The Fairmont Dallas Dallas, Texas April 26, 2008

1. The Fairmont Dallas Dallas, Texas April 26, 2008

2. Prevention Is Now a Reality:Reducing the Burden of Cervical Cancer and Other HPV-Related Diseases J. Thomas Cox, MD Director, The Women�s Clinic University of California, Santa Barbara Santa Barbara, California

3. In what percentage of your eligible patients do you offer HPV vaccination? 0%-10% 11%-25% 26%-50% 51%-75% 76%-100%

4. Faculty Disclosure Dr Cox: advisory board: Diamics, Inc., Gen-Probe, Inc., Graceway Pharmaceuticals, LLC, Takeda Pharmaceuticals, Inc., Tigris Pharmaceuticals, Inc Data and Safety Monitoring Board (DSMB) for the Quadrivalent HPV Vaccine Trial

5. Learning Objectives Describe the epidemiology and health consequences of HPV infection Review the latest efficacy and safety data from clinical trials with HPV vaccines Summarize the benefits of HPV vaccination for discussion with patients and their parents Implement practical strategies to overcome barriers to HPV vaccination

6. Approximately what percentage of sexually active individuals will be infected with HPV in their lifetimes? 10% 25% 50% 75% Unsure

7. Prevalence and Incidence of HPV Infection: United States Approximately 20 million people are currently infected with HPV in the United States1 HPV is the most common STI, with an estimated annual incidence of 6.2 million2 HPV incurs the highest direct medical costs of all STIs other than HIV, at $1.6 billion annually3 Overall, an estimated 75% of sexually active individuals will be exposed to HPV at some point in their lives4

8. Which of the following diseases are associated with HPV infection? Cervical cancer Anogenital cancers Genital warts Certain head and neck cancers All of the above

9. Common HPV Types AssociatedWith Benign and Malignant Disease I think that it is better to put all the low and high risk types that were in the previous renditions of this slide, but highlight in a different color the main ones. I understand that this is highlighting the second-tier types that appear to be benefiting from some cross-protection but this leave the impression that only these few types cause these manifestations.I think that it is better to put all the low and high risk types that were in the previous renditions of this slide, but highlight in a different color the main ones. I understand that this is highlighting the second-tier types that appear to be benefiting from some cross-protection but this leave the impression that only these few types cause these manifestations.

10. Malignancies Attributable to HPV Infection Too much on one slide. Would be better to split into two slides and will not take any longer to discuss in the lecture but will sure make it easier for the attendee to read. Also, so much has been learned in the last 10 years about the rates of HPV found in cancers. The reference here is so old (1999) that I am not surprised to see a lower rate for oropharyngeal cancers than more recently reported (25 up to over 70% in the recent Johns Hopkins study). Additionally check on the present estimate on whether esophageal cancer has been Proven to be caused by HPV. The best information on this comes from the series of articles in the 2006 Vaccine Monograph, especially Chapter 2 by Parkin. He says that there is at this time insufficient evidence to include esophagus. And he gives more up to date numbers than these 1999 articles. I will attach Parkins article.Too much on one slide. Would be better to split into two slides and will not take any longer to discuss in the lecture but will sure make it easier for the attendee to read. Also, so much has been learned in the last 10 years about the rates of HPV found in cancers. The reference here is so old (1999) that I am not surprised to see a lower rate for oropharyngeal cancers than more recently reported (25 up to over 70% in the recent Johns Hopkins study). Additionally check on the present estimate on whether esophageal cancer has been Proven to be caused by HPV. The best information on this comes from the series of articles in the 2006 Vaccine Monograph, especially Chapter 2 by Parkin. He says that there is at this time insufficient evidence to include esophagus. And he gives more up to date numbers than these 1999 articles. I will attach Parkins article.

11. Relative Contribution of HPV Types to Cervical Cancer: All World Regions Combined I have never particularly liked this graph because it takes too long for the audience to grasp why the bar graphs are getting longer and longer for types that are obscure non-important types. I think that the audience tends to focus on the length of the bar in each row as a function of the Type named with the row and not as an additive effect.I have never particularly liked this graph because it takes too long for the audience to grasp why the bar graphs are getting longer and longer for types that are obscure non-important types. I think that the audience tends to focus on the length of the bar in each row as a function of the Type named with the row and not as an additive effect.

12. Epidemiology of Cervical Cancer Cervical cancer is the second most common cancer in women worldwide1 Worldwide, there are an estimated 400,000-500,000 cases of cervical cancer diagnosed each year1,2 In the United States, the estimated incidence is 7.9 per 100,0003 In 2007, 11,150 new cases and 3670 deaths were reported4 Even though >60 million Pap smears are performed each year5 Half of the cases will occur in women never screened and an additional 10% in women not screened within the past 5 years6 The 9710 cases were the total in 2005 and since then the number of cases has risen to 10,000 plus in 2006 and over 11,000 projected in 2007. I think that we have the exact figures on other slides and I would update this as it minimizes the number of cancers and does not show that it has varied upward in the last 2 years. It is better to say the exact year for the number quoted, and not say �annually� since this is not the rate seen every year.The 9710 cases were the total in 2005 and since then the number of cases has risen to 10,000 plus in 2006 and over 11,000 projected in 2007. I think that we have the exact figures on other slides and I would update this as it minimizes the number of cancers and does not show that it has varied upward in the last 2 years. It is better to say the exact year for the number quoted, and not say �annually� since this is not the rate seen every year.

13. The Natural History of�HPV and Cervical Cancer

14. Cervical Dysplasia Mild dysplasia (CIN 1) Regression is the norm Conservative follow-up Can we put CIN 1 next to �mild dysplasia� and CIN 3 next to �severe dysplasia�?Can we put CIN 1 next to �mild dysplasia� and CIN 3 next to �severe dysplasia�?

15. Epidemiology of Genital Warts One of the most common STIs Annually, 500,000-1,000,000 new cases of genital warts occur in the United States1 ~1.4 million (1%) individuals currently have genital warts in the United States2 Way, way to much on this slide. Again, it takes no more time to discuss these points on two slides than on one, but this needs to be split into two if the audience is to stay awake. Also, why are most of the references so old when there are really good articles to provide data that are in the last 2-3 yrs?Way, way to much on this slide. Again, it takes no more time to discuss these points on two slides than on one, but this needs to be split into two if the audience is to stay awake. Also, why are most of the references so old when there are really good articles to provide data that are in the last 2-3 yrs?

16. Epidemiology of Genital Warts (cont�d) >90% of cases of genital warts are associated with HPV types 6 and 111 In women exposed to HPV 6 or 11, the cumulative incidence of genital warts was 66.2% (95% CI, 52.8%-79.2%)2 Individual episode of genital warts averages 3.1 physician visits and costs $4363 Available treatments are often painful and/or suboptimal Way, way to much on this slide. Again, it takes no more time to discuss these points on two slides than on one, but this needs to be split into two if the audience is to stay awake. Also, why are most of the references so old when there are really good articles to provide data that are in the last 2-3 yrs?Way, way to much on this slide. Again, it takes no more time to discuss these points on two slides than on one, but this needs to be split into two if the audience is to stay awake. Also, why are most of the references so old when there are really good articles to provide data that are in the last 2-3 yrs?

17. Epidemiology of Recurrent Respiratory Papillomatosis (RRP) Most common benign neoplasm of larynx among children Caused by HPV 6 and 11, which are also responsible for causing anogenital condyloma Infection occurs at birth as child passes through birth canal 200-fold increased risk for juvenile-onset RRP (JORRP) if mother has condyloma at delivery Split into two slides! And take �sub� out of subtypes. These are all individual types.Split into two slides! And take �sub� out of subtypes. These are all individual types.

18. Benefits of HPV Vaccination Reduction in incidence of Cervical cancer and its precursor lesions Vulvar and vaginal neoplasias Genital warts Potential reduction in incidence of Other HPV-associated lower genital tract neoplasias (anal, penile) Recurrent respiratory papillomatosis Head and neck cancer The goal of good slides is to try not to go over 6 lines per slide (or at least not over six not to long bulleted statements. Here there are 10.The goal of good slides is to try not to go over 6 lines per slide (or at least not over six not to long bulleted statements. Here there are 10.

19. Preventing HPV infection through vaccination with the quadrivalent HPV 6/11/16/18 vaccine has the potential to reduce what proportion of cervical cancer cases? <20% ~30% ~50% >70% Unsure

20. Quadrivalent HPV 6/11/16/18 Vaccine FDA-approved in girls and women 9 to 26 years of age Protects against most common high-risk HPV types 16, 18 (>70% of cervical cancer cases) Protects against most common low-risk HPV types 6, 11 (90% of genital warts cases) Cross-protection against infection and disease due to nonvaccine HPV types (HPV 31, 33, 45, 52, and 58) High efficacy in women 24 to 45 years of age Two slides: Quadrivalent HPV Vaccine, and Bivalent HPV Vaccine Two slides: Quadrivalent HPV Vaccine, and Bivalent HPV Vaccine

21. Bivalent HPV 16/18 Vaccine Under FDA review Protects against most common high-risk HPV types 16, 18 Cross-protection against infection due to nonvaccine HPV types (HPV 31, 33, 45, and 52) Two slides: Quadrivalent HPV Vaccine, and Bivalent HPV Vaccine Two slides: Quadrivalent HPV Vaccine, and Bivalent HPV Vaccine

22. Quadrivalent HPV 6/11/16/18 Vaccine: 3-Year Results

23. Efficacy of the Quadrivalent HPV 6/11/16/18 Vaccine: 5-Year Follow-up

24. Quadrivalent HPV 6/11/16/18 Vaccine Efficacy Against CIN 2/3 or AIS Due to Vaccine or Nonvaccine Oncogenic Types

25. Quadrivalent HPV 6/11/16/18 Vaccine: Injection Site Reactions Postvaccination Again, two slides would take no longer to discuss: one on Injection sire reactions and one on systemicAgain, two slides would take no longer to discuss: one on Injection sire reactions and one on systemic

26. Quadrivalent HPV 6/11/16/18 Vaccine: Systemic Adverse Events Postvaccination Again, two slides would take no longer to discuss: one on Injection sire reactions and one on systemicAgain, two slides would take no longer to discuss: one on Injection sire reactions and one on systemic

27. Quadrivalent HPV 6/11/16/18 Vaccine Dosage and Administration 3 separate 0.5-mL doses: Administered at 0, 2, and 6 months Minimal intervals 1 month between doses 1 and 2 3 months between doses 2 and 3 Intramuscular injection in the deltoid or thigh Single-dose vial or prefilled syringe My understanding of the CDCs recommendation on minimal interval between the 2nd and 3rd shots is 12 weeks, or 3 months. Listed here was 4 months, which is the primary recommendation.My understanding of the CDCs recommendation on minimal interval between the 2nd and 3rd shots is 12 weeks, or 3 months. Listed here was 4 months, which is the primary recommendation.

28. Phase 3 Bivalent HPV 16/18 Vaccine Interim Analysis: Efficacy Should be emphasized that this was not PPG data as they only had enough cases in the MITT group when they did the interim analysis, so the efficacy of the two vaccines cannot be directly compared without going back to the MITT group in the Future II studies.Should be emphasized that this was not PPG data as they only had enough cases in the MITT group when they did the interim analysis, so the efficacy of the two vaccines cannot be directly compared without going back to the MITT group in the Future II studies.

29. Phase 3 Bivalent HPV 16/18 Vaccine Interim Analysis: Adverse Events

30. Bivalent HPV 16/18 Vaccine Cross-Protection: Efficacy Against Persistent Infection With Nonvaccine Oncogenic Types

31. HPV Vaccines: Summary Safe and well tolerated HPV vaccines are >90% effective in preventing HPV-associated neoplasias of the lower genital tract Vaccination with the quadrivalent HPV vaccine is likely to reduce burden of HPV 6/11-associated disease Genital warts Recurrent respiratory papillomatosis Highly effective through at least 4.5 to 5 years Data support vaccination of adolescents and young adults, which is expected to reduce the morbidity and mortality of HPV-associated disease

32. For which of the following groups does the CDC recommend HPV vaccination? Girls 11 to 12 years of age Girls and women13 to 26 years of age who have notyet been vaccinated Girls 9 to 10 years of age, at the clinician�s discretion All of the above

33. Recommended Immunization Schedule for Persons Aged 7-18 Years: United States, 2008

34. Case Study

35. Case Study: 11-Year-Old Girl An 11-year-old patient arrives for her well-child visit You review her immunization status and then discuss HPV vaccination Patient�s mother seems uncomfortable with the idea, noting that her daughter is young and will not be sexually active for some time

36. Why Discuss Vaccination at This Visit? CDC recommends routine HPV vaccination with the quadrivalent HPV vaccine for females 11 to 12 years of age1 It is important to vaccinate younger adolescents prior to exposure2 Timing opportunity: younger adolescents (11 to 13 years of age) have more frequent preventive health visits than do older adolescents (>13 years of age)3 Parents look to you for credible vaccine information Healthcare providers receive the highest trustworthiness scores from parents4

37. The Most Effective Time to Vaccinate Is Before Exposure

38. Practical Approaches to Recommending HPV Vaccination Assure your patient and her mother of the established efficacy and safety of the vaccines in clinical trials Explain that the CDC recommends that all girls 11 to 12 years of age be vaccinated with the quadrivalent HPV vaccine Can be administered in females as young as 9 years of age Reinforce that vaccinating preadolescents and adolescents before they become sexually active provides the maximum health benefit

39. Case Study

40. Case Study: 18-Year-Old Woman An 18-year-old woman arrives at your clinic for a pre-college examination You review her immunization status and�note that she has not received HPV�vaccination

41. HPV vaccination should be recommended to this patient, as the prevalence of HPV disease peaks at what age among women? 10 to 14 years 15 to 19 years 20 to 24 years 25 to 29 years

42. Prevalence of Genital Warts in Females Peaks Before Age 25

43. Is this woman�s sexual history relevant to her eligibility to receive HPV vaccination? Yes No Unsure

44. While the Prevalence of HPV Infection After Sexual Debut Is High, the Infection Rate for�Any Specific Type Is Lower

45. Reasons to Discuss Vaccination CDC recommends catch-up vaccination for females 13 to 26 years of age who were not previously vaccinated However, a new CDC report found that only about 10% of women aged 18 to 26 have received at least 1 dose of the HPV�vaccine Current recommendations for cervical cancer screening have not changed for females who receive HPV vaccination While HPV is highly prevalent, the baseline infection rate for any specific HPV type is relatively low Other society (AAP, SAM, and ACHA) recommendations are in line with CDC recommendations for this patient age group

46. Q & A

47. PCE Takeaways

48. PCE Takeaways HPV vaccination offers a safe and highly effective option to reduce the incidence of HPV-related diseases Vaccinating preadolescents and adolescents who are not�yet sexually active will achieve the maximum preventive benefit Cross-protection with HPV vaccines is anticipated to expand the benefits and impact of HPV vaccination Educating patients and their parents on the benefits of�vaccination leads to increased favorable attitudes toward vaccination Routine cervical cytologic screening is still recommended

49. In what percentage of your eligible patients do you plan to offer HPV vaccination? 0%-10% 11%-25% 26%-50% 51%-75% 76%-100%

50. The Fairmont Dallas Dallas, Texas April 26, 2008