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Learning Objective

Learning Objective. To understand the rationale for prophylactic human papillomavirus (HPV) vaccination with GARDASIL ™. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 1. Cervical Cancer Occurs Despite Established Screening Programs Example of Europe.

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Learning Objective

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  1. Learning Objective • To understand the rationale for prophylactic human papillomavirus (HPV) vaccination with GARDASIL™. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 1

  2. Cervical Cancer Occurs Despite Established Screening Programs Example of Europe 1. Anttila A, Ronco G, Clifford G, et al. Br J Cancer. 2004;91:935–941. 2. van Ballegooijen M, van den Akker-van Marle E, Patnick J, et al. Eur J Cancer. 2000;36:2177–2188. 3. Ferlay J, Bray F, Pisani P, Parkin DM. Lyon, France: IARC Press; 2004. 2

  3. Targeting HPV types 6, 11, 16, and 18 with GARDASIL is expected to substantially reduce the burden of HPV-related diseases.1 Targeting High Disease Burden With GARDASIL™ *GARDASILTM is not indicated for RRP; †Undetermined proportion GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 1. Villa LL, Costa RLR, Petta CA, et al. Lancet Oncol. 2005;6:271–278.2. Gissmann L, Wolnik L, Ikenberg H, et al. Proc Natl Acad Sci USA. 1983;80:560–563.3. Clifford GM, Rana RK, Franceschi S, Smith JS, Gough G, Pimenta JM. Cancer Epidemiol Biomarkers Prev. 2005;14:1157–1164. 4. Kashima HK, Mounts P, Shah K. Obstet Gynecol Clin North Am. 1996;23:699–706. 5. Dunne EF, Nielson CM, Stone KM, et al. J Infect Dis. 2006;194:1044–1057.6. Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer. 2003;89:101–105. 7. GARDASIL Worldwide Product Circular. Merck & Co., Inc., Whitehouse Station, NJ, USA. 8. Parkin DM. Int J Cancer. 2006;118:3030–3044. 9. Castellsagué X, Bosch FX, Muñoz N. Salud Publica Mex. 2003;45(suppl 3):S345–353.10. Frisch M, Glimelius B, van den Brule AJC, et al. N Engl J Med. 1997;337:1350–1358. 3

  4. HPV Types 6, 11, 16, and 18 in Cervical Cancer and Other Anogenital Diseases Prevalence of HPV Type 1,3,4 5 2 1 1. Clifford GM, Rana RK, Franceschi S, et al. Cancer Epidemiol Biomarkers Prev. 2005;14:1157–1164.2. Clifford GM, Smith JS, Aguado T, et al. Br J Cancer. 2003;89:101–105.3. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527. 4. Clifford GM, Smith JS, Plummer M, et al. Br J Cancer. 2003;88:63–73. 5. Gissmann L, Wolnik L, Ikenberg H, et al. Proc Natl Acad Sci USA. 1983;80:560–563. 4

  5. GARDASIL™: The First Cervical Cancer Vaccine • HPV types 6, 11, 16, 181 • Recombinant vaccine (does not contain live virus)1 • Manufactured in Saccharomyces cerevisiae1 • Yeast-derived vaccines given to millions of children and adults2 • Proprietary aluminum adjuvant 225 μg per dose1 • Each 0.5-mL injection volume contains HPV types 6/11/16/18 (20/40/40/20 μg, respectively)1 • Intramuscular administration1 • 0-, 2-, 6-month dosing regimen1 GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 1. GARDASIL Worldwide Product Circular. Merck & Co., Inc., Whitehouse Station, NJ, USA. 2. Unger ER, Barr E. Human papillomavirus and cervical cancer [conference summary]. Emerg Infect Dis [serial on the Internet]. 2004 Nov [Cited October 19, 2006]. Available from http://www.cdc.gov/ncidod/EID/vol10no11/04-0623_09.htm. Accessed April 26, 2007. 5

  6. 14.6 16 18 69.7 45 25.7 17 52.5 67.6 12.6 31 33 57 58 52 Others Worldwide Prevalence of HPV Types in Cervical Cancer* HPV Type North America/ Europe South Asia Northern Africa Central/South America *A pooled analysis and multicenter case control study (N = 3607) Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278–285. 6

  7. HPV and Anogenital Warts • HPV types 6 and 11 responsible for >90% of anogenital warts1 • Estimated lifetime risk of developing genital warts ~10%2,3 • External genital warts are very contagious.4 • Infectivity >75% Images top left and top right: Reprinted with permissionfrom NZ DermNet (www.dermnetnz.org). 1. Jansen KU, Shaw AR. Annu Rev Med.2004;55:319–331. 2. Franco EL, Villa LL, Richardson H, et al. In: Franco EL, Monsonego J, eds. Oxford, UK: Blackwell Science; 1997:14–22. 3. Tortolero-Luna G. Hematol Oncol Clin North Am. 1999;13:245–257, x. 4. Soper DE. In: Berek JS, ed. Novak’s Gynecology. 13th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002:453–470. 7

  8. Clinical Program for GARDASIL™:Selection of Trial End Points1–3 CIN 2/3 are World Health Organization (WHO)–recommended surrogate end points for HPV vaccine trials.1Surrogate end points are required because it is unethical to wait for the development of cervical cancer.3 *CIN = cervical intraepithelial neoplasia GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 1. Pagliusi SR, Aguado T. Vaccine. 2004;23:569–578. 2. GARDASIL Worldwide Product Circular. Merck & Co., Inc., Whitehouse Station, NJ, USA. 3. Lowy DR, Frazer IH. Chapter 16: Prophylactic human papillomavirus vaccines. J Natl Cancer Inst Monogr. 2003:111–116. 8

  9. GARDASIL™ Yields Higher Neutralizing Anti-HPV Antibodies in Baseline Seropositive Subjects Vaccine: naïve recipient Placebo: naïve recipient Vaccine: seropositive and PCR*** -negative recipient Placebo: seropositive and PCR-negative recipient 10000 (n=14) 1000 (n=177) 100 GMT** (mMU/mL) Log10 Scale (n=15) 10 (n=170) * * * 1 0 3 7 12 18 24 30 36 Month *vaccination **GMT = geometric mean titer ***PCR = polymerase chain reaction Villa LL, Ault KA, Giuliano AR, et al. Vaccine. 2006;24:5571–5583. 9

  10. GARDASIL™ (20/40/40/20 μg) Neutralizing Anti-HPV Immunogenicity In a double-blind, placebo-controlled, dose-ranging study of quadrivalent HPV (types 6, 11, 16, 18) L1 VLP vaccine. Per-Protocol Subjects (GARDASIL) 1000 1000 HPV 6 HPV 11 100 100 10 10 * * * * * * 1 1 7 12 18 24 30 36 54 60 7 12 18 24 30 36 54 60 mMU/mL (Log Scale) GMT with 95% CI 10,000 1000 HPV 16 HPV 18 1000 100 100 10 * 10 * * * * * 1 7 12 18 24 30 36 54 60 7 12 18 24 30 36 54 60 Time Since Vaccination (Months) * vaccination GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Adapted from Olsson S-E et al. Vaccine. 2007;25:4931–4939. 10

  11. Immune memory response was proven by antigen challenge1 7000 6242 6000 5000 GARDASIL n=78 Anti-HPV 16 response (GMT levels with 95% CI) 3889 4000 3000 placebo n=70 2000 1000 0 60 61 0 2 3 6 7 12 18 24 30 36 54 V V V A Time (months) Time GARDASIL™ Demonstrated Immune Memory Vaccination series for GARDASIL V Vaccination at day 0, month 2, and month 6 Antigen challenge A Antigen challenge at month 60 When tested by antigen challenge, vaccinated subjects demonstrated classic immune memory—the hallmark of long-term protection.1 Antibody levels stabilized through at least five years… and counting.1 Antibodies were built up during the 3-dose vaccination series. Minimum protective level of antibodies is defined through breakthrough cases. Through five years, there were no breakthrough cases for GARDASIL, while there were continuing infections for placebo. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 11 1. Data on file, MSD.

  12. GARDASIL™: Durable Protection Through Five Years Per-protocol efficacy population Subjects were naïve to HPV types 6, 11, 16, and/or 18 A total of 241 subjects were entered into the five-year extension phase of Protocol 007. *One case of confirmed persistent infection: HPV 18 DNA detected at months 12 and 18 only (not a case in the five-year extension). *One case of HPV 16 DNA detected at the last visit (month 36); not a subject in the five-year extension phase. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Villa LL, Costa R, Petta R, et al. Br J Cancer. 2006;95:1459–1466. 12

  13. GARDASIL™ TOLERABILITY • Vaccination was generally well tolerated. The most common adverse event was local discomfort at the injection site. • There were no discontinuations due to serious vaccine-related adverse events. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 13

  14. Select Information About GARDASILTM • GARDASIL is a vaccine indicated in girls and women 9 to 26 years of age for the prevention of cervical cancer, precancerous or dysplastic lesions, and genital warts caused by HPV Types 6, 11, 16, and 18. • GARDASIL is contraindicated in individuals who are hypersensitive to the active substances or to any of the excipients of the vaccine. • GARDASIL does not substitute for routine cervical cancer screening, and women who receive GARDASIL should continue to undergo screening per standard of care. • Vaccination with GARDASIL may not result in protection in all vaccine recipients. • GARDASIL has not been shown to protect against diseases due to non-vaccine HPV types. • GARDASIL is not intended to be used for treatment of active genital warts; cervical cancer; CIN, VIN, or VaIN. • The vaccine-related adverse experiences that were observed among recipients of GARDASIL at a frequency of at least 1.0% and greater than placebo were pain, swelling, erythema, fever, nausea, pruritus, and dizziness.

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