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CERVICAL CANCER & OTHER HUMAN PAPILLOMAVIRUS- RELATED DISEASES Dr.Ahmed Eltigani Elmahdi Hussain Consultant Obstetrician & Gynaecologist, IRELAND

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Incidence of Cervical Cancer In Europe Globocan 2002: ASR (World) < 1.5 < 0.4 <16.6 < 4.4 Age-adjusted incidence rates per 100,000 women per year < 7.9 38 countries: European Union except Cyprus (24 countries) + Iceland, Norway, Switzerland, Belarus, Bulgaria, Moldova, Romania, Russian Federation, Ukraine, Albania, Bosnia Herzegovina, Croatia, Macedonia, Serbia and Montenegro. 27 countries: European Union except Cyprus (24 countries) + Iceland, Norway, & Switzerland (3 countries). EUROPE (38 COUNTRIES): 60,000 new cases per year EUROPE (27 COUNTRIES): 33,386 new cases per year

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* Ovary, Fallopian tube, broad ligament, round ligament, parametrium, and uterine adnexa. European Union except Cyprus (24 countries) + Iceland, Norway, & Switzerland (3 countries). Age-standardized (World) incidence & mortality rates EUROPE INCIDENCE MORTALITY 4.9 5.4 7.5 34.0 10.4 0 10 20 30 40 Thyroid Ovary &…* Melanoma of skin Cervix uteri Breast Number of cases per 100,000 women per year 1.3 1.3 1.7 2.0 5.7 0 2 4 6 Colon and rectum Brain, nervous system Lung Cervix uteri Breast SOURCE: GLOBOCAN 2002.

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Cervical cancer is the second most frequent cancer in young women (15-44 years) in Europe 1 1. Ferlay et al. Globocan 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancer-Base No.5, version 2. Lyon. IARC Press, 2004. 2. Cancer Research UK, Cancer Mortality Figures 2004 http://info.cancerresearchuk.org/images/excel/cs_mort_t6.2.xls Breakdown of cancers in the young European female population (15-44 years) in 2002 21 women die each week on average in the UK 2

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National cervical screening programme <ul><li>The NHS cervical screening programme is recognised as world leading 1 </li></ul><ul><li>Cervical cancer incidence fell by 42% between 1988 and 1997 (England and Wales). This fall is believed to be directly related to an organised cervical screening programme 2 which was introduced in 1988 </li></ul>1. http://cancerscreening.org.uk/cervical/publications/cervical-annual-review-2004.pdf Accessed 12/10/05 2. NHS. Cervical Screening pocket guide. 2004.

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<ul><li>Clinical studies have shown that in 99.7% of cases, cervical cancer is caused by a virus: human papillomavirus (HPV) 1, 2 </li></ul><ul><li>Mucosal HPV infection can also cause vulval and vaginal pre-cancerous lesions and genital warts 3 </li></ul>Human papillomavirus infection - the link to cervical cancer & other diseases 1. Munoz N. Human papillomavirus and cancer : The epidemiological evidence. J Clin Virol 2000;19:1–5. 2 Walboomers JM, Jacobs MV, Manos MM et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–19. 3 . Zur Hausen H. Papillomavirus and cancer: from basic studies to clinical application. Nat Rev Cancer 2002;2:342-350.

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HPV <ul><li>It is the most common ST infection among women, an estimated 291 million women harbour an HPV worldwide. </li></ul><ul><li>Indeed all women who are, or have been, sexually active are at risk of HPV infection. </li></ul><ul><li>80% of the infections are thought to be transient, other lead to CIN, which may or may not then progress to CA. </li></ul><ul><li>Most early lesions will regress spontaneously. </li></ul><ul><li>Cervical CA is a late & rare complications of persistent infection and is the end result of a chain of events that take usually in excess of 10 years to unfold </li></ul>

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Human papillomavirus types 6,11,16 & 18 are four common types affecting women’s health 1.Clifford, GM et al. Br J Cancer 2003; 88: 63-73. 2.Daling JR, et al. Gynecol Oncol 2002; 84: 263-270 3.Madeleine et al. J Natl Cancer Inst 1997;89:1516–1523. 4.Clifford GM, et al. Br J Cancer 2003; 89: 101–105 5.Sotlar K, et al. J Clin Microbiol 2004; 42: 3176-3184. 6.van Beurden M, et al. Cancer 1995; 75: 2879-2884. 7.Hording U, et al. Gynecol Oncol 1995; 56: 276–279. 8.Clifford GM, et al. Cancer Epidemiol Biomarkers Prev 2005; 14:1157-1164. 9.von Krogh G. Eur J Dermatol 2001; 11: 598-603. 10.Wieland U, Pfister H. Human Papilloma Virus: A clinical atlas. Ullstein Mosby; 1997. p1-18.

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Relationship of HPV infection with genital neoplasia <ul><li>Cervical cancer- third most common gynaecological malignancy </li></ul><ul><li>All cervical cancers contain HPV DNA- an estimated 99.7% prevalence </li></ul><ul><li>Significant fraction of vaginal, vulvar, penile and anal cancers </li></ul><ul><li>Oncogenic HPV types 16 and 18 cumulatively account for ~70% of all cervical cancers </li></ul><ul><li>HPV types most commonly results in sub clinical infections </li></ul><ul><li>Most infected women harbour HPV DNA without showing cytological or histological changes </li></ul>

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Risk factors <ul><li>Sexual activity- number of current and previous partners </li></ul><ul><li>In men- circumcision reduces risk of the acquisition and transmission of HPV </li></ul><ul><li>Use of latex condoms reduces the risk of HPV infection </li></ul><ul><li>Co infection with Chlamydia trachomatis or Herpes simplex virus </li></ul><ul><li>A grater rate and incidence of infection has been observed imunocompromissed renal transplant patients and HIV infected patients </li></ul><ul><li>High parity (5 or more pregnancies) </li></ul><ul><li>Active and passive cigarette smoking </li></ul><ul><li>Long term use of oral contraceptives </li></ul>

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Transmission <ul><li>HPV is transmitted by genital contact </li></ul><ul><li>Virus must have access to the basal epithelial cells, either in epithelium that is naturally thin & immature: </li></ul><ul><ul><li>TZ of the cervix </li></ul></ul><ul><ul><li>or the anal verge </li></ul></ul><ul><ul><li>microscopic tears or abrasions in the external genital skin or the introital or vaginal mucosa </li></ul></ul><ul><li>Genital-oral transmission-may be possible </li></ul><ul><li>Recurrent papillomatosis in young children can occur from the transmission of HPV 6 or 11 from a mother to a newborn baby </li></ul>

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Circumcision Castellsagué et al, NEJM 2002 Male circumcision reduces the risk of HPV infection in men and of cervical cancer in the female partner

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DISEASE CAUSED BY HPV 6/11 Causative agent of genital warts Causative agent of JORRP

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Genital warts <ul><li>Genital warts, also referred to as condyloma acuminata. </li></ul><ul><li>They are soft growths that are typically found on the skin or mucous membranes </li></ul><ul><li>Benign, very rarely become malignant. </li></ul><ul><li>More than 90% of genital wart cases are caused by HPV types 6 and 11 2, 3 </li></ul>Genital warts on male subject Genital warts on female subject

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P revalence <ul><li>HPV infection typically asymptomatic in men </li></ul><ul><li>prevalence rates of HPV in men range 16-45% </li></ul><ul><li>prevalence is similar in both sexes (both men and women develop genital warts-1%sexual active adults) </li></ul>

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Prevalence <ul><li>HPV infection most prevalent in young woman and adolescents: </li></ul><ul><li>As a result of increased transmission during the early </li></ul><ul><li>years of sexual activity </li></ul><ul><li>A lack of previous exposure that might generate a protective immune response </li></ul><ul><li>The transformation zone of cervical epithelium undergoes a process of squamosus metaplasia during puberty that exposes normally protected basal cells to infection </li></ul><ul><li>In one study using PCR-based DNA amplification systems to detect HPV DNA 32% of women 16-24 years old tested positive for HPV DNA, compared with 4% of women aged >45 years </li></ul>

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In women, peak exposure to human papillomavirus occurs in late teens and early twenties Sanofi Pasteur MSD Data on File 2006 06/004

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Percentage of 15 year old girls who have had sexual intercourse by country Adapted from Ross J, Godeau E, Dias S. Sexual health. In: Currie et al. Eds. Young people’s health in context. Health behaviour in school-aged children study : international report from the 2001/2002 survey. WHO Europe;2004.p. 153-160.

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Estimated HPV DNA prevalence in the world (Meta-analysis of 67 studies involving 139,777 cytologically normal women) GLOBAL 10.2% (10.0-10.5) AFRICA 23.4% (22.0 - 24.8) AMERICA 12.8% (12.1 - 13.5) EUROPE 8.2% (7.9 - 8.6) ASIA 7.6% (7.2 - 8.1)

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Which specific HPV types are important in cervical cancer?

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<ul><li>HPV types 16,18,31,33,35,45,52 are </li></ul><ul><li>responsible for >90%of all high grade CIN </li></ul><ul><li>grades CIN 11-111 </li></ul><ul><li>Just 2 types- 16,18 account for >70% of all </li></ul><ul><li>cervical cancers. </li></ul><ul><li>HPV 16 alone is responsible for 52% of all </li></ul><ul><li>cervical cancers) </li></ul>

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HPV PREVALENCE IN THE CERVIX BY CYTOLOGICAL / HISTOLOGICAL DIAGNOSIS <ul><li>WOMEN WITH N. CYTOLOGY 9-10 % (2-3%) </li></ul><ul><li>PRE-INVASIVE LESIONS 80-90 % (50%) </li></ul><ul><li>CERVICAL CANCER 95-100 % (70%) </li></ul>DIAGNOSIS HPV-DNA HPV 16/18 DE SANJOSE ET AL IN PREPARATION; CLIFFORD ET AL 2003; MUÑOZ ET AL 2003

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Cervical Intraepithelial neoplasia (CIN1) 1 Vulval Intraepithelial neoplasia (VIN) 4 Cervical Intraepithelial neoplasia (CIN 2/3) 2,3 Genital warts 6,7 Vaginal Intraepithelial neoplasia (ValN) 5 1.Clifford GM etal. Cancer Epidemiol Biomarkers Prev 2005; 14:1157 – 1164 2. Clifford GM, Smith JS, Aguado T et al. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: A meta-analysis. Br J Cancer 2003; 89: 101–105 3. Sotlar K, Diemer D, Dethleffs A et al. Detection and typing of human papillomavirus by E6 nested multiplex PCR. J Clin Microbiol 2004; 42: 3176-3184. 4.Madeleine MM, Daling JR, Carter JJ et al. Cofactors with human papillomavirus in a population-based study of vulvar cancer.J Natl Cancer Inst 1997;89:1516–1523. 5. Daling JR, Madeleine MM, Schwartz SM et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 2002; 84: 263-270.6.Von Krogh G. Eur J Dermatol 2001;11:598-603. 7. Wieland U., Pfister H. In:Gross, Barrasso eds Human papillomavirus: A clinical atlas.Ullstein Mosby; 1997.p1-18

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<ul><li>Oncogenic (High risk) </li></ul><ul><li>There are seven genotypes that account for 85-90% of cervical cancers worldwide 1 </li></ul><ul><li>Types 16 & 18 account for ~75% of cervical cancers in Europe 2 </li></ul><ul><li>Non-oncogenic (Low risk) </li></ul><ul><li>Types 6 & 11 account for 90% of genital warts 3,4 </li></ul>Common human papillomavirus types affecting women’s health <ul><li>Munoz et al. Int J Cancer 2004;111: 278-285. </li></ul><ul><li>Clifford, G. M et al. British Journal of Cancer, 88, 63-73. 2003 </li></ul><ul><li>Von Krogh G. Eur J Dermatol 2001;11:598–603. </li></ul><ul><li>Wieland U,& Pfister H. Human Papilloma Virus Infection, A Clinical Atlas. Gross/Barrasso; 2005. </li></ul>Images courtesy of Dr J. Monsonego Genital Warts Cervical Lesions

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Infection with human papillomavirus can lead to genital warts 4,174 people in Ireland were diagnosed in 2004 with genital warts which is an increase of 4.8% compared with 2003 1

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??? The economic burden of HPV infection ??? <ul><li>Cervical cancer screening </li></ul><ul><li>Follow- up of abnormal Pap test results </li></ul><ul><li>Treatment of invasive cancer </li></ul><ul><li>Only 10% is attributed to the treatment of invasive cervical cancer </li></ul><ul><li>Other 90% is for cervical cancer prevention </li></ul><ul><li>Diagnosis and treatment of genital warts alone also very expensive </li></ul><ul><li>Cervical cancer screening programs are not accessible to women of all social and ethnic backgrounds </li></ul>

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UK burden of disease – cervical cancer 17.9% 7.3% CC Cases * Management of abnormal findings CC Screening Hospital days for existing cervical cancer cases New cervical cancer cases £104.3 million £34.5 million £33.3 million £13.5 million 56.2% 18.6% 25.2% *No data for NI Brown RE et al. Curr Med Res Opin 2006; 22 : 663–670 Total estimated cost of cervical cancer from screening to management of the disease in the UK in 2003 is around £185.6 million Estimated cost of disease management

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The Solution!!!!!! The Vaccine ????? <ul><li>Gardasil </li></ul><ul><li>Cervarix </li></ul>

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Vaccines <ul><li>2 multivalent VLP vaccines: </li></ul><ul><li>Bivalent HPV 16 and 18 VLP- reduce cervical cancer rates(CERVARIX) </li></ul><ul><li>Quadrivalent HPV vaccine includes most common HPV disease causing types- 6,11,16,18- reduce the incidence of external genital warts in addition to preventing cervical cancer(GARDASIL) </li></ul><ul><li>In the per-protocol cohort, the vaccine was 89% effective in preventing persistent infection and 100% effective in preventing clinical disease (CIN 1/2/3) associated with the 4 HPV types </li></ul>

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Vaccines- prepared from exogenously expressed HPV major L1 capsid proteins VLPs (virus-like particles) and have been induce HPV type-specific antibody responses

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<ul><li>VLPs: </li></ul><ul><li>Do not contain genetic material </li></ul><ul><li>Are not infectious </li></ul><ul><li>Have no oncogenic potential </li></ul>

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* CIN = Cervical intraepithelial neoplasia ** World Health Organisation *** Food and Drug Administration US Proven efficacy in the prevention of cervical cancer against a truly predictive clinical endpoint 0 years 10 + years 1. Adapted from Franco EL, Harper DM. Vaccine 2005; 23:2388-94 2. Sanofi Pasteur MSD Data on File 06/008 2

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Rationale for designing a quadrivalent HPV vaccine 1. Clifford, G. M et al. British Journal of Cancer, 88, 63-73. 2003 2. Von Krogh G. Eur J Dermat . 2001;11: 598-603. 3. Koutsky L. Am J Med. 1997; 102: 3-8. Reason for choice of the human papillomavirus types Anticipated benefits 41

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HPV vaccines for prevention of infection <ul><li>Reduce the incidence of the majority of HPV- associated diseases </li></ul><ul><li>Vaccine induced immunity may reduce both horizontal (person-to-person) and vertical (mother-to-newborn) transmission </li></ul>

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HPV VACCINE <ul><li>The vaccine was shown to be 100% effective in the short term at preventing type-specific premalignant disease of the cervix. </li></ul><ul><li>The potential of such a vaccine to reduce the worldwide incidence of cervical cancer is immediately apparent. </li></ul>

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THEORETICAL IMPACT OF A VACCINE INCLUDING HPV Types 6, 11, 16 & 18 67-71% 52-60% ~35% ~20-30% ASCUS: Atypical Squamous Cell of Undetermined Significance L/HSIL: Low/High Grade Squamous Intraepithelial Lesion ICC: Invasive Cervical Cancer ICC ASCUS LSIL HSIL POTENTIAL REDUCTION Months Years Decade(s)

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Potential benefits of HPV vaccines <ul><li>Vaccination of 12-year-old girls with an HPV 16/18 vaccine would reduce the number of cervical cancer cases by >95% </li></ul><ul><li>Vaccination both men and women was predicted to be more beneficial than vaccinating only women </li></ul><ul><li>Vaccines effectively reduce the incidence of HPV-associated clinical disease will also reduce the psychological morbidity associated with diagnosis and treatment </li></ul>

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INDICATION OF VACCINE <ul><li>Prevention of: </li></ul><ul><li>high-grade cervical dysplasia (CIN 2/3) </li></ul><ul><li>cervical carcinoma </li></ul><ul><li>high-grade vulvar dysplastic lesions (VIN 2/3) </li></ul><ul><li>external genital warts (condyloma acuminata ) </li></ul><ul><li>… . causally related to Human Papillomavirus (HPV) types 6, 11, 16 and 18 </li></ul><ul><li>in adult females 16 to 26 years of age and , 9- to 15-year old children and adolescents </li></ul>

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Dosage and administration <ul><li>Primary vaccination series consist of 3 separate 0.5 ml doses, administrated IM injections </li></ul><ul><li>Following schedule : 0-2-6 month </li></ul><ul><li>Alternative schedule: 0-1-3 month </li></ul><ul><li>All 3 doses should be given within a 1 year period </li></ul><ul><li>The need for booster dose has not been established </li></ul><ul><li>Pregnancy- insufficient data- vaccinations should be postponed until after completion of pregnancy </li></ul><ul><li>Can be given breast feeding women </li></ul>

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Vaccine Generally well-tolerated <ul><li>Most commonly reported adverse events were injection site reactions and mild fever </li></ul><ul><li>Fever >38.9°C (oral temperature) within 5 days of a vaccination visit, was reported in 1.5% of the GARDASIL ® vaccinated population (n=6,040) compared to 1.1% in the placebo population (n=3,981) 1 </li></ul>Sanofi Pasteur MSD Data on File 2006 06/007

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SUMMARY <ul><li>HPV is an important health problem in Europe & worldwide </li></ul><ul><li>HPV is a common virus </li></ul><ul><li>(approximately 290 millions women are harboring HPV DNA, of whom 105 millions are positive for HPV 16/18) </li></ul><ul><li>An estimated 80% of sexually active women will be exposed to HPV in their lifetime </li></ul><ul><li>HPV types 16 & 18 have been found in > 75% cases of cervical cancer </li></ul><ul><li>HPV is casually related to: </li></ul><ul><ul><li>Benign conditions: genital warts, CIN1, RRP, </li></ul></ul><ul><ul><li>Pre-malignant conditions: CIN2/3, CIS, VaIN, VIN, AIN, PIN </li></ul></ul><ul><ul><li>Malignant conditions: cervix, vulva, vagina, penis, anus, tonsil and oropharynx </li></ul></ul>

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<ul><li>benefits of the HPV vaccine </li></ul><ul><li>Before cervical cancer occurs </li></ul><ul><li>The vaccine can prevent high-grade cervical dysplasia (CIN 2/3) </li></ul><ul><li>The vaccine has demonstrated efficacy against low-grade cervical dysplasia (CIN 1) </li></ul><ul><li>Beyond the cervix </li></ul><ul><li>The vaccine can prevent vulval pre-cancers and reduces the incidence of vaginal pre-cancers compared with placebo (0 vs 5 women) </li></ul><ul><li>The vaccine can prevent external genital warts </li></ul>Summary

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Should we offer Vaccine to boys? <ul><li>With the Rubella Vaccine they ended up having to vaccinate boys to eradicate Rubella. </li></ul><ul><li>If WE don’t vaccinate boys, Gay men are not going to be protected from HPV. </li></ul><ul><li>ARE WOMEN ALWAYS TO BE RESPONSIBLE FOR EVERYTHING TO DO WITH SEXUALLY TRANSMITTED INFECTIONS? </li></ul>

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THANK YOU