3. Population prospects for women >15 years
1. FX Bosch, X Castellsague´. S de Sanjose´. British Journal of Cancer (2008) 98(1), 15 – 21
4. Incidence (Women: all ages) - Cervical
Cancer
1. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne, F. X. Bosch. HPV and
Cervical Cancer in the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre
5. 1. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne, F. X. Bosch.
HPV and Cervical Cancer in the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at:
www.who.int/hpvcentre
Mortality (Women: all ages) - Cervical
Cancer
6. Age Specific Incidence vs Mortality
2. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in
India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
7. HPV Type Distribution - Invasive cervical
cancer
1. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne, F. X. Bosch. HPV and
Cervical Cancer in the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre
HPV
16+18=76.7%
8. 0 5 10 15 20 25 30
Cervical Breast (Female) Ovarian
Years of Life Lost to Cervical Cancer*
*In women in the United States (2003), 1. Ries LAG, Harkins D, Krapcho M, et al. (eds). SEER Cancer Statistics Review,
1975–2003, National Cancer Institute. Bethesda, MD; 2006.
26
19
18
Largest single cause of years of life lost to cancer in the developing world
9. Cervical Cancer - Disease Burden
New cervical cancer cases
diagnosed annually
India : 1,32,082, World : 4,93,243
India accounts for ~27% of new
Cervical Cancer cases in world
Deaths due to cervical cancer
annually
India : 74,118, World : 2,73,505
India - 27%
Rest of World - 73%
India accounts for 27% of deaths
due to Cervical Cancer in world
Rest of World - 73%
India - 27%
India - 27%
1. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne, F. X. Bosch. HPV and Cervical Cancer in
the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre
10. > 200 women die every day
Every 7 minutes a women dies
8 women die every hour
Cervical Cancer :
India
This ‘Cause’ need to be taken up by multiple stake holders.
Cervical Cancer in India
11. *Ray K et al, Indian J Med Res 2006; 124: 559-568
18%
6%
11% 10.5%
0
2
4
6
8
10
12
14
16
18
20
1990-93 1994-97 1998-01 2002-04
Study Period
Percentage
Genital Warts – Disease Burden: India*
Increasing trend of Genital warts in India
13. HPV 16
HPV 18
HPV 6
HPV 11
Cancer causing Types1,2,4 Non-cancer causing types1,2
• >75% of Cervical Cancer5,6
• ~50% of Vaginal & Vulvar Cancer5
90% of Anogenital warts5
HPV is a necessary cause of cervical cancer - 99.7%4
HPV
1.Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 2. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 3. Muñoz N, Bosch FX, Castellsagué X, et al. Int J
Cancer. 2004;111:278–285. Reprinted from J Virol. 1994;68:4503–4505 with permission from the American Society for Microbiology Journals Department. 4. Walboomers JM, Jacobs MV, Manos MM, et al. J
Pathol. 1999;189:12–19. 5. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne,F. X. Bosch. HPV and Cervical
Cancer in the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre6. Bhatla N et al.Vaccine (2008;26; 2811-17
Human Papillomavirus (HPV)
Human Papilloma Virus (HPV)
14. Human Papilloma Virus (HPV)
Non enveloped double stranded DNA virus: over 100 types
15–20 oncogenic
30–40 anogenital
L1: major viral capsid protein – immunogenic
L2: minor viral capsid protein – immunogenic
Capsid proteins:
L1
L2
Viral DNA
Viral exterior Viral interior
1. Baker TS, et al. Biophys J. 1991;60:1445–1456. 2. Chen XS, et al. Mol Cell. 2000;5:557–567.
17. Neutralizing Antibodies and HPV
Infection
Chen XS, et al. Molecular Cell. 2000;5:557–567.
Neutralizing
antibodies prevent
HPV infection
Nonneutralizing
antibodies do not
prevent infection
No antibodies—
viral infection
Cell surface
receptors
Antibody color legend:
Blue = Neutralizing antibodies
Yellow = Nonneutralizing antibodies
18. Antibodies
The minimum protective antibody level against HPV is not known.
USFDA and WHO: Reduction in incidence of CIN 2/3 or AIS caused
by vaccine HPV types should be criteria for licensure.
No International standards for assays have been developed as yet.
Different assay use different units so their results can not be compared
The major basis of protection against infection is neutralizing antibody
19. HPV
Prevalence
(%)
Cancer
Incidence
Rate
(×10
5
)
* Two different cohorts (cross-sectional study) followed during the same time span to measure the rate of high-risk HPV infection in one and the rate of cervical cancer in the other.
1. Adapted from Bosch FX, Lorincz A, Muñoz N, Meijer CJLM, Shah KV. J Clin Pathol. 2002;55:244–265, with permission from the BMJ Publishing Group.
0
5
10
15
20
25
20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64
Age Group (Years)
HPV infection
Cervical Cancer
25
20
15
10
5
0
(n=3752)
Peak of HPV infection
Peak of cervical cancer
Age-Specific Rates of HPV Infection &
Cancer*
Age for vaccination:
9 – 26 yrs
Age for Screening > 35yrs
20. Summary
HPV is a necessary cause of cervical cancer – 99.7%
Induction of neutralising antibodies by vaccination is critical for protection
HPV 16 & 18 cause ~75%* of cervical cancer cases while HPV 6 & 11 cause
~90% genital warts
27% of the world burden of Cervical Cancer is seen in India.
Every 7 minutes a woman dies in India due to cervical cancer
Cervical Cancer is usually diagnosed in late stages in India.
Cervical cancer screening is recommended in women >30yrs
Vaccination between 9-26yrs can be an effective strategy to help reduce this
huge disease burden.
* India
Notes de l'éditeur
Key Point Female Population greater than 5 years will continue to increase in developing countries and will remain stagnant in developed countries Background The population of women in the world continues to increase. Predictions for the period 2000–2050 clearly indicates the expected growth of the female population (ages 15+ years) in developing countries and a stable prediction in the developed countries. By age groups, these estimates reflect for girls 10–14 years and women 15–24 years, a plateau in the developing countries and a decrease in the younger populations in developed countries, largely in the age groups 15–24 years. With these population estimates, largely attributable to the increased life expectancy in women in developing countries. Ref 1) FX Bosch, X Castellsague´ and S de Sanjose´.British Journal of Cancer (2008) 98(1), 15 – 21
Key Point Female population – 15yrs and older is approximately 365 million Background WHO estimates says India has a population of 365.71 millions women ages 15 years and older who are at risk of developing cervical cancer. Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
Key Point Incidence of cervical cancer cases in India is highest as compared to other cancers in women 15-44 yrs of age Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
Key Point Mortality in India due to cervical cancer is highest as compared to other cancers in women of all ages. Second most common cause is Breast Cancer. Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
Key Point Difference between incidence of Cervical cancer vs mortality due to cervical cancer narrows for the females between age group 15-44yrs. Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
Key Point HPV 16 and 18 cause approximately 77% of Invasive cervical cancer . Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
Key Point Integration of HPV into the DNA of the infected host cell is commonly associated with high-risk oncogenic HPV types 1 and is linked to the activity of E6 and E7 proteins. 2 Background HPV infects its host by penetrating through mucosal tears in the basal membrane. 3 In benign HPV-associated skin lesions, the HPV virus maintains its genome as episomes at low copy numbers (10 – 200 copies/cell) in the basal cells of the epithelium separate from the host cell DNA. To maintain its viral DNA as an episome, viral E1 and E2 proteins are expressed. Failure to express E1 leads to the integration of the HPV genome into the host cell chromosome. 3 Integration of HPV into the DNA of the infected host cell is commonly associated with high-risk oncogenic HPV types 1 and is c onsidered an important step in tumor progression. 2 In malignant HPV-associated skin lesions, HPV DNA integration into the host cell ’ s chromosome regularly occurs through a break in the viral genome around the E1/E2 region . Integration-mediated disruption of E2 may trigger uncontrolled expression of E6 and E7, resulting in cellular transformation. 2 The E6 protein associates with the tumor suppressor protein p53 and promotes proteolytic destruction of the protein. This leads to malignant transformation and loss of regulated cell growth. The E7 protein associates with the pRB, which inactivates the cell cycle restriction function of this protein. 2 References 1. Gallo G, Bibbo M, Bagella L, et al. Study of viral integration of HPV-16 in young patients with LSIL. J Clin Pathol . 2003;56:532 – 53 6. 2. Syrj ä nen KJ, Syrj ä nen SM. Molecular biology of papillomaviruses. In: Papillomavirus Infections in Human Pathology . Chichester, United Kingdom: John Wiley & Sons, Inc.; 2000: 11 – 51. 3. Doorbar J. The papillomavirus life cycle. J Clin Virol . 2005;32(suppl):S7 – S15.
Key Point Vaccines generate a broad spectrum of antibodies, only a small proportion of which are demonstrated to neutralize viruses. Background There appears to be at least 2 distinct mechanisms in regards to antibody-mediated neutralization of HPV. By one mechanism, antibodies block the binding of HPV to cellular receptors. 1 By a second mechanism, neutralizing antibodies prevent uncoating of the virus. 2 Neutralizing antibodies against HPV are predominantly type specific. 3 Conversely, vaccination with L1 VLPs also elicits antibodies against nonneutralizing epitopes and, potentially, against other vaccine components. 4 Therefore, when quantifying the immune response to an L1 VLP vaccine, it is advantageous to measure only neutralizing antibodies. 4 Antibody color legend: Blue = Neutralizing antibodies Yellow = Nonneutralizing antibodies References Chen XS, Garcea RL, Goldberg I, Casini G, Harrison SC. Structure of small virus-like particles assembled from the L1 protein of human papillomavirus 16. Mol Cell. 2000;5:557–567. Booy FP, Roden RBS, Greenstone HL, Schiller JT, Trus BL. Two antibodies that neutralize papillomavirus by different mechanisms show distinct binding patterns at 13 Å resolution. J Mol Biol. 1998;281:95–106. Roden RBS, Hubbert NL, Kirnbauer R, Christensen ND, Lowy DR, Schiller JT. Assessment of the serological relatedness of genital human papillomaviruses by hemagglutination inhibition. J Virol . 1996;70:3298–3301. Opalka D, Lachman CE, MacMullen SA, et al. Simultaneous quantitation of antibodies to neutralizing epitopes on virus-like particles for human papillomavirus types 6, 11, 16, and 18 by a multiplexed Luminex assay. Clin Diagn Lab Immunol. 2003;10:108–115.
