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
– Safety study, Merck HPV4 in males
• Member, Data Monitoring Committee
– Merck PCV15 studies in infants & adults
• No off-label discussions
Learning Objectives
• Identify the cancers caused by HPV
• Outline US HPV vaccine recommendations
• Relate vaccine uptake’s current status
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
HPV
• Human Papillomavirus
– Infects the epithelium
– Infections can transform tissue
– Sequelae include the following:
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Common warts
Condyloma acuminata
Juvenile respiratory papillomatosis
Cervical dysplasia and cervical cancer
Other cancers including head and throat
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
>150 HPV Types
Mucosal
High-risk Types
(eg, 16 and 18)
Cutaneous
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
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
Infections with High-risk Types
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Humans only natural host for HPV infection
Spreads from mucosal contact
Virus cannot be cultured
Detected by DNA hybridization
Most infections inapparent
How HPV Begets Cervical Cancer
Within 1 Year
Initial
HPV
Infection
1 to 5 Years
Persistent
Infection
Cleared HPV Infection
CIN
2/3 or
AIS
Up to Decades
Cervical
Cancer
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
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
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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
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
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
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
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
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
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
Vulvar Cancer
• Most common symptom pruritus
• Other symptoms more rare
– Vulvar bleeding
– Dysuria
– Enlarged lymph node
• Many asymptomatic
Anal Cancer
• Anal cancer small fraction of GI cancer
• Increasing frequency over time
– Doubled in last 30 years
– Higher incidence associated with following:
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Being female
Number of lifetime partners
Genital warts
Cigarette smoking
Infection with HPV
Receptive anal sex
HIV
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
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
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
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
Head and Neck Cancer
• HPV now established in causative role
– Oropharynx
• Tonsils
• Base of tongue
– Role explains phenomenon
• Changing epidemiology
• Improved prognosis
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
Rates of HPV-caused
Head and Neck Cancers
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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
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
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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%
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
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
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
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
Basis for Adding Males in 2011
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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
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%
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
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
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Found titers inversely relate to age
Antibodies peak at 7th month
Decline to 24th month
Level out thru 36 months
Anti-HPV 1 Month after 3d Dose
Anti-HPV 16
N
9- thru 15-year-old girls
915
16- thru 26-year-old
girls and women
27- thru 34-year-old
women
35- thru 45-year-old
women
3249
435
657
GMT (95% CI)
4919
(4557, 5309)
2409
(2309, 2515)
2343
(2119, 2590)
2130
(1963, 2311)
HPV4 Efficacy in Males w/Warts
• Study of 4,055 males 16-26 years old
– 3-dose efficacy in preventing vaccine-strainspecific warts
• 89.3% (95% confidence interval 65.3 to 97.9%)
– 1-dose efficacy in preventing vaccine-strainspecific warts
• 68.1% (95% confidence interval 48.8% to 80.7%)
– No evidence of efficacy in treating existing
HPV infections
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)
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%)
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
US Uptake 13-17 Years Old (%)
Sex
HPV4
2007
2008
2009
2010
2011
2012
Girls
>1 doses
25
37
44
49
53
54
>3 doses
6
18
27
32
35
33
>1 doses
8
21
>3 doses
1
7
Boys
>3 Doses Females 13-17 Years
12-29% (11)
30-39% (27)
40-49% (11)
50-58% (2)
Reasons for Rejecting
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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
Main Reasons Given (%)
Not recommended
Not needed/not necessary
Lack of knowledge
Not appropriate age
Safety concern/side effects
Don’t know
Not sexually active
Multiple reasons
All other reasons
2008
11
14
16
6
5
7
14
7
20
2009
9
16
16
4
8
5
12
7
24
2010
9
17
17
4
16
5
11
9
17
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
VAERS
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, lifethreatening illness, or death
– Headache, nausea, vomiting, fatigue,
dizziness, syncope, and generalized
weakness
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
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
Current and Future Steps
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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
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Summary
• HPV cancers pose substantial burden
• HPV vaccines have remarkable efficacy
• Parental concerns create major obstacle