1. The Future is Now: Understanding the HPV Vaccine Guidelines E.J. Mayeaux, Jr., M.D. Professor of Family Medicine Professor of Obstetrics and Gynecology Louisiana State University Health Science Center Shreveport, LA

2. ?

3. Case #1 Your 11 year old female patient presents to the office for a sports physical and health maintenance. Her mom wants to discuss HPV vaccines with you. Correct information you can give her include: 1.The available vaccine is made from live virus. 2.It is based on virus-like particles that induce neutralizing antibodies. 3.It has only been studied in a small number of people. 4.It has not been shown to decrease abnormal Pap smears.

4. Vaccines Against HPV Epidemiologic studies suggested HPV has type-specific immunity Type-specific neutralizing antibodies Virus-like particles (VLPs) are recombinant viral capsids that induce neutralizing antibodies L1 major capsid protein VLPs are highly immunogenic ? some cross protection within families Outcome data preliminary Schiller JT et al. Nat Rev Cancer. 2004;2:343-347.

5. Vaccines Against HPV VLPs have no viral DNA Can NOT cause infection Since there is no viral DNA, It can not make oncogenic proteins There is no risk of cancer with a HPV VLP vaccine

6. Creation of VLPs 1. Berzofsky JA et al. J Clin Invest. 2004;114:450–462. 2. Kirnbauer R et al. Proc Natl Acad Sci USA. 1992;89:12180–12184. 3. Modis Y et al. EMBO J. 2002;21:4754–4762.

7. Planned Duration: 5 years Quadrivalent HPV Vaccine n=6,082 Placebo n=6,075 12,167 women, 16 to 26 years old Randomized Primary endpoint: incidence of HPV 16/18-related CIN 2/3, AIS or cancer CIN=cervical intraepithelial neoplasia; AIS=adenocarcinoma in situ; FUTURE=Females United To Universally Reduce Endo-ectocervical Disease. Phase 3 Study of Quadrivalent HPV Vaccine: FUTURE II Injections at 0, 2, and 6 months

8. Quadrivalent HPV Vaccine: Two-Year Phase III Results for CIN 2/3 and AIS Per Protocol 100% efficacy Modified ITT 97% efficacy P<.001 n=5301n=5258n=5736n=5766 Number of cases Koutsky et al. Presented at IDSA 2005.

9. n Nordic countries have organized mass-screening programs -Compulsory reporting of Paps, bx, CIN/cancer -Linkage by social security number makes registries major source for prospective studies n Phase III studies evaluate: -Duration of effectiveness -Swab with ds or warts -Long-term safety Sweden Iceland Denmark Norway Nordic Cancer Registry Extension: Long-Term Effectiveness

10. 20032004200520062007200820132010201120122009 Phase III Study Registry-Based Monitoring Cohort Vaccination US Approval 2002 Follow-up In Nordic Registries Provides a Sentinel Cohort Sentinel Cohort 4 yr 1 yr Evaluation 10 yr 7 yr Evaluation 7 yr 4 yr Evaluation

11. Pooled Efficacy of Gardasil in the Per-Protocol Analysis Population *Analysis of CIN 2/3 and AIS end points included Protocol 005. CI = confidence interval. CIN = cervical intraepithelial neoplasia. AIS = adenocarcinoma in situ. 16- to 26-year-old females naïve to the relevant vaccine HPV type at enrollment and through 30 days Post-dose 3 over a period of 2 to 4 years Cases: HPV-4 or HPV 16 L1 VLP Vaccine Cases: Placebo Vaccine Efficacy (95% CI) HPV 16/18–related CIN 2/3 or AIS* 0 (n=8,487)53 (n=8,460)100% (93–100) HPV 6/11/16/18–related CIN 1, CIN 2/3, or AIS 4 (n=7,858)83 (n=7,861)95% (87–99) HPV 6/11/16/18–related Genital Warts 1 (n=7,897)91 (n=7,899)99% (94–100)

12. (All resolved) Prophylactic Efficacy of HPV-4 CIN & AIS Per-Protocol Population (Protocols 007, 013, and 015) Endpoint ** Mean Follow-Up of 44 months HPV-4 Cases (N = 9075) Placebo Cases (N = 9075) % Efficacy95% CI HPV 6/11/16/18- related CIN or AIS 922596(92, 98) By Type HPV 6-related047100(92, 100) HPV 11-related012100(65, 100) HPV 16-related813794(89, 98) HPV 18-related16198(91, 100) By Disease CIN 1717096(91, 98) CIN 2/32*2* 11098(93, 100) AIS07100(31, 100) ** Subjects are counted only once per row, but may be in more than one row * One case was a co-infection with HPV 52, the other was a co-infection with HPV 51 & 56

13. HPV-4 Prophylactic Efficacy External Genital Lesions Per-Protocol Population (Protocols 007, 013, and 015) Endpoint* Mean Follow-Up of 44 months HPV-4 Cases (N = 9075) Placebo Cases (N = 9075) % Efficacy 95% CI HPV 6/11/16/18-related Ext Gen Lesion 222799(97, 100) By Type HPV 6-related217999(96, 100) HPV 11-related036100(89, 100) HPV 16-related046100 (92, 100) HPV 18-related013100 (68, 100) By Disease Genital Warts219399(96, 100) VIN 1 or VaIN 1028100(86, 100) VIN 2/3 or VaIN 2/3023100(83, 100) * Subjects are counted only once per row, but may be in more than one row

14. Combined Reduction in Abnormal Pap Tests Regardless of HPV Type 23%16%35%43% ASC-US HR +LSILASC-HHSIL Cases Placebo 359 1000 89 41 Cases Vaccine 285 864 59 24 Combined trial data @ 3.3years

15. Combined Reduction in Cervical Procedure Regardless of HPV Type 19%22%42% ColposcopyCervical BiopsyDefinitive therapy Cases Placebo 1077 950 230 Cases Vaccine 869 741 132 Combined trial data @ 3.3years

16. Total Cost Burden of HPV-disease in the US, 2000 Estimates Chesson HW, et al. Perspect Sex Reprod Health 2004;36:11-19.

17. Antigen Challenge Study Assessment of Immune Memory Antigen challenge study of subjects in Protocol 007 at 60 months (completed) Phase IIB 552, 16–23-year-old women in a double-blind, placebo-controlled study All extension subjects received quadrivalent HPV vaccine at month 60 to examine the extent of immune memory in response to the primary vaccination series Duration study Olsson S, Villa LL, Costa RLR, Petta CA, Andrade RP, Malmf C, et al. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine Online

18. Antigen Challenge Study HPV 11 HPV 18 HPV 6 HPV 16 Month Post Vaccination booster All patients (even at 0 titers) developed response post challenge

19. ?

20. Case #2 Your 11 year old patients mom is 29 years old and is newly single. She wants to discuss HPV immunization for herself. Correct information you can give her include: 1.The available vaccine is not currently indicated for people in her age group. 2.HPV infection is still a concern in women her age. 3.Studies show HPV vaccination in her age group decreases abnormal Pap smears and related procedures. 4.All of the above.

21. Adult Women

22. HPV Incidence In Women Prevalence (%) Age (years) Dunne EF et al. JAMA. 2007;297:813-819. Self-collected vaginal swab N=1921 National Health and Nutrition Examination Survey (NHANES 2003-2004)

23. Age (years) Rate of New Genital Warts per 1000 Person-Years Phase III Trials of Quadrivalent HPV Vaccine Conducted in Ages at Risk for HPV Disease Incidence of New Genital Warts by Age in US Young AdultsMid-AdultsAdolescents

24. Future III: Adult Women 24-45 Years n Multi-center, international study n Randomization (1:1 ratio) stratification to 24 to 34 or 35 to 45 year-olds n In 3,817 24- to 45-year-old women -No history of LEEP or hysterectomy -No history of cervical biopsy in past 5 years -No history of genital warts -Lifetime sexual partner number not exclusion criterion n Pap testing and cervicovaginal sampling at enrollment and ~6 month intervals to 48 months -PCR and serology testing performed to detect current or past HPV infection

25. Sexual History/Marriage Status at Day 1 Parameter VaccinePlacebo (N = 1911)(N = 1908) % Non-Virgins100% Median (Range) Age at Sexual Debut (Years)18 (5 to 39)18 (4 to 39) Lifetime Number of Sex Partners 0 to 258% 2 to 419% >423% Marital Status Never Married18% Separated/Divorced8%7% Widowed1% Permanent Relationship28%27% Married – first marriage40%42% Married – second or higher marriage5%6% No limits on number of sexual partners in this study

26. FUTURE III Primary Prophylactic Efficacy Results Population HPV-4 PlaceboEfficacy 95% CI P- value FUTURE III Adult Women 44191%74, 98<0.001 P007 Young-Adult Women 12696% 78, 100 <0.001 P019: 24- to 45-Year-Old Women; mean of 1.65 years follow-up P007: 16- to 23-Year-Old Women; mean of 2.33 years follow-up* * Subjects 16-23 years of age are from prior analyses and are included for comparison Combined Incidence of HPV 6/11/16/18-Related Persistent Infection or Cervical/Vulvar/Vaginal Disease - Per Protocol Efficacy Population

27. Safety, Efficacy, and Immunogenicity of HPV-4 Vaccine in Women Aged 24-45 Endpoint%Reduction95% CIP value HPV6/11/16/1891%74, 98<0.001 HPV16/1883%51, 96<0.001 HPV6/11100%79, 100<0.001 24th International Papillomavirus Congress 11/3-9/07 Beijing, China Presentation #PA1-04

28. Endpoint% Reduction95% CI ASC-US(HR+) or Worse 94%63, 100 ASC-US HR(+)86%-10, 100 LSIL or Worse100%61, 100 LSIL100%56, 100 ASC-H100%-- Safety, Efficacy, and Immunogenicity of HPV-4 Vaccine in Women Aged 24-45

29. Summary of HPV DNA Detection by Serostatus at Enrollment HPV type All subjects aged 24-45 n Day 1 Anti-HPV Serostatus Positive m (%) Negative m (%) HPV 63,815568 (14.9)3,247 (85.1) HPV 113,815186 (4.9)3,629 (95.1) HPV 163,815562 (14.7)3,253 (85.3) HPV 183,815208 (5.5)3,607 (94.5) n = number of subjects with non-missing data; m = number of subjects in indicated category.

30. HPV type All subjects aged 24-45 n Day 1 Anti-HPV Serostatus Positive m (%) Negative m (%) HPV 6 3,815568 (14.9)3,247 (85.1) PCR positive 33 (0.9)38 (1.0) PCR negative 533 (14.0)3,169 (83.1) PCR unknown 2 (0.1)40 (1.0) HPV 11 3,815186 (4.9)3,629 (95.1) PCR positive 4 (0.1)5 (0.1) PCR negative 182 (4.8)3,583 (93.9) PCR unknown 0 (0.0)41 (1.1) HPV 16 3,815562 (14.7)3,253 (85.3) PCR positive 70 (1.8)100 (2.6) PCR negative 484 (12.7)3,114 (81.6) PCR unknown 8 (0.2)39 (1.0) HPV 18 3,815208 (5.5)3,607 (94.5) PCR positive 22 (0.6)57 (1.5) PCR negative 186 (4.9)3,507 (91.9) PCR unknown 0 (0.0)43 (1.1) n = number of subjects with non-missing data; m = number of subjects in indicated category. Summary of HPV DNA Detection by Serostatus at Enrollment

31. HPV 6, 11, 16 and/or 18 All subjects aged 24-45 (n = 3,730) DNA OnlyDNA or Serology m%m% Only 1 type detected2707.289023.9 Only 2 types detected250.72667.0 Only 3 types detected30.1822.1 All 4 types detected00.0140.4 n = number of subjects with non-missing data; m = number of subjects in indicated category. Prevalence of Exposure to Multiple Vaccine HPV Types at Enrollment

32. (N = 17,622) (N = 3,817) Prevalence Summary of 14-type PCR Status at Enrollment in FUTURE I, II, and III

33. Safety of HPV Vaccines

34. Quadrivalent HPV 6/11/16/18 Vaccine: Injection Site Reactions Post Vaccination Injection Site (1 to 5 days postvaccination) Quadrivalent HPV Vaccine (N=5088) Placebo (Aluminum) (N=3470) Placebo (Saline) (N=320) Pain83.9%75.4%48.6% Swelling25.4%15.8%7.3% Erythema24.6%18.4%12.1% Pruritus3.1%2.8%0.6% Few subjects (0.1%) discontinued due to adverse experiences Vaccine-related adverse events that were observed among recipients of quadrivalent HPV vaccine occurred at a frequency of at least 1.0% and at a greater frequency than that observed among placebo recipients. GARDASIL [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2007.

35. Quadrivalent HPV 6/11/16/18 Vaccine: Systemic Adverse Events Post Vaccination Systemic Adverse Events (1 to 15 days postvaccination) Quadrivalent HPV Vaccine (N=5088) Placebo (N=3790) Fever10.3%8.6% Nausea4.2%4.1% Dizziness2.8%2.6% Vaccine-related adverse events that were observed among recipients of quadrivalent HPV vaccine occurred at a frequency of at least 1.0% and at a greater frequency than that observed among placebo recipients. GARDASIL [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2007. Few subjects (0.1%) discontinued due to adverse experiences

36. ?

37. Case #3 Mom reports she has 2 more daughters aged 7, 19, and a son aged 14 years. She wants to know if the currently available vaccine is indicated for any of them. You should inform her it is indicated for: 1.The 14 year old son. 2.The 7 year old daughter. 3.The 19 year old daughter. 4.All of the above.

38. ACIP Guidelines

39. ACIP Recommendations Licensed by FDA – June 8, 2006 Recommendations by ACIP – June 29, 2006 Routine vaccination with 3 doses of quadrivalent HPV vaccine for females 11–12 years of age Can be started in females as young as 9 years of age Catch-up vaccination for females 13–26 years not previously vaccinated or who have not completed the full vaccine series Ideally given before potential exposure to HPV. Advisory Committee on Immunization Practices (ACIP). ACIP recommendations for the use of quadrivalent HPV vaccine. Available at: http://www.cdc.gov/nip/recs/provisional_recs/hpv.pdf. Accessed December 19, 2006.

40. Most Effective Time to Vaccinate Is Before Exposure In an analysis of 1552 adolescents and young adults, the subset (n=1014) featured in this chart reported having engaged in sexual intercourse. Centers for Disease Control and Prevention. MMWR. 2002;51(RR-6):1-80; Kaiser Family Foundation. National Survey of Adolescents and Young Adults: Sexual Health Knowledge, Attitudes and Experiences. Henry J. Kaiser Family Foundation; 2003. Behavior reported in an independent study Cohorts that have had intercourse (%) 100 80 60 40 20 Suggests minimal exposure to HPV at 9 to 11 years of age 12–13 14–1516–17 11 Age at first intercourse (years) 40% 28% 7% 2%

41. 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 dose 1 and 2 3 months between dose 2 and 3 IM injection in the deltoid or thigh No preservatives (no thimerasol) OK with Tdap, Td, and MCV4.

42. ?

43. Case #4 Your next patient is a 22 year old female who desires immunization against HPV. Contraindications for her receiving the quadrivalent vaccine include: 1.She has an ASCUS Pap test with a positive Hybrid Capture II high-risk test. 2.She has HIV disease with a CD-4 count of 800. 3.She is pregnant. 4.She is lactating.

44. ACIP Recommendations Current recommendations for cervical cancer screening have not changed for quadrivalent HPV recipients. Females who have an equivocal or abnormal Pap test, a positive Hybrid Capture II high-risk test, or genital warts can receive the quadrivalent HPV vaccine. NO therapeutic effect on existing Pap test abnormalities, HPV infection, or genital warts. Vaccination would provide protection against infection with vaccine HPV types not already acquired. Lactating women can receive the vaccine. Immunocompromised females can receive the vaccine. Effectiveness might be < immunocompetent females. ACIP. Recommendations for the use of quadrivalent HPV vaccine. Available at: http://www.cdc.gov/nip/recs/provisional_recs/hpv.pdf. Accessed December 19, 2006.

45. ACIP Recommendations HPV-4 is not recommended in pregnancy. Individuals should report any exposure to the vaccine during pregnancy to the vaccine pregnancy registry. HPV-4 vaccine can be administered to females with minor acute illnesses. Vaccination of people with moderate or severe acute illnesses should be deferred until after the illness improves. ACIP. Recommendations for the use of quadrivalent HPV vaccine. Available at: http://www.cdc.gov/nip/recs/provisional_recs/hpv.pdf. Accessed December 19, 2006.

46. RecommendationsACIP 1 ACOG 2 AAFP 3 ACHA 4 Routine vaccination in 11- to 12- year-old females and catch-up vaccination in 13- to 26-year-olds Females 9–10 years old can be vaccinated N/A Vaccinate regardless of previous HPV infection or abnormal Pap N/A Continue Pap testing after vaccination N/A Organization Recommendations 1. ACIP. Recommendations for the use of quadrivalent HPV vaccine. http://www.cdc.gov/nip/recs/provisional_recs/hpv.pdf. 2. ACOG. HPV vaccination. Committee Opinion No. 344. Obstet Gynecol. 2006;108:699–705. 3. Armstrong C. Practice guidelines: Recommended adult immunization schedule, United States, 2007. Am Fam Physician. 2006;12:2115. 4. American College Health Association. ACHA Guidelines: recommendations for institutional prematriculation immunizations. http://www.acha.org/info_resources/RIPIstatement.pdf. Accessed 3/16/08. http://www.acha.org/info_resources/RIPIstatement.pdf

47. Clinical Practice Recommendation Practice Recommendation: Routine vaccination of females aged 11--12 years with 3 doses of quadrivalent HPV vaccine is recommended. The vaccination series can be started as young as age 9 years. Evidence-Based Source: National Guidelines Clearinghouse Web Site of Supporting Evidence: http://www.guideline.gov/summary/summary.aspx?doc_id=10634&nbr =005571&string=hpv+AND+vaccine Strength of Evidence: Recommendation of the Advisory Committee on Immunization Practices (ACIP)

48. 2008 Adolescent Immunization Schedule Centers for Disease Control and Prevention. MMWR. 2006;55:Q1–Q4.

49. The Future of HPV Vaccines

50. Quadrivalent Vaccine Efficacy Against CIN 2/3/AIS Due to Vaccine or Non-Vaccine Types CIN 2/3 or AIS by type% Efficacy (95% CI) HPV 6, 11, 16, 18100 (93, 100) Type 31, 4562 (10, 85) Types HPV 31, 33, 45, 52 or 5843 (7, 66) Types HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 38 (6, 60) Non-Vaccine HPV A9 Species (HPV 16 family) Types 31, 33, 35, 52, 58 45 (10, 68) Non-Vaccine HPV A7 Species (HPV 18 family) Types 39, 45, 59, 51, 56 46 (-35, 80)

51. Males (????)

52. HPV-4 Vaccine in Young Men Placebo-controlled study of 4,000 Men (600 MSM) 16- to 26-year-olds with 0 to 5 lifetime partners Genital sampling for HPV and wart inspection Primary endpoint: HPV 6/11/16/18-related Genital lesions (genital warts, penile dysplasia) Persistent infection Sub study in MSM Anal pap test/HPV testing at Q6 months Referral to high-resolution anoscopy for abnormalities Primary endpoint: HPV 6/11/16/18-related Anal Dysp Up to 4 years of follow-up

53. Vulvovaginal Disease

54. The Role of HPV in VIN and VaIN 92%76%91%64% VIN 2/3 (N=183) VaIN 2/3 (N=11) VIN = vulvar intraepithelial neoplasia. VaIN = vaginal intraepithelial neoplasia. Hampl M et al. Obstet Gynecol. 2006;108:1361–1368. Percentage From a study of 241 women in Germany, diagnosed with lower genital tract dysplastic lesions.

55. Per-protocol susceptible population External anogenital and vaginal lesions 100 (94–100) According to type of lesion Condyloma100 (92–100) Vulvar condyloma100 (92–100) Vaginal condyloma100 (14–100) VIN 1 or VaIN 1100 (49–100) VIN 2 or 3 or VaIN 2 or 3100 (49–100) Vaccine Efficacy against External Anogenital and Vaginal Lesions Associated with HPV-6/11/16/18 IPV Abstract

56. Lesions associated with any HPV type All external anogenital and vaginal lesions 34 (15–49) According to type of lesion Condyloma 51 (32–65) Vulvar condyloma 52 (32–67) Vaginal condyloma 53 (<0–82) VIN grade 1 or VaIN grade 118 (<0–46) VIN grade 2/3 or VaIN grade 2/326 (<0–63) Vulvar cancerNA Vaccine Efficacy Against External Anogenital and Vaginal Lesions - Any HPV Type

57. EGL = external genital lesions; CIN = Cervical Intraepithelial Neoplasia Jan 2003 Jan 2004 Jan 2005 Jan 2009 Jan 2006 Jan 2008 Jan 2007 Jan 2010 Jan 1998 HPV-4 Vaccine Clinical Development Program May 2000 Ph-III P020 – Ongoing Safety/Efficacy in 16- to 26-year-old men Future III - P019 – Ongoing Safety/Efficacy in 24- to 45-year-old women Ph II–P005 (N=2,391) 1 Proof of Principle 16- to 23-yo women Ph II–P026 – Ongoing 8.5 Year Follow-Up 16- to 23-year-old women (subjects from P005) VACCINE IMPACT in POPULATION Surveillance Study (All women Post-licensure) – Ongoing Phase II Phase III Phase IV / Surveillance MEN | ADLOESCENTS | WOMEN A Ph-III FUTURE II (P015) CIN 2/3 15- to 26-year-old women (N=12,167) (End Placebo Vaccinated) (P015-20) Duration of Efficacy Registry Study (Long-Term Nordic Region) - Ongoing Ph-III P016, P018 (N=1,958) Safety/Immunogenicity 9- to 15-yo female and males 5,6 Ph-III P018 – Ongoing Effectiveness in 9- to 15-yo female and male surveillance (extension of 016) Ph IIB–P007 (N=1,158) 2 Dose-ranging 16- to 23-yo women Ph IIB–P007 Antigen Challenge @ 5 y 16- to 23-yo women Placebo Vaccinated Ph-III FUTURE I (P013) CIN/EGL 16- to 24-year-old women (N=5,455) 3 Placebo Vaccinated Ph-III Concomitant Vaccines TDaP, Polio, Boostrix, Menactra, and Adacel

59. HPV Post-Test Questions

60. ?

61. For which of the following cancers is HPV known to be related? 1.Types of penile, vulvar, cervical and testicular cancers 2.Types of oropharyngeal, cervical and scrotal cancers 3.Types of cervical, oropharyngeal, vulvar and penile cancers 4.Types of testicular, vulvar and cervical cancers

62. Which of the following is NOT true about recommendations for giving quadrivalent HPV vaccine? 1.Females 11-12 years of age should have 3 doses of vaccine 2.The vaccination series can be started as young as 9 years of age. 3.Ideally vaccinations should begin before sexual activity begins 4.Females ages 13-26 should have 1 dose of vaccine if not previously immunized

63. Kathleen is an 18 year-old sexually active female who comes in requesting the HPV vaccine. She asks for advice about her risk for developing cervical cancer since she was sexually active before she received the vaccine. True or False: You should reassure her that the quadrivalent vaccine is proven to be effective against disease in persons already infected with the virulent type. 1.True 2.False

64. Which of the following is NOT true concerning the initiation of vaccination of those age 11? 1.Initiating vaccination at this age should provide vaccination prior to sexual debut in most girls. 2.High antibody titers are induced when given at this age. 3.Data has shown waning of immunity in this age. 4.Institution of vaccination at this age is consistent with young adolescent health care visit.

65. Janice, a 19 year-old female with a history of initiation of sexual activity at 17 years old and with a lifetime history of 2 male sexual partners presents as a new patient in your clinic. Which of the following tests should she receive? 1.Pap Testing 2.Chlamydia Screening 3.HPV PCR Testing 4.No screening testing at this time 5.1 and 2 6.1, 2, and 3