................... 177 131 Prevalence of condom use in Europe.............................................. 178

LIST OF TABLES - ix - List of Tables 1 Abbreviations............................................................ iii 2 Key statistics on Europe and its regions............................................ iv 3 Population (in millions) estimates in Europe for 217.................................... 3 4 Sociodemographic indicators in Europe............................................ 5 5 Incidence of cervical cancer in Europe (estimates for 212)................................. 9 6 Cervical cancer mortality in Europe (estimates for 212).................................. 24 7 Incidence of anal cancer in Europe by cancer registry and sex............................... 38 8 Incidence of vulvar cancer in Europe by cancer registry................................... 56 9 Incidence of vaginal cancer in Europe by cancer registry.................................. 64 1 Incidence of penile cancer in Europe by cancer registry................................... 72 11 Cancer incidence of pharynx (excluding nasopharynx) in Europe and its regions by sex. Includes ICD-1 codes: C9-1, C12-14 (estimates for 212)............................................... 82 12 Cancer mortality of pharynx (excluding nasopharynx) in Europe and its regions by sex. Includes ICD-1 codes: C9-1, C12-14 (estimates for 212)............................................... 83 13 Prevalence of HPV 16/18 in women with normal cytology, precancerous cervical lesions and invasive cervical cancer in Europe.......................................................... 99 14 Type-specific HPV prevalence in women with normal cervical cytology, precancerous cervical lesions and invasive cervical cancer in Europe..................................................... 115 15 Type-specific HPV prevalence among invasive cervical cancer cases in Europe by histology............. 116 16 European studies on HPV prevalence among HIV women with normal cytology.................... 117 17 European studies on HPV prevalence among anal cancer cases (male and female).................. 119 18 European studies on HPV prevalence among AIN 2/3 cases (male and female)..................... 12 19 European studies on HPV prevalence among vulvar cancer cases............................. 123 2 European studies on HPV prevalence among VIN 2/3 cases................................ 125 21 European studies on HPV prevalence among vaginal cancer cases............................ 128 22 European studies on HPV prevalence among VaIN 2/3 cases................................ 128 23 European studies on HPV prevalence among penile cancer cases............................. 131 24 European studies on HPV prevalence among PeIN 2/3 cases................................ 132 25 European studies on anogenital HPV prevalence among men............................... 134 26 European studies on anogenital HPV prevalence among men from special subgroups................. 135 27 European studies on oral HPV prevalence among healthy population.......................... 141 28 European studies on HPV prevalence among cases of oral cavity cancer......................... 143 29 European studies on HPV prevalence in cases of oropharyngeal cancer......................... 147 3 European studies on HPV prevalence in cases of hypopharyngeal or laryngeal cancer................ 152 31 Median age at first sex in Europe................................................ 163 32 Average number of sexual partners in Europe........................................ 168 33 Lifetime prevalence of anal intercourse among women in Europe............................. 17 34 Cervical cancer screening policies in Europe......................................... 172 35 HPV vaccination policies for the female population in Europe............................... 176 36 References of studies included.................................................. 179 37 Glossary............................................................... 22

1 INTRODUCTION - 1-1 Introduction Figure 1: European regions The HPV Information Centre aims to compile and centralise updated data and statistics on human papillomavirus (HPV) and HPV-related cancers. This report aims to summarise the data available to fully evaluate the burden of disease in Europe and to facilitate stakeholders and relevant bodies of decision makers to formulate recommendations on the prevention of cervical cancer and other HPV-related cancers. Data include relevant cancer statistic estimates, epidemiological determinants of cervical cancer such as demographics, socioeconomic factors, risk factors, burden of HPV infection in women and men, and cervical screening and immunisation practises. The report is structured into the following sections: Section 2, Demographic and socioeconomic factors. This section summarises the sociodemographic profile of Europe. For analytical purposes, Europe is divided into four regions: Eastern Europe, Northern Europe, Southern Europe, Western Europe (Figure 1). Section 3, Burden of HPV-related cancers. This section describes the current burden of invasive cervical cancer and other HPV-related cancers in Europe with estimates of prevalence, incidence and mortality rates. Section 4, HPV-related statistics. This section summarises reports on prevalence of HPV and HPV type-specific distribution in women with normal cytology, women with precancerous lesions and invasive cervical cancer. In addition, the burden of HPV in other anogenital cancers (anus, vulva, vagina, and penis) is presented. Section 5, Factors contributing to cervical cancer. This section describes factors that can modify the natural history of HPV and cervical carcinogenesis such as the use of smoking, parity, oral contraceptive use and co-infection with HIV. Section 6, Sexual behaviour and reproductive health indicators. This section presents sexual

1 INTRODUCTION - 2 - and reproductive behaviour indicators that may be used as proxy measures of risk for HPV infection and anogenital cancers. Section 7, HPV preventive strategies. This section presents preventive strategies that include basic characteristics and performance of cervical cancer screening status, status of HPV vaccine licensure introduction, and recommendations in national immunisation programmes. Section 8, Protective factors for cervical cancer. This section presents the prevalence of male circumcision and condom use.

2 DEMOGRAPHIC AND SOCIOECONOMIC FACTORS - 3-2 Demographic and socioeconomic factors Table 3: Population (in millions) estimates in Europe for 217 Region / Country Male Female 1-14 years 15+ years Total 1-14 years 15+ years Total Europe 1,± 19.42 296.45 356.72 18.48 325.29 382.49 Eastern Europe 1,± 7.44 112.86 137.4 7.7 131.24 154.51 Belarus 1,±.24 3.58 4.39.22 4.29 5.6 Bulgaria 1,±.17 2.9 3.42.16 3.13 3.62 Czech Rep. 1,±.27 4.36 5.19.25 4.58 5.37 Hungary 1,±.25 3.93 4.66.24 4.43 5.12 Moldova 1,a,±.1 1.62 1.95.1 1.8 2.11 Poland 1,±.94 15.67 18.64.9 17.1 19.92 Romania 1,±.54 7.8 9.31.51 8.5 9.93 Russia 1,± 3.76 53.75 66.62 3.59 64.52 76.75 Slovakia 1,±.14 2.21 2.63.13 2.39 2.8 Ukraine 1,b,± 1.4 17.4 2.58.98 2.49 23.83 Northern Europe 1,c,± 2.97 41.62 51.4 2.84 43.48 52.44 Denmark 1,±.17 2.35 2.84.16 2.42 2.88 Estonia 1,±.4.5.61.3.59.69 Finland 1,d,±.15 2.27 2.73.14 2.37 2.81 Iceland 1,±.1.13.17.1.13.17 Ireland 1,±.17 1.84 2.37.16 1.88 2.38 Latvia 1,±.5.74.89.5.91 1.5 Lithuania 1,±.7 1.9 1.3.6 1.32 1.53 Norway 1,e,±.16 2.2 2.69.15 2.18 2.64 Sweden 1,±.28 4.6 4.96.27 4.11 4.96 UK 1,± 1.87 26.31 32.32 1.78 27.45 33.19 Southern Europe 1,f,± 3.9 62.96 74.13 3.69 67.36 77.92 Albania 1.9 1.17 1.44.8 1.21 1.47 Andorra 2,±..4.4..4.4 Bosnia & H. 1,±.8 1.63 1.89.8 1.66 1.91 Croatia 1,±.11 1.71 2.3.1 1.88 2.18 Cyprus 1,g,h,±.3.51.61.3.49.58 Greece 1,±.27 4.5 5.31.26 4.82 5.58 Italy 1,± 1.46 24.93 29.9 1.38 26.78 3.71 Macedonia 1,i,±.6.86 1.4.6.88 1.5 Malta 1,±.1.18.21.1.18.21 Montenegro 1,±.2.25.31.2.26.32 Portugal 1,±.26 4.14 4.85.25 4.73 5.41 San Marino 2,±..1.2..1.2 Serbia 1, j,±.26 3.56 4.28.24 3.81 4.49 Slovenia 1,±.5.87 1.3.5.89 1.4 Spain 1,k,± 1.22 19.11 22.59 1.15 2.21 23.48 Western Europe 1,l,± 5.11 79.1 94.15 4.87 83.21 97.61 Austria 1,±.21 3.6 4.23.2 3.77 4.37 Belgium 1,±.32 4.65 5.65.31 4.84 5.79 France 1,± 2.5 25.54 31.62 1.97 27.5 33.32 Germany 1,± 1.81 34.36 39.66 1.71 35.94 4.97 Liechtenstein 2,±..2.2..2.2 Luxembourg 1,±.2.24.29.2.24.29 Monaco 2,±..1.1..1.2 Netherlands 1,±.5 7.4 8.46.47 7.23 8.57 Switzerland 1,±.21 3.55 4.19.2 3.65 4.26 Data accessed on 27 Mar 217. Please refer to original source for methods of estimation. a Including Transnistria. b Including Crimea c Including Faeroe Islands, and Isle of Man. d Including Åland Islands. e Including Svalbard and Jan Mayen Islands. f Including Andorra, Gibraltar, Holy See, and San Marino. g Including Northern-Cyprus. h Refers to the whole country i The former Yugoslav Republic of Macedonia. j Including Kosovo. k Including Canary Islands, Ceuta and Melilla. l Including Liechtenstein, and Monaco. Year of estimate: ± 217; Data sources: 1 United Nations, Department of Economic and Social Affairs, Population Division (215). World Population Prospects: The 215 Revision, DVD Edition. Available at: https://esa.un. org/unpd/wpp/download/standard/population/. [Accessed on March 21, 217]. (Continued on next page)

2 DEMOGRAPHIC AND SOCIOECONOMIC FACTORS - 4 - ( Table 3 continued from previous page) 2 International Programs Center for Demographic and Economic Studies, Population Division, U.S. Census Bureau. International Database. Available at http://www.census.gov/ population/international/data/idb/informationgateway.php. [Accessed on March 21, 217]. Figure 2: Population pyramid of Europe Males Females 8+ 75 79 7 74 65 69 6 64 55 59 5 54 45 49 4 44 35 39 3 34 25 29 2 24 15 19 1 14 5 9 Under 5 12,889,798 24,231,287 1,62,55 15,671,83 13,496,265 17,22,632 18,44,73 22,28,14 22,77,975 25,657,11 24,99,128 27,25,652 26,42,45 27,3,161 25,487,419 26,81,991 25,656,41 25,985,629 25,864,557 25,816,18 26,41,886 25,9,782 24,774,54 24,18,695 2,92,742 2,28,642 18,874,728 17,966,348 19,424,445 18,479,13 2,575,143 19,537,521 2,272,989 19,178,526 Population (in thousands) in Europe by sex and age group Data accessed on 27 Mar 217. Please refer to original source for methods of estimation. Year of estimate: 217; Data sources: United Nations, Department of Economic and Social Affairs, Population Division (215). World Population Prospects: The 215 Revision, DVD Edition. Available at: https://esa.un.org/ unpd/wpp/download/standard/population/. [Accessed on March 21, 217]. Number of women (in millions) 5 4 3 2 Figure 3: Population trends in four selected age groups in Europe for 217 Projections Women 15 24 yrs Girls 1 14 yrs 195 196 197 198 199 2 21 22 23 24 25 26 27 28 29 21 Number of women (in millions) Projections 4 All Women 35 3 25 Women 25 64 yrs 2 15 195 196 197 198 199 2 21 22 23 24 25 26 27 28 29 21 Female population trends in Europe Number of women by year and age group Data accessed on 27 Mar 217. Please refer to original source for methods of estimation. Year of estimate: 217; Data sources: United Nations, Department of Economic and Social Affairs, Population Division (215). World Population Prospects: The 215 Revision, DVD Edition. Available at: https://esa.un.org/ unpd/wpp/download/standard/population/. [Accessed on March 21, 217].

2 DEMOGRAPHIC AND SOCIOECONOMIC FACTORS - 5 - Table 4: Sociodemographic indicators in Europe Indicator Male Female Total Population in thousands 1,± 356,719.8 382,487.9 739,27.7 Population growth rate (%) 1, - -.1 Median age of the population (in years) 1, - - 41.7 Population living in urban areas (%) 2, - - 73.6 Crude birth rate (births per 1,) 1, - - 1.8 Crude death rate (deaths per 1,) 1, - - 11.1 Life expectancy at birth (in years) 3,a,b - - - Adult mortality rate (probability of dying between 15 and 6 years old - - - per 1,) 4 Under age five mortality rate (per 1, live births) 3,c - - - Density of physicians (per 1, population) 5,d - - - Gross national income per capita (PPP current international $) 6,e - - - Adult literacy rate (%) (aged 15 and older) 7, 99.4 99.1 99.2 Youth literacy rate (%) (aged 15-24 years) 7, 99.7 99.7 99.7 Net primary school enrollment ratio 7, 96.9 97.1 97 Net secondary school enrollment ratio 7,f, 91.2 91.9 91.5 Data accessed on 27 Mar 217. Please refer to original source for methods of estimation. a World Population Prospects, the 215 revision (WPP215). New York (NY): United Nations DESA, Population Division. b WHO annual life tables for 1985 215 based on the WPP215, on the data held in the WHO Mortality Database and on HIV mortality estimates prepared by UNAIDS. WHO Member States with a population of less than 9 in 215 were not included in the analysis. c Levels & Trends in Child Mortality. Report 215. Estimates Developed by the UN Inter-agency Group for Child Mortality Estimation. New York (NY), Geneva and Washington (DC): United Nations Children s Fund, World Health Organization, World Bank and United Nations; 215 (http://www.unicef.org/publications/files/child_mortality_report_215_ Web_9_Sept_15.pdf, accessed 26 March 216). d Number of medical doctors (physicians), including generalist and specialist medical practitioners, per 1 population. e GNI per capita based on purchasing power parity (PPP). PPP GNI is gross national income (GNI) converted to international dollars using purchasing power parity rates. An international dollar has the same purchasing power over GNI as a U.S. dollar has in the United States. GNI is the sum of value added by all resident producers plus any product taxes (less subsidies) not included in the valuation of output plus net receipts of primary income (compensation of employees and property income) from abroad. Data are in current international dollars based on the 211 ICP round. f UIS Estimation Year of estimate: ± 217; 21-215; 215; 214; Data sources: 1 United Nations, Department of Economic and Social Affairs, Population Division (215). World Population Prospects: The 215 Revision, DVD Edition. Available at: https://esa.un. org/unpd/wpp/download/standard/population/. [Accessed on March 21, 217]. 2 United Nations, Department of Economic and Social Affairs, Population Division (214). World Urbanization Prospects: The 214 Revision, CD-ROM Edition. Available at: https: //esa.un.org/unpd/wup/cd-rom/. [Accessed on March 21, 217]. 3 World Health Statistics 216. Geneva, World Health Organization, 216. Available at: http://who.int/entity/gho/publications/world_health_statistics/216/en/index. html. [Accessed on March 21, 217]. 4 World Health Organization. Global Health Observatory data repository. Available at: http://apps.who.int/gho/data/view.main.136?lang=en. [Accessed on March 21, 217]. 5 The 216 update, Global Health Workforce Statistics, World Health Organization, Geneva (http://www.who.int/hrh/statistics/hwfstats/). [Accessed on March 21, 217]. 6 World Bank, World Development Indicators Database. Washington, DC. International Comparison Program database. Available at: http://databank.worldbank.org/data/reports. aspx?source=world-development-indicators#. [Accessed on March 21, 217]. 7 UNESCO Institute for Statistics Data Centre [online database]. Montreal, UNESCO Institute for Statistics. Available at: http://stats.uis.unesco.org [Accessed on March 21, 217].

3 BURDEN OF HPV-RELATED CANCERS - 6-3 Burden of HPV-related cancers 3.1 Cervical cancer Cancer of the cervix uteri is the 4th most common cancer among women worldwide, with an estimated 527,624 new cases and 265,672 deaths in 212 (GLOBOCAN). The majority of cases are squamous cell carcinoma followed by adenocarcinomas. (Vaccine 26, Vol. 24, Suppl 3; Vaccine 28, Vol. 26, Suppl 1; Vaccine 212, Vol. 3, Suppl 5; IARC Monographs 27, Vol. 9) This section describes the current burden of invasive cervical cancer in Europe and its regions with estimates of the annual number of new cases, deaths, incidence and mortality. 3.1.1 Incidence KEY STATS. About 58,373 new cervical cancer cases are diagnosed annually in Europe (estimates for 212). Cervical cancer ranks as the 6 th leading cause of female cancer in Europe. Cervical cancer is the 2 nd most common female cancer in women aged 15 to 44 years in Europe. Ranking of cervical cancer incidence to other cancers among all women according to highest incidence rates (ranking 1st). Ranking is based on crude incidence rates (actual number of cervical cancer cases). Ranking using age-standardized rate (ASR) may differ. Figure 4: Age-standardised incidence rates (ASR) of cervical cancer in regions of Europe (estimates for 212) Eastern Europe 16.3 Northern Europe 8.7 Southern Europe 8.5 Data accessed on 15 Nov 215. Western Europe 7.3 1 2 Cervical cancer: Age standardised mortality rate per 1, women World Standard. Female (All ages) (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 7 - ( Figure 4 continued from previous page) Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr. Figure 5: Age-standardised incidence rates of cervical cancer in Europe (estimates for 212) Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 8 - Figure 6: Age-standardised incidence rate of cervical cancer cases attributable to HPV by country in Europe (estimates for 212) Romania Lithuania Bulgaria Serbia Montenegro Estonia Moldova Hungary Latvia Ukraine Slovakia Russia Czech Rep. Bosnia & H. Ireland Belarus Macedonia Poland Denmark Slovenia Croatia Norway Portugal Belgium Germany Iceland Spain Sweden UK Netherlands France Italy Austria Greece Albania Luxembourg Finland Cyprus Malta Switzerland San Marino Monaco Liechtenstein Andorra 2.2 19.9 19.6 18. 17.3 16.6 16.1 15.3 14.1 13.7 13.6 13.2 12.4 12.2 1.6 1.5 1. 9.8 9. 8.6 8.2 7.9 7.8 7.4 7.1 6.8 6.8 6.7 5.8 5.2 5. 4.9 4.3 4.1 3.8 3.6 26.1 24.5 23.8 28.6 1 2 3 Cervical cancer: Age standardised incidence rate per 1, women World Standard. Female (All ages) No rates are available. Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 9 - Table 5: Incidence of cervical cancer in Europe (estimates for 212) Cumulative risk (%) Ranking of CC Area N cases Crude rate a ASR a ages -74 years b All women Women 15-44 years Europe 58,373 15.2 11.4 1.1 6 2 Eastern Europe 33,882 21.7 16.3 1.5 4 2 Belarus 924 18.1 13.2 1.3 5 3 Bulgaria 1,254 32.8 24.5 2.3 4 2 Czech Republic 1,16 18.9 14.1 1.3 9 2 Hungary 1,178 22.5 18. 1.6 4 2 Poland 3,513 17.7 12.2 1.2 6 2 Republic of 475 25.7 19.6 1.9 3 1 Moldova Romania 4,343 39.4 28.6 2.8 3 2 Russian Federation 15,342 2. 15.3 1.4 5 2 Slovakia 67 21.6 16.1 1.6 5 2 Ukraine 5,23 21.5 16.6 1.5 4 2 Northern Europe 5,382 1.6 8.7.8 1 3 Denmark 363 12.9 1.6.9 1 3 Estonia 186 25.8 19.9 1.9 4 2 Finland 143 5.2 4.3.4 19 4 Iceland 14 8.6 7.9.7 12 3 Ireland 357 15.6 13.6 1.2 7 2 Latvia 284 23.6 17.3 1.6 5 2 Lithuania 615 34.9 26.1 2.5 3 1 Norway 294 11.9 9.8.9 1 3 Sweden 451 9.5 7.4.7 12 3 United Kingdom 2,659 8.4 7.1.6 12 3 Southern Europe 9,285 11.6 8.5.8 11 2 Albania 93 5.8 5..5 8 3 Andorra - - - - 8 8 Bosnia & Herzegovina 359 18.5 13.7 1.3 4 2 Croatia 325 14.3 1. 1. 1 3 Cyprus 31 5.6 4.1.4 11 3 Greece 421 7.3 5.2.5 11 2 Italy 2,918 9.4 6.7.6 15 3 Macedonia 171 16.6 12.4 1.3 6 2 Malta 12 5.7 3.8.3 16 6 Montenegro 76 23.6 2.2 1.8 4 2 Portugal 72 13.1 9..9 7 2 San Marino - - - - 1 1 Serbia 1,51 3.2 23.8 2.2 4 2 Slovenia 139 13.4 1.5.9 12 3 Spain 2,511 1.6 7.8.8 1 2 Western Europe 9,824 1.2 7.3.7 14 4 Austria 363 8.4 5.8.6 14 4 Belgium 639 11.6 8.6.8 9 4 France 2,862 8.8 6.8.6 12 4 Germany 4,995 12. 8.2.8 12 3 Luxembourg 24 9.1 4.9.6 13 16 Monaco - - - - 2 2 Netherlands 75 8.9 6.8.6 11 3 Switzerland 19 4.8 3.6.3 17 4 Data accessed on 15 Nov 215. ASR: Age-standardized rate, Standardized rates have been estimated using the direct method and the World population as the reference; Standardised rates have ben estimated using the direct method and the World population as the reference. Ranking of cervical cancer incidence to other cancers among all women ages 15-44 years according to highest incidence rates (ranking 1st). Ranking is based on crude incidence rates (actual number of cervical cancer cases). Ranking using ASR may differ. a Rates per 1, women per year. b Cumulative risk (incidence) is the probability or risk of individuals getting from the disease during ages -74 years. For cancer, it is expressed as the % of new born children who would be expected to develop from a particular cancer before the age of 75 if they had the rates of cancer observed in the period in the absence of competing causes. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 1 - Figure 7: Ranking of cervical cancer versus other cancers among all women and women aged 15-44 years, according to incidence rates in Europe (estimates for 212) Data accessed on 15 Nov 215. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 11 - Figure 8: Comparison of the ten most frequent cancers in all women in Europe and its regions (estimates for 212) Europe Southern Europe Breast 69.9 Breast 74.5 Colorectum(a) 23.6 Colorectum(a) 24.1 Lung 15.1 Corpus uteri 12.9 Corpus uteri 13.9 Lung 12.8 Cervix uteri 11.4 Ovary 9.1 Ovary 9.9 Thyroid 8.6 Melanoma of skin 8.9 Cervix uteri 8.5 Thyroid 7.8 Melanoma of skin 8.3 Stomach 6.4 Non Hodgkin lymphoma(b) 6.6 Non Hodgkin lymphoma(b) 5.9 Stomach 5.9 15 3 45 6 75 9 Eastern Europe 15 3 45 6 75 9 Western Europe Breast 47.7 Breast 91.1 Colorectum(a) 21.7 Colorectum(a) 24.9 Cervix uteri 16.3 Lung 2. Corpus uteri 15.6 Melanoma of skin 12.8 Ovary 11.4 Corpus uteri 11.6 Lung 1.4 Thyroid 8.8 Stomach 8.9 Non Hodgkin lymphoma(b) 7.7 Thyroid 7.4 Ovary 7.5 Kidney 6.1 Cervix uteri 7.3 Leukaemia 5.1 Kidney 6.5 15 3 45 6 75 9 15 3 45 6 75 9 Northern Europe Breast 89.4 Colorectum(a) Lung Melanoma of skin Corpus uteri Ovary Cervix uteri Non Hodgkin lymphoma(b) Leukaemia Pancreas 25.3 23.7 15.4 14.1 11. 8.7 8.1 6. 5.9 15 3 45 6 75 9 Age standardised incidence rate per 1, women in Europe Data accessed on 15 Nov 215. a Includes anal cancer (C21). b Includes HIV disease resulting in malignant neoplasms (B21). Data sources: (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 12 - ( Figure 8 continued from previous page) Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 13 - Figure 9: Comparison of the ten most frequent cancers in women aged 15-44 years by Europe and its regions (estimates for 212) Europe Southern Europe Breast 35. Breast 47.1 Cervix uteri 13.2 Cervix uteri 9.3 Melanoma of skin 8. Melanoma of skin 8.7 Thyroid 7.3 Ovary 5.1 Ovary 5.1 Thyroid 5.1 Colorectum(a) 3.8 Colorectum(a) 4.5 Hodgkin lymphoma 3.2 Non Hodgkin lymphoma(b) 3.4 Brain, nervous system 2.8 Hodgkin lymphoma 3.1 Corpus uteri 2.5 Brain, nervous system 2.6 Non Hodgkin lymphoma(b) 2.5 Lung 2.6 1 2 3 4 5 Eastern Europe 1 2 3 4 5 Western Europe Breast 21.6 Breast 46.6 Cervix uteri 17.6 Melanoma of skin 12.9 Thyroid 6.8 Thyroid 1.4 Ovary 6.5 Cervix uteri 9. Corpus uteri 3.4 Colorectum(a) 4.5 Hodgkin lymphoma 3.1 Lung 4.3 Melanoma of skin 3.1 Hodgkin lymphoma 3.5 Colorectum(a) 3. Non Hodgkin lymphoma(b) 2.8 Brain, nervous system 2.9 Ovary 2.8 Non Hodgkin lymphoma(b) 1.9 Brain, nervous system 2.7 1 2 3 4 5 1 2 3 4 5 Northern Europe Breast 38.8 Melanoma of skin Cervix uteri 14.1 12.7 Thyroid Ovary Colorectum(a) Brain, nervous system Hodgkin lymphoma Non Hodgkin lymphoma(b) Leukaemia 6.5 4.9 3.9 3.1 2.9 2.6 2. 1 2 3 4 5 Age standardised incidence rate per 1, women in Europe Data accessed on 15 Nov 215. a Includes anal cancer (C21). b Includes HIV disease resulting in malignant neoplasms (B21). Data sources: (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 14 - ( Figure 9 continued from previous page) Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr. Figure 1: Age-specific incidence of cervical cancer in Europe and its regions (estimates for 212) Age specific incidence rates of cervical cancer per 1, 4 3 2 1 Europe Eastern Europe Northern Europe Southern Europe Western Europe 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 15 - Figure 11: Annual number of new cases of cervical cancer by age group in European regions (estimates for 212) Eastern Europe Southern Europe Western Europe Northern Europe Annual number of new cases of cervical cancer 35, 31,5 28, 24,5 21, 17,5 14, 1,5 7, 3,5 32,345 13,249 12,775 15 39 4 64 65+ Eastern Europe 15-39 years: 7,668 cases. 4-64 years: 19,618 cases. 65+ years: 6,595 cases. Southern Europe 15-39 years: 1,765 cases. 4-64 years: 5,243 cases. 65+ years: 2,274 cases. Western Europe 15-39 years: 2, cases. 4-64 years: 5,4 cases. 65+ years: 2,82 cases. Northern Europe 15-39 years: 1,816 cases. 4-64 years: 2,48 cases. 65+ years: 1,86 cases. Data accessed on 15 Nov 215. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 16 - Figure 12: Annual number of cases and age-specific incidence rates of cervical cancer in Europe and its regions (estimates for 212) Europe 4 Age specific rates of cervical cancer(a) 3 2 1 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 75+ 32,5 32,345 3, 27,5 25, Annual number of cases of cervical cancer 22,5 2, 17,5 15, 12,5 13,242 12,775 1, 7,5 5, 2,5 15 39 4 64 65+ Europe 15-19 yrs: 22 cases. 2-24 yrs: 798 cases. 25-29 yrs: 2,639 cases. 3-34 yrs: 4,235 cases. 35-39 yrs: 5,548 cases. 4-44 yrs: 6,449 cases. 45-49 yrs: 7,2 cases. 5-54 yrs: 7,137 cases. 55-59 yrs: 6,518 cases. 6-64 yrs: 5,221 cases. Data accessed on 15 Nov 215. a Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 17 - Figure 13: Annual number of cases and age-specific incidence rates of cervical cancer in Europe and its regions (estimates for 212) (Continued) Eastern Europe Southern Europe Age specific rates of cervical cancer(a) 4 3 2 1 4 3 2 1 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 75+ 2, 19,618 Annual number of cases of cervical cancer 17,5 15, 12,5 1, 7,5 5, 2,5 7,668 6,595 15 39 4 64 65+ Northern Europe Age specific rates of cervical cancer(a) 4 3 2 1 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 75+ 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 75+ 2, 17,5 15, 12,5 1, 7,5 5, 2,5 1,765 5,243 2,274 15 39 4 64 65+ Western Europe 4 3 2 1 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 75+ 2, 2, Annual number of cases of cervical cancer 17,5 15, 12,5 1, 7,5 5, 2,5 1,816 2,48 1,86 15 39 4 64 65+ 17,5 15, 12,5 1, 7,5 5, 2,5 5,4 2, 2,82 15 39 4 64 65+ Eastern Europe 15-19 yrs: 1 cases. 2-24 yrs: 493 cases. 25-29 yrs: 1,58 cases. 3-34 yrs: 2,44 cases. 35-39 yrs: 3,145 cases. 4-44 yrs: 3,525 cases. 45-49 yrs: 3,959 cases. 5-54 yrs: 4,483 cases. 55-59 yrs: 4,317 cases. 6-64 yrs: 3,334 cases. Northern Europe 15-19 yrs: 2 cases. 2-24 yrs: 213 cases. 25-29 yrs: 427 cases. 3-34 yrs: 546 cases. 35-39 yrs: 628 cases. 4-44 yrs: 675 cases. 45-49 yrs: 64 cases. 5-54 yrs: 472 cases. 55-59 yrs: 384 cases. 6-64 yrs: 345 cases. Southern Europe 15-19 yrs: 4 cases. 2-24 yrs: 38 cases. 25-29 yrs: 251 cases. 3-34 yrs: 584 cases. 35-39 yrs: 888 cases. 4-44 yrs: 1,15 cases. 45-49 yrs: 1,23 cases. 5-54 yrs: 1,141 cases. 55-59 yrs: 968 cases. 6-64 yrs: 826 cases. Western Europe 15-19 yrs: 6 cases. 2-24 yrs: 55 cases. 25-29 yrs: 382 cases. 3-34 yrs: 667 cases. 35-39 yrs: 89 cases. 4-44 yrs: 1,144 cases. 45-49 yrs: 1,254 cases. 5-54 yrs: 1,41 cases. 55-59 yrs: 849 cases. 6-64 yrs: 716 cases. Data accessed on 15 Nov 215. (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 18 - ( Figure 13 continued from previous page) a Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 19 - Annual crude incidence rate (per 1,) Figure 14: Time trends in cervical cancer incidence type in Austria (cancer registry data) 4 3 2 1 Recent trend : 4.6 ( 5.9 to 3.4) (1, b) Overall trend : 3.7 ( 4.1 to 3.4) (1, a) All ages (2, c) 15 44 yrs (2, c) 45 74 yrs (2, c) 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 2 years, from 199-29. c The following regional cancer registries provided data and contributed to their national estimate: Tyrol, Vorarlberg. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49:3262-73. 2 Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 15: Time trends in cervical cancer incidence type in Switzerland (cancer registry data) Annual crude incidence rate (per 1,) 25 2 15 1 5 All ages (2, b) 15 44 yrs (2, b) 45 74 yrs (2, b) 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b The following regional cancer registries provided data and contributed to their national estimate: Geneva, Graubunden and Glarus, Neuchatel, St Gall-Appenzell, Valais, Vaud. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49:3262-73. 2 Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 2 - Annual crude incidence rate (per 1,) Figure 16: Time trends in cervical cancer incidence type in Spain (cancer registry data) 25 2 15 1 5 Recent trend : 1.3 ( 3.1 to.5) (1, b) Overall trend :.6 ( 1.5 to.3) (1, a) All ages (2, c) 15 44 yrs (2, c) 45 74 yrs (2, c) 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 15 years, from 1991-25. c The following regional cancer registries provided data and contributed to their national estimate: Albacete, Cuenca, Girona, Granada, Murcia, Navarra, Tarragona. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49:3262-73. 2 Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Annual crude incidence rate (per 1,) Figure 17: Time trends in cervical cancer incidence type in France (cancer registry data) 4 3 2 1 Recent trend : 2.5 ( 4.2 to.7) (1, b) Overall trend : 3.5 ( 4.1 to 3.) (1, a) All ages (2, c) 15 44 yrs (2, c) 45 74 yrs (2, c) 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 2 years, from 1983-22. c The following regional cancer registries provided data and contributed to their national estimate: Bas-Rhin, Calvados, Doubs, Haut-Rhin, Herault, Isere, Somme, Tarn. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49:3262-73. 2 Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 21 - Figure 18: Time trends in cervical cancer incidence type in the United Kingdom (cancer registry data) Annual crude incidence rate (per 1,) 25 2 15 1 5 Recent trend : 2.3 ( 2.8 to 1.7) (1, b) Overall trend : 4.1 ( 4.2 to 3.9) (1, a) All ages (2, c) 15 44 yrs (2, c) 45 74 yrs (2, c) 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 25 years, from 1983-27. c The following regional cancer registries provided data and contributed to their national estimate: Birmingham and West Midlands Region, East of England Region, Merseyside and Cheshire, North Western, Northern Ireland, Oxford, Scotland, South and Western Regions, Yorkshire. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49:3262-73. 2 Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Annual crude incidence rate (per 1,) Figure 19: Time trends in cervical cancer incidence type in Italy (cancer registry data) 25 2 15 1 5 Recent trend : 3.1 ( 4.7 to 1.5) (1, b) Overall trend : 2. ( 2.8 to 1.2) (1, a) All ages (2, c) 15 44 yrs (2, c) 45 74 yrs (2, c) 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 15 years, from 1988-22. c The following regional cancer registries provided data and contributed to their national estimate: Ferrara Province, Florence, Lombardy, Varese province, Modena, Parma, Ragusa Province, Romagna, Sassari Province, Torino. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49:3262-73. 2 Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 22 - Annual crude incidence rate (per 1,) Figure 2: Time trends in cervical cancer incidence type in Poland (cancer registry data) 7 6 5 4 3 2 1 Recent trend :.8 ( 2.1 to.5) (1, b) Overall trend : 1.1 ( 1.7 to.4) (1, a) All ages (2) 15 44 yrs (2) 45 74 yrs (2) 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 15 years, from 1988-22. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49:3262-73. 2 Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 21: Time trends in cervical cancer incidence type in the Russian Federation (cancer registry data) Annual crude incidence rate (per 1,) 3 25 2 15 1 5 Recent trend :1.7 (1.4 to 1.9) (1, b) Overall trend :.9 (.8 to 1.1) (1, a) All ages (2) 15 44 yrs (2) 45 74 yrs (2) 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 15 years, from 1994-28. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49:3262-73. 2 Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 23-3.1.2 Mortality KEY STATS. About 24,44 new cervical cancer deaths occur annually in Europe (estimates for 212). Cervical cancer ranks as the 7 th leading cause of female cancer deaths in Europe. Cervical cancer is the 2 nd most common female cancer deaths in women aged 15 to 44 years in Europe. Ranking of cervical cancer incidence to other cancers among all women according to highest incidence rates (ranking 1st). Ranking is based on crude incidence rates (actual number of cervical cancer cases). Ranking using age-standardized rate (ASR) may differ. Figure 22: Age-standardised mortality rates (ASR) of cervical cancer in European regions (estimates for 212) Eastern Europe 6.2 Southern Europe 2.4 Northern Europe 2.2 Western Europe 1.8 1 Cervical cancer: Age standardised mortality rate per 1, women World Standard. Female (All ages) Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 24 - Figure 23: Age-standardised mortality rates of cervical cancer in Europe (estimates for 212) Data accessed on 15 Nov 215. ASR: Age-standardized rate, Standardized rates have been estimated using the direct method and the World population as the reference; Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr. Table 6: Cervical cancer mortality in Europe (estimates for 212) Cumulative risk (%) Ranking of CC Area N cases Crude rate a ASR a ages -74 years b All women Women 15-44 years Europe 24,44 6.4 3.8.4 7 2 Eastern Europe 15,436 9.9 6.2.6 7 1 Belarus 372 7.3 4.7.5 6 2 Bulgaria 437 11.4 7..7 7 1 Czech Republic 315 5.9 3.2.4 11 2 Hungary 461 8.8 5.3.6 7 3 Poland 1,858 9.4 5.4.6 6 2 Republic of 21 11.4 7.9.8 3 1 Moldova Romania 1,99 17.3 1.8 1.2 4 1 Russian Federation 7,371 9.6 6.1.6 7 1 Slovakia 232 8.2 5.2.6 7 1 Ukraine 2,271 9.4 6.4.6 6 2 Northern Europe 1,963 3.9 2.2.2 16 2 Denmark 97 3.4 1.9.2 15 4 Estonia 8 11.1 5.9.7 7 2 Finland 53 1.9 1..1 19 3 Iceland 2 1.2.4. 18 23 Ireland 11 4.4 3.3.3 12 2 Latvia 135 11.2 6.3.6 8 2 Lithuania 221 12.5 7.5.8 6 1 Norway 11 4.1 2.3.2 14 2 Sweden 187 3.9 1.9.2 17 5 United Kingdom 979 3.1 1.8.2 16 2 Southern Europe 3,526 4.4 2.4.2 13 3 (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 25 - ( Table 6 continued from previous page) Cumulative risk (%) Ranking of CC Area N cases Crude rate a ASR a ages -74 years b All women Women 15-44 years Albania 35 2.2 1.8.2 12 6 Andorra - - - - 12 12 Bosnia & Herzegovina 89 4.6 2.7.3 8 2 Croatia 14 6.2 3.2.3 12 3 Cyprus 17 3.1 1.5.1 11 9 Greece 28 3.6 1.8.2 11 4 Italy 1,16 3.3 1.5.2 16 7 Macedonia 81 7.9 5.1.6 8 3 Malta 3 1.4.8.1 17 23 Montenegro 26 8.1 5.8.7 8 3 Portugal 39 7.1 3.7.4 6 2 San Marino - - - - 2 2 Serbia 69 12.2 7.7.8 5 2 Slovenia 64 6.1 3..3 12 4 Spain 848 3.6 2.1.2 13 3 Western Europe 3,479 3.6 1.8.2 15 4 Austria 178 4.1 2..2 13 5 Belgium 219 4. 1.9.2 15 4 France 1,167 3.6 1.9.2 14 3 Germany 1,566 3.8 1.7.2 16 4 Luxembourg 13 4.9 2.4.3 1 24 Monaco - - - - 2 2 Netherlands 242 2.9 1.6.2 17 5 Switzerland 94 2.4 1.1.1 18 9 Data accessed on 15 Nov 215. ASR: Age-standardized rate, Standardized rates have been estimated using the direct method and the World population as the reference; Standardised rates have ben estimated using the direct method and the World population as the reference. Ranking of cervical cancer mortality to other cancers among all women ages 15-44 years according to highest mortality rates (ranking 1st). Ranking is based on crude mortality rates(actual number of cervical cancer deaths). Ranking using AST may differ. a Rates per 1, women per year. b Cumulative risk (mortality) is the probability or risk of individuals dying from the disease during ages -74 years. For cancer, it is expressed as the % of new born children who would be expected to die from a particular cancer before the age of 75 if they had the rates of cancer observed in the period in the absence of competing causes. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 26 - Figure 24: Ranking of cervical cancer versus other cancers among all women and women aged 15-44 years, according to mortality rates in Europe (estimates for 212) Data accessed on 15 Nov 215. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 27 - Figure 25: Comparison of the ten most frequent cancer deaths in women aged 15-44 years in Europe and its regions (estimates for 212) Europe Southern Europe Breast 4.4 Breast 4.7 Cervix uteri 2.5 Lung 1.8 Lung 1.4 Cervix uteri 1.4 Brain, nervous system 1.3 Brain, nervous system 1.1 Ovary 1.2 Ovary 1. Stomach 1. Colorectum(a).9 Colorectum(a).9 Leukaemia.9 Leukaemia.9 Stomach.8 Melanoma of skin.7 Melanoma of skin.6 Non Hodgkin lymphoma(b).5 Non Hodgkin lymphoma(b).5 5 1 5 1 Eastern Europe Western Europe Cervix uteri 4.3 Breast 4.2 Breast 4.2 Lung 2.1 Ovary 1.8 Brain, nervous system 1.1 Brain, nervous system 1.5 Cervix uteri.9 Stomach 1.4 Colorectum(a).7 Colorectum(a) 1. Leukaemia.7 Leukaemia 1. Melanoma of skin.6 Lung 1. Ovary.6 Melanoma of skin.7 Stomach.5 Hodgkin lymphoma.6 Pancreas.3 5 1 5 1 Northern Europe Breast 4.8 Cervix uteri Brain, nervous system Colorectum(a) Leukaemia Melanoma of skin Ovary Lung Stomach Non Hodgkin lymphoma(b) 1.5 1.3.9.7.7.7.6.5.3 5 1 Age standardised mortality rate per 1, women in Europe Data accessed on 15 Nov 215. a Includes anal cancer (C21). b Includes HIV disease resulting in malignant neoplasms (B21). Data sources: (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 28 - ( Figure 25 continued from previous page) Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 29 - Figure 26: Comparison of the ten most frequent cancer deaths in women of all ages in Europe and its regions (estimates for 212) Europe Southern Europe Breast 16.1 Breast 14.9 Lung 11.8 Lung 1. Colorectum(a) 9.9 Colorectum(a) 8.7 Ovary 5.4 Pancreas 4.9 Pancreas 5.3 Ovary 4.4 Stomach 4.6 Stomach 4. Cervix uteri 3.8 Brain, nervous system 3.1 Brain, nervous system 3. Leukaemia 2.8 Leukaemia 2.8 Liver 2.5 Corpus uteri 2.6 Cervix uteri 2.4 5 1 15 2 Eastern Europe 5 1 15 2 Western Europe Breast 16.5 Breast 16.2 Colorectum(a) 11.7 Lung 14.8 Lung 8.3 Colorectum(a) 8.3 Stomach 7.1 Pancreas 5.8 Cervix uteri 6.2 Ovary 4.7 Ovary 6. Brain, nervous system 2.7 Pancreas 4.9 Leukaemia 2.7 Corpus uteri 3.4 Stomach 2.5 Brain, nervous system 3.2 Liver 2.1 Leukaemia 2.8 Non Hodgkin lymphoma(b) 1.9 5 1 15 2 5 1 15 2 Northern Europe Lung Breast 16.4 19.1 Colorectum(a) 9.2 Ovary Pancreas 5.9 5.6 Brain, nervous system Leukaemia Stomach Corpus uteri Oesophagus 3. 2.5 2.4 2.3 2.3 5 1 15 2 Age standardised mortality rate per 1, women in Europe Data accessed on 15 Nov 215. a Includes anal cancer (C21). b Includes HIV disease resulting in malignant neoplasms (B21). Data sources: (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 3 - ( Figure 26 continued from previous page) Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr. Figure 27: Age-specific mortality of cervical cancer in Europe and its regions (estimates for 212) Age specific mortality rates of cervical cancer per 1, 25 2 15 1 5 Europe Eastern Europe Northern Europe Southern Europe Western Europe 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 31 - Figure 28: Annual number of deaths of cervical cancer by age group in European regions (estimates for 212) Eastern Europe Southern Europe Western Europe Northern Europe Annual number of cervical cancer deaths 15, 13,5 12, 1,5 9, 7,5 6, 4,5 3, 1,5 11,779 1,413 2,212 15 39 4 64 65+ Eastern Europe 15-39 years: 1,7 cases. 4-64 years: 7,989 cases. 65+ years: 5,747 cases. Southern Europe 15-39 years: 195 cases. 4-64 years: 1,575 cases. 65+ years: 1,756 cases. Western Europe 15-39 years: 139 cases. 4-64 years: 1,421 cases. 65+ years: 1,919 cases. Northern Europe 15-39 years: 178 cases. 4-64 years: 794 cases. 65+ years: 991 cases. Data accessed on 15 Nov 215. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 32 - Figure 29: Annual number of deaths and age-specific mortality rates of cervical cancer in Europe and its regions (estimates for 212) Europe 25 2 Age specific rates of cervical cancer(a) 15 1 5 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 75+ 12,5 11,779 Annual number of deaths of cervical cancer 1, 7,5 5, 1,413 2,5 2,212 15 39 4 64 65+ Europe 15-19 yrs: 2 cases. 2-24 yrs: 32 cases. 25-29 yrs: 332 cases. 3-34 yrs: 715 cases. 35-39 yrs: 1,131 cases. 4-44 yrs: 1,565 cases. 45-49 yrs: 2,88 cases. 5-54 yrs: 2,647 cases. 55-59 yrs: 2,85 cases. 6-64 yrs: 2,629 cases. Data accessed on 15 Nov 215. a Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 33 - Figure 3: Annual number of deaths and age-specific mortality rates of cervical cancer in Europe and its regions (estimates for 212) (Continued) Eastern Europe Southern Europe Age specific rates of cervical cancer(a) 25 2 15 1 5 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 75+ 25 2 15 1 5 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 75+ Annual number of deaths of cervical cancer 8, 6, 4, 2, 1,7 7,989 5,747 8, 6, 4, 2, 1,575 1,756 15 39 4 64 65+ 195 15 39 4 64 65+ Northern Europe Western Europe Age specific rates of cervical cancer(a) 25 2 15 1 5 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 75+ 25 2 15 1 5 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 75+ Annual number of deaths of cervical cancer 8, 6, 4, 2, 794 991 178 15 39 4 64 65+ 8, 6, 4, 2, 1,919 1,421 139 15 39 4 64 65+ Eastern Europe 15-19 yrs: 1 cases. 2-24 yrs: 25 cases. 25-29 yrs: 281 cases. 3-34 yrs: 564 cases. 35-39 yrs: 829 cases. 4-44 yrs: 1,44 cases. 45-49 yrs: 1,375 cases. 5-54 yrs: 1,86 cases. 55-59 yrs: 1,988 cases. 6-64 yrs: 1,776 cases. Northern Europe 15-19 yrs: 1 cases. 2-24 yrs: 4 cases. 25-29 yrs: 29 cases. 3-34 yrs: 6 cases. 35-39 yrs: 84 cases. 4-44 yrs: 117 cases. 45-49 yrs: 145 cases. 5-54 yrs: 168 cases. 55-59 yrs: 174 cases. 6-64 yrs: 19 cases. Southern Europe 15-19 yrs: cases. 2-24 yrs: 2 cases. 25-29 yrs: 1 cases. 3-34 yrs: 53 cases. 35-39 yrs: 13 cases. 4-44 yrs: 227 cases. 45-49 yrs: 31 cases. 5-54 yrs: 351 cases. 55-59 yrs: 352 cases. 6-64 yrs: 344 cases. Western Europe 15-19 yrs: cases. 2-24 yrs: 1 cases. 25-29 yrs: 12 cases. 3-34 yrs: 38 cases. 35-39 yrs: 88 cases. 4-44 yrs: 177 cases. 45-49 yrs: 267 cases. 5-54 yrs: 322 cases. 55-59 yrs: 336 cases. 6-64 yrs: 319 cases. Data accessed on 15 Nov 215. (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 34 - ( Figure 3 continued from previous page) a Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 35-3.1.3 Comparison of incidence and mortality Figure 31: Age-specific incidence and mortality rates of cervical cancer in Europe and its regions (estimates for 212) Europe Southern Europe 4 4 3 3 2 2 1 1 Age specific rates of cervical cancer per 1, 4 3 2 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 Eastern Europe 65 69 7 74 >=75 4 3 2 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 Western Europe 65 69 7 74 >=75 1 1 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 15 19 2 24 25 29 3 34 35 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 65 69 7 74 >=75 4 Northern Europe 3 2 1 Incidence Mortality Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 36-3.2 Anogenital cancers other than the cervix Data on the role of HPV in anogenital cancers other than the cervix are limited, but there is an increasing body of evidence strongly linking HPV DNA with cancers of the anus, vulva, vagina, and penis. Although these cancers are much less frequent compared to cancer of the cervix, their association with HPV make them potentially preventable and subject to similar preventative strategies as those for cervical cancer. (Vaccine 26, Vol. 24, Suppl 3; Vaccine 28, Vol. 26, Suppl 1; Vaccine 212, Vol. 3, Suppl 5; IARC Monographs 27, Vol. 9) Figure 32: Age-standardised incidence rates of anogenital cancers other than the cervix in Europe (estimates for 212) Data accessed on 8 May 217. ASR: Age-standardized rate, rates per 1, per year. Please refer to original source for methods. Other anogenital cancer cases (vulvar, vaginal, anal, and penile). GLOBOCAN quality index for availability of incidence data: - For Albania, Greece, Hungary, Republic of Moldova, Macedonia, Montenegro: No data. - For Austria, Belgium, Bulgaria, Belarus, Cyprus, Czech Republic, Denmark, Estonia, Finland, United Kingdom, Croatia, Ireland, Iceland, Lithuania, Latvia, Malta, Netherlands, Norway, Slovakia, Slovenia, Sweden, Ukraine: High quality national data or high quality regional (coverage greater than 5%). - For Bosnia & Herzegovina, Luxembourg, Russian Federation: National data (rates). - For Switzerland, Germany, Spain, France, Italy, Serbia: High quality regional (coverage between 1% and 5%). - For Poland, Portugal: High quality regional (coverage lower than 1%). - For Romania: Regional data (rates). GLOBOCAN quality index of methods for calculating incidence: Methods to estimate the sex- and age-specific incidence rates of cancer for a specific country: - For Albania, Greece, Hungary, Luxembourg, Republic of Moldova, Macedonia, Portugal, Romania, Serbia: Estimated from national mortality estimates by modelling using incidence mortality ratios derived from recorded data in local cancer registries in neighbouring countries - For Austria, Bulgaria, Belarus, Czech Republic, Germany, Denmark, Estonia, Finland, United Kingdom, Croatia, Ireland, Iceland, Lithuania, Latvia, Malta, Netherlands, Norway, Russian Federation, Slovakia, Slovenia, Sweden: Rates projected to 212 - For Belgium, Bosnia & Herzegovina, Cyprus, Ukraine: Most recent rates applied to 212 population - For Switzerland, Spain, France, Italy, Poland: Estimated from national mortality by modelling using incidence mortality ratios derived from recorded data in country-specific cancer registries - For Montenegro: The rates are those of neighbouring countries or registries in the same area Data sources: Worldwide burden of cancer attributable to HPV by site, country and HPV type. de Martel C, Plummer M, Vignat J, Franceschi S. Int J Cancer. 217 Apr 1. doi: 1.12/ijc.3716. [Epub ahead of print]. PMID:28369882.

3 BURDEN OF HPV-RELATED CANCERS - 37 - Figure 33: Age-standardised incidence rate of other anogenital cancer cases attributable to HPV by country in Europe (estimates for 212) Denmark France Norway Netherlands Iceland Belgium Ireland UK Sweden Luxembourg Germany Slovenia Austria Serbia Montenegro Lithuania Italy Croatia Switzerland Malta Latvia Finland Estonia Spain Czech Rep. Bulgaria Slovakia Portugal Macedonia Hungary Cyprus Albania Ukraine Russia Romania Moldova Greece Poland Bosnia & H. Belarus San Marino Monaco Liechtenstein Andorra 1.5 1.5 1.4 1.4 1.3 1.3 1.3 1.2 1.2 1.1 1.1 1.1 1.1 1.1 1.1 1. 1. 1. 1. 1. 1. 1..9.9.9.9.9.9.8.8.8.8.8.7.7.6 1.8 1.7 1.7 2.2.5 1 1.5 2 2.5 Age standardised incidence rate per 1, women World Standard No rates are available. Data accessed on 8 May 217. ASR: Age-standardized rate, rates per 1, per year. Please refer to original source for methods. (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 38 - Other anogenital cancer cases (vulvar, vaginal, anal, and penile). ( Figure 33 continued from previous page) GLOBOCAN quality index for availability of incidence data: - For Belarus, Ukraine, Cyprus, Slovakia, Bulgaria, Czech Republic, Estonia, Finland, Latvia, Malta, Croatia, Lithuania, Austria, Slovenia, Sweden, United Kingdom, Ireland, Belgium, Iceland, Netherlands, Norway, Denmark: High quality national data or high quality regional (coverage greater than 5%). - For Bosnia & Herzegovina, Russian Federation, Luxembourg: National data (rates). - For Poland, Portugal: High quality regional (coverage lower than 1%). - For Greece, Republic of Moldova, Albania, Hungary, Macedonia, Montenegro: No data. - For Romania: Regional data (rates). - For Spain, Switzerland, Italy, Serbia, Germany, France: High quality regional (coverage between 1% and 5%). GLOBOCAN quality index of methods for calculating incidence: Methods to estimate the sex- and age-specific incidence rates of cancer for a specific country: - For Belarus, Russian Federation, Slovakia, Bulgaria, Czech Republic, Estonia, Finland, Latvia, Malta, Croatia, Lithuania, Austria, Slovenia, Germany, Sweden, United Kingdom, Ireland, Iceland, Netherlands, Norway, Denmark: Rates projected to 212 - For Bosnia & Herzegovina, Ukraine, Cyprus, Belgium: Most recent rates applied to 212 population - For Poland, Spain, Switzerland, Italy, France: Estimated from national mortality by modelling using incidence mortality ratios derived from recorded data in country-specific cancer registries - For Greece, Republic of Moldova, Romania, Albania, Hungary, Macedonia, Portugal, Serbia, Luxembourg: Estimated from national mortality estimates by modelling using incidence mortality ratios derived from recorded data in local cancer registries in neighbouring countries - For Montenegro: The rates are those of neighbouring countries or registries in the same area Data sources: de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 217 3.2.1 Anal cancer Anal cancer is rare in the general population with an average worldwide incidence of 1 per 1,, but is reported to be increasing in more developed regions. Globally, there are an estimated 27, new cases every year (de Martel C et al. Lancet Oncol 212;13(6):67-15). Women have higher incidences of anal cancer than men. Incidence is particularly high among populations of men who have sex with men (MSM), women with history of cervical or vulvar cancer, and immunosuppressed populations, including those who are HIV-infected and patients with a history of organ transplantation. These cancers are predominantly squamous cell carcinoma, adenocarcinomas, or basaloid and cloacogenic carcinomas. Table 7: Incidence of anal cancer in Europe by cancer registry and sex Male Female Country / Registry Period N cases a Crude rate b ASR b N cases a Crude rate c ASR c Eastern Europe Belarus 1 National 23-27 55.2.2 19.4.2 Bulgaria 1 National 23-27 167.9.5 127.6.4 Czech Rep. 1 National 23-27 192.8.5 348 1.3.7 Hungary - - - - - - - - Moldova - - - - - - - - Poland 1 Cracow 23-26 4.3.2 24 1.5.8 Kielce 23-27 9.3.2 15.5.2 Lower Silesia 23-27 55.8.5 11 1.3.7 Podkarpackie 23-27 22.4.3 35.7.3 Romania - - - - - - - - Russia 1 Saint Petersburg 23-27 22.2.1 117.9.5 Slovakia 1 National 23-27 63.5.4 14.8.4 Ukraine 1 National 23-27 438.4.3 64.5.3 Northern Europe Denmark 1 National 23-27 157 1.2.7 332 2.4 1.4 Estonia 1 National 23-27 17.5.4 48 1.3.6 (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 39 - ( Table 7 continued from previous page) Male Female Country / Registry Period N cases a Crude rate b ASR b N cases a Crude rate c ASR c Finland 1 National 23-27 65.5.3 115.9.4 Iceland 1 National 23-27 6.8.6 1 1.4.8 Ireland 1 National 23-27 64.6.5 94.9.6 Latvia 1 National 24-27 23.5.4 38.8.4 Lithuania 1 National 23-27 35.4.3 51.6.3 Norway 1 National 23-27 97.8.5 229 2. 1. Sweden 1 National 23-27 198.9.5 459 2. 1. UK 1 England 23-27 1491 1.2.7 2274 1.8 1. England, East of 23-27 134 1..6 27 1.9 1. England Region England, North Western 23-27 188 1.2.7 288 1.7.9 England, Northern and 23-27 229 1.4.8 335 2. 1.1 Yorkshire England, Oxford Region 23-27 67 1..6 134 1.9 1.1 England, South and 23-27 197 1.2.7 336 1.9.9 Western Regions England, Thames 23-27 384 1.3.9 513 1.7 1. England, Trent 25-27 71 1..6 115 1.5.7 England, West Midlands 23-27 162 1.2.7 211 1.6.9 Northern Ireland 23-27 5 1.2.8 51 1.2.8 Scotland 23-27 136 1.1.7 254 1.9 1. Wales 23-27 98 1.4.7 151 2. 1.1 Southern Europe Albania - - - - - - - - Andorra - - - - - - - - Bosnia & H. - - - - - - - - Croatia 1 National 23-27 41.4.3 73.6.3 Cyprus 1 National 23-27 8.4.3 14.7.5 Greece - - - - - - - - Italy 1 Biella 23-27 9 2..8 15 3.1 1.1 Brescia 23-26 16.8.4 43 2..9 Catania and Messina 23-25 2.8.5 24.9.5 Catanzaro 23-27 7 1.2.5 9 1.5.7 Como 23-27 19 1.4.8 29 2..9 Ferrara 23-27 21 2.5.9 23 2.5.7 Florence and Prato 23-25 42 2.4.9 46 2.5 1. Friuli-Venezia Giulia 23-27 41 1.4.6 78 2.5.8 Genoa 23-26 44 2.7 1.3 72 3.9 1.4 (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 4 - ( Table 7 continued from previous page) Male Female Country / Registry Period N cases a Crude rate b ASR b N cases a Crude rate c ASR c Latina 23-27 2 1.6.7 37 2.8 1.3 Lecco 23-27 6.8.4 9 1.1.4 Lombardy, South 23-25 5.5.3 19 1.7.7 Mantua 23-25 7 1.2.5 5.8.3 Milan 23-26 22.9.5 58 2.1 1. Modena 23-27 18 1.1.4 3 1.8.8 Naples 23-27 6.4.3 9.6.4 Nuoro 23-27 4.7.4 7 1.1.4 Palermo 23-26 27 1.1.7 24.9.5 Parma 23-27 12 1.2.6 17 1.6.6 Ragusa 23-27 9 1.2.6 18 2.3 1.2 Reggio Emilia 23-27 9.7.4 22 1.8.7 Romagna 23-27 59 2.1 1.1 78 2.6 1.2 Salerno 23-27 33 1.2.7 24.9.5 Sassari 23-27 6.5.3 13 1.1.5 Sondrio 23-27 8 1.8 1. 17 3.7 1.8 South Tyrol 23-26 11 1.2.7 31 3.2 1.5 Syracuse 23-27 1 1..6 4.4.1 Trapani 23-26 13 1.6.9 11 1.2.6 Trento 23-26 8.8.4 14 1.4.5 Turin 23-27 45 2.1 1. 65 2.8 1.3 Umbria 23-27 26 1.2.7 4 1.8.8 Varese 23-27 31 1.5.8 41 1.9.8 Veneto 23-26 58 1.3.6 72 1.5.7 Macedonia - - - - - - - - Malta 1 National 23-27 3.3.1 8.8.5 Montenegro - - - - - - - - Portugal 1 Azores 23-27 4.7.6 6 1..6 San Marino - - - - - - - - Serbia 1 Central 23-27 9.7.4 86.6.3 Slovenia 1 National 23-27 45.9.6 56 1.1.5 Spain 1 Albacete 23-27 5.5.4 1.1. Asturias 23-27 29 1.1.7 19.7.3 Basque Country 23-27 43.8.5 4.7.3 Canary Islands 23-26 28.9.6 27.8.5 Ciudad Real 24-27 7.7.4 3.3.1 Cuenca 23-27 5 1..5 5 1..6 Girona 23-27 15.9.7 14.9.4 Granada 23-27 1.5.3 13.6.3 La Rioja 23-27 2.3.1 6.8.4 Mallorca 23-27 29 1.5 1. 18.9.5 Murcia 23-27 29.8.6 15.5.2 (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 41 - ( Table 7 continued from previous page) Male Female Country / Registry Period N cases a Crude rate b ASR b N cases a Crude rate c ASR c Navarra 23-27 9.6.4 9.6.2 Tarragona 23-27 18 1..5 9.5.2 Western Europe Austria 1 National 23-27 196 1..6 378 1.8.9 Tyrol 23-27 16.9.6 38 2.1 1.3 Vorarlberg 23-27 4.4.3 13 1.4.8 Belgium 1 National 24-27 24 1..6 31 1.4.7 France 1 Bas-Rhin 23-27 12.5.3 35 1.3.7 Calvados 23-27 19 1.2.8 4 2.3 1.2 Doubs 23-27 14 1.1.8 21 1.6 1. Haut-Rhin 23-27 16.9.6 36 1.9.9 Herault 23-27 27 1.1.8 9 3.5 1.9 Isere 23-27 2.7.5 68 2.3 1.3 Loire Atlantique 23-27 32 1.1.7 78 2.5 1.5 Manche 23-27 11.9.5 25 2..7 Martinique 23-27 3.3.2 8.8.3 Somme 23-27 16 1.2.6 29 2. 1.2 Tarn 23-27 9 1..4 19 2..8 Vendee 23-27 11.8.4 36 2.4 1.3 Germany 1 Brandenburg 23-27 66 1..6 144 2.2 1. Bremen 23-27 29 1.8 1.1 35 2. 1. Free State Of Saxony 23-27 13 1..5 214 1.9.8 Hamburg 23-27 19 2.6 1.5 153 3.4 1.8 Mecklenburg-Western 23-27 41 1..6 77 1.8.8 Pomerania Munich 23-27 17 1.1.7 259 2.6 1.3 North Rhine-Westphalia 23-27 69 1.1.6 126 1.9 1. Saarland 23-27 33 1.3.7 5 1.8.9 Schleswig-Holstein 23-27 123 1.8 1. 215 3. 1.5 Luxembourg - - - - - - - - Monaco - - - - - - - - Netherlands 1 Eindhoven 23-27 13.5.3 23.9.5 National 23-27 293.7.5 374.9.5 Switzerland 1 Basel 23-27 11 1..6 21 1.9.9 Geneva 23-27 19 1.9 1.2 63 5.6 3. Graubunden and Glarus 23-27 4.7.5 1 1.7 1. Neuchatel 23-27 12 2.9 1.6 22 5.1 2.2 St Gall-Appenzell 23-27 11.8.6 22 1.6.9 Ticino 23-27 8 1..6 36 4.3 2.1 Valais 23-27 8 1.1.7 19 2.6 1.6 Vaud 23-27 24 1.5.9 76 4.5 2.3 Zurich 23-27 4 1.3.8 13 3.2 1.7 Data accessed on 5 May 215. a Accumulated number of cases during the period in the population covered by the corresponding registry. (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 42 - ( Table 7 continued from previous page) b Rates per 1, men per year. c Rates per 1, women per year. Data sources: 1 Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, Steliarova-Foucher E, Swaminathan R and Ferlay J eds (213). Cancer Incidence in Five Continents, Vol. X (electronic version) Lyon, IARC. http://ci5.iarc.fr 1 Figure 34: Time trends in anal cancer incidence in Austria (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 1 Annual crude incidence rate (per 1,) 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Tyrol, Vorarlberg. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 43-2 Figure 35: Time trends in anal cancer incidence in Croatia (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 1 All ages 15 44 yrs 45 74 yrs 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 2 Annual crude incidence rate (per 1,) 1 All ages 15 44 yrs 45 74 yrs 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 44-1 Figure 36: Time trends in anal cancer incidence in Denmark (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 1 Annual crude incidence rate (per 1,) 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 45-5 Figure 37: Time trends in anal cancer incidence in Estonia (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1968 197 1972 1974 1976 1978 198 1982 1984 1986 1988 199 1992 1994 1996 1998 2 22 24 26 Anal cancer in women 5 Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1968 197 1972 1974 1976 1978 198 1982 1984 1986 1988 199 1992 1994 1996 1998 2 22 24 26 No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 46-1 Figure 38: Time trends in anal cancer incidence in France (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 1 Annual crude incidence rate (per 1,) 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Bas-Rhin, Calvados, Doubs, Haut-Rhin, Herault, Isere, Somme, Tarn. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 47-1 Figure 39: Time trends in anal cancer incidence in Iceland (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1958 196 1962 1964 1966 1968 197 1972 1974 1976 1978 198 1982 1984 1986 1988 199 1992 1994 1996 1998 2 22 24 26 Anal cancer in women 1 Annual crude incidence rate (per 1,) 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1958 196 1962 1964 1966 1968 197 1972 1974 1976 1978 198 1982 1984 1986 1988 199 1992 1994 1996 1998 2 22 24 26 No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 48-5 Figure 4: Time trends in anal cancer incidence in Italy (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 5 Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Ferrara Province, Florence, Lombardy, Varese province, Modena, Parma, Ragusa Province, Romagna, Sassari Province, Torino. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 49 - Figure 41: Time trends in anal cancer incidence in the Netherlands (cancer registry data) 5 Anal cancer in men Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 5 Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 5 - Figure 42: Time trends in anal cancer incidence in Poland (cancer registry data) Anal cancer in men 14 Annual crude incidence rate (per 1,) 12 1 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 Anal cancer in women 14 Annual crude incidence rate (per 1,) 12 1 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the Cracow City registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 51 - Figure 43: Time trends in anal cancer incidence in the Russian Federation (cancer registry data) 5 Anal cancer in men Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 5 Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the St Petersburg registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 52-5 Figure 44: Time trends in anal cancer incidence in Slovakia (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1973 1974 1975 1976 1977 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 5 Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1973 1974 1975 1976 1977 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 53-5 Figure 45: Time trends in anal cancer incidence in Spain (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 5 Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Albacete, Cuenca, Girona, Granada, Murcia, Navarra, Tarragona. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 54-1 Figure 46: Time trends in anal cancer incidence in Switzerland (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 1 Annual crude incidence rate (per 1,) 8 6 4 2 All ages 15 44 yrs 45 74 yrs 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Geneva, Graubunden and Glarus, Neuchatel, St Gall-Appenzell, Valais, Vaud. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 55 - Figure 47: Time trends in anal cancer incidence in the United Kingdom (cancer registry data) 5 Anal cancer in men Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Anal cancer in women 5 Annual crude incidence rate (per 1,) 4 3 2 1 All ages 15 44 yrs 45 74 yrs 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Birmingham and West Midlands Region, East of England Region, Merseyside and Cheshire, North Western, Northern Ireland, Oxford, Scotland, South and Western Regions, Yorkshire. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr NOTE. Time trends in cancer incidence are shown only in countries with available data.

3 BURDEN OF HPV-RELATED CANCERS - 56-3.2.2 Vulvar cancer Cancer of the vulva is rare among women worldwide, with an estimated 27, new cases in 28, representing 4% of all gynaecologic cancers (de Martel C et al. Lancet Oncol 212;13(6):67-15). Worldwide, about 6% of all vulvar cancer cases occur in more developed countries. Vulvar cancer has two distinct histological patterns with two different risk factor profiles: (1) basaloid/warty types (2) keratinising types. Basaloid/warty lesions are more common in young women, are very often associated with HPV DNA detection (75-1%), and have a similar risk factor profile as cervical cancer. Keratinising vulvar carcinomas represent the majority of the vulvar lesions (>6%), they occur more often in older women and are more rarely associated with HPV (IARC Monograph Vol 1B) Table 8: Incidence of vulvar cancer in Europe by cancer registry Female Country Cancer registry Period N cases a Crude rate b ASR b Eastern Europe Belarus 1 National 23-27 755 2.9 1.3 Bulgaria 1 National 23-27 619 3.1 1.3 Czech Republic 1 National 23-27 1 3.8 1.8 Hungary - - - - - Poland 1 Cracow 23-26 33 2..9 Kielce 23-27 7 2.1.8 Lower Silesia 23-27 196 2.6 1.3 Podkarpackie 23-27 16 2. 1. Republic of Moldova - - - - - Romania - - - - - Russian Federation 1 Saint Petersburg 23-27 354 2.8 1.1 Slovakia 1 National 23-27 35 2.5 1.3 Ukraine 1 National 23-27 3345 2.6 1.1 Northern Europe Denmark 1 National 23-27 471 3.4 1.7 Estonia 1 National 23-27 132 3.6 1.4 Finland 1 National 23-27 376 2.8 1.2 Iceland 1 National 23-27 11 1.5.9 Ireland 1 National 23-27 217 2.1 1.3 Latvia 1 National 24-27 162 3.3 1.4 Lithuania 1 National 23-27 274 3. 1.3 Norway 1 National 23-27 451 3.9 1.9 Sweden 1 National 23-27 83 3.5 1.4 United Kingdom 1 England 23-27 448 3.4 1.6 England, East of England Region 23-27 44 3.1 1.4 England, North Western 23-27 58 3.5 1.7 England, Northern and Yorkshire 23-27 649 3.8 1.8 England, Oxford Region 23-27 21 3. 1.6 England, South and Western Regions 23-27 731 4.2 1.7 England, Thames 23-27 759 2.5 1.3 England, Trent 25-27 322 4.3 1.9 England, West Midlands 23-27 523 3.8 1.8 Northern Ireland 23-27 122 2.8 1.5 Scotland 23-27 493 3.7 1.9 Wales 23-27 342 4.5 2. Southern Europe Albania - - - - - Andorra - - - - - Bosnia & - - - - - Herzegovina Croatia 1 National 23-27 346 3. 1.2 Cyprus 1 National 23-27 39 2. 1.1 (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 57 - ( Table 8 continued from previous page) Female Country Cancer registry Period N cases a Crude rate b ASR b Greece - - - - - Italy 1 Biella 23-27 27 5.5 1.7 Brescia 23-26 5 2.3.9 Catania and Messina 23-25 72 2.7 1.1 Catanzaro 23-27 22 3.6 1.6 Como 23-27 56 3.9 1.2 Ferrara 23-27 42 4.6 1.5 Florence and Prato 23-25 72 3.9 1.1 Friuli-Venezia Giulia 23-27 131 4.2 1.1 Genoa 23-26 11 5.4 1.7 Latina 23-27 44 3.3 1.4 Lecco 23-27 21 2.6.9 Lombardy, South 23-25 42 3.8 1.3 Mantua 23-25 27 4.5 1.3 Milan 23-26 73 2.7.7 Modena 23-27 77 4.5 1.3 Naples 23-27 41 2.9 1.8 Nuoro 23-27 8 1.3.6 Palermo 23-26 78 3. 1.4 Parma 23-27 3 2.8.8 Ragusa 23-27 21 2.7 1.2 Reggio Emilia 23-27 49 3.9 1.3 Romagna 23-27 117 4. 1.1 Salerno 23-27 77 2.8 1.2 Sassari 23-27 19 1.6.8 Sondrio 23-27 19 4.2 1.3 South Tyrol 23-26 35 3.6 1.6 Syracuse 23-27 22 2.2 1. Trapani 23-26 38 4.3 1.5 Trento 23-26 41 4. 1.5 Turin 23-27 84 3.6 1. Umbria 23-27 15 4.7 1.4 Varese 23-27 67 3.1 1. Veneto 23-26 174 3.7 1.3 Macedonia - - - - - Malta 1 National 23-27 36 3.5 1.6 Montenegro - - - - - Portugal 1 Azores 23-27 8 1.3.7 San Marino - - - - - Serbia 1 Central 23-27 459 3.3 1.6 Slovenia 1 National 23-27 247 4.8 2.1 Spain 1 Albacete 23-27 29 3. 1. Asturias 23-27 11 3.6 1.2 Basque Country 23-27 16 3. 1.2 Canary Islands 23-26 62 1.9 1. Ciudad Real 24-27 24 2.4 1. Cuenca 23-27 17 3.3 1.2 Girona 23-27 43 2.7 1.1 Granada 23-27 5 2.3 1. La Rioja 23-27 22 3..8 Mallorca 23-27 68 3.5 1.5 Murcia 23-27 66 2. 1. Navarra 23-27 47 3.2 1. (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 58 - ( Table 8 continued from previous page) Female Country Cancer registry Period N cases a Crude rate b ASR b Tarragona 23-27 56 3.3 1.2 Western Europe Austria 1 National 23-27 66 3.1 1.5 Tyrol 23-27 44 2.5 1.5 Vorarlberg 23-27 27 3. 1.5 Belgium 1 National 24-27 71 3.3 1.5 France 1 Bas-Rhin 23-27 84 3.1 1.3 Calvados 23-27 26 1.5.7 Doubs 23-27 46 3.5 1.5 Haut-Rhin 23-27 51 2.7 1.3 Herault 23-27 42 1.6.5 Isere 23-27 44 1.5.7 Loire Atlantique 23-27 51 1.6.7 Manche 23-27 21 1.7.8 Martinique 23-27 3.3.2 Somme 23-27 29 2..9 Tarn 23-27 2 2.1.8 Vendee 23-27 22 1.5.9 Germany 1 Brandenburg 23-27 31 4.7 1.9 Bremen 23-27 9 5.3 2. Free State Of Saxony 23-27 63 5.5 1.8 Hamburg 23-27 257 5.8 2.5 Mecklenburg-Western Pomerania 23-27 199 4.6 1.7 Munich 23-27 42 4.2 1.7 North Rhine-Westphalia 23-27 326 4.9 2.1 Saarland 23-27 255 9.4 4.1 Schleswig-Holstein 23-27 585 8.1 3.6 Luxembourg - - - - - Monaco - - - - - Netherlands 1 Eindhoven 23-27 84 3.3 1.7 National 23-27 1416 3.4 1.7 Switzerland 1 Basel 23-27 4 3.5 1.2 Geneva 23-27 31 2.8 1.3 Graubunden and Glarus 23-27 2 3.5 1.6 Neuchatel 23-27 12 2.8 1.6 St Gall-Appenzell 23-27 34 2.5 1.1 Ticino 23-27 24 2.9.8 Valais 23-27 16 2.2.7 Vaud 23-27 56 3.3 1.4 Zurich 23-27 12 3.2 1.4 Data accessed on 5 May 215. a Accumulated number of cases during the period in the population covered by the corresponding registry. b Rates per 1, women per year. Data sources: 1 Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, Steliarova-Foucher E, Swaminathan R and Ferlay J eds (213). Cancer Incidence in Five Continents, Vol. X (electronic version) Lyon, IARC. http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 59 - Figure 48: Time trends in vulvar cancer incidence in Austria (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Tyrol, Vorarlberg. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 49: Time trends in vulvar cancer incidence in Croatia (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 5: Time trends in vulvar cancer incidence in Denmark (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 6 - Figure 51: Time trends in vulvar cancer incidence in Estonia (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1968 197 1972 1974 1976 1978 198 1982 1984 1986 1988 199 1992 1994 1996 1998 2 22 24 26 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 52: Time trends in vulvar cancer incidence in France (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Bas-Rhin, Calvados, Doubs, Haut-Rhin, Herault, Isere, Somme, Tarn. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 53: Time trends in vulvar cancer incidence in Iceland (cancer registry data) Annual crude incidence rate (per 1,) 14 12 1 8 6 4 2 1958 196 1962 1964 1966 1968 197 1972 1974 1976 1978 198 1982 1984 1986 1988 199 1992 1994 1996 1998 2 22 24 26 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 61 - Figure 54: Time trends in vulvar cancer incidence in Italy (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Ferrara Province, Florence, Lombardy, Varese province, Modena, Parma, Ragusa Province, Romagna, Sassari Province, Torino. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 55: Time trends in vulvar cancer incidence in Netherlands (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 56: Time trends in vulvar cancer incidence in Poland (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the Cracow City registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 62 - Figure 57: Time trends in vulvar cancer incidence in Russian Federation (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs Data accessed on 27 Apr 215. Data was provided by the St Petersburg registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 58: Time trends in vulvar cancer incidence in Slovakia (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1973 1974 1975 1976 1977 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 59: Time trends in vulvar cancer incidence in Spain (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Albacete, Cuenca, Girona, Granada, Murcia, Navarra, Tarragona. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 63 - Figure 6: Time trends in vulvar cancer incidence in Switzerland (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Geneva, Graubunden and Glarus, Neuchatel, St Gall-Appenzell, Valais, Vaud. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 61: Time trends in vulvar cancer incidence in United Kingdom (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Birmingham and West Midlands Region, East of England Region, Merseyside and Cheshire, North Western, Northern Ireland, Oxford, Scotland, South and Western Regions, Yorkshire. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr NOTE. Time trends in cancer incidence are shown only in countries with available data.

3 BURDEN OF HPV-RELATED CANCERS - 64-3.2.3 Vaginal cancer Cancer of the vagina is a rare cancer, with an estimated 13, new cases in 28, representing 2% of all gynaecologic cancers (de Martel C et al. Lancet Oncol 212;13(6):67-15). Although unreported and similar to cervical cancer, the majority of vaginal cancer cases (68%) occur in less developed countries. Most vaginal cancers are squamous cell carcinoma (9%) generally attributable to HPV, followed by clear cell adenocarcinomas and melanoma. Metastatic cervical cancer can be misclassified as cancer of the vagina. Invasive vaginal cancer is diagnosed primarily in old women (>=65 years) and the diagnosis is rare in women under 45 years whereas the peak incidence of carcinoma in situ is observed between ages 55 and 7 (Vaccine 28, Vol. 26, Suppl 1) Table 9: Incidence of vaginal cancer in Europe by cancer registry Female Country name Cancer registry Period N cases a Crude rate b ASR b Eastern Europe Belarus 1 National 23-27 168.6.4 Bulgaria 1 National 23-27 139.7.3 Czech Republic 1 National 23-27 247.9.5 Hungary - - - - - Poland 1 Cracow 23-26 7.4.2 Kielce 23-27 6.2.1 Lower Silesia 23-27 54.7.4 Podkarpackie 23-27 29.5.3 Republic of Moldova - - - - - Romania - - - - - Russian Federation 1 Saint Petersburg 23-27 8.6.3 Slovakia 1 National 23-27 94.7.4 Ukraine 1 National 23-27 765.6.3 Northern Europe Denmark 1 National 23-27 122.9.4 Estonia 1 National 23-27 29.8.4 Finland 1 National 23-27 97.7.3 Iceland 1 National 23-27 2.3.1 Ireland 1 National 23-27 59.6.4 Latvia 1 National 24-27 31.6.3 Lithuania 1 National 23-27 53.6.3 Norway 1 National 23-27 77.7.3 Sweden 1 National 23-27 25.9.3 United Kingdom 1 England 23-27 11.8.4 England, East of England Region 23-27 79.6.3 England, North Western 23-27 138.8.5 England, Northern and Yorkshire 23-27 151.9.4 England, Oxford Region 23-27 53.8.4 England, South and Western Regions 23-27 163.9.4 England, Thames 23-27 195.7.4 England, Trent 25-27 79 1..5 England, West Midlands 23-27 12.8.4 Northern Ireland 23-27 21.5.3 Scotland 23-27 14.8.4 Wales 23-27 7.9.4 Southern Europe Albania - - - - - Andorra - - - - - Bosnia & - - - - - Herzegovina Croatia 1 National 23-27 76.7.3 Cyprus 1 National 23-27 3.2.1 (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 65 - ( Table 9 continued from previous page) Female Country name Cancer registry Period N cases a Crude rate b ASR b Greece - - - - - Italy 1 Biella 23-27 3.6.1 Brescia 23-26 8.4.1 Catania and Messina 23-25 16.6.3 Catanzaro 23-27 8 1.3.5 Como 23-27 14 1..5 Ferrara 23-27 11 1.2.2 Florence and Prato 23-25 12.6.1 Friuli-Venezia Giulia 23-27 26.8.3 Genoa 23-26 18 1..2 Latina 23-27 4.3.1 Lecco 23-27 6.7.2 Lombardy, South 23-25 13 1.2.4 Mantua 23-25 6 1..4 Milan 23-26 23.8.3 Modena 23-27 9.5.3 Naples 23-27 6.4.3 Nuoro 23-27 2.3.1 Palermo 23-26 17.7.3 Parma 23-27 7.7.3 Ragusa 23-27 6.8.4 Reggio Emilia 23-27 1.8.3 Romagna 23-27 25.8.3 Salerno 23-27 17.6.3 Sassari 23-27 7.6.3 Sondrio 23-27 1.2.2 South Tyrol 23-26 6.6.3 Syracuse 23-27 7.7.4 Trapani 23-26 4.4.3 Trento 23-26 11 1.1.5 Turin 23-27 2.9.3 Umbria 23-27 25 1.1.4 Varese 23-27 15.7.3 Veneto 23-26 34.7.2 Macedonia - - - - - Malta 1 National 23-27 5.5.2 Montenegro - - - - - Portugal 1 Azores 23-27 5.8.4 San Marino - - - - - Serbia 1 Central 23-27 112.8.4 Slovenia 1 National 23-27 46.9.4 Spain 1 Albacete 23-27 3.3.2 Asturias 23-27 32 1.1.5 Basque Country 23-27 34.6.3 Canary Islands 23-26 11.3.2 Ciudad Real 24-27 2.2.1 Cuenca 23-27.. Girona 23-27 4.2.1 Granada 23-27 11.5.2 La Rioja 23-27 2.3.1 Mallorca 23-27 8.4.3 Murcia 23-27 14.4.2 Navarra 23-27 3.2. (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 66 - ( Table 9 continued from previous page) Female Country name Cancer registry Period N cases a Crude rate b ASR b Tarragona 23-27 5.3.2 Western Europe Austria 1 National 23-27 239 1.1.5 Tyrol 23-27 19 1.1.4 Vorarlberg 23-27 13 1.4.8 Belgium 1 National 24-27 197.9.4 France 1 Bas-Rhin 23-27 15.5.3 Calvados 23-27 12.7.4 Doubs 23-27 5.4.2 Haut-Rhin 23-27 14.7.3 Herault 23-27 15.6.3 Isere 23-27 14.5.2 Loire Atlantique 23-27 22.7.3 Manche 23-27 3.2.1 Martinique 23-27 1.9.5 Somme 23-27 12.8.3 Tarn 23-27 5.5.2 Vendee 23-27 12.8.3 Germany 1 Brandenburg 23-27 62 1..4 Bremen 23-27 18 1.1.3 Free State Of Saxony 23-27 131 1.2.4 Hamburg 23-27 63 1.4.6 Mecklenburg-Western Pomerania 23-27 45 1..4 Munich 23-27 97 1..4 North Rhine-Westphalia 23-27 61.9.4 Saarland 23-27 32 1.2.5 Schleswig-Holstein 23-27 71 1..4 Luxembourg - - - - - Monaco - - - - - Netherlands 1 Eindhoven 23-27 14.5.3 National 23-27 247.6.3 Switzerland 1 Basel 23-27 11 1..4 Geneva 23-27 5.4.2 Graubunden and Glarus 23-27 5.9.4 Neuchatel 23-27 4.9.2 St Gall-Appenzell 23-27 13 1..5 Ticino 23-27 5.6.2 Valais 23-27 1.1.1 Vaud 23-27 13.8.3 Zurich 23-27 25.8.4 Data accessed on 5 May 215. Please refer to original source (available at http://ci5.iarc.fr/ci5i-ix/ci5i-ix.htm) a Accumulated number of cases during the period in the population covered by the corresponding registry. b Rates per 1, women per year. Data sources: 1 Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, Steliarova-Foucher E, Swaminathan R and Ferlay J eds (213). Cancer Incidence in Five Continents, Vol. X (electronic version) Lyon, IARC. http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 67 - Figure 62: Time trends in vaginal cancer incidence in Austria (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Tyrol, Vorarlberg. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 63: Time trends in vaginal cancer incidence in Croatia (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 64: Time trends in vaginal cancer incidence in Denmark (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 68 - Figure 65: Time trends in vaginal cancer incidence in Estonia (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1968 197 1972 1974 1976 1978 198 1982 1984 1986 1988 199 1992 1994 1996 1998 2 22 24 26 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 66: Time trends in vaginal cancer incidence in France (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Bas-Rhin, Calvados, Doubs, Haut-Rhin, Herault, Isere, Somme, Tarn. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 67: Time trends in vaginal cancer incidence in Iceland (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1958 196 1962 1964 1966 1968 197 1972 1974 1976 1978 198 1982 1984 1986 1988 199 1992 1994 1996 1998 2 22 24 26 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 69 - Figure 68: Time trends in vaginal cancer incidence in Italy (cancer registry data) Annual crude incidence rate (per 1,) 2 1 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Ferrara Province, Florence, Lombardy, Varese province, Modena, Parma, Ragusa Province, Romagna, Sassari Province, Torino. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 69: Time trends in vaginal cancer incidence in Netherlands (cancer registry data) Annual crude incidence rate (per 1,) 2 1 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 7: Time trends in vaginal cancer incidence in Poland (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the Cracow City registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 7 - Figure 71: Time trends in vaginal cancer incidence in Russian Federation (cancer registry data) Annual crude incidence rate (per 1,) 2 1 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the St Petersburg registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 72: Time trends in vaginal cancer incidence in Slovakia (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1973 1974 1975 1976 1977 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 73: Time trends in vaginal cancer incidence in Spain (cancer registry data) Annual crude incidence rate (per 1,) 2 1 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Albacete, Cuenca, Girona, Granada, Murcia, Navarra, Tarragona. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 71 - Figure 74: Time trends in vaginal cancer incidence in Switzerland (cancer registry data) Annual crude incidence rate (per 1,) 2 1 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Geneva, Graubunden and Glarus, Neuchatel, St Gall-Appenzell, Valais, Vaud. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 75: Time trends in vaginal cancer incidence in United Kingdom (cancer registry data) Annual crude incidence rate (per 1,) 2 1 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Birmingham and West Midlands Region, East of England Region, Merseyside and Cheshire, North Western, Northern Ireland, Oxford, Scotland, South and Western Regions, Yorkshire. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr NOTE. Time trends in cancer incidence are shown only in countries with available data.

3 BURDEN OF HPV-RELATED CANCERS - 72-3.2.4 Penile cancer The annual burden of penile cancer has been estimated to be 22, cases worldwide with incidence rates strongly correlating with those of cervical cancer (de Martel C et al. Lancet Oncol 212;13(6):67-15). Penile cancer is rare and most commonly affects men aged 5-7 years. Incidence rates are higher in less developed countries than in more developed countries, accounting for up to 1% of male cancers in some parts of Africa, South America and Asia. Precursor cancerous penile lesions (PeIN) are rare. Cancers of the penis are primarily of squamous cell carcinomas (SCC) (95%) and the most common penile SCC histologic sub-types are keratinising (49%), mixed warty-basaloid (17%), verrucous (8%) warty (6%), and basaloid (4%). HPV is most commonly detected in basaloid and warty tumours but is less common in keratinising and verrucous tumours. Approximately 6-1% of PeIN lesions are HPV DNA positive. Table 1: Incidence of penile cancer in Europe by cancer registry Male Country name Cancer registry Period N cases a Crude rate b ASR b Eastern Europe Belarus 1 National 23-27 25 1.1.8 Bulgaria 1 National 23-27 228 1.2.7 Czech Republic 1 National 23-27 43 1.6 1. Hungary 2 County Szabolcs-Szatmar 1983-1987 12.8.7 County Vas 1983-1987 4.6.4 Poland 1 Cracow 23-26 21 1.5.9 Kielce 23-27 39 1.2.8 Lower Silesia 23-27 61.9.7 Podkarpackie 23-27 48.9.7 Republic of Moldova - - - - - Romania 2 County Cluj 1983-1987 17.9.8 Russian Federation 1 Saint Petersburg 23-27 73.7.5 Slovakia 1 National 23-27 147 1.1.9 Ukraine 1 National 23-27 98.9.6 Northern Europe Denmark 1 National 23-27 234 1.7 1. Estonia 1 National 23-27 44 1.4 1. Finland 1 National 23-27 119.9.6 Iceland 1 National 23-27 11 1.5.9 Ireland 1 National 23-27 111 1.1.8 Latvia 1 National 24-27 64 1.5 1. Lithuania 1 National 23-27 18 1.4 1. Norway 1 National 23-27 197 1.7 1. Sweden 1 National 23-27 412 1.8 1. United Kingdom 1 England 23-27 187 1.5.9 England, East of England Region 23-27 193 1.4.8 England, North Western 23-27 276 1.7 1.1 England, Northern and Yorkshire 23-27 261 1.6 1. England, Oxford Region 23-27 91 1.3.9 England, South and Western Regions 23-27 291 1.7 1. England, Thames 23-27 32 1.1.7 England, Trent 25-27 128 1.7 1. England, West Midlands 23-27 229 1.7 1. Northern Ireland 23-27 78 1.8 1.3 Scotland 23-27 212 1.7 1. Wales 23-27 135 1.9 1.1 Southern Europe Albania - - - - - Andorra - - - - - (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 73 - ( Table 1 continued from previous page) Male Country name Cancer registry Period N cases a Crude rate b ASR b Bosnia & - - - - - Herzegovina Croatia 1 National 23-27 114 1.1.7 Cyprus 1 National 23-27 28 1.5 1.1 Greece - - - - - Italy 1 Biella 23-27 11 2.5 1. Brescia 23-26 18.9.5 Catania and Messina 23-25 56 2.2 1.2 Catanzaro 23-27 9 1.6.9 Como 23-27 9.7.3 Ferrara 23-27 2 2.4 1. Florence and Prato 23-25 28 1.6.7 Friuli-Venezia Giulia 23-27 51 1.7.8 Genoa 23-26 23 1.4.5 Latina 23-27 3 2.3 1.3 Lecco 23-27 8 1..6 Lombardy, South 23-25 13 1.2.5 Mantua 23-25 12 2.1 1.1 Milan 23-26 21.9.4 Modena 23-27 2 1.2.6 Naples 23-27 18 1.3 1. Nuoro 23-27 9 1.5 1. Palermo 23-26 38 1.6 1. Parma 23-27 11 1.1.6 Ragusa 23-27 1 1.3.8 Reggio Emilia 23-27 9.7.4 Romagna 23-27 44 1.6.7 Salerno 23-27 53 2. 1. Sassari 23-27 9.8.5 Sondrio 23-27 5 1.1.6 South Tyrol 23-26 1 1.1.6 Syracuse 23-27 12 1.2.8 Trapani 23-26 17 2. 1.1 Trento 23-26 15 1.5.8 Turin 23-27 25 1.2.5 Umbria 23-27 52 2.5 1.1 Varese 23-27 18.9.4 Veneto 23-26 54 1.2.6 Macedonia - - - - - Malta 1 National 23-27 15 1.5.9 Montenegro - - - - - Portugal 1 Azores 23-27 7 1.2.9 San Marino - - - - - Serbia 1 Central 23-27 175 1.3.8 Slovenia 1 National 23-27 52 1.1.7 Spain 1 Albacete 23-27 2 2.1 1.1 Asturias 23-27 53 2.1 1. Basque Country 23-27 11 2..9 Canary Islands 23-26 51 1.6 1.1 Ciudad Real 24-27 21 2.1 1.2 Cuenca 23-27 2 3.9 1.9 Girona 23-27 24 1.5.8 Granada 23-27 42 2. 1.2 (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 74 - ( Table 1 continued from previous page) Male Country name Cancer registry Period N cases a Crude rate b ASR b La Rioja 23-27 11 1.5.6 Mallorca 23-27 35 1.8 1.1 Murcia 23-27 68 2. 1.3 Navarra 23-27 23 1.6.8 Tarragona 23-27 44 2.5 1.4 Western Europe Austria 1 National 23-27 249 1.2.8 Tyrol 23-27 14.8.6 Vorarlberg 23-27 5.6.4 Belgium 1 National 24-27 286 1.4.8 France 1 Bas-Rhin 23-27 42 1.6 1. Calvados 23-27 22 1.4.7 Doubs 23-27 18 1.4.9 Haut-Rhin 23-27 22 1.2.7 Herault 23-27 37 1.6.8 Isere 23-27 22.8.4 Loire Atlantique 23-27 19.6.4 Manche 23-27 19 1.6.9 Martinique 23-27 14 1.5.9 Somme 23-27 19 1.4 1. Tarn 23-27 17 1.9.7 Vendee 23-27 1.7.4 Germany 1 Brandenburg 23-27 126 2. 1.1 Bremen 23-27 23 1.4.7 Free State Of Saxony 23-27 177 1.7.8 Hamburg 23-27 61 1.4.8 Mecklenburg-Western Pomerania 23-27 93 2.2 1.2 Munich 23-27 116 1.2.7 North Rhine-Westphalia 23-27 94 1.5.8 Saarland 23-27 46 1.8.9 Schleswig-Holstein 23-27 134 1.9 1. Luxembourg - - - - - Monaco - - - - - Netherlands 1 Eindhoven 23-27 23.9.6 National 23-27 56 1.4.8 Switzerland 1 Basel 23-27 12 1.1.5 Geneva 23-27 19 1.9 1.1 Graubunden and Glarus 23-27 1 1.8.9 Neuchatel 23-27 9 2.2 1.4 St Gall-Appenzell 23-27 18 1.4.8 Ticino 23-27 13 1.7.8 Valais 23-27 6.8.6 Vaud 23-27 24 1.5.9 Zurich 23-27 36 1.2.6 Data accessed on 5 May 215. Please refer to original source (available at http://ci5.iarc.fr/ci5i-ix/ci5i-ix.htm) a Accumulated number of cases during the period in the population covered by the corresponding registry. b Rates per 1, men per year. Data sources: 1 Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, Steliarova-Foucher E, Swaminathan R and Ferlay J eds (213). Cancer Incidence in Five Continents, Vol. X (electronic version) Lyon, IARC. http://ci5.iarc.fr 2 Parkin, D.M.,Muir, C.S.,Whelan, S.L.,Gao, Y.-T.,Ferlay, J.,Powell, J., eds (1992). Cancer Incidence in Five Continents, Vol. VI. IARC Scientific Publications No. 12, Lyon, IARC.

3 BURDEN OF HPV-RELATED CANCERS - 75 - Figure 76: Time trends in penile cancer incidence in Austria (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Tyrol, Vorarlberg. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 77: Time trends in penile cancer incidence in Croatia (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 78: Time trends in penile cancer incidence in Denmark (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 76 - Figure 79: Time trends in penile cancer incidence in Estonia (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1968 197 1972 1974 1976 1978 198 1982 1984 1986 1988 199 1992 1994 1996 1998 2 22 24 26 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 8: Time trends in penile cancer incidence in France (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Bas-Rhin, Calvados, Doubs, Haut-Rhin, Herault, Isere, Somme, Tarn. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 81: Time trends in penile cancer incidence in Iceland (cancer registry data) Annual crude incidence rate (per 1,) 14 12 1 8 6 4 2 1958 196 1962 1964 1966 1968 197 1972 1974 1976 1978 198 1982 1984 1986 1988 199 1992 1994 1996 1998 2 22 24 26 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 77 - Figure 82: Time trends in penile cancer incidence in Italy (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Ferrara Province, Florence, Lombardy, Varese province, Modena, Parma, Ragusa Province, Romagna, Sassari Province, Torino. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 83: Time trends in penile cancer incidence in Netherlands (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 84: Time trends in penile cancer incidence in Poland (cancer registry data) Annual crude incidence rate (per 1,) 1 8 6 4 2 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the Cracow City registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 78 - Figure 85: Time trends in penile cancer incidence in Russian Federation (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the St Petersburg registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 86: Time trends in penile cancer incidence in Slovakia (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1973 1974 1975 1976 1977 1978 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 87: Time trends in penile cancer incidence in Spain (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Albacete, Cuenca, Girona, Granada, Murcia, Navarra, Tarragona. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr

3 BURDEN OF HPV-RELATED CANCERS - 79 - Figure 88: Time trends in penile cancer incidence in Switzerland (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Geneva, Graubunden and Glarus, Neuchatel, St Gall-Appenzell, Valais, Vaud. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr Figure 89: Time trends in penile cancer incidence in United Kingdom (cancer registry data) Annual crude incidence rate (per 1,) 5 4 3 2 1 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 All ages 15 44 yrs 45 74 yrs Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Birmingham and West Midlands Region, East of England Region, Merseyside and Cheshire, North Western, Northern Ireland, Oxford, Scotland, South and Western Regions, Yorkshire. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: http://ci5.iarc.fr NOTE. Time trends in cancer incidence are shown only in countries with available data.

3 BURDEN OF HPV-RELATED CANCERS - 8-3.3 Head and neck cancers The majority of head and neck cancers are associated with high tobacco and alcohol consumption. However, increasing trends in the incidence at specific sites suggest that other aetiological factors are involved, and infection by certain high-risk types of HPV (i.e. HPV16) have been reported to be associated with head and neck cancers, in particular with oropharyngeal cancer. Current evidence suggests that HPV16 is associated with tonsil cancer (including Waldeyer ring cancer), base of tongue cancer and other oropharyngeal cancer sites. Associations with other head and neck cancer sites such as oral cancer are neither strong nor consistent when compared to molecular-epidemiological data on HPV and oropharyngeal cancer. Association with laryngeal cancer is still unclear (IARC Monograph Vol 1B). Figure 9: Age-standardised incidence rates of head and neck cancer in Europe (estimates for 212) Data accessed on 8 May 217. ASR: Age-standardized rate, rates per 1, per year. Please refer to original source for methods. Head and neck cancer cases (oropharynx, oral cavity and larynx). GLOBOCAN quality index for availability of incidence data: - For Albania, Greece, Hungary, Republic of Moldova, Macedonia, Montenegro: No data. - For Austria, Belgium, Bulgaria, Belarus, Cyprus, Czech Republic, Denmark, Estonia, Finland, United Kingdom, Croatia, Ireland, Iceland, Lithuania, Latvia, Malta, Netherlands, Norway, Slovakia, Slovenia, Sweden, Ukraine: High quality national data or high quality regional (coverage greater than 5%). - For Bosnia & Herzegovina, Luxembourg, Russian Federation: National data (rates). - For Switzerland, Germany, Spain, France, Italy, Serbia: High quality regional (coverage between 1% and 5%). - For Poland, Portugal: High quality regional (coverage lower than 1%). - For Romania: Regional data (rates). GLOBOCAN quality index of methods for calculating incidence: Methods to estimate the sex- and age-specific incidence rates of cancer for a specific country: - For Albania, Greece, Hungary, Luxembourg, Republic of Moldova, Macedonia, Portugal, Romania, Serbia: Estimated from national mortality estimates by modelling using incidence mortality ratios derived from recorded data in local cancer registries in neighbouring countries - For Austria, Bulgaria, Belarus, Czech Republic, Germany, Denmark, Estonia, Finland, United Kingdom, Croatia, Ireland, Iceland, Lithuania, Latvia, Malta, Netherlands, Norway, Russian Federation, Slovakia, Slovenia, Sweden: Rates projected to 212 - For Belgium, Bosnia & Herzegovina, Cyprus, Ukraine: Most recent rates applied to 212 population - For Switzerland, Spain, France, Italy, Poland: Estimated from national mortality by modelling using incidence mortality ratios derived from recorded data in country-specific cancer registries - For Montenegro: The rates are those of neighbouring countries or registries in the same area Data sources: Worldwide burden of cancer attributable to HPV by site, country and HPV type. de Martel C, Plummer M, Vignat J, Franceschi S. Int J Cancer. 217 Apr 1. doi: 1.12/ijc.3716. [Epub ahead of print]. PMID:28369882.

3 BURDEN OF HPV-RELATED CANCERS - 81 - Figure 91: Age-standardised incidence rate of head and neck cancer cases attributable to HPV by country in Europe (estimates for 212) Hungary Slovakia Romania France Germany Belgium Moldova Denmark Czech Rep. Belarus Poland Luxembourg Switzerland Austria Ukraine Lithuania Russia Portugal UK Bulgaria Netherlands Latvia Ireland Estonia Slovenia Serbia Norway Croatia Sweden Montenegro Finland Spain Malta Italy Iceland Bosnia & H. Macedonia Albania Greece Cyprus San Marino Monaco Liechtenstein Andorra 2.1 2. 1.9 1.8 1.7 1.5 1.5 1.4 1.4 1.3 1.3 1.3 1.3 1.2 1.2 1. 1. 1. 1..9.9.9.9.8.8.8.8.7.7.6.6.5.5.5.5.4.4.3.2 3. 2.5 5 Age standardised incidence rate per 1, women World Standard No rates are available. Data accessed on 8 May 217. ASR: Age-standardized rate, rates per 1, per year. Please refer to original source for methods. (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 82 - Head and neck cancer cases (oropharynx, oral cavity and larynx). ( Figure 91 continued from previous page) GLOBOCAN quality index for availability of incidence data: - For Cyprus, Iceland, Malta, Finland, Sweden, Croatia, Norway, Slovenia, Estonia, Ireland, Latvia, Netherlands, Bulgaria, United Kingdom, Lithuania, Ukraine, Austria, Belarus, Czech Republic, Denmark, Belgium, Slovakia: High quality national data or high quality regional (coverage greater than 5%). - For Greece, Albania, Macedonia, Montenegro, Republic of Moldova, Hungary: No data. - For Bosnia & Herzegovina, Russian Federation, Luxembourg: National data (rates). - For Italy, Spain, Serbia, Switzerland, Germany, France: High quality regional (coverage between 1% and 5%). - For Portugal, Poland: High quality regional (coverage lower than 1%). - For Romania: Regional data (rates). GLOBOCAN quality index of methods for calculating incidence: Methods to estimate the sex- and age-specific incidence rates of cancer for a specific country: - For Cyprus, Bosnia & Herzegovina, Ukraine, Belgium: Most recent rates applied to 212 population - For Greece, Albania, Macedonia, Serbia, Portugal, Luxembourg, Republic of Moldova, Romania, Hungary: Estimated from national mortality estimates by modelling using incidence mortality ratios derived from recorded data in local cancer registries in neighbouring countries - For Iceland, Malta, Finland, Sweden, Croatia, Norway, Slovenia, Estonia, Ireland, Latvia, Netherlands, Bulgaria, United Kingdom, Russian Federation, Lithuania, Austria, Belarus, Czech Republic, Denmark, Germany, Slovakia: Rates projected to 212 - For Italy, Spain, Switzerland, Poland, France: Estimated from national mortality by modelling using incidence mortality ratios derived from recorded data in country-specific cancer registries - For Montenegro: The rates are those of neighbouring countries or registries in the same area Data sources: de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 217 3.3.1 Pharyngeal cancer (excluding nasopharynx) Table 11: Cancer incidence of pharynx (excluding nasopharynx) in Europe and its regions by sex. Includes ICD-1 codes: C9-1, C12-14 (estimates for 212). MALE FEMALE Area N cases Crude a ASR a Cum risk b N cases Crude a ASR a Cum risk b rate (%) ages rate (%) ages -74-74 Europe 28394 7.9 5.2.6 57 1.5.9.1 Eastern Europe 1187 7.4 5.3.6 141.9.5.1 Belarus 417 9.4 7..9 21.4.2. Bulgaria 179 5. 3.2.4 32.8.4. Czech Rep. 444 8.6 5.5.7 119 2.2 1.3.2 Hungary 885 18.7 12.8 1.5 172 3.3 2..2 Moldova 137 8.2 6..7 13.7.4. Poland 1256 6.8 4.6.6 237 1.2.7.1 Romania 141 13.6 9.9 1.2 96.9.5.1 Russia 3576 5.4 4..5 528.7.4. Slovakia 374 14. 1.1 1.2 37 1.3.8.1 Ukraine 159 7.3 5.2.6 146.6.3. Northern Europe 2594 5.3 3.4.4 844 1.7 1..1 Denmark 259 9.3 5.7.7 9 3.2 1.9.2 Estonia 34 5.5 3.8.5 4.6.3. Finland 86 3.2 1.9.2 27 1..6.1 Iceland 2 1.2.9.1 1.6.5.1 Ireland 84 3.7 2.8.3 32 1.4 1..1 Latvia 67 6.5 4.4.6 8.7.4. Lithuania 122 8. 5.9.7 13.7.4.1 Norway 95 3.8 2.4.3 38 1.5.9.1 Sweden 19 4. 2.4.3 78 1.6 1..1 UK 1647 5.3 3.4.4 553 1.7 1..1 Southern Europe 4137 5.3 3.4.4 731.9.5.1 Albania 41 2.5 2.1.2 11.7.5.1 Andorra - - Bosnia & H. 56 3.1 1.8.2 19 1..5.1 Croatia 28 9.8 6..7 34 1.5.8.1 Cyprus 2.3.3.... Greece 128 2.3 1.3.2 24.4.2. Italy 1241 4.2 2.4.3 348 1.1.6.1 Macedonia 26 2.5 1.8.2 3.3.1. Malta 9 4.3 2.7.4 1.5.3. Montenegro 14 4.5 3.4.4 4 1.2.9.1 Portugal 617 11.9 7.9.9 39.7.4. San Marino - - Serbia 31 6.2 4.3.5 69 1.4.9.1 Slovenia 117 11.7 7.1.9 22 2.1 1.1.1 Spain 1373 5.9 3.9.5 157.7.4. Western Europe 11476 12.3 7.5.9 2724 2.8 1.6.2 Austria 37 9. 5.5.7 1 2.3 1.3.2 Belgium 568 1.7 6.7.8 153 2.8 1.7.2 France 4168 13.5 8.8 1. 993 3. 1.9.2 (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 83 - ( Table 11 continued from previous page) MALE FEMALE Area N cases Crude a ASR a Cum risk b N cases Crude a ASR a Cum risk b rate (%) ages rate (%) ages -74-74 Germany 5569 13.8 8..9 1214 2.9 1.6.2 Liechtenstein - - Luxembourg 21 8.1 5.6.8 4 1.5 1.1.1 Monaco - - Netherlands 48 4.9 2.9.4 162 1.9 1.1.1 Switzerland 368 9.7 5.7.7 98 2.5 1.4.2 Data accessed on 15 Nov 215. a Male: Rates per 1, men per year. Female: Rates per 1, women per year. b Cumulative risk (incidence) is the probability or risk of individuals getting from the disease during ages -74 years. For cancer, it is expressed as the % of new born children who would be expected to develop from a particular cancer before the age of 75 if they had the rates of cancer observed in the period in the absence of competing causes. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr. Table 12: Cancer mortality of pharynx (excluding nasopharynx) in Europe and its regions by sex. Includes ICD-1 codes: C9-1, C12-14 (estimates for 212). MALE FEMALE Area N cases Crude a ASR a Cum risk b N cases Crude a ASR a Cum risk b rate (%) ages rate (%) ages -74-74 Europe 15245 4.3 2.7.3 2662.7.4. Eastern Europe 7277 5.3 3.8.5 885.6.3. Belarus 266 6. 4.4.5 13.3.1. Bulgaria 163 4.6 2.8.3 53 1.4.6.1 Czech Rep. 255 4.9 3.1.4 48.9.5.1 Hungary 65 12.8 8.8 1. 97 1.9 1.1.1 Moldova 135 8.1 6..7 11.6.3. Poland 781 4.2 2.8.3 14.7.4. Romania 942 9.1 6.5.8 78.7.4. Russia 2688 4.1 3..4 327.4.2. Slovakia 295 11.1 7.8 1. 32 1.1.6.1 Ukraine 1147 5.5 4..5 86.4.2. Northern Europe 1118 2.3 1.4.2 352.7.3. Denmark 115 4.1 2.4.3 36 1.3.6.1 Estonia 24 3.9 2.6.3 1.1.1. Finland 42 1.6.9.1 11.4.2. Iceland 1.6.5.1... Ireland 43 1.9 1.3.2 18.8.5.1 Latvia 53 5.2 3.5.4 9.7.3. Lithuania 17 7. 5..6 7.4.2. Norway 33 1.3.8.1 12.5.2. Sweden 8 1.7.9.1 29.6.3. UK 617 2. 1.2.1 229.7.4. Southern Europe 2342 3. 1.8.2 43.5.3. Albania 23 1.4 1.2.2 15.9.6.1 Andorra - - Bosnia & H. 14.8.4.1 13.7.3. Croatia 168 8. 4.7.6 17.7.3. Cyprus 1.2.1.... Greece 43.8.4. 9.2.1. Italy 764 2.6 1.4.2 196.6.3. Macedonia 14 1.4 1..1 4.4.2. Malta 6 2.9 1.5.1... Montenegro 9 2.9 2.2.3... Portugal 294 5.7 3.6.4 21.4.2. San Marino - - Serbia 254 5.2 3.6.4 45.9.5.1 Slovenia 8 8. 4.6.6 17 1.6.8.1 Spain 672 2.9 1.8.2 93.4.2. Western Europe 458 4.9 2.7.3 995 1..5.1 Austria 146 3.5 2.1.3 31.7.4. Belgium 224 4.2 2.5.3 55 1..5.1 France 1737 5.6 3.4.4 32.9.5.1 Germany 257 5.1 2.7.3 484 1.2.5.1 Liechtenstein - - (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 84 - ( Table 12 continued from previous page) MALE FEMALE Area N cases Crude a ASR a Cum risk b N cases Crude a ASR a Cum risk b rate (%) ages rate (%) ages -74-74 Luxembourg 6 2.3 1.4.2 2.8.5.1 Monaco - - Netherlands 182 2.2 1.2.2 66.8.4. Switzerland 156 4.1 2.4.3 55 1.4.7.1 Data accessed on 15 Nov 215. a Male: Rates per 1, men per year. Female: Rates per 1, women per year. b Cumulative risk (mortality) is the probability or risk of individuals dying from the disease during ages -74 years. For cancer, it is expressed as the % of new born children who would be expected to die from a particular cancer before the age of 75 if they had the rates of cancer observed in the period in the absence of competing causes. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 85 - Figure 92: Comparison of cancer incidence and mortality of pharynx (excluding nasopharynx) in males by age group in Europe and its regions. Includes ICD-1 codes: C9-1,C12-14 (estimates for 212). Europe Southern Europe 3 3 2 2 Age specific rates of pharyngeal cancer (excluding nasopharynx) per 1, 1 3 2 1 3 14 15 39 4 44 14 15 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 Eastern Europe 45 49 5 54 55 59 6 64 65 69 7 74 >=75 Northern Europe 1 3 2 1 14 15 39 4 44 14 15 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 Western Europe 45 49 5 54 55 59 6 64 65 69 7 74 >=75 Age group (years) 2 1 14 15 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 Incidence Mortality Data accessed on 15 Nov 215. For specific estimation methodology refer to http://globocan.iarc.fr/pages/datasource_and_methods.aspx European countries included in the Seven framework programme PREHDICT project (43 countries). Please refer to Introduction (link) to see PREHDICT project aim and coverage. Male: Rates per 1, men per year. Female: Rates per 1, women per year. (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 86 - ( Figure 93 continued from previous page) Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

3 BURDEN OF HPV-RELATED CANCERS - 87 - Figure 93: Comparison of cancer incidence and mortality of pharynx (excluding nasopharynx) in females by age group in Europe and its regions. Includes ICD-1 codes: C9-1,C12-14 (estimates for 212). 1 Europe 1 Southern Europe 5 5 Age specific rates of pharyngeal cancer (excluding nasopharynx) per 1, 5 14 15 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 1 Eastern Europe 14 15 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 1 Northern Europe 14 15 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 1 Western Europe 5 14 15 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 Age group (years) 5 14 15 39 4 44 45 49 5 54 55 59 6 64 65 69 7 74 >=75 Incidence Mortality Data accessed on 15 Nov 215. For specific estimation methodology refer to http://globocan.iarc.fr/pages/datasource_and_methods.aspx (Continued on next page)

3 BURDEN OF HPV-RELATED CANCERS - 88 - ( Figure 93 continued from previous page) Male: Rates per 1, men per year. Female: Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: http://globocan.iarc.fr.

4 HPV-RELATED STATISTICS - 89-4 HPV-related statistics HPV infection is commonly found in the anogenital tract of men and women with and without clinical lesions. The aetiological role of HPV infection among women with cervical cancer is well-established, and there is growing evidence of its central role in other anogenital sites. This section presents the HPV burden at each of the anogenital tract sites. The methodologies used to compile the information on HPV burden are derived from systematic reviews and meta-analyses of the literature. Due to the limitations of HPV DNA detection methods and study designs used, these data should be interpreted with caution and used only as a guide to assess the burden of HPV infection within the population (Vaccine 26, Vol. 24, Suppl 3; Vaccine 28, Vol. 26, Suppl 1; Vaccine 212,Vol. 3, Suppl 5; IARC Monographs 27, Vol. 9) 4.1 HPV burden in women with normal cervical cytology, cervical precancerous lesions or invasive cervical cancer The statistics shown in this section focus on HPV infection in the cervix uteri. HPV cervical infection results in cervical morphological lesions ranging from normalcy (cytologically normal women) to different stages of precancerous lesions (CIN-1, CIN-2, CIN-3/CIS) and invasive cervical cancer. HPV infection is measured by HPV DNA detection in cervical cells (fresh tissue, paraffin embedded or exfoliated cells). The prevalence of HPV increases with lesion severity. HPV causes virtually 1% of cervical cancer cases, and an underestimation of HPV prevalence in cervical cancer is most likely due to the limitations of study methodologies. Worldwide, HPV16 and 18 (the two vaccine-preventable types) contribute to over 7% of all cervical cancer cases, between 41% and 67% of high-grade cervical lesions and 16-32% of low-grade cervical lesions. After HPV16/18, the six most common HPV types are the same in all world regions, namely 31, 33, 35, 45, 52 and 58; these account for an additional 2% of cervical cancers worldwide (Clifford G, Vaccine 26;24(S3):26). Methods: Prevalence and type distribution of human papillomavirus in cervical carcinoma, low-grade cervical lesions, high-grade cervical lesions and normal cytology: systematic review and meta-analysis A systematic review of the literature was conducted regarding the worldwide HPV-prevalence and type distribution for cervical carcinoma, low-grade cervical lesions, high-grade cervical lesions and normal cytology from 199 to data as of indicated in each section. The search terms for the review were HPV AND cerv using Pubmed. There were no limits in publication language. References cited in selected articles were also investigated. Inclusion criteria were: HPV DNA detection by means of PCR or HC2, a minimum of 2 cases for cervical carcinoma, 2 cases for low-grade cervical lesions, 2 cases for highgrade cervical lesions and 1 cases for normal cytology and a detailed description of HPV DNA detection and genotyping techniques used. The number of cases tested and HPV positive extracted for each study were pooled to estimate the prevalence of HPV DNA and the HPV type distribution globally and by geographical region. Binomial 95% confidence intervals were calculated for each HPV prevalence. For more details refer to the methods document.

4 HPV-RELATED STATISTICS - 9-4.1.1 HPV prevalence in women with normal cervical cytology Figure 94: Prevalence of HPV among women with normal cervical cytology in Europe Data updated on 15 Dec 216 (data as of 3 Jun 215). The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 91 - Figure 95: Crude age-specific HPV prevalence (%) and 95% confidence interval in women with normal cervical cytology in Europe and its regions 4 35 3 25 2 15 1 5 Europe 4 35 3 25 2 15 1 5 Southern Europe <25 25 34 35 44 45 54 55 64 65+ <25 25 34 35 44 45 54 55 64 65+ 4 35 3 25 2 15 1 5 Eastern Europe 4 35 3 25 2 15 1 5 Western Europe <25 25 34 35 44 45 54 55 64 65+ <25 25 34 35 44 45 54 55 64 65+ 4 35 3 25 2 15 1 5 Northern Europe <25 25 34 35 44 45 54 55 64 65+ Data updated on 15 Dec 216 (data as of 3 Jun 215). Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 92 - Figure 96: Prevalence of HPV among women with normal cervical cytology in Europe by country and study Country Study Age N % (95% CI) Belarus Rogovskaya 213 (Minsk) 15 63 322 23.6 (19.3 28.5) Belgium Depuydt 21 (Flanders) a 14 97 57,876 14.8 (14.5 15.1) Arbyn 29 (Antwerp) 15 85 8,729 11.9 (11.3 12.6) Merckx 214 a,b 4 18 4,18 15.7 (14.6 16.8) Baay 25 (Antwerp) 2 5 2,293 6.9 (5.9 8.) Depuydt 212 3 7 1,142 8.4 (6.9 1.2) Schmitt 213 (Flanders) 15 86 913 33.3 (3.3 36.4) Weyn 213 (Brussels) >=2 96 1.8 (9. 13.) Depuydt 23 (Flanders) 17 85 287 24. (19.5 29.3) Baay 21 (Antwerp) 17 78 286 1.8 (7.7 15.) Bulgaria Kovachev 213 a,c 15 55 1,12 38.8 (36. 41.7) Croatia Kaliterna 213 (Dalmatia County) a 17 58 1,16 35. (32.3 37.8) Kaliterna 27 a,d 18 62 57 35.1 (31.3 39.1) Grahovac 27 (Zagreb,Rijeka) 25 35.6 (29.4 42.4) Czech Rep. Tachezy 213 14 79 1,32 25.6 (23.3 28.) Denmark Kjær 214 (Copenhagen) e 14 95 37,958 2.4 (2. 2.8) Nielsen 28 (Copenhagen) 2 29 1,22 15.9 (15.2 16.6) Bonde 214 f 16 88 4,642 33.3 (32. 34.7) Nielsen 28 (Copenhagen) 4 5 1,443 4.4 (3.4 5.5) Svare 1998 2 39 119 21.8 (15.4 3.1) Estonia Uusküla 21 (Tartu) a 18 35 326 36.8 (31.8 42.2) Europe Joura 215 16 26 13,862 27.5 (26.7 28.2) Paavonen 28 g 16 24 9,162 15.9 (15.2 16.7) Finland Malila 213 a 25 65 66,457 7.9 (7.7 8.1) Auvinen 25 (Helsinki) a 19 47 1,469 33. (3.7 35.5) France Clavel 21 (Reims) 15 76 7,339 1.5 (9.9 11.3) Monsonego 211 (Paris) 2 65 4,4 12.6 (11.6 13.7) Boulanger 24 (Amiens) 2 62 3,617 12.6 (11.6 13.7) Heard 213 h 16 88 3,23 18.1 (16.8 19.5) Vaucel 211 (Nantes) 17 86 98 13.1 (11.1 15.3) Baudu 214 (Franche Comté) 15 23 948 24.1 (21.4 26.9) Dalstein 23 (Besançon) 16 76 652 27. (23.7 3.5) Haguenoer 214 2 65 634 15.6 (13. 18.6) Beby Defaux 24 (Poitiers) 17 77 613 5.2 (3.7 7.3) Riethmuller 1999 i 16 76 426 25.1 (21.2 29.4) Casalegno 211 (Lyon) 15 88 32 48.3 (42.8 54.) Pannier Stockman 28 (Amiens) 18 78 289 28.7 (23.8 34.2) Monsonego 25 (Paris) 19 79 221 28.5 (23. 34.8) Germany Luyten 214 (Wolfsburg) 23,93 6.8 (6.5 7.2) Petry 23 j 3 85 7,832 5.9 (5.4 6.4) % 1% 2% 3% 4% 5% 6% (Continued on next page) Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. a Women from the general population, including some with cytological cervical abnormalities (Continued on next page)

4 HPV-RELATED STATISTICS - 93 - ( Figure 96 continued from previous page) b Flanders and Brussels c Sofia, Plovdiv, Varna, Burgas, Pleven and Vidin d Split and Dalmatian County e HPV prevalence for high-risk HPV types f Copenhagen and Frederiksberg g Czech Republic, Denmark, England, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Netherlands, Norway, Poland, Portugal, Spain, and Sweden h Alsace, Auvergne, Centre - Pays de Loire, Ile-de-France and Vaucluse i Besançon, Belfort j Hannover and Tuebingen Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 94 - Figure 97: Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued) Country Study Age N % (95% CI) Germany Schneider 2 (East Thuringia) 18 7 4,64 7.1 (6.4 7.9) Iftner 21 1 3 1,692 22.3 (2.4 24.3) de Jonge 213 a >=2 1,463 29.8 (27.5 32.2) Petry 213 (Wolfsburg) 25 27 659 25.5 (22.3 29.) Petry 213 (Wolfsburg) b 2 22 599 27.5 (24.1 31.3) Greece Agorastos 214 b 5,17 5.8 (5.2 6.5) Agorastos 215 c 25 55 3,783 1.4 (9.5 11.4) Argyri 213 (Athens) 14 7 2,218 15.7 (14.2 17.3) Tsiodras 211 1,348 39.5 (36.9 42.1) Agorastos 24 d 17 69 1,272 2. (1.4 3.) Tsiodras 21 (Athens) 21 45 1,29 1.2 (8.5 12.2) Paraskevaidis 21 (Ioannina) 17 79 738 6.4 (4.8 8.4) Panotopoulou 27 (Athens) 18 48 639 26.4 (23.2 3.) Hungary Nyári 26 2 6 491 5.5 (3.8 7.9) Ireland Anderson 213 (Northern Ireland) 2 64 5,68 13.2 (12.3 14.2) Keegan 27 (Dublin) 16 72 886 11.4 (9.5 13.7) Italy Del Mistro 214 (Veneto) b 25 64 46,694 6.9 (6.7 7.1) Carozzi 214 e 25 6 13,66 4.5 (4.2 4.9) Agarossi 29 15 73 9,148 11.3 (1.7 12.) Giorgi Rossi 211 f 25 64 3,151 9.7 (8.8 1.8) Tenti 1997 (Pavia) 16 47 1,64 12.3 (1.5 14.4) Ronco 25 (Turin) 25 7 997 7.8 (6.3 9.7) Giambi 213 g 18 26 97 13.6 (11.5 15.9) Ammatuna 28 (Sicily) 18 24 894 22.4 (19.8 25.2) Del Prete 28 (Apulia) b >=2 871 23.2 (2.5 26.1) Verteramo 29 (Rome) 17 57 737 21.7 (18.9 24.8) Panatto 213 h 16 26 566 18.2 (15.2 21.6) Centurioni 25 (Genova) 2 81 5 15.4 (12.5 18.8) Salfa 211 (Asti) 25 65 452 9.5 (7.1 12.6) Sammarco 213 (Molise) 18 63 398 32.4 (28. 37.2) Barzon 21 (Padova) 17 74 333 4.8 (35.7 46.2) Carozzi 2 (Florence) 25 64 332 5.1 (3.2 8.) Masia 29 (Sardinia) 18 46 39 17.8 (13.9 22.5) Bellaminutti 214 b 35 4. (34.7 45.6) Piana 211 (North Sardinia) 15 54 242 32.2 (26.7 38.4) Zappacosta 29 (Molise) 21 64 22 6.4 (3.8 1.4) Astori 1997 (Udine) 18 67 197 2.3 (15.3 26.5) Tornesello 26 (Milan, Naples) 18 63 183 19.7 (14.6 26.) Tornesello 28 (Naples) 17 11.2 (6.5 18.6) Latvia Silins 24 b 18 89 237 8. (5.2 12.2) % 1% 2% 3% 4% 5% (Continued on next page) Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. a Nordrhein-Westfalen, Niedersachsen, Schleswig-Holstein, Bremen and Hamburg (Continued on next page)

4 HPV-RELATED STATISTICS - 95 - ( Figure 97 continued from previous page) b Women from the general population, including some with cytological cervical abnormalities c Athens, Thessaloniki, Larissa, Patrasand Alexandroupolis d Thessaloniki, Thermi, Mihaniona, Corfu, Veria and Serres e Turin, Padua, Trento and Florence f Abruzzo, Campania, Lazio, Sardinia and Sicily g Abruzzo, Campania, Lazio, Tuscany, Emilia-Romagna and Piedmont h Turin, Milan and Genoa Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 96 - Figure 98: Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued) Country Study Age N % (95% CI) Lithuania Kliucinskas 26 a 18 5 1,1 25.1 (22.5 27.9) Gudleviciene 25 (Vilnius) 16 64 332 24.1 (19.8 29.) Simanaviciene 214 (Vilnius) 18 81 277 24.2 (19.5 29.6) Bumbuliene 212 (Vilnius) a 15 22 169 23.1 (17.4 3.) Montenegro Vujosevic 212 (Podgorica) a 23 68 189 2.1 (15. 26.4) Netherlands Rijkaart 212 (Utrecht) 29 61 25,196 4.1 (3.8 4.3) Bulkmans 24 (Amsterdam) 3 6 21,245 3.6 (3.3 3.9) Rijkaart 212 3 56 19,373 4. (3.7 4.2) Jacobs 2 (Amsterdam) 16 68 3,299 4.4 (3.8 5.2) Rozendaal 2 (Amsterdam) 34 54 2,25 5.4 (4.5 6.4) Lenselink 28 a,b 18 29 2,65 19. (17.4 2.8) Boers 214 3 6 9 3.8 (2.7 5.2) Hesselink 213 (Utrecht region) 31 6 858 8.2 (6.5 1.2) Zielinski 21 (Zeeland) 34 54 114 6.1 (3. 12.1) Norway Molden 25 (Oslo) 3 69 3,97 9.3 (8.4 1.2) Skjeldestad 28 a,c 16 24 896 25.9 (23.1 28.9) Molden 26 (Oslo) <=3 275 3.9 (25.7 36.6) Gjøoen 1996 (Oslo) 2 44 222 15.3 (11.2 2.6) Poland Bardin 28 (Warsaw) 18 59 799 14.4 (12.1 17.) Portugal Pista 211 18 64 2,172 16.5 (15. 18.1) Vieira 213 18 76 463 17.1 (13.9 2.8) Pista 211 d 18 67 425 25.4 (21.5 29.8) Dutra 28 (Açores) a 16 81 286 1.5 (7.4 14.6) Romania Moga 214 (Brasov County) 17 57 81 34.3 (31.1 37.7) Ursu 211 (Northeast) 2 61 164 25.6 (19.5 32.8) Russia Bdaizieva 21 (Moscow) a 15 69 33,112 25.7 (25.2 26.1) Kubanov 25 (Moscow) 8,533 15. (14.3 15.8) Goncharevskaya 211 (Moscow) 15 77 5,182 13.4 (12.5 14.4) Rogovskaya 213 e 16 76 833 25.9 (23.1 29.) Shipitsyna 211 (St Petersburg) 3 65 741 9.9 (7.9 12.2) Komarova 21 (Moscow) 16 76 352 48.3 (43.1 53.5) Alexandrova 1999 f 15 45 39 29.1 (24.3 34.4) Shargorodskaya 211 (Moscow) 18 3 266 28.2 (23.1 33.9) Shipulina 211 (Moscow) 13 19 177 4.1 (33.2 47.5) Slovenia Ucakar 212 2 64 4,199 1.7 (9.8 11.7) Ucakar 214 2 64 944 8.8 (7.1 1.8) Spain Castellsagué 212 18 65 3,59 13. (11.9 14.2) Martorell 21 (Valencia) a 18 64 1,956 13. (11.6 14.5) Bernal 28 (Zaragoza) 1,2 17.5 (15.5 19.8) Dillner 28 (Maresme) 14 82 939 7.3 (5.8 9.2) % 1% 2% 3% 4% 5% 6% (Continued on next page) Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. a Women from the general population, including some with cytological cervical abnormalities (Continued on next page)

4 HPV-RELATED STATISTICS - 97 - b Arnhem, Nijmegen, and Den Bosch c Oslo, Trondheim, and Levanger d Lisbon area and southern region e Moscow and Novgorod f St. Petersburg Data sources: See references in Section 9. ( Figure 98 continued from previous page)

4 HPV-RELATED STATISTICS - 98 - Figure 99: Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued) Country Study Age N % (95% CI) Spain Lloveras 213 (Barcelona) 23 89 898 14.7 (12.5 17.2) de Sanjose 23 (Barcelona) 14 75 847 1.3 (.7 2.3) Ortiz 26 (Madrid and Alicante) a 14 67 818 1.8 (8.8 13.1) González 26 (Alicante) 73 7.8 (6.1 1.) Muñoz 1996 b 18 75 329 5.2 (3.3 8.1) Sweden Naucler 27 c 29 46 5,877 5.5 (4.9 6.1) Elfström 214 c 23 4 5,584 8.1 (7.4 8.8) Gyllensten 212 (Uppsala County) a 55 76 2,16 6.2 (5.2 7.3) Ylitalo 2 (Uppsala) 15 49 617 5.8 (4.2 8.) Kjellberg 1998 d 2 63 295 4.1 (2.3 7.) Stenvall 27 (Uppsala) a 35 5 117 25.6 (18.6 34.2) Switzerland Bigras 25 e 17 93 13,349 6.3 (5.9 6.7) UK Kitchener 26 (Manchester) 2 64 21,38 1.4 (1. 1.8) Hibbitts 214 (Wales) 2 22 1,89 2.6 (19.9 21.4) Cuzick 23 f 3 6 9,79 5.5 (5.1 6.) Hibbitts 28 (South Wales) 2 65 8,434 7. (6.5 7.6) Peto 24 (Manchester) 15 64 6,128 7.2 (6.6 7.9) Kavanagh 214 (Scotland) a 2 21 4,679 58.3 (56.9 59.7) Cuschieri 24 (Edinburgh) 16 78 3,89 12.7 (11.6 13.9) Cuzick 1999 (London) 34 7 2,855 3.3 (2.7 4.) Howell Jones 21 g 25 64 2,44 1.2 (9. 11.5) Cuzick 1995 (London) 17 59 1,818 3.5 (2.8 4.5) Geraets 214 (Scotland) a 2 68 998 16.9 (14.7 19.4) Herbert 27 (London) 2 49 813 12.9 (1.8 15.4) Grainge 25 (Nottingham) 21 51 656 13.6 (11.2 16.4) % 1% 2% 3% 4% 5% 6% Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. a Women from the general population, including some with cytological cervical abnormalities b Alava, Girona, Guipuzcoa, Murcia, Navarra, Salamanca, Sevilla, Vizcaya, Zaragoza c Gothenburg, Malmö, Uppsala, Umeå, and Stockholm d Västerbotten County e Geneve, Vaud, Neuchatel, Fribourg, Valais and Tessin f Birmingham, Edinburg, London, Manchester and Mansfield g Gateshead, Birmingham, London, Gloucestershire and Norfolk Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 99-4.1.2 HPV type distribution among women with normal cervical cytology, precancerous cervical lesions and cervical cancer Table 13: Prevalence of HPV 16/18 in women with normal cytology, precancerous cervical lesions and invasive cervical cancer in Europe Normal cytology Low-grade lesions High-grade lesions Cervical cancer Country /Region No. HPV Prev No. HPV Prev No. HPV Prev No. HPV Prev tested (95% CI) tested (95% CI) tested (95% CI) tested (95% CI) Europe 232,291 3.8 (3.7-3.9) 19,41 27.1 (26.5-27.7) 21,14 54.5 (53.8-55.2) 18,46 74. (73.4-74.6) Eastern Europe 7,818 9.7 (9.1-1.4) 1,58 31.8 (29.-34.6) 661 6.5 (56.7-64.2) 1,677 84.7 (82.9-86.3) Belarus 322 7.1 (4.8-1.5) 94 35.1 (26.2-45.2) 91 56. (45.8-65.8) 26 65.4 (46.2-8.6) Bulgaria - - - - - - - - - 127 8.3 (72.6-86.3) Czech Rep. 1,32 6.6 (5.4-8.1) 676 33.7 (3.3-37.4) 311 63.3 (57.9-68.5) 27 79.3 (74.-83.7) Hungary - - - - - - 75 61.3 (5.-71.5) 38 94.7 (82.7-98.5) Moldova - - - - - - - - - - - - Poland 799 3.4 (2.3-4.9) - - - - - - 1,1 88.1 (86.-9.) Romania 81 1.1 (8.2-12.4) 194 16. (11.5-21.8) 93 48.4 (38.5-58.4) - - - Russia 2,14 9.4 (8.2-1.7) 94 35.1 (26.2-45.2) 91 56. (45.8-65.8) 26 73.8 (67.4-79.3) Slovakia - - - - - - - - - - - - Ukraine - - - - - - - - - - - - Northern Europe 119,652 4.5 (4.4-4.6) 4,949 3.6 (29.3-31.9) 8,448 54.9 (53.8-56.) 5,921 77. (75.9-78.1) Denmark 54,382 6.2 (6.-6.4) 414 27.1 (23.-31.5) 2,46 57.4 (55.4-59.3) 348 74.1 (69.3-78.5) Estonia - - - - - - - - - - - - Finland - - - - - - - - - 46 88.5 (85.2-91.1) Iceland - - - - - - 441 59. (54.3-63.5) 14 72.1 (64.2-78.9) Ireland 5,647 4.3 (3.8-4.9) 14 42.3 (33.3-51.9) 353 78.8 (74.2-82.7) 97 74.2 (64.7-81.9) Latvia - - - 94 35.1 (26.2-45.2) 91 56. (45.8-65.8) 247 7. (64.1-75.4) Lithuania 69 6.1 (4.4-8.3) 15 6.7 (1.2-29.8) 186 53.2 (46.1-6.3) 266 62.8 (56.8-68.4) Norway 4,192 2.4 (2.-2.9) 6 13.3 (6.9-24.2) 1,67 38.7 (36.4-41.1) 45 78.2 (74.2-81.8) Sweden 12,373 2.5 (2.2-2.8) 1,494 32.9 (3.6-35.4) 383 48. (43.1-53.) 773 7.5 (67.2-73.6) UK 42,449 3.2 (3.-3.4) 2,768 29.6 (27.9-31.3) 2,927 58.6 (56.8-6.4) 3,14 79. (77.6-8.4) Southern Europe 5,59 3.2 (3.-3.4) 1,519 25.4 (24.6-26.2) 5,866 53.2 (51.9-54.5) 4,37 68. (66.5-69.4) Albania - - - - - - - - - - - - Andorra - - - - - - - - - - - - Bosnia & H. - - - - - - - - - 297 68. (62.5-73.1) Croatia 25 18. (13.4-23.9) 1,271 13.5 (11.8-15.5) 941 2.6 (18.2-23.3) 117 82.9 (75.1-88.7) Cyprus - - - - - - - - - - - - Greece 1,289 2.9 (2.6-3.2) 1,983 21.7 (19.9-23.6) 368 55.4 (5.3-6.4) 331 52.3 (46.9-57.6) Italy 29,538 3.3 (3.1-3.5) 4,638 29.2 (27.9-3.5) 2,553 64.6 (62.7-66.4) 1,372 72.2 (69.8-74.5) Macedonia - - - - - - - - - - - - Malta - - - - - - - - - - - - Montenegro - - - - - - - - - - - - Portugal 425 5.6 (3.8-8.3) 444 45.3 (4.7-49.9) 875 56.3 (53.-59.6) 168 81.5 (75.-86.7) San Marino - - - - - - - - - - - - Serbia - - - - - - - - - - - - Slovenia 4,199 3.4 (2.9-4.) - - - 261 67. (61.1-72.5) 264 77.7 (72.3-82.3) Spain 5,43 2.7 (2.3-3.2) 2,183 23.7 (21.9-25.5) 868 46.3 (43.-49.6) 1,488 63.1 (6.6-65.5) Western Europe 57,216 2.6 (2.5-2.7) 2,875 25.2 (23.7-26.8) 3,62 59.4 (57.7-61.1) 3,28 78.7 (77.2-8.1) Austria - - - - - - 24 6.3 (53.4-66.8) 2 78.5 (72.3-83.6) Belgium 14,556 3.5 (3.2-3.8) 1,25 26.4 (24.-29.) 463 51.8 (47.3-56.4) 111 81.1 (72.8-87.3) France 4,764 4.7 (4.1-5.3) 639 26.3 (23.-29.8) 688 6.6 (56.9-64.2) 1,434 75.6 (73.3-77.7) Germany 1,988 3.2 (2.9-3.5) 688 21.2 (18.3-24.4) 819 5.5 (47.1-54.) 68 76.5 (65.1-85.) Liechtenstein - - - - - - - - - - - - Luxembourg - - - - - - - - - 58 89.7 (79.2-95.2) Monaco - - - - - - - - - - - - Netherlands 26,98 1.5 (1.4-1.7) 27 22.7 (17.5-28.9) 855 7.2 (67.-73.1) 1,157 82.1 (79.8-84.2) Switzerland - - - 136 3.9 (23.7-39.1) 33 75.8 (59.-87.2) - - - Data updated on 19 May 217 (data as of 3 Jun 215 / 3 Jun 215). 95% CI: 95% Confidence Interval; High-grade lesions: CIN-2, CIN-3, CIS or HSIL; Low-grade lesions: LSIL or CIN-1; Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 1 - Figure 1: Prevalence of HPV 16 among women with normal cervical cytology in Europe by country and study Country Study N % (95% CI) Belarus Rogovskaya 213 322 7.1 (4.8 1.5) Belgium Arbyn 29 8,729 2.3 (2.1 2.7) Baay 25 2,293 2.1 (1.6 2.8) Depuydt 212 1,142 1.4 (.9 2.3) Schmitt 213 913 5.6 (4.3 7.3) Weyn 213 96 2.1 (1.3 3.3) Depuydt 23 287 4.2 (2.4 7.2) Baay 21 286 2.8 (1.4 5.4) Croatia Grahovac 27 25 15.6 (11.3 21.2) Czech Rep. Tachezy 213 1,32 4.8 (3.8 6.1) Denmark Kjær 214 37,958 4.2 (4. 4.4) Nielsen 28 11,663 4. (3.6 4.3) Bonde 214 4,642 5.4 (4.8 6.1) Svare 1998 119 8.4 (4.6 14.8) France Heard 213 3,23 3. (2.5 3.7) Vaucel 211 98 3.6 (2.6 4.9) Casalegno 211 32 1.6 (7.6 14.6) Pannier Stockman 28 289 9.3 (6.5 13.3) Beby Defaux 24 17 1.8 (.6 5.1) Germany Klug 27 7,833 1.1 (.9 1.4) Iftner 21 1,692 6.6 (5.5 7.8) de Jonge 213 1,463 4.9 (3.9 6.2) Greece Agorastos 215 3,783 2.1 (1.7 2.6) Argyri 213 2,218 2.6 (2. 3.4) Tsiodras 211 1,348 4. (3.1 5.2) Agorastos 24 1,272.4 (.2.9) Tsiodras 21 1,29. (..4) Panotopoulou 27 639.5 (.2 1.4) Ireland Anderson 213 5,68 3.2 (2.7 3.7) Keegan 27 579 1.7 (.9 3.1) Italy Carozzi 214 13,66 1.8 (1.6 2.1) Agarossi 29 9,148 3. (2.7 3.4) Giorgi Rossi 211 3,151 2.1 (1.7 2.7) Ronco 25 997 2.7 (1.9 3.9) Panatto 213 566 2.8 (1.7 4.5) Centurioni 25 5 8.8 (6.6 11.6) Salfa 211 452.9 (.3 2.3) Barzon 21 333 6. (3.9 9.1) Sammarco 213 244 6.6 (4.1 1.4) Astori 1997 197 5.1 (2.8 9.1) % 1% 2% 3% (Continued on next page) Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 11 - Figure 11: Prevalence of HPV 16 among women with normal cervical cytology in Europe by country and study (continued) Country Study N % (95% CI) Italy Tornesello 26 183 8.7 (5.5 13.7) Tornesello 28 17 2.8 (1. 7.9) Lithuania Gudleviciene 25 332 6.9 (4.7 1.2) Simanaviciene 214 277 4.3 (2.5 7.4) Netherlands Bulkmans 27 21,245 1. (.9 1.1) Jacobs 2 3,299.9 (.7 1.3) Rozendaal 2 2,25 2.7 (2.1 3.4) Zielinski 21 114 1.8 (.5 6.2) Norway Molden 25 3,97 1.3 (1. 1.7) Gjøoen 1996 222 6.3 (3.8 1.3) Poland Bardin 28 799 2.8 (1.8 4.1) Portugal Pista 211 425 5.2 (3.4 7.7) Romania Moga 214 81 7.5 (5.9 9.5) Russia Rogovskaya 213 833 7.1 (5.5 9.) Shipitsyna 211 741 2.7 (1.8 4.1) Alexandrova 1999 39 7.4 (5. 1.9) Komarova 21 257 24.1 (19.3 29.7) Slovenia Ucakar 212 4,199 2.5 (2.1 3.) Spain Castellsagué 212 3,59 2.5 (2. 3.1) de Sanjose 23 847.4 (.1 1.) Dillner 28 721 3.1 (2. 4.6) González 26 447 1.3 (.6 2.9) Muñoz 1996 329 1.8 (.8 3.9) Sweden Naucler 27 5,877 1.7 (1.4 2.) Elfström 214 5,584 2. (1.6 2.3) Ylitalo 2 617 5.8 (4.2 8.) Kjellberg 1998 295 1. (.3 2.9) UK Sargent 28 21,364 1.5 (1.3 1.7) Hibbitts 214 1,89 4.3 (3.9 4.7) Cuschieri 24 3,89 4.4 (3.7 5.2) Cuzick 1999 2,855.1 (..3) Cuzick 1995 1,818 1.3 (.9 2.) Hibbitts 26 1,777 1.4 (.9 2.) Grainge 25 656 1.4 (.7 2.6) % 1% 2% 3% Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 12 - Figure 12: Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study Country Study N % (95% CI) Belarus Kulmala 27 94 35.1 (26.2 45.2) Belgium Depuydt 23 369 2.3 (16.5 24.7) Beerens 25 324 18.5 (14.7 23.1) Arbyn 29 243 23.5 (18.6 29.2) Weyn 213 211 1. (6.6 14.7) Baay 21 58 24.1 (15. 36.5) Croatia Grce 21 1,28 11.6 (9.8 13.7) Grce 1997 183 6. (3.4 1.4) Grce 24 6 8.3 (3.6 18.1) Czech Rep. Tachezy 211 676 28.4 (25.1 31.9) Denmark Kjær 214 287 17.1 (13.2 21.9) Kjaer 28 86 12.8 (7.3 21.5) Hording 1995 41 31.7 (19.6 47.) France Prétet 28 397 21.4 (17.7 25.7) Vaucel 211 117 14.5 (9.3 22.) Bergeron 1992 48 2.8 (11.7 34.3) Humbey 22 4 3. (18.1 45.4) Monsonego 28 37 5.4 (1.5 17.7) Germany de Jonge 213 441 17.5 (14.2 21.3) Meyer 21 13 13.1 (8.3 19.9) Klug 27 52 11.5 (5.4 23.) Nindl 1999 49 12.2 (5.7 24.2) Merkelbach Bruse 1999 16 68.8 (44.4 85.8) Greece Argyri 213 821 14.5 (12.3 17.1) Panotopoulou 27 516 6.8 (4.9 9.3) Tsiodras 211 314 17.8 (14. 22.4) Kroupis 27 235 23.4 (18.4 29.2) Labropoulou 1997 51 11.8 (5.5 23.4) Mammas 28 46 21.7 (12.3 35.6) Ireland Keegan 214 49 4.8 (28.2 54.8) Murphy 23 29 72.4 (54.3 85.3) Butler 2 26. (. 12.9) Italy Voglino 2 1,499 24.7 (22.6 27.) Spinillo 214 1,24 25.6 (23.2 28.1) Chironna 21 385 13. (1. 16.7) Agarossi 29 383 19.8 (16.2 24.1) Spinillo 29 343 36.7 (31.8 42.) Capra 28 149 11.4 (7.2 17.5) Astori 1997 111 24.3 (17.3 33.1) Tornesello 26 11 36.6 (27.9 46.4) % 1% 2% 3% 4% 5% 6% 7% 8% 9% (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; Low-grade lesions: LSIL or CIN-1; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 13 - Figure 13: Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study (continued) Country Study N % (95% CI) Italy Agodi 29 96 32.3 (23.8 42.2) Gargiulo 27 83 15.7 (9.4 25.) Giorgi Rossi 21 76 21.1 (13.4 31.5) Sandri 29 47 21.3 (12. 34.9) Zerbini 21 43 14. (6.6 27.3) Venturoli 22 4 7.5 (2.6 19.9) Laconi 2 2 3. (14.5 51.9) Menegazzi 29 12 16.7 (4.7 44.8) Venturoli 28 1 2. (5.7 51.) Latvia Kulmala 27 94 35.1 (26.2 45.2) Lithuania Gudleviciene 25 15 6.7 (1.2 29.8) Netherlands Bollen 1997 134 12.7 (8.1 19.4) Prinsen 27 38 7.9 (2.7 2.8) Reesink Peters 21 35 28.6 (16.3 45.1) Norway Roberts 26 4 5. (1.4 16.5) Molden 25 2 25. (11.2 46.9) Portugal Medeiros 25 416 44.2 (39.5 49.) Nobre 21 28 1.7 (3.7 27.2) Romania Ursu 211 17 5.6 (2.6 11.7) Anton 211 87 11.5 (6.4 19.9) Russia Kulmala 27 94 35.1 (26.2 45.2) Spain de Oña 21 1,356 12.2 (1.6 14.1) Martín 211 387 24.8 (2.8 29.3) Herraez Hernandez 213 236 39.8 (33.8 46.2) García Sierra 29 18 17.6 (11.6 25.8) Conesa Zamora 29 75 29.3 (2.2 4.4) Doménech Peris 21 21 23.8 (1.6 45.1) Sweden Söderlund Strand 211 1,35 24.2 (21.6 26.9) Brismar Wendel 29 223 2.6 (15.8 26.4) Kalantari 1997 141 17.7 (12.3 24.9) Andersson 25 5 2. (11.2 33.) Zehbe 1996 45 4. (27. 54.5) Switzerland Dobec 211 136 25. (18.5 32.9) UK Sargent 28 878 17.3 (15. 2.) Howell Jones 21 697 2.5 (17.7 23.7) Anderson 213 417 24. (2.1 28.3) Cuschieri 24 243 28. (22.7 33.9) Hibbitts 28 126 27.8 (2.7 36.2) Giannoudis 1999 118 12.7 (7.9 19.9) Jamison 29 97 27.8 (19.9 37.5) % 1% 2% 3% 4% 5% 6% (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; Low-grade lesions: LSIL or CIN-1; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 14 - Figure 14: Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study (continued) Country Study N % (95% CI) UK Woo 21 6 41.7 (3.1 54.3) Cuzick 1999 5 12. (5.6 23.8) Southern 21 49 1.2 (4.4 21.8) Arends 1993 2 15. (5.2 36.) Cuzick 1994 13 23.1 (8.2 5.3) % 1% 2% 3% 4% 5% 6% Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; Low-grade lesions: LSIL or CIN-1; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 15 - Figure 15: Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study Country Study N % (95% CI) Austria Rössler 213 24 55.9 (49. 62.5) Belarus Kulmala 27 91 56. (45.8 65.8) Belgium Depuydt 23 134 5. (41.7 58.3) Beerens 25 123 43.1 (34.7 51.9) Arbyn 29 19 34.9 (26.6 44.2) Baay 21 97 56.7 (46.8 66.1) Croatia Grce 21 783 17.1 (14.6 19.9) Grce 24 158 2.3 (14.7 27.2) Czech Rep. Tachezy 211 311 58.2 (52.7 63.5) Denmark Kjær 214 1,156 52.1 (49.2 54.9) Thomsen 215 732 35.8 (32.4 39.3) Kirschner 213 225 46.2 (39.8 52.7) Kjaer 28 177 48. (4.8 55.3) Bonde 214 16 34.9 (26.5 44.4) Sebbelov 1994 34 85.3 (69.9 93.6) Hording 1995 3 5. (33.2 66.8) Europe Tjalma 213 3,13 47.2 (45.5 49.) France Prétet 28 493 62.3 (57.9 66.4) Vaucel 211 141 42.6 (34.7 5.8) Monsonego 28 54 33.3 (22.2 46.6) Germany Meyer 21 288 46.2 (4.5 52.) de Jonge 213 247 34.4 (28.8 4.5) Merkelbach Bruse 1999 88 61.4 (5.9 7.9) Nindl 1997 85 36.5 (27. 47.1) Nindl 1999 65 56.9 (44.8 68.2) Klug 27 46 54.3 (4.2 67.8) Greece Argyri 213 78 37.2 (27.3 48.3) Panotopoulou 27 6 36.7 (25.6 49.3) Tsiodras 211 54 5. (37.1 62.9) Labropoulou 1997 5 36. (24.1 49.9) Agorastos 25 43 58.1 (43.3 71.6) Daponte 26 29 51.7 (34.4 68.6) Paraskevaidis 21 28 35.7 (2.7 54.2) Kroupis 27 26 5. (32.1 67.9) Hungary Szoke 23 75 57.3 (46.1 67.9) Iceland Sigurdsson 27 441 51.2 (46.6 55.9) Ireland Keegan 214 242 69.4 (63.4 74.9) Murphy 23 64 78.1 (66.6 86.5) Butler 2 27 7.4 (51.5 84.1) O'Leary 1998 2 95. (76.4 99.1) 1% 2% 3% 4% 5% 6% 7% 8% 9% 1% (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; High-grade lesions: CIN-2, CIN-3, CIS or HSIL; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 16 - Figure 16: Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study (continued) Country Study N % (95% CI) Italy Spinillo 214 1,344 48.4 (45.8 51.1) Carozzi 21 529 62.9 (58.8 67.) Carozzi 214 24 53.9 (47.1 6.6) Zerbini 21 89 5.6 (4.4 6.7) Sandri 29 76 73.7 (62.8 82.3) Agarossi 29 73 53.4 (42.1 64.4) Gargiulo 27 67 38.8 (28. 5.8) Tornesello 26 65 47.7 (36. 59.6) Venturoli 28 56 6.7 (47.6 72.4) Laconi 2 36 5. (34.5 65.5) Capra 28 14 42.9 (21.4 67.4) Latvia Kulmala 27 91 56. (45.8 65.8) Lithuania Simanaviciene 214 157 51.6 (43.8 59.3) Gudleviciene 25 29 48.3 (31.4 65.6) Netherlands Tang 29 253 7.8 (64.9 76.) Bulkmans 25 236 6.6 (54.2 66.6) Reesink Peters 21 216 56.9 (5.3 63.4) Cornelissen 1992 89 52.8 (42.5 62.8) Prinsen 27 41 51.2 (36.5 65.7) van Duin 23 2 65. (43.3 81.9) Norway Roberts 26 885 44.1 (4.8 47.4) Sjoeborg 21 63 2.6 (17.7 24.) Kraus 24 67 49.3 (37.7 6.9) Molden 25 25 28. (14.3 47.6) Portugal Pista 213 518 55.6 (51.3 59.8) Pista 211 191 27.7 (21.9 34.5) Medeiros 25 132 74.2 (66.2 8.9) Nobre 21 34 32.4 (19.1 49.2) Romania Anton 211 52 48.1 (35.1 61.3) Ursu 211 41 31.7 (19.6 47.) Russia Kulmala 27 91 56. (45.8 65.8) Slovenia Kovanda 29 261 62.5 (56.4 68.1) Spain de Oña 21 36 28.8 (24. 34.1) Bosch 1993 157 49. (41.3 56.8) Muñoz 1992 157 51. (43.2 58.7) Martín 211 82 48.8 (38.3 59.4) Herraez Hernandez 213 68 69.1 (57.4 78.8) Conesa Zamora 29 39 33.3 (2.6 49.) Darwich 211 34 61.8 (45. 76.1) García Sierra 29 25 36. (2.2 55.5) 1% 2% 3% 4% 5% 6% 7% 8% 9% (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; High-grade lesions: CIN-2, CIN-3, CIS or HSIL; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 17 - Figure 17: Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study (continued) Country Study N % (95% CI) Sweden Kalantari 1997 164 35.4 (28.5 42.9) Andersson 25 116 37.1 (28.8 46.1) Zehbe 1996 13 5.5 (41. 59.9) Switzerland Dobec 211 33 57.6 (4.8 72.8) UK Howell Jones 21 1,425 54.1 (51.5 56.7) Sargent 28 562 46.8 (42.7 5.9) Cuzick 214 354 31.1 (26.5 36.1) Geraets 214 99 43.4 (34.1 53.3) Cuschieri 24 94 48.9 (39.1 58.9) Hibbitts 28 93 4.9 (31.4 51.) Cuzick 1994 73 63. (51.5 73.2) Anderson 213 72 56.9 (45.4 67.7) Jamison 29 51 49. (35.9 62.3) Arends 1993 4 5. (35.2 64.8) Herrington 1995 38 57.9 (42.2 72.1) Southern 1998 26 61.5 (42.5 77.6) 2% 3% 4% 5% 6% 7% 8% Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; High-grade lesions: CIN-2, CIN-3, CIS or HSIL; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 18 - Figure 18: Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study Country Study N % (95% CI) Austria Bachtiary 22 16 65.1 (55.6 73.5) Widschwendter 23 94 75.5 (66. 83.1) Belarus Kulmala 27 26 65.4 (46.2 8.6) Belgium Baay 21 111 68.5 (59.3 76.4) Bulgaria Todorova 21 127 7.9 (62.4 78.1) Croatia Hadzisejdic 26 66 3.3 (2.6 42.2) Dabic 28 51 62.7 (49. 74.7) Czech Rep. Tachezy 211 172 73.3 (66.2 79.3) Slama 29 49 61.2 (47.2 73.6) Tachezy 1999 49 59.2 (45.2 71.8) Denmark Kirschner 213 245 6.8 (54.6 66.7) Hording 1997 5 18. (9.8 3.8) Sebbelov 2 34 7.6 (53.8 83.2) Kjær 214 19 57.9 (36.3 76.9) Europe Tjalma 213 2,881 55.9 (54.1 57.7) de Sanjose 21(a) 2,32 57.4 (55.4 59.4) Finland Iwasawa 1996 46 63.5 (59. 67.7) France Prétet 28 516 72.9 (68.9 76.5) de Cremoux 29 515 55.5 (51.2 59.8) Lombard 1998 297 5.5 (44.8 56.1) Riou 199 16 54.7 (45.2 63.9) Germany Milde Langosch 1995 51 51. (37.7 64.1) Bosch 1995 17 76.5 (52.7 9.4) Greece Panotopoulou 27 165 24.2 (18.3 31.3) Dokianakis 1999 75 2.7 (.7 9.2) Koffa 1994 39 35.9 (22.7 51.6) Labropoulou 1997 35 54.3 (38.2 69.5) Adamopoulou 29 17 47.1 (26.2 69.) Hungary Kónya 1995 38 63.2 (47.3 76.6) Iceland Sigurdsson 27 14 57.1 (48.9 65.) Ireland Skyldberg 1999 38 23.7 (13. 39.2) Butler 2 29 93.1 (78. 98.1) O'Leary 1998 2 8. (58.4 91.9) Fay 29 1 8. (49. 94.3) Italy Sideri 29 268 63.4 (57.5 69.) Carozzi 21 193 67.9 (61. 74.1) Spinillo 214 176 54.5 (47.2 61.7) Tornesello 211 171 58.5 (51. 65.6) Voglino 2 145 71. (63.2 77.8) Ciotti 26 12 57.8 (48.1 67.) 1 2 3 4 5 6 7 8 9 1 (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. a Includes cases from Bosnia-Herzegovina, Croatia, Czech Republic, France, Greece, Italy, Netherlands, Poland, Portugal, and Spain Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 19 - Figure 19: Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study (continued) Country Study N % (95% CI) Italy Tornesello 26 65 6. (47.9 71.) Del Mistro 26 4 75. (59.8 85.8) Garzetti 1998 32 5. (33.6 66.4) Gargiulo 27 31 61.3 (43.8 76.3) Rolla 29 18 66.7 (43.7 83.7) Latvia Silins 24 221 6.6 (54.1 66.8) Kulmala 27 26 65.4 (46.2 8.6) Lithuania Gudleviciene 25 191 56.5 (49.5 63.4) Simanaviciene 214 75 5.7 (39.6 61.7) Luxembourg Ressler 27 58 79.3 (67.2 87.7) Netherlands Tang 29 34 63.5 (58.3 68.5) Baay 1996 162 61.7 (54.1 68.9) Bulk 26 153 54.2 (46.3 61.9) Krul 1999 128 58.6 (49.9 66.8) Baalbergen 213 113 32.7 (24.8 41.8) De Boer 25 15 43.8 (34.7 53.4) Zielinski 23 77 32.5 (23.1 43.5) Van Den Brule 1991 5 84. (71.5 91.7) Resnick 199 29 75.9 (57.9 87.8) Norway Karlsen 1996 361 68.4 (63.5 73.) Bertelsen 26 89 52.8 (42.5 62.8) Poland Kwasniewska 29 57 58.4 (54.3 62.4) Baay 29 113 85.8 (78.2 91.1) Biesaga 212 85 8. (7.3 87.1) Bardin 28 84 75. (64.8 83.) Pirog 2 82 36.6 (27. 47.4) Dybikowska 22 53 47.2 (34.4 6.3) Bosch 1995 23 78.3 (58.1 9.3) Portugal Pista 213 64 7.3 (58.2 8.1) Medeiros 25 6 8. (68.2 88.2) Nobre 21 44 61.4 (46.6 74.3) Russia Kleter 1999 18 64.4 (57.2 71.1) Kulmala 27 26 65.4 (46.2 8.6) Slovenia Jancar 29 264 65.2 (59.2 7.6) Spain Muñoz 1992 159 54.1 (46.3 61.6) Martró 212 73 47.9 (36.9 59.2) Darwich 211 72 79.2 (68.4 86.9) Rodriguez 1998 54 61.1 (47.8 73.) Bosch 1995 46 54.3 (4.2 67.8) Mazarico 212 37 43.2 (28.7 59.1) 2 3 4 5 6 7 8 9 1 (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 11 - Figure 11: Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study (continued) Country Study N % (95% CI) Spain González Bosquet 28 21 52.4 (32.4 71.7) Herraez Hernandez 213 14 78.6 (52.4 92.4) Sweden Du 211 154 58.4 (5.5 65.9) Andersson 21 131 23.7 (17.2 31.6) Graflund 24 11 79.1 (7.6 85.6) Wallin 1999 14 47.1 (37.8 56.6) Andersson 23 82 34.1 (24.8 44.9) Hagmar 1992 71 38. (27.6 49.7) Andersson 25 45 66.7 (52.1 78.6) Skyldberg 1999 38 23.7 (13. 39.2) Zehbe 1997 38 63.2 (47.3 76.6) UK Mesher 215 1,235 63. (6.3 65.6) Howell Jones 21 555 62.5 (58.4 66.5) Cuschieri 214 37 55.9 (5.9 6.9) Cuschieri 21 363 56.5 (51.3 61.5) Powell 29 269 67.7 (61.9 73.) Tawfik El Mansi 26 119 46.2 (37.5 55.2) Cuzick 2 116 65.5 (56.5 73.5) Arends 1993 47 53.2 (39.2 66.7) Giannoudis 1999 43 81.4 (67.4 9.3) Crook 1992 23 73.9 (53.5 87.5) 1 2 3 4 5 6 7 8 9 1 Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 111 - Figure 111: Comparison of the ten most frequent HPV oncogenic types among women with and without cervical lesions in Europe and its regions Europe Eastern Europe Northern Europe Normal cytology HPV type 16 31 53 51 7 52 66 18 39 56 2.8 1.6 1.6 1.4 1.4 1.4 1.1 1..9.9 16 31 39 56 52 18 33 45 51 53 8. 4.2 2.5 2. 1.9 1.7 1.7 1.7 1.3 1.2 16 52 31 53 51 66 7 18 39 82 3.2 2.1 2. 1.8 1.8 1.5 1.5 1.3 1.2 1.2 Low grade lesions HPV type 16 51 31 53 66 52 56 18 39 58 2.7 1. 9.9 8.7 7.7 7.6 6.6 6.4 5.2 4.8 16 33 18 31 45 58 51 56 35 66 6.1 5.9 5.5 4.1 3.9 3.6 3.1 2.5 2.1 25.9 16 51 31 53 18 66 56 52 39 33 21.9 1.6 1.5 9.6 8.7 8.7 8.2 7.3 7. 6.2 High grade lesions HPV type 16 31 33 52 18 51 58 53 45 39 12.4 8.8 8.5 7.1 5.8 4.5 4.1 3.5 3.4 47.4 16 33 31 18 58 45 56 52 51 39 1.4 9.2 5.4 3.5 3.3 2.6 2.6 2.5 1.9 55.1 16 31 33 52 18 51 45 58 39 66 14.3 1.5 1. 8.5 6.6 5. 5. 4.8 3.6 46.4 Cervical Cancer HPV type 16 18 33 45 31 52 35 39 58 73 15.2 4.4 4.3 3.8 1.9 1.4 1.2 1.2.9 58.8 16 18 45 31 33 58 56 52 39 73 7.4 3.7 3.3 1.8 1.7 1.5.9.9 2.1 64.6 16 18 45 33 31 52 35 39 59 68 4.4 4.2 3.6 1.9 1.5 1.3.9.9 17.6 59.4 2 4 6 Prevalence (%) 2 4 6 Prevalence (%) 2 4 6 Prevalence (%) Data updated on 19 May 217 (data as of 3 Jun 215). High-grade lesions: CIN-2, CIN-3, CIS or HSIL; Low-grade lesions: LSIL or CIN-1; The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 112 - Figure 112: Comparison of the ten most frequent HPV oncogenic types among women with and without cervical lesions in Europe and its regions (continued) Southern Europe Western Europe Normal cytology 16 31 53 7 66 51 18 52 56 39 2.4 1.1 1. 1..9.8.8.7.6.6 16 7 53 31 51 56 66 18 52 59 2. 1.5 1.4 1.1 1..6.6.6.6.5 Low grade lesions 16 31 51 52 53 66 56 18 58 33 2.1 1.1 9.7 9.1 8.3 6. 5.9 5.3 4.8 4.1 16 53 51 66 31 52 39 18 56 33 18.6 12.1 11.6 1.9 9.9 7.2 6.8 6.6 6.1 4.6 High grade lesions 16 31 52 18 51 33 53 58 39 45 13. 11.6 7.8 7.3 6.3 5.3 4.8 3.4 3.2 45.4 16 31 33 51 52 18 58 35 53 39 12.5 9.3 7. 6.5 6.4 4.8 4.1 3.8 3.4 53. Cervical Cancer 16 18 31 33 45 52 51 35 58 56 1.8 5.3 4.8 4. 2.6 2. 1.9 1.5 1.5 57.2 16 18 33 45 31 52 58 68 73 59 4.4 3.5 3.1 1.3 1.3 1.1 1.1.8 18.7 6. 2 4 6 Prevalence (%) 2 4 6 Prevalence (%) Data updated on 19 May 217 (data as of 3 Jun 215). High-grade lesions: CIN-2, CIN-3, CIS or HSIL; Low-grade lesions: LSIL or CIN-1; The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 113 - Figure 113: Comparison of the ten most frequent HPV oncogenic types among women with invasive cervical cancer by histology in Europe and its regions Europe Eastern Europe Northern Europe Any Histology HPV type 16 18 33 45 31 52 35 39 58 73 15.2 4.4 4.3 3.8 1.9 1.4 1.2 1.2.9 58.8 16 18 45 31 33 58 56 52 39 73 2.1 7.4 3.7 3.3 1.8 1.7 1.5.9.9 64.6 16 18 45 33 31 52 35 39 59 68 17.6 4.4 4.2 3.6 1.9 1.5 1.3.9.9 59.4 Squamous cell carcinoma HPV type 16 18 33 45 31 52 35 58 39 56 11.4 4.6 4. 4. 2.1 1.3 1.3 1.2 1.1 61.7 16 18 45 31 33 56 58 52 39 35 18.4 7.8 4.6 4.4 2.7 2. 1.6.7.5 66.9 16 18 33 45 31 52 39 58 68 59 13.9 4.5 4.2 3.9 2.1 1.4 1.1 1. 1. 64. Adenocarcinoma HPV type 16 18 45 31 33 51 52 39 35 82 6. 2.3 1.5 1.4 1. 1..5.2 38.4 35.3 18 16 45 52 31 33 35 8th 9th 1th 8.3 1.5 1.5.8.8 41.5 37.7 18 16 45 33 31 39 52 68 59 51 6.7 1.6 1.4 1.1.9.4.4.4 37.1 35. Unespecified HPV type 16 18 33 31 45 35 52 58 39 59 14.2 6.9 4.8 4.2 2.9 1.5 1.4 1.3.9 63.7 16 18 45 31 58 33 39 35 52 56 11.4 5.6 2.8 2.5 1.9 1.9 1.4 1.2.6 72.2 16 18 33 35 31 45 39 52 56 82 13.4 6.3 4.7 3.8 3.4 2.2 1.9.6.5 63.7 3 6 9 Prevalence (%) 3 6 9 Prevalence (%) 3 6 9 Prevalence (%) No data available. No more types than shown were tested or were positive. Data updated on 19 May 217 (data as of 3 Jun 215). The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 114 - Figure 114: Comparison of the ten most frequent HPV oncogenic types among women with invasive cervical cancer by histology in Europe and its regions (continued) Southern Europe Western Europe Any Histology 16 18 31 33 45 52 51 35 58 56 1.8 5.3 4.8 4. 2.6 2. 1.9 1.5 1.5 57.2 16 18 33 45 31 52 58 68 73 59 18.7 4.4 3.5 3.1 1.3 1.3 1.1 1.1.8 6. Squamous cell carcinoma 16 18 33 31 45 52 35 56 51 58 8. 4.9 4.5 3.8 2.7 1.9 1.8 1.7 1.5 57.4 16 18 31 33 45 52 58 68 39 35 12. 3.6 3.5 2.9 1.6 1.4 1.4.9.8 65.5 Adenocarcinoma 16 18 31 51 45 33 52 39 35 66 6.2 5.3 4. 3.3 3.1 2.2 1.2.9 25.6 47.7 18 16 45 31 39 35 58 52 33 51 5.9 1.1.7.7.5.5.2.2 45.6 37.3 Unespecified 16 18 31 33 45 35 58 52 56 51 12.9 8. 5.3 4.8 2.1 1.7 1.7 1.1 1.1 62.5 16 18 33 45 31 59 58 68 52 51 17.2 14.6 3.7 3.4 3.1 1.5.8.5.5 61.7 3 6 9 Prevalence (%) 3 6 9 Prevalence (%) No data available. No more types than shown were tested or were positive. Data updated on 19 May 217 (data as of 3 Jun 215). The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 115 - Table 14: Type-specific HPV prevalence in women with normal cervical cytology, precancerous cervical lesions and invasive cervical cancer in Europe Normal cytology Low-grade lesions High-grade lesions Cervical cancer HPV Type No. HPV Prev No. HPV Prev No. HPV Prev No. HPV Prev tested % (95% CI) tested % (95% CI) tested % (95% CI) tested % (95% CI) ONCOGENIC HPV TYPES High-risk HPV types 16 232,291 2.8 (2.7-2.9) 19,41 2.7 (2.1-21.2) 21,14 47.4 (46.8-48.1) 18,46 58.8 (58.1-59.5) 18 23,519 1. (1.-1.1) 18,972 6.4 (6.-6.7) 2,697 7.1 (6.7-7.4) 18,328 15.2 (14.7-15.7) 31 213,41 1.6 (1.5-1.6) 18,55 9.9 (9.5-1.3) 2,2 12.4 (11.9-12.9) 16,82 3.8 (3.6-4.2) 33 213,41.7 (.7-.8) 18,233 4.8 (4.5-5.1) 2,312 8.8 (8.4-9.2) 16,74 4.4 (4.1-4.8) 35 22,237.4 (.4-.4) 14,15 3.2 (3.-3.5) 17,923 3. (2.7-3.2) 15,13 1.4 (1.2-1.6) 39 2,452.9 (.9-1.) 12,984 5.2 (4.8-5.6) 17,575 3.4 (3.2-3.7) 13,552 1.2 (1.-1.3) 45 23,777.8 (.8-.9) 14,489 3.6 (3.3-3.9) 17,944 3.5 (3.3-3.8) 14,711 4.3 (4.-4.6) 51 22,329 1.4 (1.3-1.4) 11,648 1. (9.5-1.6) 17,14 5.8 (5.4-6.1) 13,589.9 (.8-1.1) 52 22,543 1.4 (1.3-1.4) 12,892 7.6 (7.2-8.1) 17,53 8.5 (8.1-8.9) 14,152 1.9 (1.7-2.1) 56 22,33.9 (.8-.9) 12,792 6.6 (6.2-7.) 17,595 2.5 (2.3-2.8) 13,31.9 (.8-1.1) 58 23,642.6 (.6-.7) 13,272 4.8 (4.4-5.2) 17,174 4.5 (4.2-4.8) 14,85 1.2 (1.-1.4) 59 198,931.6 (.6-.6) 11,34 4.2 (3.8-4.5) 15,866 1.5 (1.3-1.7) 13,153.7 (.6-.8) Probable/possible carcinogen 26 24,48.1 (.-.1) 4,439.3 (.2-.5) 5,18.3 (.2-.5) 5,751.1 (.-.2) 3 3,517.3 (.2-.5) 1,242.4 (.2-.9) 1,77. (.-.4) 2,986.2 (.1-.4) 34 11,28.1 (.1-.2) 2,45.1 (.-.4) 1,767.2 (.1-.5) 3,993.1 (.-.2) 53 95,588 1.6 (1.5-1.6) 9,586 8.7 (8.2-9.3) 1,426 4.1 (3.7-4.5) 8,175.7 (.6-1.) 66 145,3 1.1 (1.-1.2) 11,953 7.7 (7.2-8.1) 15,331 2.4 (2.2-2.7) 11,552.4 (.3-.5) 67 9,357.3 (.2-.4) 3,855 1.9 (1.6-2.4) 3,79.5 (.3-.8) 4,72.2 (.1-.3) 68 2,131.7 (.7-.7) 1,98 2.4 (2.2-2.7) 14,286 2.1 (1.8-2.3) 12,165.8 (.7-1.) 69 5,342. (.-.1) 3,812.3 (.1-.5) 3,73.2 (.1-.4) 4,472. (.-.1) 7 68,469 1.4 (1.3-1.5) 7,42 2.4 (2.1-2.8) 7,319 1.8 (1.5-2.1) 7,295.2 (.1-.3) 73 32,38.3 (.3-.4) 6,275 2.7 (2.4-3.2) 6,992 1.5 (1.3-1.8) 6,345.9 (.7-1.1) 82 33,125.5 (.4-.5) 6,338 1.3 (1.1-1.6) 6,972 1. (.8-1.3) 6,538.1 (.1-.3) 85 7,647. (.-.1) 1,56.1 (.-.5) 1,165.2 (.-.6) - - 97 1,479 3.6 (2.8-4.7) - - - - 37.3 (.-1.5) NON-ONCOGENIC HPV TYPES 6 134,117 1.3 (1.2-1.3) 12,72 7. (6.5-7.4) 1,473 3.4 (3.1-3.7) 8,735.7 (.6-.9) 11 124,29.4 (.3-.4) 12,119 3.2 (2.9-3.6) 9,537 1.3 (1.1-1.6) 8,579.5 (.4-.7) 32 5,128.2 (.1-.3) 549. (.-.7) - - 6. (.-.6) 4 72,726.2 (.2-.3) 2,49 1.9 (1.4-2.5) 2,841.5 (.3-.8) 4,728. (.-.1) 42 72,818.8 (.8-.9) 2,49 11.7 (1.5-13.) 2,175 3. (2.4-3.8) 4,797.2 (.1-.4) 43 7,263.3 (.2-.3) 2,334 2. (1.5-2.6) 2,464.6 (.4-1.) 4,2. (.-.1) 44 75,996.9 (.8-1.) 3,289 8.8 (7.8-9.8) 3,32 4.2 (3.6-5.) 4,63.3 (.2-.5) 54 66,578.8 (.7-.8) 1,121 2.3 (1.6-3.4) 2,382.8 (.5-1.2) 5,136.4 (.3-.6) 55 - - - - - - - - 57 14,231. (.-.1) 549. (.-.7) 829. (.-.5) 928. (.-.4) 61 19,13 1.2 (1.1-1.4) 941 1.2 (.7-2.1) 1,18 1.4 (.8-2.2) 3,96.1 (.-.3) 62 13,433 1.2 (1.-1.4) 941 1.2 (.7-2.1) 1,18 1.7 (1.1-2.6) 1,128.3 (.1-.8) 64 - - - - - - - - 71 16,187.1 (.-.1) 834.8 (.4-1.7) 1,18. (.-.3) 1,541. (.-.2) 72 17,393.2 (.1-.2) 834.4 (.1-1.1) 1,18.3 (.1-.9) 1,356. (.-.3) 74 48,27 1. (.9-1.1) 836 1.3 (.7-2.3) 2,31.9 (.6-1.5) 3,522.1 (.-.2) 81 17,818.7 (.6-.9) 834 1.4 (.8-2.5) 1,18 1.1 (.6-1.9) 1,44.1 (.-.5) 83 2,877.7 (.6-.8) 598.3 (.1-1.2) 1,112.3 (.1-.8) 1,273. (.-.3) 84 21,454.5 (.5-.6) 941 1.4 (.8-2.3) 1,18.3 (.1-.7) 1,128.4 (.1-.9) 86 2,611.1 (.-.3) - - - - - - 87 1,812.4 (.2-.9) 549. (.-.7) - - - - 89 16,997.2 (.1-.3) 785 1.7 (1.-2.8) 897.3 (.1-1.) 1,287.1 (.-.4) 9 3,347.9 (.6-1.2) 549. (.-.7) - - 42. (.-.9) 91 1,246.5 (.2-1.) 549. (.-.7) - - 2,722. (.-.2) Data updated on 19 May 217 (data as of 3 Jun 215 / 3 Jun 215). 95% CI: 95% Confidence Interval; High-grade lesions: CIN-2, CIN-3, CIS or HSIL; Low-grade lesions: LSIL or CIN-1; The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 116 - Table 15: Type-specific HPV prevalence among invasive cervical cancer cases in Europe by histology Any Histology Squamous cell carcinoma Adenocarcinoma Unespecified HPV Type No. HPV Prev No. HPV Prev No. HPV Prev No. HPV Prev tested % (95% CI) tested % (95% CI) tested % (95% CI) tested % (95% CI) ONCOGENIC HPV TYPES High-risk HPV types 16 18,46 58.8 (58.1-59.5) 13,161 61.7 (6.9-62.6) 2,57 38.4 (36.6-4.3) 2,815 63.7 (61.9-65.4) 18 18,328 15.2 (14.7-15.7) 13,161 11.4 (1.9-12.) 2,57 35.3 (33.5-37.2) 2,737 14.2 (12.9-15.5) 31 16,82 3.8 (3.6-4.2) 11,877 4. (3.6-4.3) 2,123 2.3 (1.7-3.) 2,222 4.8 (4.-5.7) 33 16,74 4.4 (4.1-4.8) 12,419 4.6 (4.3-5.) 2,242 1.5 (1.1-2.1) 2,183 6.9 (5.9-8.1) 35 15,13 1.4 (1.2-1.6) 11,517 1.3 (1.1-1.5) 1,882.5 (.3-.9) 1,754 2.9 (2.2-3.8) 39 13,552 1.2 (1.-1.3) 1,831 1.2 (1.-1.4) 1,812 1. (.6-1.6) 1,49 1.3 (.8-2.2) 45 14,711 4.3 (4.-4.6) 11,195 4. (3.7-4.4) 2,47 6. (5.-7.1) 1,69 4.2 (3.3-5.3) 51 13,589.9 (.8-1.1) 1,731.8 (.7-1.) 1,832 1.4 (.9-2.) 1,166.7 (.3-1.3) 52 14,152 1.9 (1.7-2.1) 11,38 2.1 (1.8-2.3) 1,926 1. (.7-1.6) 1,328 1.5 (1.-2.3) 56 13,31.9 (.8-1.1) 1,426 1.1 (.9-1.3) 1,721.1 (.-.4) 1,294.8 (.4-1.4) 58 14,85 1.2 (1.-1.4) 11,126 1.3 (1.1-1.5) 1,754.2 (.1-.6) 1,345 1.4 (.9-2.2) 59 13,153.7 (.6-.8) 1,398.8 (.6-.9) 1,779.2 (.1-.5) 1,116.9 (.5-1.6) Probable/possible carcinogen 26 5,751.1 (.-.2) - - - - - - 3 2,986.2 (.1-.4) 2,494.2 (.1-.5) 26. (.-1.5) 232. (.-1.6) 34 3,993.1 (.-.2) 3,212.1 (.-.3) 41. (.-.9) 38. (.-1.) 53 8,175.7 (.6-1.) - - - - - - 66 11,552.4 (.3-.5) 9,141.4 (.3-.6) 1,563.1 (.-.5) 848.5 (.2-1.2) 67 4,72.2 (.1-.3) 3,893.2 (.1-.3) 52. (.-.8) 37.7 (.2-2.3) 68 12,165.8 (.7-1.) 9,762 1. (.8-1.2) 1,488.1 (.-.4) 915.5 (.2-1.3) 69 4,472. (.-.1) - - - - - - 7 7,295.2 (.1-.3) - - - - - - 73 6,345.9 (.7-1.1) - - - - - - 82 6,538.1 (.1-.3) 5,128.1 (.-.2) 647.2 (.-.9) 763.4 (.1-1.1) 97 37.3 (.-1.5) 37.3 (.-1.5) - - - - NON-ONCOGENIC HPV TYPES 6 8,735.7 (.6-.9) - - - - - - 11 8,579.5 (.4-.7) - - - - - - 32 6. (.-.6) - - - - - - 4 4,728. (.-.1) - - - - - - 42 4,797.2 (.1-.4) 4,61.1 (.1-.3) 377. (.-1.) 359 1.1 (.4-2.8) 43 4,2. (.-.1) - - - - - - 44 4,63.3 (.2-.5) 3,858.3 (.2-.5) 423.5 (.1-1.7) 322.6 (.2-2.2) 54 5,136.4 (.3-.6) - - - - - - 55 - - - - - - - - 57 928. (.-.4) - - - - - - 61 3,96.1 (.-.3) - - - - - - 62 1,128.3 (.1-.8) - - - - - - 64 - - - - - - - - 71 1,541. (.-.2) - - - - - - 72 1,356. (.-.3) - - - - - - 74 3,522.1 (.-.2) - - - - - - 81 1,44.1 (.-.5) - - - - - - 83 1,273. (.-.3) - - - - - - 84 1,128.4 (.1-.9) - - - - - - 89 1,287.1 (.-.4) - - - - - - 9 42. (.-.9) - - - - - - 91 2,722. (.-.2) - - - - - - Data updated on 19 May 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 117-4.1.3 HPV type distribution among HIV+ women with normal cervical cytology Table 16: European studies on HPV prevalence among HIV women with normal cytology HPV detection method and targeted HPV prevalence Country Study HPV types No. Tested % (95% CI) Denmark Melbye 1996 PCR-L1, TS (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52) 52 46.2 (32.2-6.5) Germany Kuhler-Obbarius 1994 PCR-MY11/MY9, No genotyping 34 52.9 (35.1-7.2) Germany Weissenborn 23 PCR-GP5+/GP6+, TS (HPV 16, 18, 31, 33, 45, 56) Italy Ammatuna 2 PCR- (MY9/MY11, GP5/GP6), No genotyping Italy Cappiello 1997 PCR-MY9/MY11, RFLP, (HPV 6, 11,16, 18, 26, 3-35, 39, 4, 42, 44, 45, 51-59, 61, 62, 64, 66-73, 77, 81-84) Italy Del mistro 21 PCR-MY9/MY11, RFLP, (HPV 6, 11, 16, 18, 26, 3-35, 39, 4, 42, 44, 45, 51-59, 61, 62, 64, 66-73, 77, 81-84) Italy Tanzi 29 PCR-MY9/MY11, RFLP, (HPV 6, 11, 16, 18, 26, 3-35, 39, 4, 42, 44, 45, 51-59, 61, 62, 64, 66-73, 77, 81-84) Italy Branca 2 PCR-MY9/MY11, RFLP,(HPV 6, 11, 16, 18, 26, 3-35, 39, 4, 42, 44, 45, 51-59, 61, 62, 64, 66-73, 77, 81-84) Italy Uberti-Foppa 1998 HC2 (HPV 6, 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 68), No genotyping Italy Tornesello 28 PCR-(GP5+/GP6+, MY9/MY11), sequencing (DSA) Netherlands Jong 28 PCR-SPF1, RHA, (HPV 6, 11, 16, 18, 31, 33-35, 39, 4, 42-45, 51-54, 56, 58, 59, 66, 68, 7, 71, 74) 212 57.5 (5.6-64.3) 51 33.3 (2.8-47.9) 86 2.9 (12.9-31.) 72 23.6 (14.4-35.1) 13 39.8 (3.3-49.9) 155 22.6 (16.3-3.) 111 51.4 (41.7-61.) 79 2.3 (12.-3.8) 19 36.8 (16.3-61.6) Netherlands Van Doornum 1993 PCR-,TS (HPV 6/11, 16, 18, 33), DBH 25 32. (14.9-53.5) Spain Cañadas 21 PCR (E6/E7), TS, (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) Spain Gonzalez 28 PCR (E6/E7), HC2, TS, (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) Spain De Sanjose 2 PCR (MY9/11),EIA, DBH, (HPV6, 11, 16, 18, 31, 33, 35, 39, 4, 41, 45, 51, 52, 53, 54, 56, 58, 59, 66, 73, 81) United Kingdom Cubie 2 HC2 (HPV 6, 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 68), No genotyping 168 38.7 (31.3-46.5) 7 42.9 (9.9-81.6) 52 34.6 (22.-49.1) 44 25. (13.2-4.3) Data updated on 31 Jul 213 (data as of 31 Dec 211). Only for European countries. 95% CI: 95% Confidence Interval; DBH: Dot Blot Hybridization; EIA: Enzyme ImmunoAssay; HC2: Hybrid Capture 2; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; RHA: Reverse Hybridization Assay; SPF: Short Primer Fragment; TS: Type Specific; Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 118-4.1.4 Terminology Cytologically normal women No abnormal cells are observed on the surface of their cervix upon cytology. Cervical Intraepithelial Neoplasia (CIN) / Squamous Intraepithelial Lesions (SIL) SIL and CIN are two commonly used terms to describe precancerous lesions or the abnormal growth of squamous cells observed in the cervix. SIL is an abnormal result derived from cervical cytological screening or Pap smear testing. CIN is a histological diagnosis made upon analysis of cervical tissue obtained by biopsy or surgical excision. The condition is graded as CIN 1, 2 or 3, according to the thickness of the abnormal epithelium (1/3, 2/3 or the entire thickness). Low-grade cervical lesions (LSIL/CIN-1) Low-grade cervical lesions are defined by early changes in size, shape, and number of abnormal cells formed on the surface of the cervix and may be referred to as mild dysplasia, LSIL, or CIN-1. High-grade cervical lesions (HSIL/ CIN-2 / CIN-3 / CIS) High-grade cervical lesions are defined by a large number of precancerous cells on the surface of the cervix that are distinctly different from normal cells. They have the potential to become cancerous cells and invade deeper tissues of the cervix. These lesions may be referred to as moderate or severe dysplasia, HSIL, CIN-2, CIN-3 or cervical carcinoma in situ (CIS). Carcinoma in situ (CIS) Preinvasive malignancy limited to the epithelium without invasion of the basement membrane. CIN 3 encompasses the squamous carcinoma in situ. Invasive cervical cancer (ICC) / Cervical cancer If the high-grade precancerous cells invade the basement membrane is called ICC. ICC stages range from stage I (cancer is in the cervix or uterus only) to stage IV (the cancer has spread to distant organs, such as the liver). Invasive squamous cell carcinoma Invasive carcinoma composed of cells resembling those of squamous epithelium. Adenocarcinoma Invasive tumour with glandular and squamous elements intermingled.

4 HPV-RELATED STATISTICS - 119-4.2 HPV burden in anogenital cancers other than the cervix Methods: Prevalence and type distribution of human papillomavirus in carcinoma of the vulva, vagina, anus and penis: systematic review and meta-analysis A systematic review of the literature was conducted on the worldwide HPV-prevalence and type distribution for anogenital carcinomas other than cervix from January 1986 to data as of indicated in each section. The search terms for the review were HPV AND (anus OR anal) OR (penile) OR vagin OR vulv using Pubmed. There were no limits in publication language. References cited in selected articles were also investigated. Inclusion criteria were: HPV DNA detection by means of PCR, a minimum of 1 cases by lesion and a detailed description of HPV DNA detection and genotyping techniques used. The number of cases tested and HPV positive cases were extracted for each study to estimate the prevalence of HPV DNA and the HPV type distribution. Binomial 95% confidence intervals were calculated for each HPV prevalence. 4.2.1 Anal cancer and precancerous anal lesions Anal cancer is similar to cervical cancer with respect to overall HPV DNA positivity, with approximately 88% of cases associated with HPV infection worldwide (de Martel C et al. Lancet Oncol 212;13(6):67-15). HPV16 is the most common type detected, representing 73% of all HPV-positive tumours. HPV18 is the second most common type detected and is found in approximately 5% of cases. HPV DNA is also detected in the majority of precancerous anal lesions (AIN) (91.5% in AIN1 and 93.9% in AIN2/3) (De Vuyst H et al. Int J Cancer 29; 124: 1626-36). In this section, the HPV prevalence among anal cancer cases and precancerous anal lesions in Europe are presented. Table 17: European studies on HPV prevalence among anal cancer cases (male and female) HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Tachezy 211 (Czech Rep.) Serup-Hansen 214 (Denmark) Alemany (Europe) 215 a Abramowitz 211 (France) PCR L1-Consensus primer,, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 74, 8, 81, 82, 83, 84, 85, 86, 87, 89, 9, 91) PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 16, 18, 31, 33, 45, 52, 58) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 91) PCR-SPF1, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 82) 26 73.1 (53.9-86.3) HPV 16 (73.1%) 137 87.6 (81.-92.1) HPV 16 (81.%) HPV 33 (5.1%) HPV 18 (2.2%) HPV 58 (.7%) 169 87.6 (81.8-91.7) HPV 16 (73.4%) HPV 6 (3.6%) HPV 18 (3.6%) HPV 11 (3.%) HPV 33 (2.4%) 728 96.7 (95.1-97.8) HPV 16 (75.5%) HPV 18 (5.9%) HPV 11 (3.7%) HPV 6 (3.%) HPV 52 (2.6%) (Continued on next page)

4 HPV-RELATED STATISTICS - 12 - HPV detection ( Table 17 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Valmary-Degano 213 (France) Vincent-Salomon 1996 (France) Rödel 215 (Germany) Varnai 26 (Germany) Indinnimeo 1999 (Italy) Laytragoon-Lewin 27 (Sweden) Baricevic 215 (UK) PCR-E6, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 82) PCR L1-Consensus primer, PCR-E6, TS (HPV 6, 11, 16, 18, 33) PCR-SPF1, PCR- MULTIPLEX, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 81, 82) PCR-MY9/11, TS, Sequencing (HPV 6, 11, 16, 18, 31, 33, 45, 58) 73 98.6 (92.6-99.8) HPV 16 (89.%) HPV 39 (4.1%) HPV 33 (2.7%) HPV 6 (1.4%) HPV 11 (1.4%) 27 74.1 (55.3-86.8) HPV 16 (63.%) HPV 18 (7.4%) 91 1. (95.9-1.) HPV 16 (94.5%) HPV 11 (2.2%) HPV 31 (2.2%) HPV 35 (2.2%) HPV 18 (1.1%) 47 83. (69.9-91.1) HPV 16 (74.5%) HPV 33 (6.4%) HPV 18 (2.1%) HPV 31 (2.1%) HPV 45 (2.1%) PCR, TS (HPV 6, 11, 16, 18) 14 64.3 (38.8-83.7) HPV 16 (42.9%) PCR-MY9/11, Sequencing (HPV 16, 18, 33) PCR-L1C1/C2, PCR L1-Consensus primer, PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 45, 52, 58) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom Data sources: See references in Section 9. 72 9.3 (81.3-95.2) HPV 16 (69.4%) HPV 18 (34.7%) HPV 33 (2.8%) 151 95.4 (9.7-97.7) HPV 16 (88.7%) HPV 6 (11.9%) HPV 33 (6.6%) HPV 18 (4.6%) HPV 58 (4.6%) Alemany (Europe) Table 18: European studies on HPV prevalence among AIN 2/3 cases (male and female) HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) 215 a Hampl 26 (Germany) Silling 212 b (Germany) Varnai 26 (Germany) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 91), PCR-MY9/11, Sequencing (HPV 6, 11, 2, 21, 22, 23, 26, 3, 32) PCR- MULTIPLEX (HPV 6, 11, 16, 18, 26, 3, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 67, 68, 7, 71, 72, 73, 81, 82, 83, 84, 89), PCR-MY9/11, TS, Sequencing (HPV 6, 11, 16, 18, 31, 33, 45, 58) 23 95.7 (79.-99.2) HPV 16 (65.2%) HPV 6 (8.7%) HPV 18 (8.7%) HPV 51 (8.7%) HPV 74 (8.7%) 16 87.5 (64.-96.5) - 42 1. (91.6-1.) HPV 16 (69.%) HPV 11 (23.8%) HPV 18 (23.8%) HPV 6 (19.%) HPV 67 (19.%) 24 95.8 (79.8-99.3) HPV 16 (7.8%) HPV 11 (12.5%) HPV 6 (8.3%) HPV 58 (4.2%) (Continued on next page)

4 HPV-RELATED STATISTICS - 121 - HPV detection ( Table 18 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Wieland 26 b PCR, EIA (HPV 6, 11, 16, 18, 31, 18 1. (82.4-1.) HPV 16 (88.9%) (Germany) 33, 34, 35, 42, 44, 45, 52, 53, 54, 56, 58, 59, 66, 68, 7, 72, 73, 81, 82, 83, 84, 89) HPV 18 (44.4%) HPV 83 (38.9%) HPV 52 (33.3%) HPV 58 (27.8%) Tanzi (Italy) 29 b Richel 214 b (Netherlands) García-Espinosa 213 b (Spain) Sirera (Spain) Torres (Spain) 213 b 213 b PCR-MY9/11, PCR L1-Consensus primer, RFLP (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 81, 83, 84) PCR L1-Consensus primer, PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 67, 68, 69, 7, 73, 74) PCR-GP5/6, PCR L1-Consensus primer, DBH (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 84) PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) LBA (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 81, 82, 83, 84) Fox 25 b (UK), PCR-MY9/11, (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) 62 91.9 (82.5-96.5) HPV 6 (38.7%) HPV 16 (37.1%) HPV 11 (27.4%) HPV 58 (8.1%) HPV 18 (4.8%) 17 1. (81.6-1.) HPV 16 (58.8%) HPV 31 (17.6%) HPV 18 (11.8%) HPV 53 (11.8%) HPV 58 (11.8%) 2 1. (83.9-1.) HPV 16 (5.%) HPV 44 (35.%) HPV 58 (35.%) HPV 6 (3.%) HPV 31 (3.%) 69 84.1 (73.7-9.9) HPV 16 (55.1%) HPV 58 (34.8%) HPV 33 (29.%) HPV 51 (23.2%) HPV 18 (21.7%) 44 97.7 (88.2-99.6) HPV 16 (59.1%) HPV 6 (34.1%) HPV 66 (31.8%) HPV 52 (29.5%) HPV 53 (29.5%) 74 97.3 (9.7-99.3) HPV 16 (64.9%) HPV 18 (25.7%) HPV 33 (24.3%) HPV 58 (21.6%) HPV 31 (18.9%) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; AIN 2/3: Anal intraepithelial neoplasia of grade 2/3; DBH: Dot Blot Hybridization; EIA: Enzyme ImmunoAssay; LBA: Line-Blot Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom b HIV positive cases Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 122 - Figure 115: Comparison of the ten most frequent HPV types in anal cancer cases in Europe and the World Europe (a) World (b) 16 73.4 16 71.4 6 3.6 18 4.2 18 3.6 33 3. 11 3. 6 2.4 33 2.4 31 2. 35 1.8 35 1.6 74 1.8 58 1.6 31 1.2 11 1.4 3.6 39 1.2 52.6 1 2 3 4 5 6 7 8 52 1.2 1 2 3 4 5 6 7 8 Type specific HPV prevalence (%) of anal cancer cases Data updated on 9 Feb 217 (data as of 3 Jun 214). a Includes cases from Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom. b Includes cases from Europe (Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom); America (Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay and United States); Africa (Mali, Nigeria and Senegal); Asia (Bangladesh,India and South Korea) Data sources: See references in Section 9. Figure 116: Comparison of the ten most frequent HPV types in AIN 2/3 cases in Europe and the World Europe (a) World (b) 74 8.7 6 9.3 16 65.2 16 72.1 18 8.7 11 7. 51 8.7 18 4.7 6 8.7 31 4.7 11 4.3 51 4.7 31 4.3 74 4.7 35 4.3 35 2.3 44 4.3 44 2.3 45 4.3 1 2 3 4 5 6 7 8 45 2.3 1 2 3 4 5 6 7 8 Type specific HPV prevalence (%) of AIN 2/3 cases Data updated on 9 Feb 217 (data as of 3 Jun 214). AIN 2/3: Anal intraepithelial neoplasia of grade 2/3; a Includes cases from Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom b Includes cases from Europe (Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom); America (Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay) Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 123-4.2.2 Vulvar cancer and precancerous vulvar lesions HPV attribution for vulvar cancer is 43% worldwide (de Martel C et al. Lancet Oncol 212;13(6):67-15). Vulvar cancer has two distinct histological patterns with two different risk factor profiles: (1) basaloid/warty types (2) keratinising types. Basaloid/warty lesions are more common in young women, are frequently found adjacent to VIN, are very often associated with HPV DNA detection (86%), and have a similar risk factor profile as cervical cancer. Keratinising vulvar carcinomas represent the majority of the vulvar lesions (>6%). These lesions develop from non HPV-related chronic vulvar dermatoses, especially lichen sclerosus and/or squamous hyperplasia, their immediate cancer precursor lesion is differentiated VIN, they occur more often in older women, and are rarely associated with HPV (6%) or with any of the other risk factors typical of cervical cancer. HPV prevalence is frequently detected among cases of high-grade VIN (VIN2/3) (85.3%). HPV 16 is the most common type detected followed by HPV 33 (De Vuyst H et al. Int J Cancer 29; 124:1626-36). In this section, the HPV prevalence among vulvar cancer cases and precancerous vulvar lesions in Europe are presented. Table 19: European studies on HPV prevalence among vulvar cancer cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Tachezy 211 (Czech Rep.) Bryndorf 24 (Denmark) Hørding 1993 (Denmark) Hørding 1994 (Denmark) Madsen 28 (Denmark) de Sanjosé 213 a (Europe) Iwasawa 1997 (Finland) Choschzick 211 (Germany) Hampl 26 (Germany) Milde-Langosch 1995 (Germany) PCR L1-Consensus primer,, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 74, 8, 81, 82, 83, 84, 85, 86, 87, 89, 9, 91) PCR-SPF1, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 44, 45, 51, 52, 56, 58) PCR-E6, PCR-E7, TS (HPV 6, 11, 16, 18, 33) PCR-E6, PCR-E7, TS (HPV 6, 11, 16, 18, 33) EIA, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 44, 45, 51, 52, 56, 58, 61, 67, 73) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 91) PCR-MY9/11, PCR L1-Consensus primer, PCR-E6, TS (HPV 6, 11, 16, 18, 33) PCR-MY9/11, Sequencing (HPV 6, 11, 16, 18, 33) PCR-MY9/11, Sequencing (HPV 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 35, 42, 44, 45, 51, 52, 56, 58, 61, 67, 73, 91) PCR-MY9/11, TS (HPV 6, 11, 16, 18, 31, 33, 35) 46 41.3 (28.3-55.7) HPV 16 (23.9%) HPV 33 (8.7%) HPV 6 (2.2%) HPV 42 (2.2%) HPV 45 (2.2%) 1 6. (31.3-83.2) HPV 16 (4.%) HPV 33 (2.%) HPV 56 (1.%) 62 3.6 (2.6-43.) HPV 16 (21.%) HPV 18 (4.8%) HPV 33 (4.8%) 78 3.8 (21.6-41.7) HPV 16 (28.2%) HPV 33 (3.8%) 6 51.7 (39.3-63.8) HPV 16 (36.7%) HPV 33 (11.7%) HPV 73 (3.3%) HPV 6 (1.7%) HPV 51 (1.7%) 93 19.3 (16.8-22.) HPV 16 (13.8%) HPV 33 (1.2%) HPV 18 (.6%) HPV 31 (.6%) HPV 44 (.4%) 74 36.5 (26.4-47.9) HPV 16 (25.7%) HPV 18 (12.2%) HPV 33 (1.4%) 39 46.2 (31.6-61.4) HPV 16 (43.6%) HPV 33 (2.6%) 48 6.4 (46.3-73.) HPV 16 (39.6%) HPV 33 (8.3%) HPV 31 (4.2%) HPV 18 (2.1%) 4 27.5 (16.1-42.8) HPV 16 (25.%) (Continued on next page)

4 HPV-RELATED STATISTICS - 124 - HPV detection ( Table 19 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Reuschenbach 213 (Germany) Bonvicini 25 (Italy) Kagie 1997 (Netherlands) Trietsch 213 (Netherlands) van de Nieuwenhof 29 (Netherlands) van der Avoort 26 (Netherlands) Bujko 212 (Poland) Liss 1998 (Poland) Alonso 211 (Spain) Guerrero 211 (Spain) Lerma 1999 (Spain) Larsson 212 (Sweden) Lindell 21 (Sweden) Abdel-Hady 21 (UK) PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 68, 7, 71, 73, 82) PCR-MY9/11 (HPV 16, 18, 31, 33, 35, 45, 52, 58) PCR-CPI/CPIIG, Sequencing (HPV 6, 11, 16, 31, 33, 45) PCR, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 82) PCR L1-Consensus primer, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 45, 51, 52, 53, 54, 56, 58, 66, 73) PCR L1-Consensus primer, PCR-SPF1, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 44, 45, 51, 52, 56, 58) PCR, LBA (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) PCR-MY9/11, PCR L1-Consensus primer, PCR-E6, PCR-E7, RFLP (HPV 6, 11, 16, 18, 31, 33, 35, 45, 52, 58) PCR-SPF1, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 45, 51, 52, 53, 54, 56, 58, 66) PCR L1-Consensus primer, (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) PCR L1-Consensus primer, TS (HPV 16, 18) PCR-E6, (HPV 6, 11, 16, 18, 31, 33, 39, 45, 51, 52, 56, 58, 59) PCR-CPI/CPIIG, TS, Sequencing (HPV 6, 11, 16, 18, 33, 52) 183 43.7 (36.7-51.) HPV 16 (36.1%) HPV 18 (2.7%) HPV 33 (1.1%) HPV 6 (.5%) HPV 11 (.5%) 16. (.-19.4) - 66 19.7 (11.9-3.8) HPV 16 (16.7%) HPV 33 (1.5%) HPV 45 (1.5%) 18 16.7 (1.8-24.8) HPV 16 (1.2%) HPV 33 (5.6%) HPV 18 (1.9%) 13 34.6 (27.-43.1) HPV 16 (15.4%) HPV 33 (5.4%) HPV 18 (2.3%) HPV 52 (1.5%) HPV 54 (1.5%) 16. (.-19.4) - 44 34.1 (21.9-48.9) HPV 16 (2.5%) HPV 11 (11.4%) HPV 44 (4.5%) HPV 52 (4.5%) HPV 58 (4.5%) 18 16.7 (5.8-39.2) HPV 16 (16.7%) 98 19.4 (12.8-28.3) HPV 16 (14.3%) HPV 33 (2.%) HPV 31 (1.%) HPV 51 (1.%) HPV 52 (1.%) 3 16.7 (7.3-33.6) HPV 59 (1.%) HPV 6 (3.3%) HPV 16 (3.3%) HPV 18 (3.3%) 57 12.3 (6.1-23.2) HPV 16 (12.3%) 13 3.8 (23.5-39.2) HPV 16 (23.8%) HPV 33 (3.8%) HPV 18 (1.5%) HPV 56 (.8%) HPV 59 (.8%) 75 3.7 (21.4-41.8) HPV 16 (21.3%) HPV 18 (2.7%) HPV 33 (2.7%) HPV 52 (1.3%) TS (HPV 6, 11, 16, 18, 31, 33) 11 27.3 (9.7-56.6) HPV 16 (27.3%) HPV 33 (18.2%) HPV 18 (9.1%) (Continued on next page)

4 HPV-RELATED STATISTICS - 125 - HPV detection ( Table 19 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Riethdorf 24 b PCR L1-Consensus primer, TS 71 87.3 (77.6-93.2) HPV 16 (87.3%) (World) (HPV 16) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; LBA: Line-Blot Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom b Includes cases from Germany and United States of America Data sources: See references in Section 9. Table 2: European studies on HPV prevalence among VIN 2/3 cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Tachezy 211 (Czech Rep.) Junge 1995 (Denmark) de Sanjosé 213 a (Europe) Hampl 26 (Germany) Tsimplaki 212 (Greece) Bonvicini 25 (Italy) van Beurden 1995 (Netherlands) van der Avoort 26 (Netherlands) van Esch 214 (Netherlands) Lerma 1999 (Spain) Abdel-Hady 21 (UK) PCR L1-Consensus primer,, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 74, 8, 81, 82, 83, 84, 85, 86, 87, 89, 9, 91) PCR-E6, PCR-E7, TS (HPV 6, 11, 16, 18, 31, 33) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 91) PCR-MY9/11, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 35, 42, 44, 45, 51, 52, 56, 58, 61, 67, 73, 74, 91) (HPV 6, 11, 16, 18, 31, 33, 35, 4, 42, 43, 44, 45, 51, 52, 53, 56, 58, 59, 66, 73) PCR-MY9/11 (HPV 16, 18, 31, 33, 35, 45, 52, 58) PCR-CPI/CPIIG, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 45) PCR L1-Consensus primer, PCR-SPF1, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, 56, 58, 59, 74) 94 94.7 (88.1-97.7) HPV 16 (71.3%) HPV 33 (8.5%) HPV 18 (5.3%) HPV 6 (4.3%) HPV 11 (2.1%) 58 87.9 (77.1-94.) HPV 16 (77.6%) HPV 33 (1.3%) 312 86.9 (82.7-9.2) HPV 16 (69.6%) HPV 33 (11.2%) HPV 18 (2.2%) HPV 6 (1.6%) HPV 52 (1.3%) 168 1. (97.8-1.) HPV 16 (79.8%) HPV 33 (1.7%) HPV 31 (4.2%) HPV 18 (3.%) 14 78.6 (52.4-92.4) HPV 16 (64.3%) HPV 18 (7.1%) HPV 51 (7.1%) HPV 52 (7.1%) HPV 53 (7.1%) 25 44. (26.7-62.9) HPV 16 (36.%) HPV 35 (8.%) HPV 33 (4.%) HPV 52 (4.%) 46 95.7 (85.5-98.8) HPV 16 (89.1%) HPV 33 (2.2%) HPV 45 (2.2%) 32 56.3 (39.3-71.8) HPV 16 (4.6%) HPV 6 (6.3%) HPV 31 (6.3%) HPV 33 (3.1%) TS (HPV 16, 18, 33, 73) 43 1. (91.8-1.) HPV 16 (81.4%) HPV 33 (14.%) HPV 73 (2.3%) PCR L1-Consensus primer, TS 18 27.8 (12.5-5.9) HPV 16 (27.8%) (HPV 16, 18) TS (HPV 6/11, 16, 18, 31, 33) 32 71.9 (54.6-84.4) HPV 16 (62.5%) HPV 6/11 (18.8%) HPV 31 (3.1%) HPV 33 (3.1%) (Continued on next page)

4 HPV-RELATED STATISTICS - 126 - HPV detection ( Table 2 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Baldwin 23 (UK) PCR L1-Consensus primer, Sequencing (HPV 6, 11, 16, 18, 31, 33) Bryant 211 (UK) PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 35, 4, 42, 43, 44, 45, 51, 52, 53, 56, 58, 59, 66, 73) Daayana 21 (UK) Winters 28 (UK) EIA, (HPV 6, 11, 16, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) EIA, (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) PCR L1-Consensus primer, TS (HPV 16) 11 1. (74.1-1.) HPV 16 (9.9%) HPV 33 (9.1%) 49 81.6 (68.6-9.) HPV 16 (67.3%) HPV 33 (16.3%) HPV 6 (1.2%) HPV 18 (2.%) HPV 31 (2.%) 19 78.9 (56.7-91.5) HPV 16 (73.7%) HPV 33 (5.3%) HPV 42 (5.3%) HPV 84 (5.3%) 2 85. (64.-94.8) HPV 16 (75.%) HPV 18 (5.%) HPV 33 (5.%) 6 68.3 (55.8-78.7) HPV 16 (68.3%) Riethdorf 24 b (World) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; VIN 2/3: Vulvar intraepithelial neoplasia of grade 2/3; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom b Includes cases from Germany and United States of America Data sources: See references in Section 9. Figure 117: Comparison of the ten most frequent HPV types in cases of vulvar cancer in Europe and the World Europe (a) World (b) 16 13.8 16 19.4 33 1.2 33 1.8 18.6 18 1.5 31.6 45.9 44.4 6.6 51.4 31.6 53.3 44.6 58.3 52.5 74.3 51.4 35.2 1 2 56.4 1 2 Type specific HPV prevalence (%) of vulvar cancer cases Data updated on 9 Feb 217 (data as of 3 Jun 214). VIN 2/3: Vulvar intraepithelial neoplasia of grade 2/3; a Includes cases from Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom. b Includes cases from America (Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Uruguay, United States of America and Venezuela); Africa (Mali, Mozambique, Nigeria, and Senegal); Oceania (Australia and New Zealand); Europe (Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom); and in Asia (Bangladesh, India, Israel, South Korea, Kuwait, Lebanon, Philippines, Taiwan and Turkey) Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 127 - Figure 118: Comparison of the ten most frequent HPV types in VIN 2/3 cases in Europe and the World Europe (a) World (b) 16 69.6 16 67.1 33 11.2 33 1.2 18 2.2 6 2.4 6 1.6 18 2.4 52 1.3 31 1.9 56 1.3 52 1.4 44 1. 51 1.2 66 1. 56.9 74 1. 74.9 31.6 1 2 3 4 5 6 7 66.7 1 2 3 4 5 6 7 Type specific HPV prevalence (%) of VIN 2/3 cases Data updated on 9 Feb 217 (data as of 3 Jun 214). VIN 2/3: Vulvar intraepithelial neoplasia of grade 2/3; a Includes cases from Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom. b Includes cases from America (Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Uruguay and Venezuela); Oceania (Australia and New Zealand); Europe (Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom); and in Asia (Bangladesh, India, Israel, South Korea, Kuwait, Lebanon, Philippines, Taiwan and Turkey) Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 128-4.2.3 Vaginal cancer and precancerous vaginal lesions Vaginal and cervical cancers share similar risk factors and it is generally accepted that both carcinomas share the same aetiology of HPV infection although there is limited evidence available. Women with vaginal cancer are more likely to have a history of other anogenital cancers, particularly of the cervix, and these two carcinomas are frequently diagnosed simultaneously. HPV DNA is detected among 7% of invasive vaginal carcinomas and 91% of high-grade vaginal neoplasias (VaIN2/3). HPV16 is the most common type in high-grade vaginal neoplasias and it is detected in at least 7% of HPV-positive carcinomas (de Martel C et al. Lancet Oncol 212;13(6):67-15; De Vuyst H et al. Int J Cancer 29; 124: 1626-36). In this section, the HPV prevalence among vaginal cancer cases and precancerous vaginal lesions in Europe are presented. Table 21: European studies on HPV prevalence among vaginal cancer cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Madsen 28 (Denmark) Alemany (Europe) 214 a Ferreira 28 (Portugal) Fuste 21 (Spain) Larsson 213 (Sweden) EIA, (HPV 6, 11, 16, 18, 31, 33, 35, 39, 4, 42, 44, 45, 51, 52, 56, 58) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 35, 39, 42, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 73, 82) PCR, (HPV 6, 11, 16, 18, 31, 33, 35, 4, 42, 44, 45, 51, 52, 56, 58) PCR-SPF1, (HPV 6, 11, 16, 18, 31, 33, 35, 39, 4, 42, 45, 51, 52, 56, 58, 59, 68) PCR-E6, (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; a Includes cases from Austria, Belarus, Czech Republic, France, Germany, Greece, Poland, Spain and United Kingdom Data sources: See references in Section 9. 27 88.9 (71.9-96.1) HPV 16 (77.8%) HPV 33 (7.4%) HPV 18 (3.7%) HPV 39 (3.7%) HPV 45 (3.7%) 152 71.1 (63.4-77.7) HPV 16 (47.4%) HPV 18 (3.3%) HPV 73 (3.3%) HPV 33 (2.6%) HPV 56 (2.6%) 21 81. (6.-92.3) HPV 16 (33.3%) HPV 31 (28.6%) HPV 4 (14.3%) HPV 6 (9.5%) HPV 18 (9.5%) 32 78.1 (61.2-89.) HPV 16 (56.3%) HPV 52 (6.3%) HPV 35 (3.1%) HPV 51 (3.1%) HPV 58 (3.1%) 69 53.6 (42.-64.9) HPV 16 (37.7%) HPV 18 (2.9%) HPV 31 (2.9%) HPV 33 (2.9%) HPV 52 (2.9%) Table 22: European studies on HPV prevalence among VaIN 2/3 cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Alemany 214 (Europe) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 35, 39, 42, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 73, 82) (Continued on next page) 96 97.9 (92.7-99.4) HPV 16 (65.6%) HPV 33 (7.3%) HPV 18 (5.2%) HPV 52 (3.1%) HPV 73 (3.1%)

4 HPV-RELATED STATISTICS - 129 - HPV detection ( Table 22 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Hampl 26 (Germany) Tsimplaki 212 (Greece) PCR-MY9/11, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 35, 4, 44, 52, 56, 58) (HPV 6, 11, 16, 18, 31, 33, 35, 39, 4, 42, 44, 45, 51, 52, 53, 56, 58, 66, 7) 11 9.9 (62.3-98.4) HPV 16 (63.6%) 1 4. (16.8-68.7) HPV 16 (2.%) HPV 33 (2.%) Frega 27 (Italy) PCR, TS (HPV 16, 18) 3 1. (88.6-1.) HPV 16 (86.7%) HPV 18 (13.3%) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; VAIN 2/3: Vaginal intraepithelial neoplasia of grade 2/3; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; TS: Type Specific; Based on systematic reviews (up to 28) performed by ICO for the IARC Monograph on the Evaluation of Carcinogenic Risks to Humans volume 1B and IARC s Infections and Cancer Epidemiology Group. The has updated data until June 215. Reference publications: 1) Bouvard V, Lancet Oncol 29;1:321 2) De Vuyst H, Int J Cancer 29;124:1626 Alemany L, Eur J Cancer 214; 5: 2846 Frega A, Cancer Lett 27; 249: 235 Hampl M, Obstet Gynecol 26; 18: 1361 Tsimplaki E, J Oncol 212; 212: 893275 Data sources: See references in Section 9. Figure 119: Comparison of the ten most frequent HPV types in vaginal cancer cases in Europe and the World Europe (a) World (b) 16 47.4 16 43.6 18 3.3 31 3.9 73 3.3 18 3.7 33 2.6 33 3.7 56 2.6 45 2.7 58 2.6 58 2.7 31 2. 52 2.2 35 1.3 51 1.7 45 1.3 73 1.7 52 1.3 1 2 3 4 5 39 1.5 1 2 3 4 5 Type specific HPV prevalence (%) of vaginal cancer cases Data updated on 9 Feb 217 (data as of 3 Jun 214). VAIN 2/3: Vaginal intraepithelial neoplasia of grade 2/3; a Includes cases from Austria, Belarus, Czech Republic, France, Germany, Greece, Poland, Spain and United Kingdom. b Includes cases from Europe (Austria, Belarus, Czech Republic, France, Germany, Greece, Poland, Spain and United Kingdom); America (Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Mexico, Paraguay, Uruguay, United states of America and Venezuela); Africa (Mozambique, Nigeria); Asia (Bangladesh, India, Israel, South Korea, Kuwait, Philippines, Taiwan and Turkey); and Oceania (Australia) Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 13 - Figure 12: Comparison of the ten most frequent HPV types in VaIN 2/3 cases in Europe and the World Europe (a) World (b) 16 65.6 16 56.1 33 7.3 18 5.3 18 5.2 52 5.3 52 3.1 73 4.8 73 3.1 33 4.2 35 2.1 59 3.7 53 2.1 56 2.6 56 2.1 51 2.1 59 2.1 6 1.6 3 1. 1 2 3 4 5 6 7 35 1.6 1 2 3 4 5 6 7 Type specific HPV prevalence (%) of VaIN 2/3 cases Data updated on 9 Feb 217 (data as of 3 Jun 214). VAIN 2/3: Vaginal intraepithelial neoplasia of grade 2/3; a Includes cases from Austria, Belarus, Czech Republic, France, Germany, Greece, Poland, Spain and United Kingdom. b Includes cases from Europe (Austria, Belarus, Czech Republic, France, Germany, Greece, Poland, Spain and United Kingdom); America (Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Mexico, Paraguay, Uruguay, United states of America and Venezuela); Asia (Bangladesh, India, Israel, South Korea, Kuwait, Philippines, Taiwan and Turkey); and Oceania (Australia) Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 131-4.2.4 Penile cancer and precancerous penile lesions HPV DNA is detectable in approximately 5% of all penile cancers (de Martel C et al. Lancet Oncol 212;13(6):67-15). Among HPV-related penile tumours, HPV16 is the most common type detected, followed by HPV18 and HPV types 6/11 (Miralles C et al. J Clin Pathol 29;62:87-8). Over 95% of invasive penile cancers are SCC and the most common penile SCC histologic sub-types are keratinising (49%), mixed warty-basaloid (17%), verrucous (8%), warty (6%), and basaloid (4%). HPV is commonly detected in basaloid and warty tumours but is less common in keratinising and verrucous tumours. In this section, the HPV prevalence among penile cancer cases and precancerous penile lesions in Europe are presented. Table 23: European studies on HPV prevalence among penile cancer cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Mannweiler 213 (Austria) D Hauwers 212 (Belgium) Alemany 216 (Europe) Humbey 23 (France) Perceau 23 (France) Poetsch 211 (Germany) Barzon 214 (Italy) Gentile 26 (Italy) Tornesello 28 (Italy) Heideman 27 (Netherlands) PCR L1-Consensus primer, PCR-SPF1, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 72, 73, 74, 82) PCR-E6, PCR-E7, qpcr (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 31, 32, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 9, 91) PCR-MY9/11, PCR L1-Consensus primer, TS (HPV 6, 11, 16, 18, 31, 33, 35, 45, 51, 52, 58, 68) 123 58.5 (49.7-66.9) HPV 16 (45.5%) HPV 33 (4.9%) HPV 18 (4.1%) HPV 45 (3.3%) HPV 6 (.8%) 36 61.1 (44.9-75.2) HPV 16 (47.2%) HPV 59 (5.6%) HPV 6 (2.8%) HPV 11 (2.8%) HPV 33 (2.8%) 419 32.2 (27.9-36.8) HPV 16 (23.4%) HPV 52 (1.2%) HPV 6 (1.%) HPV 33 (1.%) HPV 45 (.7%) 36 66.7 (5.3-79.8) HPV 16 (25.%) TS (HPV 16, 18, 31, 33) 17 17.6 (6.2-41.) HPV 16 (17.6%) PCR- MULTIPLEX, TS (HPV 6/11, 16, 18) qpcr,, TS (HPV 16, 18, 26, 31, 33, 35, 39, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 82) PCR-MY9/11, PCR L1-Consensus primer, Sequencing (HPV 16, 18, 53) PCR-MY9/11, PCR-L1C1/C2, PCR-E6, PCR-E7, Sequencing (HPV 6, 16, 18, 33, 35) PCR-E6, PCR-E7, EIA, (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) 52 38.5 (26.5-52.) HPV 16 (32.7%) HPV 6/11 (3.8%) HPV 18 (1.9%) 54 29.6 (19.1-42.8) HPV 16 (25.9%) HPV 45 (1.9%) HPV 68 (1.9%) 11 72.7 (43.4-9.3) HPV 16 (45.5%) HPV 18 (18.2%) HPV 53 (9.1%) 61 47.5 (35.5-59.8) HPV 16 (42.6%) HPV 18 (3.3%) HPV 35 (1.6%) 171 29.2 (22.9-36.5) HPV 16 (22.8%) HPV 18 (2.3%) HPV 45 (1.8%) HPV 33 (1.2%) HPV 56 (.6%) (Continued on next page)

4 HPV-RELATED STATISTICS - 132 - HPV detection ( Table 23 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Ferrándiz-Pulido 213 (Spain) Guerrero 28 (Spain) Pascual 27 (Spain) Stankiewicz 211 (UK) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 7, 73, 74) (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) PCR-MY9/11, PCR L1-Consensus primer, Sequencing (HPV 6, 11, 16, 18) PCR L1-Consensus primer, PCR-SPF1 (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 82) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; TS: Type Specific; Data sources: See references in Section 9. 78 37.2 (27.3-48.3) HPV 16 (26.9%) HPV 58 (3.8%) HPV 6 (2.6%) HPV 33 (1.3%) HPV 45 (1.3%) 24 45.8 (27.9-64.9) HPV 16 (45.8%) HPV 39 (4.2%) 49 77.6 (64.1-87.) HPV 16 (65.3%) HPV 18 (8.2%) 12 55.9 (46.2-65.1) HPV 16 (45.1%) HPV 11 (9.8%) HPV 6 (5.9%) HPV 45 (5.9%) HPV 31 (4.9%) Table 24: European studies on HPV prevalence among PeIN 2/3 cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study Method No. Tested % (95% CI) HPV type (%) Mannweiler 213 (Austria) D Hauwers 212 (Belgium) Alemany 216 (Europe) Wikström 212 (Sweden) PCR L1-Consensus primer, PCR-SPF1, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 72, 73, 74, 82) PCR-E6, PCR-E7, qpcr (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 32, 33, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 9, 91) PCR-MY9/11, PCR L1-Consensus primer (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 53, 56, 58, 59, 66, 68, 7, 73, 82) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; PeIN 2/3: Penile intraepithelial neoplasia of grade 2/3; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; Data sources: See references in Section 9. 43 76.7 (62.3-86.8) HPV 16 (62.8%) HPV 18 (9.3%) HPV 33 (2.3%) HPV 73 (2.3%) 13 84.6 (57.8-95.7) HPV 16 (61.5%) HPV 18 (23.1%) HPV 11 (15.4%) HPV 53 (15.4%) HPV 56 (15.4%) 64 89.1 (79.1-94.6) HPV 16 (73.4%) HPV 33 (6.3%) HPV 6 (3.1%) HPV 18 (3.1%) HPV 31 (3.1%) 28 85.7 (68.5-94.3) HPV 16 (39.3%) HPV 6 (21.4%) HPV 31 (7.1%) HPV 33 (7.1%) HPV 45 (7.1%)

4 HPV-RELATED STATISTICS - 133 - Figure 121: Comparison of the ten most frequent HPV types in penile cancer cases in Europe and the World Europe (a) World (b) 16 23.4 16 22.8 52 1.2 6 1.6 6 1. 33 1.2 33 1. 35 1. 45.7 45 1. 58.7 52.9 18.5 11.7 31.5 18.7 35.5 59.7 44.5 1 2 3 74.6 1 2 3 Type specific HPV prevalence (%) of penile cancer cases Data updated on 9 Feb 217 (data as of 3 Jun 215). a Includes cases from Czech Republic, France, Greece, Poland, Portugal, Spain and United Kingdom b Includes cases from Australia, Bangladesh, India, South Korea, Lebanon, Philippines, Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Venezuela and United States, Mozambique, Nigeria, Senegal, Czech Republic, France, Greece, Poland, Portugal, Spain and United Kingdom. Data sources: See references in Section 9. Figure 122: Comparison of the ten most frequent HPV types in PeIN 2/3 cases in Europe and the World Europe (a) World (b) 16 73.4 16 69.4 33 6.3 33 5.9 6 3.1 58 4.7 18 3.1 31 3.5 31 3.1 51 3.5 45 3.1 52 3.5 51 3.1 6 2.4 52 3.1 18 2.4 58 3.1 45 2.4 43 1.6 1 2 3 4 5 6 7 8 53 2.4 1 2 3 4 5 6 7 8 Type specific HPV prevalence (%) of PeIN 2/3 cases Data updated on 9 Feb 217 (data as of 3 Jun 215). a Includes cases from Czech Republic, France, Greece, Poland, Portugal, Spain and United Kingdom b Includes cases from Australia, Bangladesh, India, South Korea, Lebanon, Philippines, Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Venezuela, Mozambique, Nigeria, Senegal, Czech Republic, France, Greece, Poland, Portugal, Spain and United Kingdom. Data sources: See references in Section 9.

4 HPV-RELATED STATISTICS - 134-4.3 HPV burden in men The information to date regarding anogenital HPV infection is primarily derived from cross-sectional studies of selected populations such as general population, university students, military recruits, and studies that examined husbands of control women, as well as from prospective studies. Special subgroups include mainly studies that examined STD (sexually transmitted diseases) clinic attendees, MSM (men who have sex with men), HIV positive men, and partners of women with HPV lesions, CIN (cervical intraepithelial neoplasia), cervical cancer or cervical carcinoma in situ. Globally, prevalence of external genital HPV infection in men is higher than cervical HPV infection in women, but persistence is less likely. As with genital HPV prevalence, high numbers of sexual partners increase the acquisition of oncogenic HPV infections (Vaccine 212, Vol. 3, Suppl 5). In this section, the HPV burden among men in Europe is presented. Methods HPV burden in men was based on published systematic reviews and meta-analyses (Dunne EF, J Infect Dis 26; 194: 144, Smith JS, J Adolesc Health 211; 48: 54, Olesen TB, Sex Transm Infect 214; 9: 455, and Hebnes JB, J Sex Med 214; 11: 263) up to October 31, 215. The search terms for the review were human papillomavirus, men, polymerase chain reaction (PCR), hybrid capture (HC), and viral DNA. References cited in selected articles were also investigated. Inclusion criteria were: HPV DNA detection by means of PCR or HC (ISH if data are not available for the country), and a detailed description of HPV DNA detection and genotyping techniques used. The number of cases tested and HPV positive cases were extracted for each study to estimate the anogenital prevalence of HPV DNA. Binomial 95% confidence intervals were calculated for each anogenital HPV prevalence. Table 25: European studies on anogenital HPV prevalence among men Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Croatia Grce 1996 Urethra Filter hybridization (slot-blot, TS 6,11,16,18) Denmark Finland Germany Vardas Penis RT-PCR-Multiplex 211 a or Biplex Hebnes 215 Kjaer 25 Hippeläinen 1993 Coronal sulcus, glans, preputial cavity, scrotum, shaft and perineum Glans and corona sulcus Glans, prepuce, corona sulcus, urethral meatus HC2 PCR-LIPAv2 PCR-GP5+/6+ TS oligoprobes PCR-MY9/11 TS 6,11,16,18,31,33 Kero 211 Urethra PCR-MY9/11 and GP5+/6+ Grussendorf- Conen 1987 Coronal sulcus and glans ISH Family planning clinic attendees Heterosexual men enrolled in a HPV vaccine trial Male employees and conscripts at military barracks Male employees and conscripts at military barracks - 79 26.6 (17.3-37.7) Median 2 (15-24) Mean 23 (18-65) Mean 23 (18-65) 3132 21.2 (19.8-22.7) 2436 22.2 (2.6-24.) 2436 41.8 (39.9-43.8) Military conscripts 18-29 337 33.8 (28.8-39.2) Voluntary conscripts Sexual partners of pregnant women Blood donors or patients from department of dermatology Mean 2 285 16.5 (12.4-21.3) 19-46 128 22.7 (15.7-3.9) 16-79 53 5.8 (4.-8.2) ( Table 25 continued from previous page)

4 HPV-RELATED STATISTICS - 135 - ( Table 25 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Italy Spain Sweden Vardas Penis RT-PCR-Multiplex 211 a or Biplex Lorenzon 214 Nasca 26 Franceschi 22 Coronal sulcus, shaft, prepuce, and urethral Penis Glans, corona, urethra PCR-Roche Linear Array HPV Genotyping test PCR-MY9/11 and GP5+/6+ PCR-GP5+/6+ Vardas Penis RT-PCR-Multiplex 211 a or Biplex Forslund 1993 Kataoka 1991 Urethra Urethra PCR-TS (6,11,16,18,31,33,35) and unespecified consensus primer PCR-TS 6,11,16,18,33 Heterosexual men enrolled in a HPV vaccine trial Heterosexual men for routine HPV testing Hospital based controls attending clinic for nongenital complaints Husbands of control women Heterosexual men enrolled in a HPV vaccine trial Median 2 (15-24) 3132 21.2 (19.8-22.7) 18-68 378 4.5 (35.5-45.6) 27-79 46 8.7 (2.4-2.8) 24-78 168 3.6 (1.3-7.6) Median 2 (15-24) 3132 21.2 (19.8-22.7) Military conscripts 2-23 138 8.7 (4.6-14.7) Army conscripts with normal epithelium Data updated on 28 Jun 217 (data as of 31 Oct 215). 95% CI: 95% Confidence Interval; HC2: Hybrid Capture 2; ISH: In Situ Hybridization; PCR: Polymerase Chain Reaction; RT-PCR: Real Time Polymerase Chain Reaction; TS: Type Specific; a Includes cases from Australia, Brazil, Canada, Croatia, Germany, Mexico, Spain, and USA. Data sources: See references in Section 9. 18-23 66 12.1 (5.4-22.5) Table 26: European studies on anogenital HPV prevalence among men from special subgroups Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Croatia Denmark France Goldstone 211 Svare 22 Aynaud 23 Anus Penis Coronal sulcus, glans, perianal area, scrotum, and shaft Meatal urethra RT-PCR-Multiplex or Biplex RT-PCR-Multiplex or Biplex PCR-GP5+/6+ and TS 6,11,16,18,31,33 PCR-TS 6,11,42,16,18,33 HIV- MSM HIV- MSM STD clinic attendees Men with normal peniscopy whose female partners have genital HPV lesions Median 22 (16-27) Median 22 (16-27) 62 42.4 (38.4-46.4) 62 18.4 (15.4-21.8) >=18 198 44.9 (37.9-52.2) Mean 3 34 2.9 (.1-15.3) ( Table 26 continued from previous page)

4 HPV-RELATED STATISTICS - 136 - ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Germany Greece Ireland Italy Damay 21 Philibert 214 Piketty 24 Goldstone 211 Schneider 1988 Wieland 215 Anal canal Anus PCR- PapilloCheck PCR-Cobas HR-HPV Men with penile and urethral lesions whose female partners have genital HPV lesions HIV+ MSM HIV- MSM HIV+ MSM Mean 29 55 87.3 (75.5-94.7) Median 45 (39-49.5) Mean 46.4 (SD=9.4) Mean 46.4 (SD=9.4) 67 74.6 (62.5-84.5) 16 75 (47.6-92.7) 82 76.8 (66.2-85.4) Anal canal PCR-MY9/11 HIV+ MSM 27-62 45 8 (65.4-9.4) Anus Penis Glans, prepuce, fossa navicularis, shaft Anus RT-PCR-Multiplex or Biplex RT-PCR-Multiplex or Biplex Filter hybridization DNA/DNA PCR-Multiplex and hybridization HIV- MSM HIV- MSM Sexual partners of women with HPV associated lesions of the cervix HadjivassiliouUrethra HC2 HR, LR HIV- STD clinic 27 attendees without genital warts and sexual partners of women with genital warts Sadlier 214 Barzon 21 Benevolo 28 Median 22 (16-27) Median 22 (16-27) Mean 36.5 62 42.4 (38.4-46.4) 62 18.4 (15.4-21.8) 156 39.1 (31.4-47.2) HIV+ MSM 18-8 81 91.5 (89.4-93.3) Anus PCR-TS 16,18,31 HIV- MSM Mean 32 (SD=8) Glans, corona, shaft, perianal area, urethra, and semen Coronal sulcus, urethra, prepuce, shaft PCR-General primers for L1 (MY9/11, GP5 + /6+) PCR-L1 HIV+ MSM Mean 4 (SD=1) Men referred for HPV testing. Indications for testing: STD screening, HPV suspected lesions, HPV-positive partners Male partners of women with CIN and/or positive HPV 15-65 64 2.3 (11.3-32.2) 8 61.3 (49.7-71.9) 83 77.1 (66.6-85.6) 2-72 947 41.7 (38.5-44.9) 2-61 71 35.2 (24.2-47.5) ( Table 26 continued from previous page)

4 HPV-RELATED STATISTICS - 137 - ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Netherlands Chiarini 1998 Della Torre 1992 Urethra Urethra PCR-Generic primers in E1 PCR-TS 6,11,16,18 Men with symptoms of nongonococcal urethritis Partners of women with HPV Dona 215 Anus PCR-Linear Array HIV- MSM Median 32 (IQR=27-39) Garbuglia 215 Giovannelli 27 Orlando 28 Pierangeli 28 Sammarco 216 Bleeker 22 HIV+ MSM - 247 31.2 (25.5-37.4) - 64 21.9 (12.5-34.) Median 41 (IQR=33-47) Anus PCR-MY9/11 HIV+ MSM Median 39 (IQR=33-44) Coronal sulcus, frenulum, glans, prepuce, shaft PCR-LiPA, GP5+/6+ and MY9/11 Partners of women with HPV Anus HC2 HIV+ Median 34 (IQR=3-42) 437 72.1 (67.6-76.2) 172 93 (88.1-96.3) 22 88.6 (83.7-92.5) 23-58 47 68.1 (52.9-8.9) 233 87.1 (82.1-91.1) Anal canal PCR-MY9/11 HIV- MSM 28-62 9 88.9 (51.8-99.7) Anus Coronal sulcus Urethra Glans, corona, frenulum, prepuce Bleeker Corona, 25 a frenulum, glans, inner prepuce Bleeker Corona, 25 b frenulum, glans, inner prepuce van der Snoek 23 Coronal sulcus Perianal area PCR-Multiplex and RFLP and sequencing PCR-Multiplex and RFLP and sequencing PCR-Multiplex and RFLP and sequencing PCR-GP5+/6+ PCR-GP5+/6+ PCR-GP5+/6+ PCR-TS primers and LiPA PCR-TS primers and LiPA HIV+ MSM 25-65 18 94.4 (72.7-99.9) HIV+ MSM Mean 38 (IQR=2-53) HIV+ MSM Mean 38 (IQR=2-53) HIV+ MSM Mean 38 (IQR=2-53) Partners of women with CIN Men visiting department of dermatology for non-sti complaints Partners of women with dyskaryosis and/or CIN 5 56 (41.3-7.) 5 22 (11.5-36.) 5 1 (3.3-21.8) 24-58 119 58.8 (49.4-67.8) 22.8-73.2 83 25.3 (16.4-36.) 22.5-57.7 181 72.9 (65.8-79.3) HIV- MSM 19-76 241 15.8 (11.4-21.) HIV+ MSM 29-59 17 23.5 (6.8-49.9) HIV- MSM 19-76 241 32.8 (26.9-39.1) ( Table 26 continued from previous page)

4 HPV-RELATED STATISTICS - 138 - ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Van Doornum 1994 van 214 Vriend 213 Welling 215 Rijn Corona, urethra, anus, rectum Anal canal Penile shaft PCR-TS 6/11,16,18,33 PCR-LIPA TS 16,18,31,33,45,52,58 PCR-LIPA TS 16,18,31,33,45,52,58 HIV+ MSM 29-59 17 64.7 (38.3-85.8) STD clinic attendees HIV- MSM HIV+ MSM HIV- MSM HIV+ MSM Anal canal PCR-LIPA MSM STD clinic attendees MSW STD clinic attendees Penis PCR-LIPA MSM STD clinic attendees Anus Penis PCR-SPF DEIA LIPA PCR-SPF DEIA LIPA Russia Wirtz 215 Anus PCR-TS 6,11,16,18,31,33 MSW STD clinic attendees HIV- MSM HIV+ MSM HIV- MSM HIV+ MSM HIV- MSM HIV+ MSM Mean 37 85 28.2 (19.-39.) Median 37.6 (IQR=33.6-42.2) Median 45.6 (IQR=39.4-52.5) Median 37.6 (IQR=33.6-42.2) Median 45.6 (IQR=39.4-52.5) Median 22 (16-24) Median 22 (16-24) Median 22 (16-24) Median 22 (16-24) Median 38 (IQR=33-42) Median 46 (IQR=39-53) Median 38 (IQR=33-42) Median 46 (IQR=39-53) Median 29 (19-5) Median 29 (19-5) 441 33.6 (29.2-38.2) 36 56.9 (51.1-62.5) 441 11.1 (8.3-14.4) 36 23.2 (18.6-28.3) 56 3.6 (.4-12.3) 124 33.1 (24.9-42.1) 56 26.8 (15.8-4.3) 124 16.1 (1.1-23.8) 461 6.1 (55.5-64.6) 317 78.2 (73.3-82.7) 461 29.5 (25.4-33.9) 317 49.5 (43.9-55.2) 65 3.8 (19.9-43.4) 58 5 (36.6-63.4) ( Table 26 continued from previous page)

4 HPV-RELATED STATISTICS - 139 - ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Slovenia Golob 214 Penis PCR-Linear Array Men from infertile couples Spain Milosevic 21 Álvarez- Argüelles 213 Franceschi 22 Goldstone 211 Hidalgo- Tenorio 215 Sendagorta 214 Sendagorta 215 Torres 213 Videla 213 Mean 33 299 37.1 (31.6-42.9) Anal canal PCR-Linear Array HIV- MSM 16-8 116 75 (66.1-82.6) Anus Balanopreputial Glans, corona, urethra Anus Penis Anus Anus Anus Anus Anus PCR-General primers in L1 (MY9/11, GP5 + /6+), PCR with TS primers in E6/E7 for typing PCR-General primers in L1 (MY9/11, GP5 + /6+), PCR with TS primers in E6/E7 for typing PCR-GP5+/6+ RT-PCR-Multiplex or Biplex RT-PCR-Multiplex or Biplex PCR-GeneAmp HR-HPV PCR-Genomic amplification PCR-HR Clart HPV2 PCR-Roche Linear Array HPV Genotyping test PCR-TS primers in E6/E7 F-HPVTM typing (Molgentix SL, Spain) HIV+ MSM 2-57 2 95 (75.1-99.9) STD clinic attendees STD clinic attendees Husbands of women with cervical carcinoma in situ Husbands of women with invasive cervical cancer HIV- MSM HIV- MSM HIV+ MSM HIV+ MSM/bisexual men HIV+ MSM HIV+ MSM HIV+ Heterosexual men attending an outpatient HIV clinic HIV+ MSM attending an outpatient HIV clinic 17-87 123 49.6 (4.5-58.8) 17-87 1318 36.9 (34.3-39.5) 22-76 12 21.6 (14.-3.8) 25-74 84 11.9 (5.9-2.8) Median 22 (16-27) Median 22 (16-27) Mean 37.4 (SD=9.5) 62 42.4 (38.4-46.4) 62 18.4 (15.4-21.8) 197 8.2 (73.9-85.5) >=18 298 93 (89.4-95.6) Median 42 (IQR=33-5) IQR=28.2-4.1 11 82.2 (73.3-89.1) 1439 95.8 (94.6-96.7) 4-48 195 41.5 (34.5-48.8) 36-47 538 84.2 (8.8-87.2) ( Table 26 continued from previous page)

4 HPV-RELATED STATISTICS - 14 - ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Sweden UK Kataoka 1991 Löwhagen 1999 Strand 1993 Voog 1997 Wikström 1991 Wikström 2 Bissett 211 Cuschieri 211 Hillman 1993 Coronal sulcus, glans, urethra, shaft Urethra PCR-TS primers in E6/E7 F-HPVTM typing (Molgentix SL, Spain) PCR-TS 6,11,16,18,33 HIV+ Heterosexual men attending an outpatient HIV clinic HIV+ MSM attending an outpatient HIV clinic Army conscripts with aceto-white epithelium 4-48 191 27.2 (21.-34.1) 36-47 457 24.9 (21.-29.2) 18-23 39 25.6 (13.-42.1) Anus PCR-MY9/11 HIV- MSM 26-62 13 53.8 (25.1-8.8) Coronal sulcus, glans, preputium, and shaft Glans and prepuce Coronal sulcus, inner part of the prepuce, urethra Corona, glans, and prepuce Glans, prepuce, shaft, scrotum PCR-MY9/11 and GP5+/6+ PCR-MY9/11 and GP5+/6+ PCR-TS primers followed by dot blot PCR-GP5+/6+ PCR-General primers (GP5 + /6+), Bio-Plex array technology for typing HIV+ MSM 27-54 17 94.1 (71.3-99.9) STD clinic attendees STD clinic attendees STD clinic attendees STD clinic attendees Genitourinary clinic attendees with multiple sexual partners or diagnosis of genital warts within 6 months Shaft PCR-INNO-LiPA Drop-in sexual health service attendees Urethra PCR-GP5+/6+ Men infected with gonorrhea Jalal 27 Urethra PCR-General primers for L1 (MY9/11, GP5 + /6+) and RLH King 215 Anus PCR-Multiplex and Bio-Plex Any nonavalent vaccine HPV types Lacey 1999 Coronal sulcus, glans, penis shaft, scrotum and perianal area PCR-Multiplex and Bio-Plex Any nonavalent vaccine HPV types Genitourinary clinic attendees MSM MSM 2-53 65 29.2 (18.6-41.8) 19-67 2 25 (8.7-49.1) 17-58 228 53.9 (47.2-6.5) 18-54 235 13.2 (9.1-18.2) - 87 49.4 (38.5-6.4) 16-25 117 29.1 (21.-38.2) 17-55.6 1 18 (11.-26.9) 15-77 437 2.8 (17.1-24.9) Median 3 (IQR=25-35) Median 3 (IQR=25-35) 454 4.1 (35.5-44.8) 446 36.1 (31.6-4.7) Anal canal PCR-GP5+/6+ HIV+ MSM 19-62 57 84.2 (72.1-92.5) ( Table 26 continued from previous page)

4 HPV-RELATED STATISTICS - 141 - ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Data updated on 28 Jun 217 (data as of 31 Oct 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; HC2: Hybrid Capture 2; LiPA: Line Probe Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; RLH: Reverse Line Hybridisation; RT-PCR: Real Time Polymerase Chain Reaction; SPF: Short Primer Fragment; TS: Type Specific; MSM: Men who have sex with men; MSW:Men who have sex with women; STD: sexually transmitted diseases; a Bleeker MC, Int J Cancer 25; 113: 36 b Bleeker MC, Clin Infect Dis 25; 41: 612 Data sources: See references in Section 9. 4.4 HPV burden in the head and neck The last evaluation of the International Agency for Research in Cancer (IARC) on the carcinogenicity of HPV in humans concluded that (a) there is enough evidence for the carcinogenicity of HPV type 16 in the oral cavity, oropharynx (including tonsil cancer, base of tongue cancer and other oropharyngeal cancer sites), and (b) limited evidence for laryngeal cancer (IARC Monograph Vol 1B). There is increasing evidence that HPV-related oropharyngeal cancers constitute an epidemiological, molecular and clinical distinct form as compared to non HPV-related ones. Some studies indicate that the most likely explanation for the origin of this distinct form of head and neck cancers associated with HPV is a sexually acquired oral HPV infection that is not cleared, persists and evolves into a neoplastic lesion. The most recent figures estimate that 25.6% of all oropharyngeal cancers are attributable to HPV infection with HPV16 being the most frequent type (de Martel C. Lancet Oncol. 212;13(6):67). In this section, the HPV burden in the head and neck in Europe is presented. 4.4.1 Burden of oral HPV infection in healthy population Table 27: European studies on oral HPV prevalence among healthy population Method HPV detection Prev. of 5 most specimen method frequent collection and and targeted Age No. HPV prevalence HPVs Study anatomic site HPV types Population (years) Tested % (95% CI) HPV type (%) MEN Eike 1995 (Denmark) Kero 212 (Finland) Montaldo 27 (Italy) Kujan 26 (UK) WOMEN Oral smear taken with a wooden stick, used on the right border of the tongue and right buccal mucosa Cytobrush from the buccal mucosa Saliva samples Two brushes: 1.-cervex brush into each side of buccal mucosa and 2.-cytobrush lateral border of the tongue PCR-MY9/11. Genotyping by amplification with TS primers (6, 11, 16, 18) and RFLP PCR-GP5+/GP6+ and MY9/MY11. Genotyping with Multimerix kit (6, 11, 16, 18, 31, 33, 39, 42, 43, 44, 45, 51, 52, 58, 59, 68, 7, 73, 82) PCR-MY9/MY11 and GP5+N. Genotyping by sequencing PCR-Roche master mix and HC2 digene (both able to detect the following HR types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68). No further genotyping Patients with unrelated disease (otosclerosis, nasal complaints)and their accompanying relatives Fathers-to-be of cohort study Dental clinic visitors Healthy volunteers from university dental hospital. 2-79 31. (.-11.2) - - 131 18.3 (12.1-26.) HPV 16 (9.2%) HPV 33 (2.3%) HPV 82 (2.3%) HPV 6 (.8%) HPV 11 (.8%) 4-77 69 14.5 (7.2-25.) HPV 16 (13.%) HPV 31 (1.5%) - 26 3.9 (.1-19.6) - (Continued on next page)

4 HPV-RELATED STATISTICS - 142 - ( Table 27 continued from previous page) Method HPV detection Prev. of 5 most specimen method frequent collection and and targeted Age No. HPV prevalence HPVs Study anatomic site HPV types Population (years) Tested % (95% CI) HPV type (%) Eike 1995 (Denmark) Kero 211 (Finland) Leimola- Virtanen 1996 (Finland) Montaldo 27 (Italy) Oral smear taken with a wooden stick, used on the right border of the tongue and right buccal mucosa Cytobrush from the buccal mucosa Oral smears collected from three sites of clinically healthy oral mucosa (i.e., buccal surface, palate, and tongue) with use of a sterile interdental brush Saliva samples Cañadas Toothbrush on the 24 (Spain) oral cavity Kujan 26 (UK) Two brushes: 1.-cervex brush into each side of buccal mucosa and 2.-cytobrush lateral border of the tongue BOTH OR UNSPECIFIED Eike 1995 (Denmark) Kero 211 (Finland) Kero 212 (Finland) Leimola- Virtanen 1996 (Finland) Lambropoulos 1997 (Greece) Oral smear taken with a wooden stick, used on the right border of the tongue and right buccal mucosa Cytobrush from the buccal mucosa Cytobrush from the buccal mucosa Oral smears collected from three sites of clinically healthy oral mucosa (i.e., buccal surface, palate, and tongue) with use of a sterile interdental brush Cytobrush from the buccal mucosa PCR-MY9/11. Genotyping by amplification with TS primers (6, 11, 16, 18) and RFLP PCR-GP5+/GP6+ and MY9/MY11. Genotyping with Multimerix kit (6, 11, 16, 18, 31, 33, 39, 42, 43, 44, 45, 51, 52, 58, 59, 68, 7, 73, 82) PCR-GP5/GP6. No genotyping PCR-MY9/MY11 and GP5+N. Genotyping by sequencing PCR-MY9/MY11. Genotyping by DBH with TS probes (6, 11, 16, 18, 26, 31-33, 35, 39, 4, 45, 51-56, 58, 59, 61, 66-68, 7, 71 (AE8), 72, 73, 81 (AE7), 83 (PAP291), 84 (PAP155), 85 (AE5), AE2 (IS39), and AE6) PCR-Roche master mix and HC2 digene (both able to detect the following HR types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68). No further genotyping PCR-MY9/11. Genotyping by amplification with TS primers (6, 11, 16, 18) and RFLP PCR-GP5+/GP6+ and MY9/MY11. Genotyping with Multimerix kit (6, 11, 16, 18, 31, 33, 39, 42, 43, 44, 45, 51, 52, 58, 59, 68, 7, 73, 82) PCR-GP5+/GP6+ and MY9/MY11. Genotyping with Multimerix kit (6, 11, 16, 18, 31, 33, 39, 42, 43, 44, 45, 51, 52, 58, 59, 68, 7, 73, 82) PCR-GP5/GP6. No genotyping PCR-MY9/MY11. Genotyping by SBH with TS probes (6, 11, 16, 18, 33) Patients with unrelated disease (otosclerosis, nasal complaints)and their accompanying relatives Spouses in 3rd trimestres of pregnancy of the fathers-to-be of cohort study Post-menopausal women participating in annual mass-screening program for the detection of cervical precancerous lesions Dental clinic visitors Female sex workers who attended a dermatology or STD clinic. Healthy volunteers from university dental hospital. Patients with unrelated disease (otosclerosis, nasal complaints)and their accompanying relatives Spouses in 3rd trimestres of pregnancy of the fathers-to-be of cohort study Fathers-to-be of cohort study Post-menopausal women participating in annual mass-screening program for the detection of cervical precancerous lesions Healthy population receiving routine oral examination (Continued on next page) 2-79 3. (.-11.6) - - 128 17.2 (11.1-24.9) HPV 16 (13.3%) HPV 6 (2.3%) HPV 58 (.8%) 55 131 1.7 (6.-17.3) - 4-77 95 21.1 (13.4-3.6) HPV 16 (14.7%) HPV 31 (6.3%) - 188 8.5 (4.9-13.5) HPV 6 (2.7%) HPV 16 (2.1%) HPV 11 (.5%) - 24 12.5 (2.7-32.4) - 2-79 61. (.-5.9) - - 128 17.2 (11.1-24.9) HPV 16 (13.3%) HPV 6 (2.3%) HPV 58 (.8%) - 131 18.3 (12.1-26.) HPV 16 (9.2%) HPV 33 (2.3%) HPV 82 (2.3%) HPV 6 (.8%) HPV 11 (.8%) 55 131 1.7 (6.-17.3) - 14-85 169 9.5 (5.5-14.9) HPV 6 (3.6%) HPV 16 (2.4%) HPV 11 (.6%)

4 HPV-RELATED STATISTICS - 143 - ( Table 27 continued from previous page) Method HPV detection Prev. of 5 most specimen method frequent collection and and targeted Age No. HPV prevalence HPVs Study anatomic site HPV types Population (years) Tested % (95% CI) HPV type (%) Migaldi 212Cytobrush from the (Italy) buccal mucosa Montaldo 27 (Italy) Saliva samples Cañadas Toothbrush on the 24 (Spain) oral cavity Kujan 26 (UK) Two brushes: 1.-cervex brush into each side of buccal mucosa and 2.-cytobrush lateral border of the tongue PCR-GP5+/GP6+, MY9/11, LCRS/E7AS, pu-1m and pu-2r. Genotyping by sequencing PCR-MY9/MY11 and GP5+N. Genotyping by sequencing PCR-MY9/MY11. Genotyping by DBH with TS probes (6, 11, 16, 18, 26, 31-33, 35, 39, 4, 45, 51-56, 58, 59, 61, 66-68, 7, 71 (AE8), 72, 73, 81 (AE7), 83 (PAP291), 84 (PAP155), 85 (AE5), AE2 (IS39), and AE6) PCR-Roche master mix and HC2 digene (both able to detect the following HR types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68). No further genotyping Patients undergoing to routine oral examination Dental clinic visitors Female sex workers who attended a dermatology or STD clinic. Healthy volunteers from university dental hospital. 49-77 81 1.2 (.-6.7) HPV 9 (1.2%) 4-77 164 18.3 (12.7-25.1) HPV 16 (14.%) HPV 31 (4.3%) - 188 8.5 (4.9-13.5) HPV 6 (2.7%) HPV 16 (2.1%) HPV 11 (.5%) - 5 8. (2.2-19.2) - Data updated on 15 Dec 214 (data as of 29 Feb 212). Only for European countries. 95% CI: 95% Confidence Interval; DBH: Dot Blot Hybridization; HC2: Hybrid Capture 2; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; SBH: Southern Blot Hybridization; TS: Type Specific; Data sources: See references in Section 9. 4.4.2 HPV burden in head and neck cancers Table 28: European studies on HPV prevalence among cases of oral cavity cancer HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) MEN Nemes 26 (Hungary) Herrero 23 (Ireland) Herrero 23 (Italy) Cruz 1996 (Netherlands) MY9/MY11 (L1) Hybridization with TS probes (16. 18. 31. 33. 45. 51. 52. 58) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers and hybridization with TS probes (2. 4. 6. 1. 11. 13. 16. 18. 25. 31. 33. 46. 51. 52) 67 44.8 (33.5-56.6) - 22 4.5 (.8-21.8) HPV 16 (4.5%) 32. - - 22 63.6 (43.-8.3) HPV 16 (54.5%) HPV 6 (4.5%) (Continued on next page)

4 HPV-RELATED STATISTICS - 144 - HPV detection ( Table 28 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Herrero 23 (Poland) Kozomara 25 (Serbia) Kansky 23 (Slovenia) Herrero 23 (Spain) Llamas-Martínez 28 (Spain) Dahlgren 24 (Sweden) WOMEN Nemes 26 (Hungary) Herrero 23 (Ireland) Herrero 23 (Italy) Cruz 1996 (Netherlands) Herrero 23 (Poland) Kozomara 25 (Serbia) Kansky 23 (Slovenia) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) TS-PCR E6 for 16. L1 for 18. E4 for 31 and E1 for 33 Amplification with TS primers (16. 18. 31. 33) PGMY9/11 (L1). GP5+/GP6+ (L1) and WD72/76/66/67/154 (E6) RFLP GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) WD-66/67/72/76/154 (E6) RFLP (6. 11. 16. 18. 31. 33. 39. 42. 45. 52) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers (16. 18. 33) and sequencing MY9/MY11 (L1) Hybridization with TS probes (16. 18. 31. 33. 45. 51. 52. 58) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers and hybridization with TS probes (2. 4. 6. 1. 11. 13. 16. 18. 25. 31. 33. 46. 51. 52) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) TS-PCR E6 for 16. L1 for 18. E4 for 31 and E1 for 33 Amplification with TS primers (16. 18. 31. 33) PGMY9/11 (L1). GP5+/GP6+ (L1) and WD72/76/66/67/154 (E6) RFLP 53. - - 42 61.9 (46.8-75.) - 48 4.2 (1.2-14.) HPV 33 (2.1%) HPV 58 (2.1%) 14 5.7 (2.9-1.9) HPV 16 (5.7%) 19 47.4 (27.3-68.3) - 51 3.9 (1.1-13.2) - 12 25. (8.9-53.2) - 8 25. (7.1-59.1) HPV 16 (25.%) 21 9.5 (2.7-28.9) HPV 16 (9.5%) 13 38.5 (17.7-64.5) HPV 16 (23.1%) 3. - - 8 75. (4.9-92.9) - 7 14.3 (2.6-51.3) HPV 16 (14.3%) (Continued on next page)

4 HPV-RELATED STATISTICS - 145 - HPV detection ( Table 28 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Herrero 23 (Spain) Llamas-Martínez 28 (Spain) Dahlgren 24 (Sweden) BOTH OR UNSPECIFIED Koskinen 23 (Finland) Klussmann 21 (Germany) Ostwald 23 (Germany) Weiss 211 (Germany) Aggelopoulou 1999 (Greece) Romanitan 28 (Greece) Nemes 26 (Hungary) Szarka 29 (Hungary) Herrero 23 (Ireland) Badaracco 2 (Italy) Badaracco 27 (Italy) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) WD-66/67/72/76/154 (E6) RFLP (6. 11. 16. 18. 31. 33. 39. 42. 45. 52) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers (16. 18. 33) and sequencing 32 6.3 (1.7-2.1) HPV 16 (6.3%) 14 35.7 (16.3-61.2) - 34. - - SPF1 (L1) LiPA 25 28 64.3 (45.8-79.3) HPV 16 (46.4%) HPV 33 (21.4%) A1/A5-A6/A8 (L1) and 22 18.2 (7.3-38.5) HPV 16 (13.6%) CP62/7-CP65/69a (L1) HPV 19 (4.5%) Sequencing TS-PCR E6 for 6/11/16/18 Hybridization with TS probes (6/11. 16. 18) RT-PCR E6/E7 for 16 Hybridization with TS probes (16) L1 consensus primers and TS-PCR E7 for 16/18 Amplification with TS primers (16. 18) GP5+/GP6+ (L1). CPI/CPIIG (E1) and TS-PCR E6/E7 for 16 Amplification with TS primers (16) MY9/MY11 (L1) Hybridization with TS probes (16. 18. 31. 33. 45. 51. 52. 58) MY9/MY11 (L1) and GP5+/GP6+ (L1) RFLP GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) MY9/MY11 (L1) Amplification with TS primers (6. 16) and hybridization with TS probes (11. 16. 18. 31. 45. 56. 57) MY9/MY11 (L1) and GP5+/GP6+ (L1) Sequencing 118 43.2 (34.6-52.2) HPV 16 (29.7%) HPV 18 (13.6%) 34 2.9 (.5-14.9) HPV 16 (2.9%) 81 49.4 (38.8-6.) HPV 18 (27.2%) HPV 16 (6.2%) 75 1.3 (.2-7.2) - 79 41.8 (31.5-52.8) HPV 16 (34.2%) HPV 18 (6.3%) HPV 31 (3.8%) HPV 33 (2.5%) 65 47.7 (36.-59.6) HPV 16 (27.7%) HPV 11 (6.2%) HPV 18 (6.2%) HPV 33 (3.1%) HPV 31 (1.5%) 3 1. (3.5-25.6) HPV 16 (1.%) 38 26.3 (15.-42.) HPV 18 (13.2%) HPV 6 (1.5%) HPV 16 (1.5%) HPV 11 (5.3%) HPV 56 (5.3%) 53 11.3 (5.3-22.6) HPV 16 (7.5%) HPV 33 (1.9%) HPV 58 (1.9%) (Continued on next page)

4 HPV-RELATED STATISTICS - 146 - HPV detection ( Table 28 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Herrero 23 (Italy) Rittà 29 (Italy) Scapoli 29 (Italy) Braakhuis 24 (Netherlands) Cruz 1996 (Netherlands) Eu- Mork (Northern rope) 21 a Matzow 1998 (Norway) Herrero 23 (Poland) Snietura 21 (Poland) Kozomara 25 (Serbia) Kansky 23 (Slovenia) Herrero 23 (Spain) Llamas-Martínez 28 (Spain) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) MY9/MY11 (L1) and GP5+/GP6+ (L1) Sequencing RT-PCR for 16/18/31/45 Hybridization with TS probes (16. 18. 31. 45) GP5+/GP6+ (L1) and TS-PCR RLBH (6. 11. 16. 18. 26. 31. 33. 34. 35. 39. 4. 42. 43. 44. 45. 51. 52. 53. 54. 55. 56. 57. 58. 59. 61. 66. 68. 7. 72. 73. 82/MM4. 83. 84. 82/IS39. 71/CP861. 81/CP834. 89) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers and hybridization with TS probes (2. 4. 6. 1. 11. 13. 16. 18. 25. 31. 33. 46. 51. 52) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers (6. 11. 16. 18. 33) GP5+/GP6+ (L1). CPI/CPIIG (E1) and TS-PCR for 6/16/18/31/33 Amplification with TS primers (6. 16. 18. 31. 33) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) Real-time High Risk HPV test (Abbott Molecular) using L1 consensus primers Amplification with TS primers (16. 18. 31. 33. 35. 39. 45. 51. 52. 56. 58. 59. 66 and 68 - the technique only differentiates 16-18-other) TS-PCR E6 for 16. L1 for 18. E4 for 31 and E1 for 33 Amplification with TS primers (16. 18. 31. 33) PGMY9/11 (L1). GP5+/GP6+ (L1) and WD72/76/66/67/154 (E6) RFLP GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) WD-66/67/72/76/154 (E6) RFLP (6. 11. 16. 18. 31. 33. 39. 42. 45. 52) 53 3.8 (1.-12.8) HPV 16 (3.8%) 25 36. (2.2-55.5) HPV 16 (36.%) 247 1.2 (.4-3.5) HPV 16 (1.2%) 16 9.4 (5.2-16.5) HPV 16 (9.4%) 35 54.3 (38.2-69.5) HPV 16 (42.9%) HPV 6 (2.9%) 91 7.7 (3.8-15.) HPV 16 (4.4%) HPV 6 (1.1%) HPV 11 (1.1%) HPV 33 (1.1%) 3. - - 83. - - 45 4.4 (1.2-14.8) HPV 16 (4.4%) 5 64. (5.1-75.9) HPV 31 (32.%) HPV 16 (26.%) HPV 18 (26.%) 55 5.5 (1.9-14.9) HPV 16 (1.8%) HPV 33 (1.8%) HPV 58 (1.8%) 172 5.8 (3.2-1.4) HPV 16 (5.8%) 33 42.4 (27.2-59.2) HPV 16 (33.3%) HPV 6 (3.3%) HPV 31 (9.1%) (Continued on next page)

4 HPV-RELATED STATISTICS - 147 - HPV detection ( Table 28 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Dahlgren 24 (Sweden) Sand 2 (Sweden) Lopes 211 (UK) Snijders 1996 (UK) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers (16. 18. 33) and sequencing MY9/MY11 (L1) Amplification with TS primers (6b/11. 16. 18) GP5+/GP6+ (L1) and qpcr for 16/18 Hybridization with TS probes (16. 18) GP5+/GP6+ (L1) Amplification with TS primers and SBH with TS probes (6. 11. 16. 18. 31. 33) Yeudall 1991 (UK) TS-PCR E6/E7 for 16. E6 for 18 and specific for 4 Hybridization with TS probes (4. 16. 18) Ribeiro 211 b PGMY9/11 (L1) Amplification (World) with TS primers (16) 85 2.4 (.6-8.2) HPV 16 (2.4%) 24 12.5 (4.3-31.) HPV 16 (4.2%) HPV 18 (4.2%) 142 3.5 (1.5-8.) HPV 16 (2.1%) HPV 18 (2.1%) 25 2. (8.9-39.1) HPV 16 (2.%) 39 46.2 (31.6-61.4) HPV 16 (25.6%) HPV 18 (2.5%) 132. - - Data updated on 28 Jun 217 (data as of 31 Dec 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; LiPA: Line Probe Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; RLBH: Reverse Line Blot Hybridization; RT-PCR: Real Time Polymerase Chain Reaction; SBH: Southern Blot Hybridization; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Norway, Sweden and Finland b Includes cases from Argentina, Brazil, Cuba, Russia, Slovakia, Czech Republic, Romania and Poland Data sources: See references in Section 9. Table 29: European studies on HPV prevalence in cases of oropharyngeal cancer HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) MEN Rotnáglová 211 (Czech Rep.) Charfi 28 (France) Hoffmann 21 (Germany) Krupar 214 (Germany) Reimers 27 (Germany) Herrero 23 (Italy) Hannisdal 21 (Norway) GP5+/GP6+ (L1) RBLH (6. 11. 16. 18. 26. 31. 33. 34. 35. 39. 4. 42. 43. 44. 45. 51. 52. 53. 54. 55. 56. 57. 58. 59. 61. 66. 68. 7. 71. 72. 73. 81. 82. 83. 84. 89) GP5+/GP6+ (L1) and TS-PCR for 6/11/16/18/33 Amplification with TS primers (6. 11. 16. 18. 33) GP5+/GP6+ (L1). MY9/MY11 (L1) and TS-PCR for 6/11/16/18 Hybridization with TS probes - Multiplex luminex PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 66, 68) A1/A5-A6/A8 (L1) and CP62/7-CP65/69a (L1) Sequencing GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) 9 64.4 (54.2-73.6) - 36 55.6 (39.6-7.5) - 31 54.8 (37.8-7.8) HPV 16 (51.6%) HPV 35 (6.5%) 34 5. (34.1-65.9) HPV 16 (5.%) 83 25.3 (17.2-35.6) - 3 23.3 (11.8-4.9) HPV 16 (2.%) HPV 33 (3.3%) HPV 35 (3.3%) GP5+/GP6+ (L1) Sequencing 99 56.6 (46.7-65.9) - (Continued on next page)

4 HPV-RELATED STATISTICS - 148 - HPV detection ( Table 29 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Herrero 23 (Spain) Attner 21 (Sweden) Dahlgren 24 (Sweden) Hammarstedt 26 (Sweden) Näsman 29 (Sweden) Lindel 21 (Switzerland) WOMEN Rotnáglová 211 (Czech Rep.) Charfi 28 (France) Hoffmann 21 (Germany) Reimers 27 (Germany) Herrero 23 (Italy) Hannisdal 21 (Norway) Herrero 23 (Spain) Attner 21 (Sweden) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) 4 5. (1.4-16.5) HPV 16 (5.%) GP5+/GP6+ (L1). CPI/IIG (E1) 65 75.4 (63.7-84.2) - and TS-PCR E6/7 for 16/33 Amplification with TS primers (16. 33) and sequencing GP5+/GP6+ (L1) and CPI/CPII 18 44.4 (24.6-66.3) - (L1) Amplification with TS primers (16. 18. 33) and sequencing GP5+/GP6+ (L1). CPI/CPIIG 145 48.3 (4.3-56.3) - (E1) and TS-PCR E6 for 16 Sequencing GP5+/GP6+ (L1). CPI/CPIIG 76 81.6 (71.4-88.7) - (E1) and TS-PCR E6 for 16 Sequencing SPF1 (L1) Sequencing 75 8. (3.7-16.4) - GP5+/GP6+ (L1) RBLH (6. 11. 16. 18. 26. 31. 33. 34. 35. 39. 4. 42. 43. 44. 45. 51. 52. 53. 54. 55. 56. 57. 58. 59. 61. 66. 68. 7. 71. 72. 73. 81. 82. 83. 84. 89) 19 68.4 (46.-84.6) - GP5+/GP6+ (L1) and TS-PCR for 16 75. (5.5-89.8) - 6/11/16/18/33 Amplification with TS primers (6. 11. 16. 18. 33) GP5+/GP6+ (L1). MY9/MY11 8 5. (21.5-78.5) HPV 16 (5.%) (L1) and TS-PCR for 6/11/16/18 Hybridization with TS probes - Multiplex luminex A1/A5-A6/A8 (L1) and 23 39.1 (22.2-59.2) - CP62/7-CP65/69a (L1) Sequencing GP5+/GP6+ (L1) Hybridization 6. - - with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) GP5+/GP6+ (L1) Sequencing 38 39.5 (25.6-55.3) - GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) GP5+/GP6+ (L1). CPI/IIG (E1) and TS-PCR E6/7 for 16/33 Amplification with TS primers (16. 33) and sequencing 4 5. (15.-85.) HPV 16 (5.%) 3 73.3 (55.6-85.8) - (Continued on next page)

4 HPV-RELATED STATISTICS - 149 - HPV detection ( Table 29 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Dahlgren 24 (Sweden) Hammarstedt 26 (Sweden) Näsman 29 (Sweden) Lindel 21 (Switzerland) BOTH OR UNSPECIFIED Klozar 28 (Czech Rep.) Rotnáglová 211 (Czech Rep.) Jouhi 215 (Finland) Charfi 28 (France) Fonmarty 215 (France) Fouret 1997 (France) Andl 1998 (Germany) Hoffmann 1998 (Germany) Hoffmann 21 (Germany) Holzinger 212 (Germany) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers (16. 18. 33) and sequencing 7 28.6 (8.2-64.1) - GP5+/GP6+ (L1). CPI/CPIIG 58 5. (37.5-62.5) - (E1) and TS-PCR E6 for 16 Sequencing GP5+/GP6+ (L1). CPI/CPIIG 22 95.5 (78.2-99.2) - (E1) and TS-PCR E6 for 16 Sequencing SPF1 (L1) Sequencing 24 33.3 (18.-53.3) - GP5+/GP6+ (L1) RLBH (6. 11. 16. 18. 26. 31. 33. 34. 35. 39. 4. 42. 43. 44. 45. 51. 52. 53. 54. 55. 56. 57. 58. 59. 61. 66. 68. 7. 71. 72. 73. 81. 82. 83. 84. 89) GP5+/GP6+ (L1) RBLH (6. 11. 16. 18. 26. 31. 33. 34. 35. 39. 4. 42. 43. 44. 45. 51. 52. 53. 54. 55. 56. 57. 58. 59. 61. 66. 68. 7. 71. 72. 73. 81. 82. 83. 84. 89) PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 53, 56, 58, 59, 66, 68, 7, 73, 82) GP5+/GP6+ (L1) and TS-PCR for 6/11/16/18/33 Amplification with TS primers (6. 11. 16. 18. 33) PCR, LiPA (HPV 6, 11, 16, 18, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 82) TS-PCR E6 for 16/18/31/33/45 Hybridization with TS probes (16. 18. 31. 33. 45) TS-PCR for 6/11/16/18 Hybridization with TS probes (6. 11. 16. 18) and cycle sequencing system of BRL MY9/MY11 (L1) and TS-PCR for 6/11/16/18/33 SBH (6. 11. 16. 18. 31. 33. 45) GP5+/GP6+ (L1). MY9/MY11 (L1) and TS-PCR for 6/11/16/18 Hybridization with TS probes - Multiplex luminex PCR-GP5+/6+, PCR L1-Consensus primer, PCR- MULTIPLEX (HPV 16, 18, 33, 35) 2 45. (25.8-65.8) HPV 16 (4.%) HPV 33 (5.%) 19 65.1 (55.8-73.4) HPV 16 (6.6%) HPV 33 (1.8%) HPV 18 (.9%) HPV 26 (.9%) HPV 52 (.9%) 35 51.4 (35.6-67.) HPV 16 (45.7%) HPV 18 (2.9%) HPV 45 (2.9%) 52 61.5 (48.-73.5) HPV 16 (51.9%) HPV 33 (1.9%) 71 31. (21.4-42.5) HPV 16 (28.2%) HPV 33 (2.8%) HPV 6 (1.4%) 58 17.2 (9.6-28.9) HPV 16 (15.5%) 21 52.4 (32.4-71.7) HPV 16 (38.1%) HPV 33 (4.8%) 23 26.1 (12.5-46.5) HPV 16 (8.7%) HPV 45 (8.7%) HPV 6 (4.3%) 39 53.8 (38.6-68.4) HPV 16 (51.3%) HPV 35 (5.1%) 199 5.3 (43.4-57.1) HPV 16 (48.7%) HPV 18 (.5%) HPV 33 (.5%) HPV 35 (.5%) (Continued on next page)

4 HPV-RELATED STATISTICS - 15 - HPV detection ( Table 29 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Klussmann 21 (Germany) Krupar 214 (Germany) Reimers 27 (Germany) Weiss 211 (Germany) Wittekindt 25 (Germany) Romanitan 28 (Greece) Boscolo-Rizzo 29 (Italy) Herrero 23 (Italy) Licitra 26 (Italy) Rittà 29 (Italy) Braakhuis 24 (Netherlands) Henneman 215 (Netherlands) van Monsjou 212 (Netherlands) Hannisdal 21 (Norway) A1/A5-A6/A8 (L1) and CP62/7-CP65/69a (L1) Sequencing PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 66, 68) A1/A5-A6/A8 (L1) and CP62/7-CP65/69a (L1) Sequencing RT-PCR E6/E7 for 16 Hybridization with TS probes (16) A1/A5-A6/A8 (L1) and (L1) Sequencing GP5+/GP6+ (L1). CPI/CPIIG (E1) and TS-PCR E6/E7 for 16 Amplification with TS primers (16) MY9/MY11 (L1) RFLP and amplification with TS primers E6/E2 for 16 GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) RT-PCR E1 for 16/18 Hybridization with TS probes (16. 18) MY9/MY11 (L1) and GP5+/GP6+ (L1) Sequencing GP5+/GP6+ (L1) and TS-PCR RLBH (6. 11. 16. 18. 26. 31. 33. 34. 35. 39. 4. 42. 43. 44. 45. 51. 52. 53. 54. 55. 56. 57. 58. 59. 61. 66. 68. 7. 72. 73. 82/MM4. 83. 84. 82/IS39. 71/CP861. 81/CP834. 89) PCR-SPF1, LiPA (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) PCR, LiPA (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 72, 73, 82) 33 45.5 (29.8-62.) HPV 16 (42.4%) HPV 5 (3.%) HPV 33 (3.%) HPV 96 (3.%) 34 5. (34.1-65.9) HPV 16 (5.%) 16 28.3 (2.6-37.5) HPV 16 (27.4%) HPV 33 (.9%) 86 38.4 (28.8-48.9) HPV 16 (38.4%) 34 52.9 (36.7-68.5) HPV 16 (5.%) HPV 33 (2.9%) 28 42.9 (26.5-6.9) HPV 16 (32.1%) 22 18.2 (7.3-38.5) HPV 16 (18.2%) 36 19.4 (9.8-35.) HPV 16 (16.7%) HPV 33 (2.8%) HPV 35 (2.8%) 9 18.9 (12.1-28.2) HPV 16 (18.9%) 22 5. (3.7-69.3) HPV 16 (5.%) 37 37.8 (24.1-53.9) HPV 16 (37.8%) 146 34.9 (27.7-43.) HPV 16 (32.2%) HPV 33 (2.1%) HPV 35 (.7%) 2 65. (43.3-81.9) HPV 16 (6.%) HPV 35 (5.%) GP5+/GP6+ (L1) Sequencing 137 51.8 (43.5-6.) HPV 16 (48.9%) HPV 31 (2.9%) HPV 18 (2.2%) HPV 33 (.7%) HPV 67 (.7%) (Continued on next page)

4 HPV-RELATED STATISTICS - 151 - HPV detection ( Table 29 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Snietura 21 (Poland) Szkaradkiewicz 22 (Poland) Herrero 23 (Spain) Attner 21 (Sweden) Dahlgren 24 (Sweden) Hammarstedt 26 (Sweden) Lindquist 212 (Sweden) Näsman 29 (Sweden) Lindel 21 (Switzerland) Anderson 27 (UK) Conway 212 (UK) Real-time High Risk HPV test (Abbott Molecular) using L1 consensus primers Amplification with TS primers (16. 18. 31. 33. 35. 39. 45. 51. 52. 56. 58. 59. 66 and 68 - the technique only differentiates 16-18-other) MY9/MY11 (L1) Amplification with TS primers (16. 18) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes (2. 6. 11. 16. 18. 31. 33. 35. 39. 4. 42. 43. 44. 45. 51. 52. 56. 58. 59. 66. 68) GP5+/GP6+ (L1). CPI/IIG (E1) and TS-PCR E6/7 for 16/33 Amplification with TS primers (16. 33) and sequencing GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers (16. 18. 33) and sequencing GP5+/GP6+ (L1). CPI/CPIIG (E1) and TS-PCR E6 for 16 Sequencing GP5+/GP6+ (L1) and CPI/CPIIG (E1) Amplification with TS primers (16) and Multiplex Luminex (6. 11. 16. 18. 26. 31. 33. 35. 39. 42. 43. 44. 45. 51. 52. 53. 56. 58. 59. 66. 68. 7. 73. 82) GP5+/GP6+ (L1). CPI/CPIIG (E1) and TS-PCR E6 for 16 Sequencing 14 5. (26.8-73.2) HPV 16 (5.%) 28 1.7 (3.7-27.2) - 44 9.1 (3.6-21.2) HPV 16 (9.1%) 95 74.7 (65.2-82.4) HPV 16 (64.2%) HPV 33 (7.4%) HPV 35 (2.1%) HPV 58 (1.1%) 25 4. (23.4-59.3) HPV 16 (28.%) HPV 33 (4.%) HPV 35 (4.%) HPV 38 (4.%) 23 48.8 (42.-55.6) HPV 16 (42.9%) HPV 33 (1.5%) HPV 35 (.5%) HPV 45 (.5%) 56 64.3 (51.2-75.5) HPV 16 (64.3%) 98 84.7 (76.3-9.5) HPV 16 (78.6%) HPV 33 (1.%) HPV 35 (1.%) HPV 59 (1.%) SPF1 (L1) Sequencing 99 14.1 (8.6-22.3) HPV 16 (11.1%) HPV 33 (1.%) HPV 35 (1.%) HPV 45 (1.%) GP5+/GP6+ (L1) Hybridization with Roche LBA (6. 11. 16. 18. 26. 31. 33. 35. 39. 4. 42. 45. 51. 52. 53. 54. 55. 56. 58. 59. 61. 62. 64. 66. 67. 68. 69. 7. 71. 72. 73. 81. 82. 83. 84. 89) PCR-GP5+/6+, TS, Sequencing (HPV 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 74, 8, 81, 82, 83, 84, 85, 86, 87, 89, 9, 91) Evans 213 (UK) PCR-GP5+/6+, EIA (HPV 6, 11, 16, 18, 31, 33, 35, 39, 4, 42, 43, 44, 45, 51, 52, 56, 58, 59, 66, 68) (Continued on next page) 36 22.2 (11.7-38.1) HPV 16 (19.4%) HPV 11 (2.8%) 2 4. (21.9-61.3) HPV 16 (4.%) 83 83.1 (73.7-89.7) HPV 16 (8.7%) HPV 18 (1.2%) HPV 33 (1.2%) HPV 56 (1.2%)

4 HPV-RELATED STATISTICS - 152 - HPV detection ( Table 29 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Schache 211 (UK) Thavaraj 211 (UK) TS-PCR E6 for 16 Amplification with TS primers (16) GP5+/GP6+ (L1) Luminex 2 IS (16. 18. 26. 31. 33. 35. 39. 45. 51. 52. 53. 56. 58. 59. 66. 68. 73. 82) Wells 215 (UK) PCR- MULTIPLEX (HPV 16, 18, 35, 51, 82) Ribeiro (World) 211 a PGMY9/11 (L1) Amplification with TS primers (16) 98 4.8 (31.6-5.7) HPV 16 (4.8%) 142 7.4 (62.5-77.3) HPV 16 (64.1%) HPV 33 (2.1%) HPV 18 (.7%) HPV 35 (.7%) 57 5.9 (38.3-63.4) HPV 16 (45.6%) HPV 18 (5.3%) HPV 35 (1.8%) HPV 51 (1.8%) HPV 82 (1.8%) 136.7 (.1-4.) HPV 16 (.7%) Data updated on 29 Jun 217 (data as of 31 Dec 215 / 31 Dec 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; LBA: Line-Blot Assay; LiPA: Line Probe Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; RLBH: Reverse Line Blot Hybridization; RT-PCR: Real Time Polymerase Chain Reaction; SBH: Southern Blot Hybridization; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Argentina, Brazil, Cuba, Russia, Slovakia, Czech Republic, Romania and Poland Data sources: See references in Section 9. Table 3: European studies on HPV prevalence in cases of hypopharyngeal or laryngeal cancer HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) MEN Hoffmann 26 (Germany) Hoffmann 29 (Germany) Azzimonti 24 (Italy) Cattani 1998 (Italy) Gallo 29 (Italy) Lie 1996 (Norway) Morshed 28 (Poland) MY9/MY11 (L1) and TS-PCR for 6/11/16/18/33 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes (6. 11. 16. 18. 31. 33. 45) 17 23.5 (9.6-47.3) HPV 16 (23.5%) MY9/MY11 (L1) and TS-PCR 21 33.3 (17.2-54.6) HPV 16 (19.%) for 6/11/16/18 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes (6. 11. 16. 18. 31. 33. 45) GP5+/GP6+ (L1) Sequencing 23 56.5 (36.8-74.4) HPV 16 (43.5%) HPV 18 (13.%) MY9/MY11 (L1) and TS-PCR 7 3. (2.5-41.5) - for 33 Hybridization with TS probes (6. 11. 16. 18. 31) and amplification with TS primer (33) MY9/MY11 (L1). LCRF1. 36. - - LCRF2. LCRF3. LCRF4. E7R1. E7R2. E7R3. E7R4 (E6) and TS-PCR E1 for 6/11/16/18-31/33 Sequencing CP (E1). MY9/MY11 (L1) and 38 7.9 (2.7-2.8) HPV 16 (2.6%) GP5+/GP6+ (L1) Amplification with TS primers (6. 11. 16. 18. 31. 33. 35) SPF1 (L1) LiPA 25 78 34.6 (25.-45.7) - (Continued on next page)

4 HPV-RELATED STATISTICS - 153 - WOMEN HPV detection ( Table 3 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Hoffmann 26 (Germany) Hoffmann 29 (Germany) Azzimonti 24 (Italy) Cattani 1998 (Italy) Gallo 29 (Italy) Lie 1996 (Norway) Morshed 28 (Poland) BOTH OR UNSPECIFIED Gudleviciene 214 (Belarus) Duray 211 (Belgium) Lindeberg 1999 (Denmark) Koskinen 23 (Finland) Fouret 1997 (France) MY9/MY11 (L1) and TS-PCR for 6/11/16/18/33 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes (6. 11. 16. 18. 31. 33. 45) 3 33.3 (6.1-79.2) HPV 16 (33.3%) MY9/MY11 (L1) and TS-PCR 6 16.7 (3.-56.4) - for 6/11/16/18 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes (6. 11. 16. 18. 31. 33. 45) GP5+/GP6+ (L1) Sequencing 2 5. (9.5-9.5) HPV 16 (5.%) MY9/MY11 (L1) and TS-PCR for 33 Hybridization with TS probes (6. 11. 16. 18. 31) and amplification with TS primer (33) 28 21.4 (1.2-39.5) HPV 16 (21.4%) MY9/MY11 (L1). LCRF1. 4. - - LCRF2. LCRF3. LCRF4. E7R1. E7R2. E7R3. E7R4 (E6) and TS-PCR E1 for 6/11/16/18-31/33 Sequencing CP (E1). MY9/MY11 (L1) and 1. - - GP5+/GP6+ (L1) Amplification with TS primers (6. 11. 16. 18. 31. 33. 35) SPF1 (L1) LiPA 25 15 4. (19.8-64.3) - PCR-GP5+/6+, PCR-PGMY9/11, PCR L1-Consensus primer, PCR-E6, PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, 82) GP5+/GP6+ (L1) and RT-PCR E6/E7 for 6. 11. 16. 18. 31. 33. 35. 39. 45. 51. 52. 53. 56. 58. 59. 66. 67-L1. 68 TS real-time and consensus PCR E6/E7 (6. 11. 16. 18. 31. 33. 35. 39. 45. 51. 52. 53. 56. 58. 59. 66. 67-L1. 68) MY9/MY11 (L1). GP5+/GP6+ (L1) and CPII/II (L1) Hybridization with TS probes (6. 11. 16. 18. 3. 31. 33. 35) 34 5.9 (1.6-19.1) HPV 6 (2.9%) HPV 16 (2.9%) 59 79.7 (67.7-88.) HPV 16 (62.7%) HPV 18 (16.9%) HPV 51 (8.5%) HPV 33 (5.1%) HPV 66 (5.1%) 3 3.3 (.6-16.7) - SPF1 (L1) LiPA 25 28 5. (32.6-67.4) HPV 16 (46.4%) HPV 33 (14.3%) HPV 6 (1.7%) HPV 11 (3.6%) HPV 51 (3.6%) TS-PCR E6 for 16/18/31/33/45 13 6.8 (3.3-13.4) HPV 16 (6.8%) Hybridization with TS probes (16. 18. 31. 33. 45) (Continued on next page)

4 HPV-RELATED STATISTICS - 154 - HPV detection ( Table 3 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Fischer 23 (Germany) Hoffmann 1998 (Germany) Hoffmann 26 (Germany) Hoffmann 29 (Germany) Kleist 2 (Germany) Klussmann 21 (Germany) Krupar 214 (Germany) Gorgoulis 1999 (Greece) Vlachtsis 25 (Greece) Major 25 (Hungary) Azzimonti 24 (Italy) Badaracco 2 (Italy) Badaracco 27 (Italy) Boscolo-Rizzo 29 (Italy) Cattani 1998 (Italy) L1-CP65F. 66F. 69F. 7F Sequencing MY9/MY11 (L1) and TS-PCR for 6/11/16/18/33 SBH (6. 11. 16. 18. 31. 33. 45) MY9/MY11 (L1) and TS-PCR for 6/11/16/18/33 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes (6. 11. 16. 18. 31. 33. 45) MY9/MY11 (L1) and TS-PCR for 6/11/16/18 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes (6. 11. 16. 18. 31. 33. 45) MY9/MY11 (L1) Amplification with TS primers (16. 18) A1/A5-A6/A8 (L1) and CP62/7-CP65/69a (L1) Sequencing PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 66, 68) MY9/MY11 (L1) and GP5/GP6 (L1) Amplification with TS primers (6. 11. 16. 18. 31. 33. 35) and confirmation by DBH with TS probes (6. 11. 16. 18. 31. 33. 35). TS-PCR for 16/18 Amplification with TS primers (16. 18) MY9/MY11 (L1) and GP5+/GP6+ (L1) RFLP (6. 11. 16. 18) 47 34. (22.2-48.3) HPV 73 (4.3%) HPV 21 (2.1%) HPV 22 (2.1%) HPV 38 (2.1%) HPV 41 (2.1%) 51 21.6 (12.5-34.6) HPV 16 (3.9%) HPV 18 (2.%) HPV 45 (2.%) 2 25. (11.2-46.9) HPV 16 (25.%) 27 29.6 (15.9-48.5) HPV 16 (14.8%) 35 2. (1.-35.9) HPV 16 (8.6%) HPV 18 (8.6%) 3 16.7 (7.3-33.6) HPV 16 (13.3%) HPV 19 (3.3%) 49. - - 91 2.9 (13.8-3.3) HPV 16 (14.3%) HPV 6 (3.3%) HPV 18 (3.3%) HPV 33 (3.3%) 9 4. (3.5-5.3) HPV 16 (34.4%) HPV 18 (6.7%) 22 54.5 (34.7-73.1) HPV 11 (18.2%) HPV 6 (13.6%) HPV 16 (13.6%) GP5+/GP6+ (L1) Sequencing 25 56. (37.1-73.3) HPV 16 (44.%) HPV 18 (12.%) MY9/MY11 (L1) Amplification with TS primers (6. 16) and hybridization with TS probes (11. 16. 18. 31. 45. 56. 57) MY9/MY11 (L1) and GP5+/GP6+ (L1) Sequencing MY9/MY11 (L1) RFLP and amplification with TS primers E6/E2 for 16 MY9/MY11 (L1) and TS-PCR for 33 Hybridization with TS probes (6. 11. 16. 18. 31) and amplification with TS primer (33) 22 5. (3.7-69.3) HPV 16 (27.3%) HPV 6 (18.2%) HPV 45 (4.5%) 3 16.7 (7.3-33.6) HPV 16 (1.%) HPV 6 (6.7%) 45 4.4 (1.2-14.8) HPV 16 (4.4%) 75 29.3 (2.2-4.4) HPV 16 (12.%) HPV 18 (1.7%) HPV 33 (1.3%) (Continued on next page)

4 HPV-RELATED STATISTICS - 155 - HPV detection ( Table 3 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Gallo 29 (Italy) Gudleviciene 29 (Lithuania) Gudleviciene 214 (Lithuania) Koskinen 27 a (Northern Europe) Mork 21 a (Northern Europe) Lie 1996 (Norway) Morshed 28 (Poland) Snietura 211 (Poland) Poljak 1997 (Slovenia) Alvarez Alvarez 1997 (Spain) Pérez-Ayala 199 (Spain) Adams 1999 (Switzerland) Anderson 27 (UK) MY9/MY11 (L1). LCRF1. LCRF2. LCRF3. LCRF4. E7R1. E7R2. E7R3. E7R4 (E6) and TS-PCR E1 for 6/11/16/18-31/33 Sequencing Consensus primers from Master Mix Amplification with TS primers (16. 18) PCR-GP5+/6+, PCR-PGMY9/11, PCR L1-Consensus primer, PCR-E6, PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, 82) MY9/MY11 (L1). GP5+/GP6+ (L1) and SPF1 (L1) LiPA 25 4. - - 25 32. (17.2-51.6) HPV 16 (12.%) 53 2.8 (12.-33.5) HPV 6 (1.9%) HPV 16 (1.9%) HPV 31 (1.9%) HPV 39 (1.9%) HPV 58 (1.9%) 69 4.3 (1.5-12.) HPV 16 (1.4%) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers (6. 11. 16. 18. 33) 4 2.5 (.4-12.9) HPV 16 (2.5%) CP (E1). MY9/MY11 (L1) and 39 7.7 (2.7-2.3) HPV 16 (2.6%) GP5+/GP6+ (L1) Amplification with TS primers (6. 11. 16. 18. 31. 33. 35) SPF1 (L1) LiPA 25 93 35.5 (26.5-45.6) HPV 16 (3.1%) HPV 18 (6.5%) HPV 33 (5.4%) Real-time High Risk HPV test 65. - - (Abbott Molecular) using L1 consensus primers RT-PCR (16. 18. 31. 33. 35. 39. 45. 51. 52. 56. 58. 59. 66. 68) PGMY9/11 (L1). GP5+/GP6+ 3 3.3 (.6-16.7) HPV 16 (3.3%) (L1) and WD72/76/66/67/154 (E6) Amplification with TS primers (6. 11. 16. 18. 31. 33. 51) TS-PCR E6 and L1 for 6b/16/18 Amplification with TS primers (6b. 16. 18) TS-PCR E6 for 6/11 Hybridization with TS probes (11. 16) MY9/MY11 (L1) RFLP (6. 11. 16. 18. 31. 33. 35. 51. 53. 56) GP5+/GP6+ (L1) Hybridization with Roche LBA (6. 11. 16. 18. 26. 31. 33. 35. 39. 4. 42. 45. 51. 52. 53. 54. 55. 56. 58. 59. 61. 62. 64. 66. 67. 68. 69. 7. 71. 72. 73. 81. 82. 83. 84. 89) 35 25.7 (14.2-42.1) HPV 6 (22.9%) HPV 16 (5.7%) 51 56.9 (43.3-69.5) HPV 16 (56.9%) 36 16.7 (7.9-31.9) HPV 16 (16.7%) 64. - - (Continued on next page)

4 HPV-RELATED STATISTICS - 156 - HPV detection ( Table 3 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Conway 212 (UK) PCR-GP5+/6+, TS, Sequencing (HPV 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 74, 8, 81, 82, 83, 84, 85, 86, 87, 89, 9, 91) Salam 1995 (UK) MY9/MY11 (L1) RFLP (6. 11. 16. 18. 33) Snijders 1996 (UK) Ribeiro (World) 211 b GP5+/GP6+ (L1) Amplification with TS primers and SBH with TS probes (6. 11. 16. 18. 31. 33) PGMY9/11 (L1) Amplification with TS primers (16) 12. - - 36 22.2 (11.7-38.1) HPV 6 (8.3%) HPV 16 (5.6%) HPV 11 (2.8%) 31 19.4 (9.2-36.3) HPV 16 (19.4%) 239.8 (.2-3.) HPV 16 (.8%) Data updated on 28 Jun 217 (data as of 31 Dec 215). 95% CI: 95% Confidence Interval; DBH: Dot Blot Hybridization; LBA: Line-Blot Assay; LiPA: Line Probe Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; RT-PCR: Real Time Polymerase Chain Reaction; SBH: Southern Blot Hybridization; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Norway, Sweden and Finland b Includes cases from Argentina, Brazil, Cuba, Russia, Slovakia, Czech Republic, Romania and Poland Data sources: See references in Section 9.

5 FACTORS CONTRIBUTING TO CERVICAL CANCER - 157-5 Factors contributing to cervical cancer HPV is a necessary cause of cervical cancer, but it is not a sufficient cause. Other cofactors are necessary for progression from cervical HPV infection to cancer. Tobacco smoking, high parity, long-term hormonal contraceptive use, and co-infection with HIV have been identified as established cofactors. Co-infection with Chlamydia trachomatis and herpes simplex virus type-2, immunosuppression, and certain dietary deficiencies are other probable cofactors. Genetic and immunological host factors and viral factors other than type, such as variants of type, viral load and viral integration, are likely to be important but have not been clearly identified. (Muñoz N, Vaccine 26; 24(S3): 1-1). In this section, the prevalence of smoking, parity (fertility), oral contraceptive use, and HIV in Europe are presented. Figure 123: Prevalence of female tobacco smoking in Europe Data accessed on 22 Mar 217. Adjusted and age-standardized prevalence estimates of tobacco use by country, for the year 213. These rates are constructed solely for the purpose of comparing tobacco use prevalence estimates across countries, and should not be used to estimate the number of smokers in the population. Data sources: WHO report on the global tobacco epidemic, 215: The MPOWER package. Geneva, World Health Organization, 215. Available at http://www.who.int/tobacco/global_ report/215/en/index.html

5 FACTORS CONTRIBUTING TO CERVICAL CANCER - 158 - Figure 124: Total fertility rates in Europe Data accessed on 22 Mar 217. For Austria, Belgium, Bulgaria, Belarus, Germany, United Kingdom, Hungary, Netherlands, Romania, Sweden: The number of women by age is estimated by the United Nations Population Division and published in World Population Prospects: the 215 Revision. Data sources: For Channel Islands, Bosnia & Herzegovina, Republic of Moldova: United Nations, Department of Economic and Social Affairs, Population Division (215). World Fertility Data 215 (POP/DB/Fert/Rev215). Available at: http://www.un.org/en/development/desa/population/publications/dataset/fertility/wfd215.shtml. [Accessed on March 22, 217]. Albania, Austria, Belgium, Bulgaria, Belarus, Switzerland, Cyprus, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Liechtenstein, Lithuania, Luxembourg, Latvia, Macedonia, Malta, Montenegro, Netherlands, Norway, Poland, Portugal, Romania, Russian Federation, Serbia, Slovakia, Slovenia, Sweden, Ukraine: Eurostat - Statistical office of the European Comission [web site]. Luxembourg: European Commission; 215. Available at: http://ec.europa.eu/ eurostat/tgm/table.do?tab=table&init=1&language=en&pcode=tsdde22&plugin=1. [Accessed on March 22, 217].

5 FACTORS CONTRIBUTING TO CERVICAL CANCER - 159 - Figure 125: Prevalence of hormonal contraceptive use in Europe Data accessed on 22 Mar 217. Proportion (%) of women using hormonal contraception (pill, injectable or implant), among those of reproductive age who are married or in union. For Belgium: Data pertain to sexually active women of reproductive age. For Bulgaria, Germany, Estonia, Lithuania, Romania: Data pertain to women with co-resident male partner. For Czech Republic, Russian Federation: Data pertain to women with a partner. For Denmark: Data pertain to women in a steady sexual relationship. For United Kingdom: Excluding Northern Ireland. For Greece, Poland: Data pertain to women who were sexually active during the month prior to the interview. For Croatia: Data pertain to all women of reproductive age, irrespective of marital status. For Malta: Data pertain to married women who visited a practitioner belonging to the Malta College of Family Doctors. For Norway: Data pertain to women who were sexually active during the three months prior to the interview. For Portugal: Data pertain to non-pregnant women. For Slovakia: Data pertain to women exposed to the risk of pregnancy. For Sweden: Data pertain to women who have ever had sex. Data sources: United Nations, Department of Economic and Social Affairs, Population Division (216). World Contraceptive Use 216 (POP/DB/CP/Rev216). http://www.un.org/en/ development/desa/population/publications/dataset/contraception/wcu216.shtml. Available at: [Accessed on March 22, 217].

5 FACTORS CONTRIBUTING TO CERVICAL CANCER - 16 - Figure 126: Prevalence of HIV in Europe Data accessed on 22 Mar 217. Estimates include all people with HIV infection, regardless of whether they have developed symptoms of AIDS. For Greece, Italy: Antiretroviral therapy data was not available at the time of publication Data sources: UNAIDS database [internet]. Available at: http://aidsinfo.unaids.org/ [Accessed on March 22, 217]

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 161-6 Sexual behaviour and reproductive health indicators Sexual intercourse is the primary route of transmission of genital HPV infection. Information about sexual and reproductive health behaviours is essential to the design of effective preventive strategies against anogenital cancers. In this section, we describe sexual and reproductive health indicators that may be used as proxy measures of risk for HPV infection and anogenital cancers. Several studies have reported that earlier sexual debut is a risk factor for HPV infection, although the reason for this relationship is still unclear. In this section, information on sexual and reproductive health behaviour in Europe is presented. Figure 127: Percentage of 15-year-old girls who report sexual intercourse in Europe Data accessed on 16 Mar 217. For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Fifteenyear-olds teenagers only were asked whether they had ever had sexual intercourse. For Albania, Bulgaria, Switzerland, Spain, France, Greece, Croatia, Ireland, Lithuania, Latvia, Republic of Moldova, Macedonia, Portugal, Romania, Russian Federation, Slovenia, Ukraine: Indicates a significant gender difference (at p<.5). For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Year of estimation: 213-214 Data sources: For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Growing up unequal: gender and socioeconomic differences in young people s health and well-being. Health Behaviour in School-aged Children (HBSC) study: international report from the 213/214 survey. Inchley J, Currie D, Young T, et al. Copenhagen, WHO Regional Office for Europe, 216 (Health Policy for Children and Adolescents, No. 7). Available at: http: //www.euro.who.int/ data/assets/pdf_file/3/33438/hsbc-no.7-growing-up-unequal-full-report.pdf?ua=1

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 162 - Figure 128: Percentage of 15-year-old boys who report sexual intercourse in Europe Data accessed on 16 Mar 217. Please refer to original source for methods of estimation For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Fifteenyear-olds teenagers only were asked whether they had ever had sexual intercourse. For Albania, Bulgaria, Switzerland, Spain, France, Greece, Croatia, Ireland, Lithuania, Latvia, Republic of Moldova, Macedonia, Portugal, Romania, Russian Federation, Slovenia, Ukraine: Indicates a significant gender difference (at p<.5). For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Year of estimation: 213-214 Data sources: For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Growing up unequal: gender and socioeconomic differences in young people s health and well-being. Health Behaviour in School-aged Children (HBSC) study: international report from the 213/214 survey. Inchley J, Currie D, Young T, et al. Copenhagen, WHO Regional Office for Europe, 216 (Health Policy for Children and Adolescents, No. 7). Available at: http: //www.euro.who.int/ data/assets/pdf_file/3/33438/hsbc-no.7-growing-up-unequal-full-report.pdf?ua=1

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 163 - Table 31: Median age at first sex in Europe MALE FEMALE TOTAL Median age Median age Median age Country Study Year/period Birth cohort N at first sex N at first sex N at first sex Albania Albania BBSS 25 a 25 1956-1987 312 17. 317 2. 629 19. Albania DHS 28-29 1959-1963 535 23.4 179 21.1 - - 28/29 Albania DHS 28-29 1959-1983 - 22.6-2.7 - - 28/29 b Albania DHS 28-29 1959-1983 - 22. - 21.3 - - 28/29 c Albania DHS 28-29 1959-1983 194 22.3 4894 2.9 - - 28/29 Albania DHS 28-29 1964-1968 497 23.2 1216 21.3 - - 28/29 Albania DHS 28-29 1969-1973 366 21.9 171 2.8 - - 28/29 Albania DHS 28-29 1974-1978 262 2.8 817 2.6 - - 28/29 Albania DHS 28-29 1979-1983 244 2.4 711 2.8 - - 28/29 Albania DHS 28-29 1984-1988 268 19.9 516 - - - 28/29 d Albania DHS 28-29 1984-1993 397-697 - - - 28/29 d Albania DHS 28-29 1989-1993 129-182 - - - 28/29 d Austria Cibula 28 e,f,a 26 1957-1991 - - 57 16.6 - - Belarus Belgium Syrjanen 1998-21 1913-1983 - - 722 18.4 - - 23 g,h,f Syrjanen 23 i,h,f 1998-21 1913-1983 - - 761 19. - - Syrjanen 23 h, j,f 1998-21 1913-1983 - - 1692 19.6 - - Fronteira 25-26 1986-1989 - - - - 369 15.2 29 k,f,a Hubert 1998 l 1993 1932-1941 245 2.4 252 2.9 - - Hubert 1998 l 1993 1942-1951 385 19. 48 2. - - Hubert 1998 l 1993 1952-1961 411 18.5 59 18.8 - - Hubert 1998 l 1993 1962-1966 199 18. 24 18.6 - - Hubert 1998 l 1993 1967-1971 216 18.1 229 18.7 - - Hubert 1998 l 1993 1972-1973 15 17.4 9 18. - - Bosnia & H. Arza 212 f,m 27-29 - 1871 17.3 1788 18.2 - - Croatia Delva 27 n,f 24 1989-1993 418 15.5 232 16.3 - - Croatia KABP 21 1985-1992 - - - - 861 17. 21 (Landripet 211) Hirsl-Hecej 1997 1978-1982 - - - - 686 16. 26 k,o Hirsl-Hecej 21 1982-1986 - - - - 624 16. 26 k,o Stulhofer 29 25 1981-1987 433 17. 46 17. - - Czech Rep. Crochard 29 26-27 1982-1988 53 17. 59 17. - - Czech Republic 1993 1969-1978 - - 158 17.5 - - RHS 1993 Fronteira 25-26 1986-1989 - - - - 392 16.4 29 k,f,a Denmark Hubert 1998 l 1989 1932-1941 232 18.4 295 19. - - Estonia Hubert 1998 l 1989 1942-1951 269 18.2 351 18.3 - - Hubert 1998 l 1989 1952-1961 328 17.8 39 17.7 - - Hubert 1998 l 1989 1962-1966 179 17.1 199 16.8 - - Hubert 1998 l 1989 1967-1971 178 17.5 26 17. - - Hubert 1998 l 1989 1972-1973 164 17.4 22 16.7 - - Jensen 211 25 1959-1963 - - - 16. - - Jensen 211 25 1964-1968 - - - 16. - - Jensen 211 25 1969-1973 - - - 16.5 - - Jensen 211 25 1974-1978 - - - 16. - - Jensen 211 25 1979-1982 - - - 16. - - Jensen 211 25 1983-1986 - - - 16. - - Fronteira 25-26 1986-1989 - - - - 435 15.3 29 k,f,a Haldre 212 1994 1949-1953 - - - 2.1 - - Haldre 212 24/25 1949-1953 - 18.6-2.2 - - Haldre 212 1996 1951-1955 - 18. - 2. - - Haldre 212 1994 1964-1968 - - - 19.3 - - Haldre 212 24/25 1964-1968 - 18.2-19.1 - - Haldre 212 1996 1966-197 - 18. - 18. - - Haldre 212 25 1976-198 - 17.5-17.4 - - Haldre 212 27 1978-1982 - 17.4-17.5 - - Part 27 24-25 196-1969 - - 68 18. - - (Continued on next page)

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 164 - ( Table 31 continued from previous page) MALE FEMALE TOTAL Median age Median age Median age Country Study Year/period Birth cohort N at first sex N at first sex N at first sex Part 27 24-25 197-1979 - - 77 18. - - Part 27 24-25 198-1986 - - 98 17. - - Part 27 24-25 1987-1988 - - 9 15. - - Uusk la 28 f 25-26 197-1987 - - - - 526 17.6 Finland Hubert 1998 l 1992 1922-1931 148 18.8 187 2.7 - - Hubert 1998 l 1992 1932-1941 134 18.7 149 2. - - Hubert 1998 l 1992 1942-1951 227 18.2 29 19. - - Hubert 1998 l 1992 1952-1961 256 18. 246 17.7 - - Hubert 1998 l 1992 1962-1966 123 17.3 19 17.8 - - Hubert 1998 l 1992 1967-1971 113 18. 121 18. - - Hubert 1998 l 1992 1972-1973 46 18. 4 16.6 - - France Bajos 21 26 1937-1988 - 17.2-17.6 - - Bajos 21 197 1939-18.1-22. - - Crochard 29 26-27 1982-1988 446 16. 482 17. - - France KABP 1994 194-1976 516 16.6 653 17.6 - - 25 France KABP 1998 1944-198 838 16.7 874 17.4 - - 25 France KABP 21 1947-1983 1149 16.8 1452 17.3 - - 25 France KABP 24 195-1986 1281 16.6 169 17.2 - - 25 France KABP 21 1956-1992 - 16.5-17.2 - - 21 p Hubert 1998 q,l 1992 1922-1931 14 18. 1 21.1 - - Hubert 1998 q,l 1992 1932-1941 2 18.4 161 2.6 - - Hubert 1998 q,l 1992 1942-1951 432 18.1 341 19.3 - - Hubert 1998 q,l 1992 1952-1961 679 17.6 56 18.3 - - Hubert 1998 q,l 1992 1962-1966 52 17.4 386 18.2 - - Hubert 1998 q,l 1992 1967-1971 539 17.7 471 18.3 - - Hubert 1998 q,l 1992 1972-1973 15 17. 159 18.1 - - Germany Griesinger 27 r,f 24 1984-199 - - 521 15.2 - - Hubert 1998 s,l 199 1922-1931 125 2.2 161 2.9 - - Hubert 1998 s,l 199 1932-1941 23 19. 237 19.7 - - Hubert 1998 s,l 199 1942-1951 263 18.4 325 18.6 - - Hubert 1998 s,l 199 1952-1961 362 18. 454 17.5 - - Hubert 1998 s,l 199 1962-1966 263 17.7 241 17.6 - - Hubert 1998 s,l 199 1967-1971 182 17.7 198 17.7 - - Greece Hubert 1998 l 199 1932-1941 54 17.3 57 22.8 - - Hubert 1998 l 199 1942-1951 213 17.3 258 2.6 - - Hubert 1998 l 199 1952-1961 259 17.5 322 19.5 - - Hubert 1998 l 199 1962-1966 136 17.6 163 19.2 - - Hubert 1998 l 199 1967-1971 152 17.5 155 19. - - Tsitsika 21 t,f 27-28 1991-1997 185 13. 61 14.5 246 14. Iceland Bender 1999 f,o 1996 1976-1979 273 15.4 1423 15.4 1696 15.4 Hubert 1998 l 1992 1932-1941 33 17.8 39 18.7 - - Hubert 1998 l 1992 1942-1951 85 17.5 1 18. - - Hubert 1998 l 1992 1952-1961 143 16.9 143 17.2 - - Hubert 1998 l 1992 1962-1966 67 16.8 87 17.1 - - Hubert 1998 l 1992 1967-1971 56 16.8 76 16.9 - - Hubert 1998 l 1992 1972-1973 49 16.4 63 16.3 - - Jensen 211 25 1959-1963 - - - 16. - - Jensen 211 25 1964-1968 - - - 16. - - Jensen 211 25 1969-1973 - - - 16. - - Jensen 211 25 1974-1978 - - - 16. - - Jensen 211 25 1979-1982 - - - 16. - - Jensen 211 25 1983-1986 - - - 16. - - Ireland Crochard 29 26-27 1982-1988 398 16. 43 17. - - ISSHR 26 a 26 1942-1946 25 22. 242 23. - - ISSHR 26 a 26 1947-1951 32 2. 368 22. - - ISSHR 26 a 26 1952-1956 265 19. 366 21. - - ISSHR 26 a 26 1957-1961 39 19. 389 2. - - ISSHR 26 a 26 1962-1966 347 19. 441 2. - - ISSHR 26 a 26 1967-1971 3 18. 573 19. - - ISSHR 26 a 26 1972-1976 247 18. 357 18. - - ISSHR 26 a 26 1977-1981 454 17. 587 18. - - ISSHR 26 a 26 1982-1988 759 17. 98 17. - - (Continued on next page)

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 165 - ( Table 31 continued from previous page) MALE FEMALE TOTAL Median age Median age Median age Country Study Year/period Birth cohort N at first sex N at first sex N at first sex O Connell 29 u 24-25 197-1988 - - 215 17. - - Israel Ben-Zur 2 v 1995-1996 1976-1982 - - - - 231 15. Italy Crochard 29 w 26-27 1982-1988 453 16. 371 16. - - Panatto 29 w 26-27 1982-1987 282 16. 493 16. 775 16. Panatto 29 x 26-27 1982-1999 377 15. 914 15. 1291 15. Pannato 212 y 28-211 1984-1994 1166 16. 2739 16. 395 16. Signorelli 26 22 1953-1957 - - - - 266 18. Signorelli 26 22 1958-1962 - - - - 34 18. Signorelli 26 22 1963-1967 - - - - 226 18. Signorelli 26 22 1968-1972 - - - - 261 18. Signorelli 26 22 1973-1977 - - - - 297 18. Signorelli 26 22 1978-1984 - - - - 36 17. Tafuri 21 z,f 28 1978-1992 - 16.7-16.8 96 16.8 Latvia Syrjanen 23 h, j,f 1998-21 1913-1983 - - 1692 19.6 - - Syrjanen 23 i,h,f 1998-21 1913-1983 - - 761 19. - - Syrjanen 1998-21 1913-1983 - - 722 18.4 - - 23 g,h,f Macedonia Delva 27 n,f 24 1989-1993 418 15.5 232 16.3 - - Malta Malta HIS 22 22 <=1986 - - - - 4854 2. Montenegro Delva 27 n,f 24 1989-1993 418 15.5 232 16.3 - - Labovic 211 f 29 1985-1994 411 16.6 194 18.4 65 17.2 Netherlands Crochard 29 26-27 1982-1988 526 16. 481 16. - - degraaf 21 f 25 198-1993 1273 16.8 136 16.7 - - degraaf 21 f 25 1981-1984 - - - - 1214 17.5 degraaf 21 f 25 1985-1988 - - - - 1124 16.5 degraaf 21 f 25 1989-1993 - - - - 295 14.4 Hubert 1998 l 1989 1932-1941 28 21.2 39 21.6 - - Hubert 1998 l 1989 1942-1951 94 19.1 162 19.7 - - Hubert 1998 l 1989 1952-1961 154 18.2 195 18.4 - - Hubert 1998 l 1989 1962-1966 73 17.8 93 17.8 - - Hubert 1998 l 1989 1967-1971 52 18.3 74 18.3 - - Lenselink 28 A,f 27 1978-1989 - - 1944 16.7 - - Norway Bakken 27 B,f 25 1975-1987 132 17.5 - - - - Hubert 1998 l 1992 1932-1941 256 19.3 271 19.5 - - Hubert 1998 l 1992 1942-1951 442 18.8 536 18.8 - - Hubert 1998 l 1992 1952-1961 548 18.3 714 17.7 - - Hubert 1998 l 1992 1962-1966 38 18.4 392 17.5 - - Hubert 1998 l 1992 1967-1971 311 18.3 396 17.6 - - Hubert 1998 l 1992 1972-1973 125 18.1 143 17.5 - - Jensen 211 a 25 1959-1963 - - - 17. - - Jensen 211 a 25 1964-1968 - - - 17. - - Jensen 211 a 25 1969-1973 - - - 17. - - Jensen 211 a 25 1974-1978 - - - 17. - - Jensen 211 a 25 1979-1982 - - - 17. - - Jensen 211 a 25 1983-1986 - - - 16. - - Pedersen 23 C,f 1992 1976-198 646 17.9 753 17.3 - - Trfen 23 1987 1965-1969 - 18.2-17.2 - - Trfen 23 1997 1975-1979 - 18.2-17.4 - - Trfen 23 22 198-1984 - 17.5-17.1 - - Poland Crochard 29 26-27 1982-1988 489 17. 49 18. - - Olszewski 28 1981-199 - - 993 18.7 - - 21 D,f Portugal Aboim 212 f 27 1942-1989 - 17.2-19.5 355 - Romania Ferreira 211 x,f 25 1986-199 - - - - 24 15.5 Fronteira 25-26 1986-1989 - - - - 361 15.6 29 k,f,a Hubert 1998 l 1991 1932-1941 29 16.4 39 24.3 - - Hubert 1998 l 1991 1942-1951 383 16.8 334 21.9 - - Hubert 1998 l 1991 1952-1961 379 16.5 394 2.3 - - Hubert 1998 l 1991 1962-1966 142 16.8 147 19.8 - - Hubert 1998 l 1991 1967-1971 256 17.1 234 19.9 - - Hubert 1998 l 1991 1972-1973 66 16.2 68 > 19. - - Romania RHS 1993 1949-1953 - - 697 2.2 - - 1993 a Romania RHS 1993 1949-1978 - - 4832 2.2 - - 1993 a Romania RHS 1993 a 1993 1954-1958 - - 877 2.1 - - (Continued on next page)

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 166 - ( Table 31 continued from previous page) MALE FEMALE TOTAL Median age Median age Median age Country Study Year/period Birth cohort N at first sex N at first sex N at first sex Romania RHS 1993 1959-1963 - - 792 19.9 - - 1993 a Romania RHS 1993 1964-1968 - - 828 2.1 - - 1993 a Romania RHS 1993 1969-1973 - - 888 2.5 - - 1993 a Romania RHS 1999 1955-1959 - - 186 2.1 - - 1999 Romania RHS 1999 1955-1984 - - 5627 19.8 - - 1999 Romania RHS 1999 196-1964 - - 946 19.9 - - 1999 Romania RHS 1999 1965-1969 - - 1343 19.9 - - 1999 Romania RHS 1999 197-1974 - - 1242 19.9 - - 1999 Romania RHS 1999 1975-1979 - - 963 19.5 - - 1999 Romania RHS 1999 198-1984 - - 237 - - - 1999 d Russia Bobrova 25 f 22 1973-1987 - - - - 929 17.7 Crochard 29 26-27 1982-1988 637 16. 574 17. - - Syrjanen 23 h, j,f 1998-21 1913-1983 - - 1692 19.6 - - Syrjanen 23 i,h,f 1998-21 1913-1983 - - 761 19. - - Syrjanen 1998-21 1913-1983 - - 722 18.4 - - 23 g,h,f Serbia Delva 27 n,f 24 1989-1993 418 15.5 232 16.3 - - Slovenia Klavs 26 a 1999-21 1957-1988 849 17. 93 18. - - Spain Sweden Castellsague 27-28 1942-1952 - - 479 22.7 - - 212 E,f Castellsague 27-28 1982-199 - - 1617 16.7 - - 212 E,f de Sanjose 28 f 25 1935-1987 - - 6249 2.9 - - Gomez 27 F,f 21-23 1981-199 - - 384 16.5 - - Spain ESHS 23 23 1954-1963 - 18. - 19. - 19. Spain ESHS 23 23 1964-1973 - 18. - 18. - 18. Spain ESHS 23 23 1974-1985 - 17. - 18. - 18. Vaccarella 26 F,f 1998-2 1925-1984 - - 98 21. - - Hdggstrvm- 29 1989-1994 - - - - 29 15. Nordin 21 k Jensen 211 25 1959-1963 - - - 16. - - Jensen 211 25 1964-1968 - - - 17. - - Jensen 211 25 1969-1973 - - - 17. - - Jensen 211 25 1974-1978 - - - 17. - - Jensen 211 25 1979-1982 - - - 16. - - Jensen 211 25 1983-1986 - - - 16. - - Priebe 29 k,f 23-24 1983-1987 1558 15.7 819 15.9 - - Stenhammar 214 1979-1997 - - 359 16.7 - - 215 f,g Switzerland Hubert 1998 l 1992 1942-1951 239 19.2 229 19.5 - - Hubert 1998 l 1992 1952-1961 495 18.5 478 18.7 - - Hubert 1998 l 1992 1962-1966 237 18.7 224 18.5 - - Hubert 1998 l 1992 1967-1971 227 18.1 233 18.4 - - Hubert 1998 l 1992 1972-1973 128 18.2 123 18.4 - - Turkey Turkey DHS 1998 H 1998 1934-1948 226 2.9 - - - - Turkey DHS 1998 1934-1973 - 19. - - - - 1998 H,c Turkey DHS 1998 1934-1973 - 19.8 - - - - 1998 H,b Turkey DHS 1998 1934-1973 1859 19.2 - - - - 1998 H Turkey DHS 1998 1949-1953 24 19.3 - - - - 1998 H Turkey DHS 1998 1954-1958 335 19. - - - - 1998 H Turkey DHS 1998 1959-1963 352 18.8 - - - - 1998 H Turkey DHS 1998 1964-1968 364 18.9 - - - - 1998 H Turkey DHS 1998 1969-1973 342 19.2 - - - - 1998 H UK Hubert 1998 l 1991 1932-1941 1318 19.1 198 2.9 - - Hubert 1998 l 1991 1942-1951 1924 18.3 236 19.5 - - Hubert 1998 l 1991 1952-1961 2268 17.5 331 18.2 - - (Continued on next page)

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 167 - ( Table 31 continued from previous page) MALE FEMALE TOTAL Median age Median age Median age Country Study Year/period Birth cohort N at first sex N at first sex N at first sex Hubert 1998 l 1991 1962-1966 122 17.2 1629 17.9 - - Hubert 1998 l 1991 1967-1971 864 17.1 1125 17.4 - - Hubert 1998 l 1991 1972-1973 288 17. 35 17.3 - - Wellings 21 a 21 1957-1961 578 17. 613 17. - - Wellings 21 a 21 1957-1985 4743 17. 6364 17. - - Wellings 21 a 21 1962-1966 646 17. 824 17. - - Wellings 21 a 21 1967-1971 88 17. 116 17. - - Wellings 21 a 21 1972-1976 981 17. 1357 17. - - Wellings 21 a 21 1977-1981 93 17. 1279 16. - - Wellings 21 a 21 1982-1985 827 16. 1131 16. - - Wellings 213 a 21-212 1936-1945 657 18. 85 19. - - Wellings 213 a 21-212 1936-1994 627 17. 8746 17. - - Wellings 213 a 21-212 1946-1955 758 18. 115 18. - - Wellings 213 a 21-212 1956-1965 78 17. 116 17. - - Wellings 213 a 21-212 1966-1975 792 17. 1196 17. - - Wellings 213 a 21-212 1976-1985 158 17. 2469 16. - - Wellings 213 a 21-212 1986-1994 1712 16. 211 16. - - Ukraine Ukraine DHS 27 a 27 1958-1962 59 18.8 18 2.3 - - Ukraine DHS 27 1958-1982 - 18.5-19.7 - - 27 c Ukraine DHS 27 1958-1982 - 19.1-19.5 - - 27 b Ukraine DHS 27 1958-1982 2259 18.7 4972 19.6 - - 27 Ukraine DHS 27 1958-1987 2679 18.6 5762 19.6 - - 27 a Ukraine DHS 27 1958-1987 - 18.5-19.6 - - 27 c Ukraine DHS 27 1958-1987 - 19. - 19.5 - - 27 b Ukraine DHS 27 1963-1967 398 18.9 929 19.8 - - 27 a Ukraine DHS 27 1968-1972 446 18.6 143 19.4 - - 27 a Ukraine DHS 27 1973-1977 474 18.6 967 19.1 - - 27 a Ukraine DHS 27 1978-1982 43 18.4 954 19.3 - - 27 a Ukraine DHS 27 1983-1987 421 18.3 79 19.4 - - 27 a Ukraine DHS 27 1983-1992 568 19.3 93 22.4 - - 27 Ukraine DHS 27 1988-1992 147-14 - - - 27 d Data accessed on 16 Mar 217. a Number of subjects refers to the number of surveyed men/women (not all sexually active). b Rural. c Urban. d Data omitted because less than 5 percent of respondents had intercourse for the first time before reaching the beginning of the age group. e Data pertain to women randomly selected from a panel of more than three million women who had stated in a previous internet interview. f Mean age at first sex. g Data pertain to women attending a sexually transmitted disease clinic. h Data pertain to women attending six clinics in Belarus, Latvia and Russian Federation. i Data pertain to gynecological patients. j Data pertain to women participating in cervical cancer screening. k Data pertain to high school students. l Not especified if estimations are among sexually active or surveyed. m Sarajevo, Tuzla, Mostar, Banja Luka. n Data pertain to high school students in Bosnia (Sarajevo), the FYR of Macedonia (Skopje), and Serbia and Montenegro (Belgrade and Podgorica). o Not especified if estimations are among sexually active or surveyed (provided N among surveyed). p Ile-de-France. q Data from the Analysis on Sexual Behaviour in France (ACSF). r Data pertain to women attending a sample of gyneacologists in Berlin. s Data from the Survey performed in the Federal Republic of Germany (before reunification). t Data pertain to students attending 2 public junior high and high schools. u Data pertain to students attending student health units in three high education institutions (two universities and one institute of education). v Data pertain to Jewish adolescents. w Data pertain to workers. x Data pertain to secondary schools students. y Data pertain to secondary school students from Genova, Florence, Turin, Sassari and Cagliari. z Data pertain to school-leavers attending a pre-university study course. A Data pertain to unscreened women. B Data pertain to men recruited at student health services. C Data pertain to schools students. D Data pertain to high school and secondary schools students. E Data pertain to women attending routine cervical cancer screening. F Data pertain to population attending family planning centers or screening centers. G Swedish female university students from Uppsala undergoing contraceptive counseling at the students health center. H Data pertain to husbands. Data sources: See references in Section 9.

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 168 - Table 32: Average number of sexual partners in Europe Period MALE FEMALE TOTAL Country Study of estimate Year/Period Birth cohort Mean(N) Mean(N) Mean(N) Albania Albania DHS 28-9 Lifetime 28-29 (1959-1969) 2.1 (123) 1. (2294) - (-) Albania DHS 28-9 Lifetime 28-29 (1969-1979) 3.1 (621) 1.1 (1887) - (-) Albania DHS 28-9 Lifetime 28-29 (1979-1984) 3.3 (242) 1.1 (71) - (-) Albania DHS 28-9 Lifetime 28-29 (1984-1989) 3.5 (266) 1.1 (516) - (-) Albania DHS 28-9 Lifetime 28-29 (1984-1994) 3. (395) 1.1 (698) - (-) Albania DHS 28-9 Lifetime 28-29 (1989-1994) 1.9 (129) 1. (181) - (-) Belarus Syrjanen 23 a,b Last 2 years 1998 - - (-) 2.2 (722) - (-) Syrjanen 23 c,b Last 2 years 1998 - - (-) 1.7 (761) - (-) Syrjanen 23 d,b Last 2 years 1998 - - (-) 1.6 (1692) - (-) Belgium Hubert 1998 e Last year 1993 (1944-1975) 1.4 (1233) 1. (138) - (-) Czech Rep. Crochard 29 f Lifetime 26-27 (1982-1989) 4. (518) 3. (55) - (-) Denmark Buttmann 211 g Lifetime 26-27 (1961-1989) 8. (2241) - (-) - (-) Kjaer 27 g Lifetime 24-25 (1959-1987) - (-) 8.4 (22173) - (-) Estonia Lõhmus 23 Last year 22-23 (1973-1978) 2.1 (395) 1.4 (575) 1.7 (97) Lõhmus 23 Last year 22-23 (1978-1984) 3. (524) 1.9 (773) 2.3 (1272) Lõhmus 23 Last year 22-23 (1984-1987) 3.8 (251) 1.9 (392) 2.7 (643) Lõhmus 23 Last year 22-23 (1987-1989) 2.7 (94) 1.9 (112) 2.3 (25) Part 27 Lifetime 24-25 (196-197) - (-) 5.9 (68) - (-) Part 27 Last year 24-25 (196-197) - (-) 1.1 (68) - (-) Part 27 Lifetime 24-25 (197-198) - (-) 7.5 (77) - (-) Part 27 Last year 24-25 (197-198) - (-) 1.5 (77) - (-) Part 27 Lifetime 24-25 (198-1987) - (-) 4.5 (98) - (-) Part 27 Last year 24-25 (198-1987) - (-) 1.5 (98) - (-) Part 27 Lifetime 24-25 (1987-1989) - (-) 2.7 (9) - (-) Part 27 Last year 24-25 (1987-1989) - (-) 1.7 (9) - (-) France Bajos 21 g Lifetime 197 <=195 11.8 (125) 1.8 (1375) - (-) Bajos 21 g Lifetime 197 <=192 12.2 (125) 1.6 (1375) - (-) Bajos 21 g Lifetime 197 (1921-194) 12.8 (125) 1.9 (1375) - (-) Bajos 21 g Lifetime 197 (1941-195) 9.4 (125) 2. (1375) - (-) Bajos 21 g Lifetime 1992 (1923-1942) 1.3 (8948) 2. (1198) - (-) Bajos 21 g Lifetime 1992 (1923-1974) 11. (8948) 3.3 (1198) - (-) Bajos 21 g Lifetime 1992 (1943-1962) 12.6 (8948) 4. (1198) - (-) Bajos 21 g Lifetime 1992 (1963-1972) 1.4 (8948) 3.9 (1198) - (-) Bajos 21 g Lifetime 26 (1937-1956) 12.9 (554) 3.9 (6824) - (-) Bajos 21 g Lifetime 26 (1937-1988) 11.6 (554) 4.4 (6824) - (-) Bajos 21 g Lifetime 26 (1957-1976) 12.9 (554) 5.1 (6824) - (-) Bajos 21 g Lifetime 26 (1977-1986) 7.7 (554) 3.8 (6824) - (-) Crochard 29 f Lifetime 26-27 (1982-1989) 4. (419) 3. (46) - (-) Hubert 1998 g,h Lifetime 1991-1992 (1942-1974) 11.5 (6551) 3.8 (7777) - (-) Hubert 1998 e,h Last year 1991-1992 (1942-1974) 1.4 (6252) 1.1 (743) - (-) Germany Griesinger 27 i Lifetime 24 (1984-199) - (-) 3.5 (521) - (-) Hubert 1998 j,k Last year 199 (1941-1972) 1.4 (927) 1.1 (156) - (-) Greece Hubert 1998 k Last year 199 (1941-1972) 1.2 (743) 1. (839) - (-) Kordoutis 2 f Lifetime - - 4. (179) 2. (279) - (-) Hungary Takacs 26 l Lifetime 23-24 (1976-1988) 19.1 (24) 1.8 (12) 16.5 (36) Takacs 26 l Last year 23-24 (1976-1988) 4.6 (24) 4.2 (12) 4.5 (36) Iceland Kjaer 27 g Lifetime 24-25 (1959-1987) - (-) 8.8 (1525) - (-) Ireland Crochard 29 f,m Lifetime 26-27 (1982-1989) 6. (371) 4. (377) - (-) ISSHR 26 n Lifetime 24-25 (194-1987) 9.1 (3188) 3.1 (4253) - (-) ISSHR 26 n Last 5 years 24-25 (194-1987) 9.1 (3188) 3.1 (4253) - (-) ISSHR 26 n Last year 24-25 (194-1987) 9.1 (3188) 3.1 (4253) - (-) O Connell 29 o Lifetime 24-25 (197-1988) - (-) 4.7 (215) - (-) Israel Ben-Zur 2 p Lifetime 1995-1996 (1977-1982) - (-) - (-) 3.6 (231) Chemtob 26 g Last 3 months 2 (1955-1965) - (-) - (-) 1.1 (276) Chemtob 26 g Last 3 months 2 (1955-1982) 1.9 (398) 1.5 (42) 1.3 (8) Chemtob 26 g Last 3 months 2 (1966-1975) - (-) - (-) 1.3 (276) Chemtob 26 g Last 3 months 2 (1976-1982) - (-) - (-) 1.6 (248) Italy Crochard 29 f Lifetime 26-27 (1982-1989) 5. (41) 3. (314) - (-) Panatto 212 q,r Lifetime 28-211 (1984-1991) 3. (277) 2. (733) - (-) Panatto 212 q,r Lifetime 28-211 (1989-1994) 3. (548) 2. (1288) - (-) Panatto 212 q,r Lifetime 28-211 (1992-1997) 2. (312) 1. (668) - (-) Latvia Syrjanen 23 a,b Last 2 years 1998 - - (-) 2.2 (722) - (-) Syrjanen 23 c,b Last 2 years 1998 - - (-) 1.7 (761) - (-) Syrjanen 23 d,b Last 2 years 1998 - - (-) 1.6 (1692) - (-) Moldova Moldova DHS 25 Lifetime 25 (1956-1965) 6.3 (529) 1.5 (2142) - (-) Moldova DHS 25 Lifetime 25 (1966-1975) 7.1 (425) 1.7 (1746) - (-) Moldova DHS 25 Lifetime 25 (1976-198) 8. (211) 1.8 (918) - (-) Moldova DHS 25 Lifetime 25 (1981-1985) 6.6 (233) 1.8 (867) - (-) (Continued on next page)

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 169 - ( Table 32 continued from previous page) Period MALE FEMALE TOTAL Country Study of estimate Year/Period Birth cohort Mean N Mean Moldova DHS 25 Lifetime 25 (1981-199) 5.7 (41) 1.7 (1175) - (-) Moldova DHS 25 Lifetime 25 (1986-199) 4.4 (167) 1.6 (38) - (-) Montenegro Labovic 211 Last year 29 (1985-1994) 2.6 (398) 1.3 (194) - (-) Netherlands Crochard 29 f,m Lifetime 26-27 (1982-1989) 4. (476) 3. (463) - (-) degraaf 21 Lifetime 25 (198-1993) 4.9 (1273) 3.3 (136) - (-) degraaf 21 Lifetime 25 (1981-1984) - (-) - (-) 4.7 (1214) degraaf 21 Lifetime 25 (1985-1988) - (-) - (-) 3.4 (1124) degraaf 21 Lifetime 25 (1989-1993) - (-) - (-) 3.8 (295) Hubert 1998 e Last year 1989 (194-1971) 1.2 (392) 1.1 (551) - (-) Kuyper 21 k Lifetime 25-26 (1935-1987) - (-) 4.1 (1965) - (-) Norway Bakken 27 f Last year 25 (1975-1987) 2. (132) - (-) - (-) Bakken 27 f Last 6 months 25 (1975-1987) 1. (973) - (-) - (-) Hubert 1998 g Lifetime 1992 (1943-1974) 11.7 (1684) 5.5 (2116) - (-) Hubert 1998 e Last year 1992 (1943-1974) 1.5 (1454) 1.2 (1944) - (-) Kjaer 27 g Lifetime 24-25 (1959-1987) - (-) 7.4 (16575) - (-) Træen 23 s Lifetime 1997 (1975-1979) 7. (-) 6. (-) - (-) Træen 23 t Lifetime 1997 (1975-1979) 6. (-) 6. (-) - (-) Træen 23 s Lifetime 22 (198-1984) 7. (-) 6. (-) - (-) Træen 23 t Lifetime 22 (198-1984) 6. (-) 7. (-) - (-) Poland Crochard 29 f Lifetime 26-27 (1982-1989) 3. (481) 2. (44) - (-) Portugal Hubert 1998 e Last year 199-1991 (1941-1973) 1.8 (112) 1. (131) - (-) Russia Crochard 29 f,m Lifetime 26-27 (1982-1989) 5. (63) 3. (573) - (-) Syrjanen 23 a,b Last 2 years 1998 - - (-) 2.2 (722) - (-) Syrjanen 23 c,b Last 2 years 1998 - - (-) 1.7 (761) - (-) Syrjanen 23 d,b Last 2 years 1998 - - (-) 1.6 (1692) - (-) Takacs 26 l Lifetime 23-24 (1976-1988) 14.1 (14) 4.1 (16) 8.8 (3) Takacs 26 l Last year 23-24 (1976-1988) 3.6 (14) 1.8 (16) 2.7 (3) Slovenia Klavs 29 g Lifetime 1999-21 (195-1966) 9.5 (33) 3.1 (352) - (-) Klavs 29 g Last 5 years 1999-21 (195-1966) 2.1 (37) 1.1 (357) - (-) Klavs 29 g Last year 1999-21 (195-1966) 1.2 (36) 1. (357) - (-) Klavs 29 g Lifetime 1999-21 (195-1983) 8.3 (812) 3.2 (879) - (-) Klavs 29 g Last 5 years 1999-21 (195-1983) 3.2 (815) 1.5 (884) - (-) Klavs 29 g Last year 1999-21 (195-1983) 1.4 (812) 1. (889) - (-) Klavs 29 g Lifetime 1999-21 (1965-1976) 7.9 (186) 3.4 (214) - (-) Klavs 29 g Last 5 years 1999-21 (1965-1976) 3.1 (186) 1.4 (216) - (-) Klavs 29 g Last year 1999-21 (1965-1976) 1.3 (185) 1. (217) - (-) Klavs 29 g Lifetime 1999-21 (1975-1983) 6.5 (323) 2.9 (313) - (-) Klavs 29 g Last 5 years 1999-21 (1975-1983) 5.5 (322) 2.5 (311) - (-) Klavs 29 g Last year 1999-21 (1975-1983) 1.8 (321) 1.1 (315) - (-) Spain Castellsague 212 u Lifetime 27-28 (1942-1952) - (-) 1.4 (479) - (-) Castellsague 212 u Lifetime 27-28 (1982-199) - (-) 2.8 (1617) - (-) Gomez 27 v Lifetime 21-23 (1981-199) - (-) 1.9 (384) - (-) HSBS 23 Last year 23 (1954-1963) 2.2 (-) 1. (-) 1.6 (-) HSBS 23 Last year 23 (1954-1985) 2.6 (-) 1.2 (-) 1.9 (-) HSBS 23 Last year 23 (1964-1973) 2.8 (-) 1.1 (-) 2. (-) HSBS 23 Last year 23 (1974-1985) 2.8 (-) 1.4 (-) 2.1 (-) Vaccarella 26 v Lifetime 1998-2 (1923-1986) - (-) 1.5 (98) - (-) Sweden Häggström-Nordin 21 w,f Lifetime 29 (1989-1994) 3. (91) 2. (118) 2. (29) Kjaer 27 g Lifetime 24-25 (1959-1987) - (-) 8.6 (15713) - (-) Langstrom 26 g Lifetime 1996 (1936-1978) 1.4 (1244) 1.2 (1142) - (-) Tyden 212 g,x Lifetime 29 - - (-) 11. (35) - (-) Tyden 212 g,x Last year 29 - - (-) 2.6 (35) - (-) Switzerland Jeannin 29 y,g,f Lifetime 27 (1962-1976) 6. (-) 4. (-) - (-) Jeannin 29 y,g,f Last year 27 (1962-1976) 1. (-) 1. (-) - (-) Jeannin 29 y,g,f Lifetime 27 (1977-1986) 5. (-) 3. (-) - (-) Jeannin 29 y,g,f Last year 27 (1977-1986) 1. (-) 1. (-) - (-) Jeannin 29 y,g,f Lifetime 27 (1987-199) 2. (-) 1. (-) - (-) Jeannin 29 y,g,f Last year 27 (1987-199) 1. (-) 1. (-) - (-) Jeannin 29 z Last year 27 (1933-1946) 1. (-).6 (-).8 (3291) Jeannin 29 z Last year 27 (1947-1961) 1.3 (-).9 (-) 1.1 (42) Jeannin 29 z Last year 27 (1962-1976) 1.4 (-) 1.1 (-) 1.2 (489) Jeannin 29 z Last year 27 (1977-199) 2.2 (-) 1.3 (-) 1.7 (2262) UK Almonte 211 g,a Lifetime 23-27 (1959-1972) - (-) 5.6 (195) - (-) Almonte 211 g,a Lifetime 23-27 (1959-199) - (-) 7.5 (436) - (-) Almonte 211 g,a Lifetime 23-27 (1969-1982) - (-) 7.7 (168) - (-) Almonte 211 g,a Lifetime 23-27 (1979-199) - (-) 12. (73) - (-) Hubert 1998 g Lifetime 199-1991 (1941-1973) 1.4 (6414) 3.7 (849) - (-) (Continued on next page)

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 17 - ( Table 32 continued from previous page) Period MALE FEMALE TOTAL Country Study of estimate Year/Period Birth cohort Mean N Mean Hubert 1998 e Last year 199-1991 (1941-1973) 1.3 (6134) 1.1 (779) - (-) Johnson 21 n Lifetime 1999-21 (1955-1966) 16. (1691) 6.8 (2356) - (-) Johnson 21 n Last 5 years 1999-21 (1955-1966) 2.2 (1669) 1.5 (2332) - (-) Johnson 21 n Lifetime 1999-21 (1955-1985) 12.7 (4762) 6.5 (6399) - (-) Johnson 21 n Last 5 years 1999-21 (1955-1985) 3.8 (4762) 2.4 (6399) - (-) Johnson 21 n Lifetime 1999-21 (1965-1976) 13.6 (1759) 7.3 (2486) - (-) Johnson 21 n Last 5 years 1999-21 (1965-1976) 4.2 (1751) 2.2 (2474) - (-) Johnson 21 n Lifetime 1999-21 (1975-1985) 6.9 (1211) 5. (1433) - (-) Johnson 21 n Last 5 years 1999-21 (1975-1985) 5.3 (12) 3.8 (1422) - (-) Mercer 29 n Last year 1999-21 (1955-1985) 1.8 (4762) 1.3 (6399) - (-) Ukraine Ukraine DHS 27 Lifetime 27 (1958-1967) 6.8 (747) 2.1 (1916) - (-) Ukraine DHS 27 Lifetime 27 (1968-1977) 6. (743) 2.2 (1917) - (-) Ukraine DHS 27 Lifetime 27 (1978-1982) 5.6 (367) 2.1 (97) - (-) Ukraine DHS 27 Lifetime 27 (1983-1987) 5.3 (392) 2.2 (768) - (-) Ukraine DHS 27 Lifetime 27 (1983-1992) 4.6 (527) 2.1 (94) - (-) Ukraine DHS 27 Lifetime 27 (1988-1992) 2.9 (135) 1.6 (136) - (-) Data accessed on 8 Aug 213. N: number of subjects sexually active; a Data pertain to women attending a sexually transmitted disease clinic. b Data pertain to women attending six clinics in Belarus, Latvia and Russian Federation. c Data pertain to gynecological patients. d Data pertain to women participating in cervical cancer screening. e Data among responders who ever had a heterosexual partner. f Median number of sexual partners. g Number of surveyed people (not all sexually active). h Data from the Analysis on Sexual Behaviour in France (ACSF). i Data pertain to women attending a sample of gyneacologists in Berlin. j Data from the Survey performed in the Federal Republic of Germany (before reunification). k Data from "every man/woman who presents herself as heterosexual"; all partners are included. l Data pertain to heterosexual members from 12 social networks. m Weighted data based on national age distributions for Ireland, the Netherlands and Russia. n Number of heterosexual partners among surveyed (not all sexually active). o Data pertain to students attending student health units in three high education institutions (two universities and one institute of education) p Data pertain to Jewish adolescents. q Data pertain to secondary schools students. r Data pertain to students who reported regular sexual activity after their sexual debut. s Data pertain to heterosexuals not living with a partner. t Data pertain to heterosexuals married or living with a partner. u Data pertain to women attending routine cervical cancer screening. v Data pertain to population attending family planning centers or screening centers. w Data pertain to high school students. x Data pertain to university students. y Data from the EPSS (Enquête téléphonique périodique sur la Prévention du VIH/sida en Suisse). z Data from the ESS 27 (Enquête Suisse sur la Santé). Some of the questions that were only included in the EPSS survey were also integrated into the Swiss Health Survey (ESS) in 27. This allowes the documentation of these aspects also for people aged 46 to 74 years. A The authors used the following formula to estimate the Number of lifetime partners in year 2 in women aged 17-45 years= Number of lifetime partners - Number of new partners in the last 5 years. Data sources: See references in Section 9. Table 33: Lifetime prevalence of anal intercourse among women in Europe FEMALE % among Country Study Year/Period Birth cohort N surveyed N sexual active sexually active Belgium Hubbert 1998 a,b 1993 (1934-1978) - 631 2. Croatia Stulhofer 29 25 (1981-1987) 574 475 21.5 Stulhofer 211 21 (1985-1992) 495-29.8 Czech Rep. Brody 211 c 1993 <=1978-542 16.6 Brody 211 c 1998 <=1983-696 18. Brody 211 c 23 <=1988-799 17.4 Brody 211 c 28 <=1993-843 19.7 Estonia Part 27 d 24-25 (1987-1989) 194 9 7.2 Part 27 d 24-25 (198-1987) 168 98 25.1 Part 27 d 24-25 (197-198) 721 77 32.9 Part 27 d 24-25 (196-197) 689 68 24.7 Finland Hubbert 1998 a 1991-1992 (1917-1974) - 57 23. France Bajos 21 197 <=195 1375-15. Bajos 21 197 (1941-195) 1375-16. (Continued on next page)

6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS - 171 - ( Table 33 continued from previous page) FEMALE % among Country Study Year/Period Birth cohort N surveyed N sexual active sexually active Bajos 21 197 (1921-194) 1375-14. Bajos 21 1992 (1923-1974) 1198-28.1 Bajos 21 1992 (1963-1972) 1198-23.8 Bajos 21 1992 (1943-1962) 1198-3.3 Bajos 21 26 (1937-1988) 6824-4.8 Bajos 21 26 (1977-1986) 6824-36.8 Bajos 21 26 (1957-1976) 6824-42.5 Germany Hubbert 1998 e,a 199 (1921-1972) - 856 15.5 Greece Hubbert 1998 a 199 (1941-1975) - 721 1.1 Ireland ISSHR 26 c,f,g 24-25 (194-1987) 4253-8. ISSHR 26 c,f,g 24-25 (198-1987) 1497-4. ISSHR 26 c,f,g 24-25 (197-198) 953-6. ISSHR 26 c,f,g 24-25 (196-197) 829-7. ISSHR 26 c,f,g 24-25 (195-196) 736-13. ISSHR 26 c,f,g 24-25 (194-195) 264-9. Montenegro Labovic 211 d 29 (1985-1994) 544 194 16.4 Netherlands Bakker 26 h,f,g 25-26 (1936-1987) 246 1689 22.7 Hubbert 1998 a,i 1989 (1939-1971) - 461 11.6 Slovenia Klavs 29 1999-21 (1975-1983) 312-19.6 Klavs 29 1999-21 (195-1983) 864-22.3 Klavs 29 1999-21 (1965-1976) 213-3.6 Klavs 29 1999-21 (195-1966) 339-18.3 - - 186 719 6. 29 (1989-1994) 213 118 15.4 Spain Faílde Garrido 28 j,g Sweden Häggström- Nordin 21 k,d Tyden 212 l,d 1999-333 - 27. Tyden 212 l,d 24-315 - 32. Tyden 212 l,d 29-35 - 39. UK Johnson 21 c,f 199-1991 (1946-1975) 7765-6.5 Johnson 21 c,f 1999-21 (1955-1985) 6399-11.3 Stone 26 c,m 23-25 (1984-199) 765-9.3 Data accessed on 8 Aug 213. N: number of subjects; a Data pertain to women in current steady heterosexual relationship. b Proportion among women who ever practice receptive anal intercourse with current partner. c Instead of number of women sexually active, this time was number of women who answered the question on anal intercourse. d Proportion among surveyed women (not all sexually active). e Data from the Survey performed in the Federal Republic of Germany (before reunification). f Data pertain to heterosexual women. g Proportion among women who ever practice receptive anal intercourse in the last 6 months. h Data on anal intercourse was not provided by the authors but calculated from percentage of those that have never practice anal intercourse. i Proportion among women who recently practice receptive anal intercourse with current partner. j Data pertain to adolescents and young adults. k Data pertain to high school students. l Data pertain to university students. m Data pertain to full and part time students. Data sources: See references in Section 9.

7 HPV PREVENTIVE STRATEGIES - 172-7 HPV preventive strategies It is established that well-organised cervical screening programmes or widespread good quality cytology can reduce cervical cancer incidence and mortality. The introduction of HPV vaccination could also effectively reduce the burden of cervical cancer in the coming decades. This section presents indicators on basic characteristics and performance of cervical cancer screening, status of HPV vaccine licensure, and introduction in Europe. 7.1 Cervical cancer screening practices Screening strategies differ between countries. Some countries have population-based programmes, where in each round of screening women in the target population are individually identified and invited to attend screening. This type of programme can be implemented nationwide or only in specific regions of the country. In opportunistic screening, invitations depend on the individual s decision or on encounters with health-care providers. The most frequent method for cervical cancer screening is cytology, and there are alternative methods such as HPV DNA tests and visual inspection with acetic acid (VIA). VIA is an alternative to cytology-based screening in low-resource settings (the see and treat approach). HPV DNA testing is being introduced into some countries as an adjunct to cytology screening ( co-testing ) or as the primary screening test to be followed by a secondary, more specific test, such as cytology. Table 34: Cervical cancer screening policies in Europe Country Availability of cervical cancer screening programme α Quality assurance structure and mandate to supervise and to monitor the screening process β Active invitation to screening γ Main screening test used for primary screening Demonstration projects Screening ages (years) Screening interval or frequency of screenings Albania Yes No No Cytology Above 2 2-3 Years Andorra Yes No No Cytology - - Austria Yes No No Cytology Above 18 1 year Belarus Yes No No Cytology Above 18 1 year No Cytology 25-64 3 years Belgium Yes No. Varies by region A Bosnia & H. Yes Yes B No Cytology 21-7 1 year Bulgaria Yes No No Cytology 3-59 3 years Croatia Yes Yes A,B No Cytology 25-64 3 years Cyprus Yes No No Cytology 24-65 - Czech Rep. Yes Yes No Cytology 25-6 1 year Denmark Yes Yes A Yes Cytology 23-65 3 years (ages 23-49), 5 years (ages 5-65) Estonia Yes Yes A Yes Cytology 3-59 5 years Finland Yes Yes A Yes Cytology 3-6 5 years France Yes Yes A,B Yes Cytology 25-65 3 years Germany Yes No No Cytology HPV test Above 2 1 year Greece Yes No No Cytology Above 2 1 year Hungary Yes Yes A Yes Cytology 25-65 3 years Iceland Yes Yes Yes Cytology 2-69 2 years (ages 2-39), 4 years (ages 4-69) Ireland Yes Yes Yes Cytology 25-6 3 years (ages 25-44), 5 years (ages 45-6) (Continued on next page)

7 HPV PREVENTIVE STRATEGIES - 173 - ( Table 34 continued from previous page) Country Availability of cervical cancer screening programme α Quality assurance structure and mandate to supervise and to monitor the screening process β Active invitation to screening γ Main screening test used for primary screening Demonstration projects Screening ages (years) Screening interval or frequency of screenings Italy Yes Yes A,B Yes Cytology/HPV test 25-64 3 years (Cytology), 5 years (HPV test) Latvia Yes Yes A,B Yes Cytology 25-7 3 years Lithuania Yes Yes A,B Yes Cytology 25-6 3 years Luxembourg Yes No No Cytology Above 15 1 year Macedonia Yes No No Cytology 3-55 3 years Malta Yes Yes Yes Cytology/HPV test Above 25 (cytology), Above 3 (HPV test) Cytology every 3 years (ages 25-5), VIA every 5 years (above 5 years old). HPV test every 5 years Moldova Yes No No Cytology Above 2 2 years Monaco Yes - No Cytology 21-65 3 years after 2 consecutive annual negative tests Montenegro Yes Yes B No Cytology 25-64 3 years Netherlands Yes Yes A Yes Cytology/HPV 3-6 5 years test Norway Yes Yes Yes Cytology 25-69 3 years Poland Yes Yes A Yes Cytology 25-59 3 years Portugal Yes Yes A Yes Cytology 25-64 3 years Romania Yes Yes A,B Yes Cytology 25-64 5 years Russia Yes No No Cytology Above 18 1 year San Marino Yes - Yes Cytology/HPV test 25-3 (cytology), 3-65 (HPV test) 3 years (cytology), 5 years (HPV test) Serbia Yes Yes B Yes Cytology 25-65 3 years Slovakia Yes No No Cytology 23-64 3 years Slovenia Yes Yes Yes Cytology 2-64 3 years Spain Yes No. Varies by region No. Varies by region Cytology/HPV test 25-65 (cytology), 3-65 (HPV test) 3 years (cytology), 5 years (HPV test) Sweden Yes Yes A Yes Cytology 23-6 3 years (ages 23-5), 5 years (ages 5-6) Switzerland Yes No No Cytology Above 2 3 years (Continued on next page)

7 HPV PREVENTIVE STRATEGIES - 174 - ( Table 34 continued from previous page) Country Availability of cervical cancer screening programme α Quality assurance structure and mandate to supervise and to monitor the screening process β Active invitation to screening γ Main screening test used for primary screening Demonstration projects Screening ages (years) Screening interval or frequency of screenings UK Yes Yes A Yes Cytology/HPV test 25-64 3 years (ages 25-49), 5 years (ages 5-64) Ukraine Yes No No Cytology 18-65 1 year Data accessed on 31 Dec 216. A Information about performance indicators in organized and population-based cervical cancer screening programmes in European countries is found in the following document "Cancer Screening in the European Union (217). Report on the implementation of the Council: Recommendation on cancer screening. International Agency for Research on Cancer. European Commission. January 217. Available at: https://ec.europa.eu/health/sites/health/files/major_chronic_diseases/docs/217_cancerscreening_2ndreportimplementation_ en.pdf." B Implementation is in progress. C To replace Pap-test by hrhpv DNA test as the primary screening instrument (starting in 216). D Screening program since 1968. α Public national cervical cancer screening program in place (Cytology/VIA/HPV testing). Countries may have clinical guidelines or protocols, and cervical cancer screening services in a private sector but without a public national program. Publicly mandated programmes have a law, official regulation, decision, directive or recommendation that provides the public mandate to implement the programme with an authorised screening test, examination interval, target group and funding and co-payment determined. β Self-reported quality assurance: Organised programmes provide for a national or regional team responsible for implementation and require providers to follow guidelines, rules, or standard operating procedures. They also define a quality assurance structure and mandate supervision and monitoring of the screening process. To evaluate impact, organised programmes also require ascertainment of the population disease burden. Quality assurance consists of the management and coordination of the programme throughout all levels of the screening process (invitation, testing, diagnosis and follow-up of screen-positives) to assure that the programme performs adequately and provides services that are effective and in-line with programme standards. The quality assurance structure is self-reported as part of the national cancer programs or plans. γ Self-reported active invitation or recruitment, as organised population-based programmes, identify and personally invite each eligible person in the target population to attend a given round of screening. Data sources: Data sources are detailed at the country-specific report

7 HPV PREVENTIVE STRATEGIES - 175-7.2 HPV vaccination 7.2.1 HPV vaccine licensure and introduction Figure 129: Status of HPV vaccination programmes in Europe Data accessed on 31 Dec 216. Data sources: Adapted from Bruni L, Diaz M, Barrionuevo-Rosas L, Herrero R, Bray F, Bosch FX, de Sanjosé S, Castellsagué X. Global estimates of human papillomavirus vaccination coverage by region and income level: a pooled analysis. Lancet Glob Health. 216 Jul;4(7):e453-63