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The Burden of HPV Disease and the Impact We Could Have

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. Disclosures. Member, Safety Review Committee

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The Burden of HPV Disease and the Impact We Could Have

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  1. The Burden of HPV Disease and the Impact We Could Have Robert M Jacobson, MD, FAAPProfessor of Pediatrics, Mayo ClinicPresident, SEMICMed Dir, Mayo’s Primary Care Immun ProgramPresident, MN Chap AmerAcad 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 HaraldzurHausen • 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 cervicalcancer • 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 Mucosal Cutaneous 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 Within 1 Year 1 to 5 Years Up to Decades Persistent Infection CIN 2/3 or AIS Cervical Cancer Initial HPV Infection Cleared HPV Infection

  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-causedHead 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 93.5to 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 7th month • Decline to 24th month • Level out thru 36 months

  37. Anti-HPV 1 Month after 3d Dose

  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 (%)

  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 (%)

  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 • Nostatistically 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

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