1. Burden of Disease Professor Xavier Bosch Institut Català d’Oncologia Barcelona, Spain

2. The HPV Infections of the Genital Tract The most common genital infection worldwide Sexually transmitted Clinically silent and self limiting most of the times Some women remain persistent carriers of the viral infection and become at high risk of progression to precancer and cancer of the cervix, vulva, vagina and anal canal May cause cancers in the penis and anal canal in HPV infected men Cancers at other sites Prof Xavier Bosch

3. De Sanjose et al. Lancet 2007 The Prevalence of HPV DNA Literature Review January 1995 – January 2005 Reports with cross sectional data with at least 100 women with normal cytology PCR or HC2 Entered: - 108 studies (n= 169,341) - 78 studies with normal cytology (n=157,879) Results on HPV DNA Prevalence: –Crude, in women with normal cytology, –adjusted in women with normal cytology Prof Xavier Bosch

4. GLOBAL10.4% (10.2-10.7) Africa22.1% (20.9-23.4) America13.0% (12.4-13.5) Europe8.1% (7.8-8.4) Asia7.9 % (7.5-8.4) HPV DNA Prevalence in 160,000 Women With Normal Cytology (Adjusted Model) Prof Xavier Bosch De Sanjose et al. 2007, The Lancet

5. Age-Specific HPV Prevalence Among Women With Normal Cytology* *Adjusted Prof Xavier Bosch De Sanjose et al. 2007, The Lancet

6. 0 5 10 15 20 25 30 < 2525-3435-4445-54> 54 AGE GROUP Africa CS. America Asia N. America Europe Age-Specific HPV Prevalence in Women with Normal Cytology By Continent Prof Xavier Bosch De Sanjose et al. 2007, The Lancet

7. Developed CountriesDeveloping Countries Site ATTRIB TO HPV (%) Total Cancers Attrib to HPV % All Cancer Total Cancers Attrib to HPV % All Cancer Cervix10083,400 1.7%409,400 7.0% Penis405,2002,1000.0%21,1008,4000.1% Vulva, Vagina 4018,3007,3000.1%21,7008,7000.1% Anus9014,50013,1000.3%15,90014,3000.2% Mouth391,2002,7000.1%183,1005,5000.1% Orophar1224,4002,9000.1%27,7003,3000.1% All Sites 5,016,100111,5002.2%5,827,500449,6007.7% Parkin M et al. Int J Cancer 2006 HPV Infection-Attributable Cancer In 2002 Prof Xavier Bosch

8. Globocan 2002 Africa IncidenceMortality Prof Xavier Bosch The Seven Most Frequent Cancers in Women: Incidence and Mortality

9. Five Most Common Cancers in Women in Africa Africa 1 st 2 nd 3 rd 4 th 5 th EasternCERVIX 42.7 BREAST 19.5 KAPOSI SRC. 9.5 LIVER 8.6 OESOPHAGUS 8.0 MiddleCERVIX 28.0 BREAST 16.5 LIVER 13.4 STOMACH 12.6 KAPOSI SRC. 8.6 Northern BREAST 23.2 CERVIX 12.1 COLON & RECTUM 4.0 BLADDER 3.6 LEUKAEMIA 2.7 Southern CERVIX 38.2 BREAST 33.4 COLON & RECTUM 8.9 OESOPHAGUS 7.0 LUNG 6.9 WesternCERVIX 29.3 BREAST 27.8 LIVER 5.6 OVARY. 4.6 STOMACH 3.6 Prof Xavier Bosch Globocan 2002

10. < 87.3* < 16.1 < 32.6 < 9.2 < 26.2 N. AMERICA 14,670 C-S. AMERICA 71,862 AFRICA 78,897 ASIA 265,884 EUROPE 59,931 (*per 100,000) Estimated Number of Cases of Cervical Cancer (2002) Prof Xavier Bosch Globocan 2002

11. <25.1 Incidence of Cervix uteri cancer : ASR <29.3 <33.6<42.7 <68.6 Prof Xavier Bosch Globocan 2002 Incidence of Cervical Cancer in Africa

12. INCIDENCE – CASES MORTALITY - DEATHS 1,664 1,354 2716 2178 1726 1391 218 175 1550 1247 284 229 Algeria Libya Egypt Sudan Tunisia Morocco Prof Xavier Bosch <25.1 Incidence of Cervix uteri cancer : ASR <29.3 <33.6<42.7 <68.6 Globocan 2002 Incidence and Mortality of Cervical Cancer in Northern Africa Region - 8158 6574

13. Syria118 55 Region - 8193 4151 Incidence and Mortality of Cervical Cancer in the Middle East Iraq252 129 Saudi Arabia271 143 Yemen370 206 Kuwait5 3 Qatar34 17 Iran1,118 581 Afganistan511 254 Pakistan2,962 1,605 Arab Emirates73 36 Oman46 25 INCIDENCE – CASES MORTALITY - DEATHS Globocan 2002 Turkey1364 726

14. 16.8 13.5 9.9 8.2 8.0 6.9 6.9 6.5 6.1 4.6 4.4 4.2 3.9 3.3 2.0 024681012141618 ARMENIA TURKMENISTAN ARAB EMIRATES AZERBAIJAN YEMEN OMAN AFGHANISTAN PAKISTAN KUWAIT SAUDI ARABIA IRAN JORDAN QATAR IRAQ SYRIAN ARAB R. (118) (252) (5) (60) (1,118) (271) (34) (2,962) (511) (46) (370) (345) (73) (274) Globocan 2002 Age Adjusted Incidence Rates in the Middle East

15. 0123456 5.6 5.2 4.6 3.9 3.6 3.4 2.8 2.5 2.4 2.3 2.2 1.8 1.0 ARMENIA TURKMENISTAN ARAB EMIRATES AZERBAIJAN YEMEN OMAN AFGHANISTAN PAKISTAN KUWAIT SAUDI ARABIA IRAN JORDAN QATAR IRAQ SYRIAN ARAB R. (55) (129) (3) (32) (581) (143) (113) (17) (1605) (254) (25) (206) (36) (96) (130) Globocan 2002 Age Adjusted Mortality Rates in the Middle East

16. ALGERIA BREAST CERVIX UTERI COL/RECTUM N-HODGKIN LYMPHOMA OVARY 23.5 15.6 5.0 3.4 3.7 EGYPT BREAST CERVIX BLADDER LEUKEMIA LIVER 24.2 9.7 7.0 3.3 MOROCCO 22.5 BREAST CERVIX COL/RECTUM N-HODGKIN LYMPHOMA OVARY 13.2 5.5 3.4 3.5 NORTHERN AFRICA COL/RECTUM LIBYA 0510152025 BREAST CERVIX BLADDER LEUKEMIA 23.4 11.9 4.1 2.7 3.7 Prof Xavier Bosch Globocan 2002

17. Africa, Americas excluding Northern America, Asia excluding Japan, and Oceania excluding Australia and New Zealand Source: 2005 estimates. United Nations, Population Division. World Population Prospects-the 2004 revision. New York, 2005. Prof Xavier Bosch Developing Regions Projections Women 25-64 yrs All Women 1000 2000 3000 4000 Girls 10-14 yrs Women 15-24 yrs 100 200 300 400 500 600 195019551960196519701975198019851990199520002005 2010 20152020 202520302035 204020452050 0 Number of women (in millions)

18. Women 25-64 yrs All Women 200 300 400 500 600 700 Girls 10-14 yrs Women 15-24 yrs 20 40 60 80 19501955196019651970 1975198019851990199520002005 2010 2015 2020 20252030 2035 204020452050 100 Number of women (in millions) Developed Regions Northern America, Europe, Japan, Australia and New Zealand Prof Xavier Bosch Source: 2005 estimates. United Nations, Population Division. World Population Prospects-the 2004 revision. New York, 2005. Projections

19. Girls 10-14 years. Population Prospects 300 0 50 100 150 200 250 19501955196019651970197519801985199019952000200520102015202020252030203520402045 2050 Developing Regions Developed Regions Number of girls (in millions) Prof Xavier Bosch Source: 2005 estimates. United Nations, Population Division. World Population Prospects-the 2004 revision. New York, 2005.

20. 0 500 1000 1500 2000 2500 3000 1950 19551960196519701975198019851990199520002005201020152020202520302035204020452050 Developing Regions Developed Regions Number of women (in millions) Prof Xavier Bosch Women  15 years. Population Prospects Source: 2005 estimates. United Nations, Population Division. World Population Prospects-the 2004 revision. New York, 2005. Projected number of cervical cancer cases in Northern Africa will increase by 15%

21. *Projections assume that rates estimated for 2002 continue into the future 20022020* (% CHANGE) 2020* (% BURDEN) WORLD493,000702,500 (42%)100% Women aged <65396,500549,000 (38%)78% Women aged  65 96,500153,500 (59%)22% LESS DEV. AREAS409,000639,500 (56%)83% Women aged <65336,000507,500 (51%)79% Women aged  65 73,000132,000 (80%)21% MORE DEV. AREAS83,00092,500 (11%)17% Women aged <6560,00062,500 (30%)67% Women aged  65 23,00030,000 (31%)33% Parkin M & Bray Vaccine 2006 Predicted Number of Cervical Cancer Cases in 2020 by World Area and Age Prof Xavier Bosch

22. *Projections assume that rates estimated for 2002 continue into the future 2002 2020* (% CHANGE ) 2020* (% BURDEN) AFRICA78897 121962 (55%) 100% Eastern3390350680 (49%)42% Middle820113944 (71%)10% Northern81758846 (15%)7% Southern76988846 (15%)7% Western2091933678 (61%)28% Predicted Number of Cervical Cancer Cases in 2020, by Africa, Area and Age Prof Xavier Bosch Globocan 2002

23. INCIDENCE RATE PER 100,000 Prof Xavier Bosch Globocan 2002 Age-Specific Incidence of Cervical Cancer in Africa and the World 0 20 40 60 80 100 120 140 160 0-1415-4445-5455-64 65+ World Eastern Africa Middle Africa Northern Africa Southern Africa Western Africa

24. The Role Of HPV In Cervical Cancer Causality Established Prof Xavier Bosch

25. 96.2 90919293949596979899100 Africa Sub-Saharan Africa North Africa C-S. America S. Asia Europe / N. America Total 97.8 95.1 95.7 94.7 96.7 96.2 HPV POSITIVE (%) HPV DNA Prevalence in Cervical Cancer Specimens Using GP5+/6+ PCR By Region Prof Xavier Bosch Adapted From Muñoz N, et.al. Int J Cancer 2004

26. Africa Sub-Saharan Northern C-s. America S. Asia Total 0102030405060708090100 FALSE NEGATIVES POOR SPECIMEN HPV TEST squamous (N=2281) adeno/mixed (N = 196) HPV Positive (%) Europa & N. America HPV DNA Prevalence in Cervical Cancer by Histology Prof Xavier Bosch Muñoz N, Et Al. Int J Cancer Castellsagué X, et al., J Natl Cancer Inst

27. *OR ADJUSTED BY COUNTRY AND AGE-GROUPOR* (LOGARITHM) SquamousControl 0102030405060708090100 0.11101001200 OR* (95% CI) 94.1 15.9 Overall 90.0 (71.3-113.5) 97.0 17.3 Brazil 177.0 (65.5-478.3) 96.9 33.3 Mali 97.1 21.6 113.7 (42.3-305.3) 98.1 19.8 208.1 (46.4-932.8) Philippines 96.4 9.2 96.5 15.7 Thailand 163.5 (82.0-325.9) 95.3 17.7 Peru 115.9 (48.6-276.4) 82.4 6.5 Spain 67.4 (30.3-149.8) 78.4 16.9 Colombia 18.4 ( 9.4-36.0) 96.0 27.7 India 64.1 (28.1-146.3) Algeria 12.4 92.4 110.1 (45.1-268.9) Morocco Paraguay 109.2 (10.6-1119.0) 276.8 (139.7-548.3) % Prevalence of HPV DNA and or by Country Squamous Cell Carcinoma Prof Xavier Bosch Vaccine HPV Monograph, 2006

28. OR* (LOGARITHM) 84.87 (1.9 to + ) 36.71 (5.6 to + ) OR (95% CI) 100.0 94.4 100.0 92.3 85.7 92.0 90.9 92.3 93.0 12.4 17.3 27.7 21.6 19.8 17.7 9.2 15.7 16.5 0 1020 304050608090 100 0.1 110100 1000 76.23 (8.6 to 672.4) 35.82 (4.0 to 318.0) 55.34 (11.6 to 263.6) 112.70 (30.8 to 412.0) 111.40 (24.5 to 507.1) 81.27 (42.0 to 157.1) 79.55 (12.2 to + ) 70 Overall Brazil Philippines Thailand Peru India Algeria Morocco Paraguay *OR ADJUSTED BY COUNTRY AND AGE-GROUP % Prevalence of HPV DNA and or by Country Adenocarcinoma Prof Xavier Bosch AdenosquamousControl Vaccine HPV Monograph, 2006

29. Association of HPV and Cervical Cancer in Rabat, Morocco Cases 214Controls 203 Odds Ratio (95%CI) HPV DNANumber% % Negative105.414779.51.00 Positive17694.63820.561.65 (29.24-129.99) 1612667.784.3201.60 (76.31-532.59) 18158.121.193.02 (18.09-478.35) 31, 35, 3573.821.139.27(6.82-225.94) 4594.831.654.84 (12.08-248.87) Prof Xavier Bosch N Chaouki, FX Bosch, N Muñoz, Int J Cancer 1998

30. OR* 7.5 HPV X HPV 16-18 HPV 68 HPV 11 HPV 6 HPV 73 HPV 59 HPV 35 HPV 56 HPV 51 HPV 33 HPV 58 HPV 52 HPV 31 HPV 45 HPV 18 HPV 16 0.11001,0001 281.9 222.5 157.9 124.9 190.6 91.3 573.4 88.3 70.3 62 205.8 164.5 3.6 44.4 146.2 26.1 OR *OR adjusted by country and age HPV Type Specific Odds Ratios for Cervical Carcinoma Prof Xavier Bosch Vaccine HPV Monograph, 2006

31. 0 5 10 15 20 25 0.04.515.027.039.051.063.075.087.099.0111.0119.5 FOLLOW-UP TIME (MONTHS) CUMULATIVE INCIDENCE RATE OF CIN 3 (%) HPV16+ HPV18+/HPV16- HPV+/HPV16-/HPV18- HPV- Khan et al. JNCI, 2005 Cumulative Incidence of CIN 3+ 13,000 Women Over a Ten Year Period (As a Function of a Single HPV Test Result at Enrolment) Prof Xavier Bosch

32. 020406080100 16 53.5 18 17.2 45 6.7 31 2.9 33 2.6 52 2.3 58 2.2 35 1.4 59 1.3 56 1.2 51 1.0 39 0.7 68 0.6 73 0.5 82 0.3 Other 1.2 X 4.4 53.5% 70.7% 77.4% 80.3% 82.9% 85.2% 87.4% 88.8% HPV type Munoz N et al. Int J Cancer 2004 Type-Specific HPV Prevalence in Cervical Cancer Cases (All world regions combined) Prof Xavier Bosch

33. HPV 16 HPV 18 HPV 45 HPV 33 HPV 31 HPV 45 HPV 33 HPV 31 HPV 52 HPV 58 HPV 52 HPV 35 Muñoz N., Bosch FX., et al. Int J Cancer 2004 Smith J., et al. In Press Bosch X., et al In Preparation HPV 16 HPV 18 HPV 45 HPV 33 HPV 31 HPV 52 HPV 58 IARC POOLEDMETA-ANALYSIS 1 2 3 4 5 6 7 8 HPV TT HPV 35 Prof Xavier Bosch The 8 Most Common HPV Types in Cervical Cancer - World

34. Epidemiological Conclusions MENA generates an estimated number of 15,000 new cases of cervical cancer per year All cervical cancer cases are related to persistent HPV infections. HPV 16 & 18 account for 70% of cases worldwide Rates of cervical cancer are lower than world averages However cervical cancer remains the second most common cancer in women in MENA Predictions are that these numbers might increase by 15% in the next decade Prof Xavier Bosch