1. The Burden of HPV Disease and the Impact We Could Have Robert M Jacobson, MD, FAAP Professor of Pediatrics, Mayo Clinic President, SEMIC Med Dir, Mayo’s Primary Care Immun Program President, MN Chap Amer Acad of Pediatrics

2. Disclosures Member, Safety Review Committee –Safety study, Merck HPV4 in males Member, Data Monitoring Committee –Merck PCV15 studies in infants & adults No off-label discussions

3. Learning Objectives Identify the cancers caused by HPV Outline US HPV vaccine recommendations Relate vaccine uptake’s current status

4. Historical Perspective 1983 Harald zur Hausen –Used DNA hybridization to identify specific DNA –Found HPV types 16 and 18 found in cervical Ca –Knew to look because of HPV associated with warts including genital warts 1933 work with rabbit papilloma virus & horny tumors Original idea from 1911 work with chicken sarcomas 1991-1993 NCI and 3 universities –HPV L1 self assembles as virus-like particles –VLPs form capsids, induces neutralizing Abs

5. HPV Human Papillomavirus –Infects the epithelium –Infections can transform tissue –Sequelae include the following: Common warts Condyloma acuminata Juvenile respiratory papillomatosis Cervical dysplasia and cervical cancer Other cancers including head and throat

6. The Virus Small double-stranded DNA Six early or E proteins –Viral gene regulation –Cell transformation Two late or L proteins that make up shell Regulatory DNA sequences –Long control region Strains –More than 150 types

7. >150 HPV Types MucosalCutaneous High-risk Types (eg, 16 and 18) Low-risk Types (eg, 6 and 11 ) Common Warts Low-grade abnormalities High-grade abnormalities Pre-cancers Various cancers Respiratory and laryngeal papillomas Low-grade abnormalities Genital warts

8. High-Risk Types High-risk types –Of the 40 mucosal types, 16 are high-risk –Detected in 99.7% of cervical cancers –16 causes 50% of cervical cancers worldwide –18 causes another 20% –31, 33, 35, 39, 45, 51-2, 56, 58-9, 68-9, 73, 82 Manifestations –Low-grade cellular abnormalities –High-grade cellular abnormalities –Cancers

9. Infections with High-risk Types Humans only natural host for HPV infection Spreads from mucosal contact Virus cannot be cultured Detected by DNA hybridization Most infections inapparent

10. How HPV Begets Cervical Cancer Initial HPV Infection Cleared HPV Infection Within 1 Year Persistent Infection 1 to 5 Years CIN 2/3 or AIS Up to Decades Cervical Cancer

11. Supportive Findings Epidemiologic studies show association HPV DNA is usually present Viral oncogenes E6 and E7 in lesions –Interact with host cell growth-regulating proteins –Malignancies of cell lines need E6/E7 expression

12. HPV Epidemiology In terms of anogenital HPV infection –6.2 million new cases a year –20 million in United States currently infected –Most common in adolescents and young adults Prevalence of HPV in adolescent girls as high as 64% 75% of new infections occur in 15 to 24 years old 33% of 9th-graders report ever having sex 53% of 11th-graders report ever having sex 8% adolescents report having been forced to have sex –75-80% sexually active adults infected by age 50

13. Cervical Cancer HPV detected in 91% of all cervical cancer 11,300 new cases a year in United States –At a minimum 10,300 caused by HPV 4000 deaths a year as a result Mean age 48 years

14. Risk Factors Exposed to infection –Multiple partners –Earlier onset sexual activity –High-risk sexual partner –History of STDs –History of other HPV-related dysplasia, cancer Compromised immunity to infection –Immunosuppression (e.g. HIV) –Smoking (squamous cell carcinoma) Inherited risk factors not yet identified

15. HPV-caused Cancers in the US 26,200 HPV-caused Ca a year in the US –17,400 cancers/year in women 10,300 cervical Ca –8800 cancers/year in men Other cancers –Vaginal –Vulvar –Anal –Penile –Head and neck

16. Vaginal Cancer Most primary vaginal cancer HPV –75% due to HPV –In one study >50% positive for HPV 16 or 18 –Most squamous cell 694 cases diagnosed annually in US –500 caused by HPV at a minimum Risk factors same as in cervical cancer –Multiple lifetime sexual partners –Early age at first intercourse –Being a current smoker

17. Vaginal Cancer Most common symptoms vaginal bleeding –Postcoital –Postmenopausal Other presentations –Watery, blood-tinged, or malodorous discharge –Vaginal mass –Urinary symptoms –Gastrointestinal complaints –20% asymptomatic

18. Vulvar Cancer 90% of vulvar cancer is squamous cell –HPV responsible for 69% of vulvar cancer –In premenopausal women etiology is HPV –HPV types 16, 18, and 33 3039 cases diagnosed annually in US –2100 caused by HPV In last 2 decades rise in vulvar intraepitheIial neoplasia (IEN) HPV more likely in young smokers

19. Vulvar Cancer Most common symptom pruritus Other symptoms more rare –Vulvar bleeding –Dysuria –Enlarged lymph node Many asymptomatic

20. Anal Cancer Anal cancer small fraction of GI cancer Increasing frequency over time –Doubled in last 30 years –Higher incidence associated with following: Being female Number of lifetime partners Genital warts Cigarette smoking Infection with HPV Receptive anal sex HIV

21. Anal Cancer Epidemiology resembles genital cancers –4771 cases annually in US, 65% female –4300 caused by HPV: 1500 male & 2800 female Thirty years ago –Thought due to chronic inflammation –Managed with abdomino-peritoneal resection –Permanent colostomy Current approach with 91% due to HPV –Majority can be cured –Anal sphincter can be preserved

22. Penile Cancer Rare cancer in US –1003 cases diagnosed annually in US –600 caused by HPV –Much more common in developing countries Primary epithelial squamous cell cancer Risk factors –Previous penile injury –Phimosis –HPV infection –HIV infection

23. Penile Cancer Role of HPV –63% of penile cancer in US caused by HPV –Of those, 60% HPV 16 and 13% HPV 18 –Association with HIV appears HPV-mediated Presents as lump on the penis –Average age 60 years of age –Men of any age can be affected Management –Stage T1 local excision –Stages T2-4 or bulky lesions, amputation

24. Head and Neck Cancers Vast majority Mucosa of the upper aerodigestive tract Predominantly squamous cell in origin Epidemiology –Highest rates in older males Primary risk smoking and smokeless tobacco Roles for alcohol and heredity –Increasing rates Females Younger adults Nonsmokers

25. Head and Neck Cancer HPV now established in causative role –Oropharynx Tonsils Base of tongue –Role explains phenomenon Changing epidemiology Improved prognosis

26. Role of HPV HPV cancers of head and neck –None of the standard risk factors Smoking and smokeless tobacco Alcohol consumption –HPV 16 causes overwhelming majority –Rarely HPV 18, 31, and 33 Switch-over starting late 1980s –Drop in smoking, laryngeal cancers –No change, then rise in oropharyngeal cancers

27. Rates of HPV-caused Head and Neck Cancers In late 1990s 50% HPV Most recent studies 70% to 80% Increasing role in laryngeal cancer too 11,629 cases a year in the US, 80% male –8400 due to HPV; 6700 male, 1700 female

28. HPV Oral Infections NHANES 2009-2010 survey –Methods Men and women aged 14 to 69 years Volunteers examined in mobile stations Swish-and-spit samples of oral cells –Overall rate of current infection with HPV Any HPV 6.9% HPV 16 1.0% 30 to 34 years 7.3% 60 to 64 years 11.4% Females 3.6% and males 10.1%

29. Risk Factors for Current Oral HPV A history of any type of sexual contact –No reported sexual contact 0.9% –Reported sexual contact of any kind 7.5% –(80% of sexually active 15-44 yr olds have oral sex with partners of opposite sex) Other independent risk factors –Number of lifetime sexual partners –Number of cigarettes smoked per day

30. ACIP HPV Recommendations Latest as of December 23, 2011 Males (Gardasil or HPV4 only) –Routine 11-12 years old –Catch-up 13-21 years old –Catch-up 22-26 years old in special populations Males who are immunocompromised Males infected with HIV Males who have sex with males –Continue permissive language 22-26 years old –Permission to begin at 9 years old

31. Previous Recommendations Still current –Females (HPV2 or HPV4) Routine administration 11-12 years of age Catch-up administration 13-26 years of age Permission to begin at 9 years old Now superseded –Males (HPV4 only) Permission to use 9-26 years of age

32. 2 HPV Vaccines Available HPV2 (Licensed for females only in 2009) –Human Papillomavirus vaccine, bivalent –Cervarix® –HPV types 16 and 18 –GlaxoSmithKline HPV4 (Licensed for both sexes since 2006) –Human Papillomavirus vaccine, quadrivalent –Gardasil® –HPV types 6, 11, 16, and 18 –Merck & Co

33. Basis for Adding Males in 2011 Burden of disease in males increasing Vaccine efficacy data now available Bridging immunogenicity data now available Vaccine safety data in males now available Cost-effectiveness given poor female uptake Programmatic considerations given poor female uptake

34. Original Efficacy Data Studies of 16,957 females 16-26 years old –Per protocol 3 doses completed in 1 year –Negative for HPV thru third dose –Followed for an average of 4 years –4 randomized clinical trials Of 8493 females receiving HPV4 –2 cases of CIN 2/3 or AIS Of 8464 females receiving adjuvant alone (placebo) –112 cases of CIN 2/3 or AIS –98.2 % efficacy with a 95%CI of 93.5 to 99.8%

35. Health Care Utilization Re reduction of definitive cervical therapy Studies 2, 3, and 4 HPV4 versus placebo N=18,150 girls and women 23.9 percent reduction –95% CI: 15.2%, 31.7% Numbers needed to treat 4.18 –95% CI: 3.15 to 6.58

36. Bridging Data with Girls 9 to 15 Minimum protective anti-HPV titer unknown Assessed immunogenicity of HPV –23,951 9- through 45-year-old girls and women GARDASIL N = 12,634 AAHS control or saline placebo N = 11,317 Found titers inversely relate to age Antibodies peak at 7 th month Decline to 24 th month Level out thru 36 months

37. Anti-HPV 1 Month after 3d Dose Anti-HPV 16NGMT (95% CI) 9- thru 15-year-old girls915 4919 (4557, 5309) 16- thru 26-year-old girls and women 3249 2409 (2309, 2515) 27- thru 34-year-old women 435 2343 (2119, 2590) 35- thru 45-year-old women 657 2130 (1963, 2311)

38. HPV4 Efficacy in Males w/Warts Study of 4,055 males 16-26 years old –3-dose efficacy in preventing vaccine-strain- specific warts 89.3% (95% confidence interval 65.3 to 97.9%) –1-dose efficacy in preventing vaccine-strain- specific warts 68.1% (95% confidence interval 48.8% to 80.7%) –No evidence of efficacy in treating existing HPV infections

39. Efficacy w/Anal Ca Precursors Substudy: 598 males who have sex w/ males Higher risk for warts and anal cancers Study examined anal cancer in early stages –Anal Intraepithelial Neoplasia or AIN AIN 1 (low-grade, most common, most resolve) AIN 2/3 (high grade, much rarer, more likely to progress to cancer)

40. Vaccine-Strain-Specific Results 3-dose efficacy in preventing warts –88.1% (95% CI 13.9 to 99.7%) 3-dose efficacy in preventing AIN1/2/3 –77.5% (95% CI 39.6 to 93.3%) 3-dose efficacy in preventing AIN2/3 –74.9% (95% CI 8.8 to 95.4%)

41. HPV Bridging Data for Males Seroconversion high for all four serotypes Males 9-15 years old significantly higher titers than 16-26 In 500 from this 9-15 year group now 6 years out… –No cases of persistent vaccine-strain-specific HPV infection –No cases of vaccine-strain-specific HPV disease

42. US Uptake 13-17 Years Old (%) SexHPV4200720082009201020112012 Girls>1 doses253744495354 >3 doses61827323533 Boys>1 doses821 >3 doses17

43. >3 Doses Females 13-17 Years 12-29% (11) 30-39% (27) 40-49% (11) 50-58% (2)

44. Reasons for Rejecting US NIS-TEEN surveys 2008 thru 2010 Parents of teens Based on vaccination data on med record Asked about intent to complete series For those answering “Not too likely” and “Not likely at all,” asked their main reason

45. Main Reasons Given (%) 200820092010 Not recommended1199 Not needed/not necessary141617 Lack of knowledge16 17 Not appropriate age644 Safety concern/side effects5816 Don’t know755 Not sexually active141211 Multiple reasons779 All other reasons202417

46. HPV Safety Post Licensure From June 2006 through March 2013 –56,000,000 doses of HPV4 distributed US From October 2009 through May 2013 –611,000 doses of HPV2 were distributed in US Analysis based on HPV4 (99% doses) –Vaccine Adverse Event Reporting System –21,194 adverse event reports –Primarily but not restricted to females –Postlicensure approximates prelicensure data

47. VAERS

48. Nonserious and Serious AEs Nonserious –Generalized symptoms: syncope, dizziness, nausea, headache, fever, and urticaria –Injection-site pain, redness, and swelling Serious –Hospitalization, prolongation of an existing hospitalization, permanent disability, life- threatening illness, or death –Headache, nausea, vomiting, fatigue, dizziness, syncope, and generalized weakness

49. Post Licensure Population Based Studies CDC, Vaccine Safety Datalink (600,559) Guillain-Barré syndrome, stroke, appendicitis, seizures, allergic reactions, anaphylaxis, syncope, and venous thromboembolism No statistically significant increase in risk Merck FDA Requirement (346,972) –All HCUP diagnosis categories Syncope on the day of vaccination Skin infections* in 2 weeks following vaccine –Autoimmune conditions No statistically significant increase

50. Issue with Syncope ACIP recommends providers consider observing all patients for 15 minutes post vaccination, including HPV Known issue for adolescents In practice, good to point out symptoms

51. Current and Future Steps Notify clinicians when due in office Measure and report clinician rates Nurse-visits with standing orders In-office clinician efforts (C.A.S.E.) Reminder-recalls with education School-based clinics 

52. Summary HPV cancers pose substantial burden HPV vaccines have remarkable efficacy Parental concerns create major obstacle