Embassy Suites RaleighDurhamResearch Triangle

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2008
Symposia Series 2

• Embassy Suites Raleigh-Durham/Research Triangle
• Cary, North Carolina
• June 21, 2008

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Prevention Is Now a RealityReducing the Burden
of Cervical Cancer and Other HPV-Related Diseases

• Daron G. Ferris, MD
• Professor
• Department of Family Medicine
• Department of Obstetrics and Gynecology
• Director, Gynecologic Cancer Prevention Center
• Medical College of Georgia
• Augusta, Georgia

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Faculty Disclosure

• Dr Ferris consultant/speakers bureau Merck
  Co., Inc. research grants GlaxoSmithKline,
  Merck Co., Inc.

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In what percentage of your eligible patients do
you offer HPV vaccination?
?
KEY QUESTION

• 0-10
• 11-25
• 26-50
• 51-75
• 76-100

Use your keypad to vote now!
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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

HPV human papillomavirus.
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Approximately what percentage of sexually active
individuals will be infected with HPV in their
lifetimes?
?
KEY QUESTION

• 10
• 25
• 50
• 75
• Unsure

Use your keypad to vote now!
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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

STI sexually transmitted infection. 1. Cates W
Jr and the American Social Health Association
Panel. Sex Transm Dis. 199926(suppl 4)S2-S7
2. Steinbrook R. N Engl J Med.
20063541109-1112 3. The American Social Health
Association and Kaiser Family Foundation. STDs in
America How Many Cases and At What Cost? Menlo
Park, CA 1998 4. Koutsky L. Am J Med.
19971023-8.
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Which of the following diseases are associated
with HPV infection?
?
KEY QUESTION

• Cervical cancer
• Anogenital cancers
• Genital warts
• Certain head and neck cancers
• All of the above

Use your keypad to vote now!
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Common HPV Types AssociatedWith Benign and
Malignant Disease
Manifestations
HPV Types
High risk
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,
68, 73, 82
Low-grade cervical changes1 High-grade cervical
changes1 Cervical cancer1,2 Other anogenital
cancers1 Head and neck cancer3
Low risk
6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81
Benign low-grade cervical changes1 Condylomata
acuminata1 (genital warts) Recurrent respiratory
papillomatosis4
1. Koutsky LA et al. Epidemiol Rev.
198810122-163 2. Muñoz N et al. N Engl J Med.
2003348518-527 3. Hansson BG et al. Acta
Otolaryngol. 20051251337-1344 4. Wiatrak BJ.
Curr Opin Otolaryngol Head Neck Surg.
200311433-441.
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Malignancies Attributable to HPV Infection
Attributable to HPV ()
Type of Cancer
Parkin DM, Bray F. Vaccine. 200624(suppl
3)S11-S25 Ryan DP et al. N Engl J Med.
2000342792-800.
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Relative Contribution of HPV Types to Cervical
Cancer All World Regions Combined
Percent
Muñoz N et al. Int J Cancer. 2004111278-285.
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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 gt60 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

1. Schiffman M et al. JAMA. 200028387-93 2.
Parkin DM, Bray F. Vaccine. 200624(suppl
3)511-525 3. CDC. United States Cancer
Statistics Data. 2004 4. National Cancer
Institute. Cervical Cancer. Available at
http//www.cancer.gov/cancertopics/types/cervical.
Accessed February 12, 2008 5. Sirovich BE,
Welch HG. J Gen Intern Med 200419243-250 6.
Cervical Cancer. NIH Consensus Statement Online
1996 April 1-314-38.
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The Natural History of HPV and Cervical Cancer
HPV infection
6, 11, other
16, 18, other
Genital warts
Transient
Persistent
Regression
Therapy
CIN 2/3
CIN 1/2
Immune response
LSIL
Protection (?)
Cancer
Regression
CIN cervical intraepithelial neplasia. Adapted
from Schiffman M, Kjaer SK. J Natl Cancer Inst
Monogr. 20033114-19.
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Diagnosis of Cervical Abnormalities

• Cytology (Pap smear test)
• Useful screening test to detect cervical
  dysplasia
• Indirect evidence of HPV because it detects
  squamous epithelial cell changes typically caused
  by HPV
• DNA testing
• FDA approved for 2 indications
• Triage women with atypical cells of undetermined
  significance with the Pap test
• As an addition to the Pap test for cervical
  cancer screening in women 30 years of age
• Unnecessary in the initial management of women
  with ASC-H, LSIL or HSIL Pap result, since the
  vast majority are infected with HPV. Also not
  used in the initial management of AGC Pap
  results.

AGC atypical glandular cells ASC-H atypical
squamous cells, cannot exclude HSIL ASC-US
atypical squamous cells of undetermined
significance HSIL high-grade squamous
intraepithelial lesion LSIL low-grade squamous
intraepithelial lesion.Sawaya GF et al. N Engl J
Med. 20013441603-1607 Wright TC et al. Am J
Obstet Gynecol. 2007197346-355.
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Diagnosis of Cervical Abnormalities (contd)

• Colposcopy
• Main diagnostic test for women with abnormal Pap
  test findings
• Indications for cervical biopsy
• Ecto- and endocervical lesions

ASC-Hatypical squamous cells, cannot exclude
high-grade squamous intraepithelial
lesion. Sawaya GF et al. N Engl J Med.
20043441603-1607.
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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

1. Koshiol JE et al. Sex Transm Dis.
200431748-752 2. Koutsky LA. Am J Med.
19971023-8 2005191731-738.
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Epidemiology of Genital Warts (contd)

• gt90 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

1. Brown DR et al. J Clin Microbiol.
1999373316-3322 2. Winer RL et al. J Infect
Dis. 2005191731-738. 3. Insinga RP et al. Clin
Infect Dis. 2003361397-1403.
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Epidemiology of Recurrent Respiratory
Papillomatosis (RRP)

• Caused by HPV 6 and 11, which are also
  responsible for causing anogenital condyloma
• Infection occurs in newborns
• 200-fold increased risk for juvenile-onset RRP
  (JORRP) if mother has condyloma at delivery

Freed GL, Derkay CS. Int J Pediatr
Otorhinolaryngol. 2006701799-1803 Derkay CS.
Laryngoscope. 200111157-69.
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Epidemiology of Recurrent Respiratory
Papillomatosis (RRP) (contd)

• JORRP is typically more aggressive repeated
  surgical procedures necessary to maintain airway
• Adult-onset RRP (AORRP) has peak at 2130 years
  of age
• Mode of transmission thought to be adult
  exposure
• 1500 new cases per year in the United States,
  and 15,000 surgical procedures at a cost of
  100 million per year

Freed GL, Derkay CS. Int J Pediatr
Otorhinolaryngol. 2006701799-1803 Derkay CS.
Laryngoscope. 200111157-69.
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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

Lowy DR, Frazer IH. J Natl Cancer Inst Monogr.
200331111-116 Gillison ML. J Natl Cancer
Inst. 200092709-720.
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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?
?
KEY QUESTION

• lt20
• 30
• 50
• gt70
• Unsure

Use your keypad to vote now!
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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 (gt70 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

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Quadrivalent HPV 6/11/16/18 Vaccine 3-Year
Results
HPV16/18-Associated CIN 2/3 and AIS
HPV 6/11/16/18-Associated Genital Warts and
Vulvar/Vaginal Neoplasia
Per protocol
Unrestricted
98 (95 CI, 86-100)
100 (95 CI, 94-100)
95 (95 CI, 85-99)
95 (95 CI, 87-99)
Vaccine Efficacy ()
n5305
n5865
n2261
n2667
Subjects who were seronegative and PCR negative
for vaccine types at enrollment were included,
even if abnormal cervical cytology protocol
violations were present. AIS adenocarcinoma in
situ. Future II Study Group. N Engl J Med.
20073561915-1927 Garland SM et al. N Engl J
Med. 20073561928-1943.
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Efficacy of the Quadrivalent HPV 6/11/16/18
Vaccine 5-Year Follow-up
100 (95 CI, 12-100)
96 (95 CI, 84-100)
Vaccine Efficacy ()
HPV 6/11/16/18-Related Persistent Infection or
Disease
HPV 6/11/16/18-Related CINor Genital Warts
N241 women (aged 16-23 years). Villa LL et al.
Br J Cancer. 2006951459-1466.
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Quadrivalent HPV 6/11/16/18 Vaccine Efficacy
Against CIN 2/3 or AIS Due to Vaccine or
Nonvaccine Oncogenic Types
Brown D, for the FUTURE Study Group. Presented at
the 47th Interscience Conference on Antimicrobial
Agents and Chemotherapy, September 17-20, 2007
Chicago, Ill.
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Is there any benefit to offering HPV vaccination
to sexually active women older than 26 years of
age?
?
KEY QUESTION

• Yes
• No
• Unsure

Use your keypad to vote now!
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Quadrivalent HPV 6/11/16/18 Vaccine Efficacy in
Mid-Adult Women (Aged 24-45 Years)
Vaccine Efficacy ()
Combined incidence of disease related to HPV
6/11/16/18. Plt.001 across all age groups. Luna
J et al, for the FUTURE III Investigators.
Presented at The 24th International
Papillomavirus Congress November 3-9, 2007
Beijing, China. Poster PA1-04.
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Quadrivalent HPV 6/11/16/18 Vaccine Injection
Site Reactions Postvaccination

• 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.
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Quadrivalent HPV 6/11/16/18 Vaccine Systemic
Adverse Events Postvaccination

• 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.
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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

Gardasil package insert. Whitehouse Station,
NJ Merck Co., Inc. 2007 Markowitz LE et al.
MMWR. 200756(RR-2)1-24.
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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)

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Phase 3 Bivalent HPV 16/18 Vaccine Interim
Analysis Efficacy
90.4 (95 CI, 53.4-99.3)
89.2 (95 CI, 59.4-98.5)
80.4 (95 CI, 70.4-87.4)
75.9 (95 CI, 47.7-90.2)
Vaccine Efficacy ()
Persistent Infection (6 months)
Persistent Infection (12 months)
CIN 2 Associated With HPV 16/18
CIN 1 Associated With HPV 16/18
Mean follow-up 14.8 months. Included subjects
with normal or low-grade cytology at month 0, who
received at least 1 dose of vaccine. Paavonen J
et al. Lancet. 20073692161-2170.
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Phase 3 Bivalent HPV 16/18 Vaccine Interim
Analysis Adverse Events
Participants who reported a specified symptom
within 7 days of vaccine injection.Defined as
axillary or oral temperature 37.5C. Paavonen J
et al. Lancet. 20073692161-2170.
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Bivalent HPV 16/18 Vaccine Cross-Protection
Efficacy Against Persistent Infection With
Nonvaccine Oncogenic Types
Harper DM et al. Lancet. 20063671247-1255.
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HPV Vaccines Summary

• Safe and well tolerated
• HPV vaccines are gt90 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

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Recommended Immunization Schedule for Persons
Aged 7-18 Years United States, 2008
Vaccination series can be started as young as 9
years of age, at the clinicians discretion.
Centers for Disease Control and Prevention.
Recommended Immunization Schedule for Persons
Aged 7-18 Years. http//www.cdc.gov/vaccines/recs
/schedules/downloads/child/2008/08_7-18yrs_schedul
e_pr.pdf. Accessed May 2, 2008.
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Case Study
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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
• Patients mother seems uncomfortable with the
  idea, noting that her daughter is young and will
  not be sexually active for some time

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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 (gt13
  years of age)3
• Parents look to you for credible vaccine
  information
• Healthcare providers receive the highest
  trustworthiness scores from parents4

1. Markowitz LE et al. MMWR. 200756(RR-2)1-24
2. Centers for Disease Control and Prevention.
MMWR Recomm Rep. 200251(RR-6)1-80 3. Oster NV
et al. J Am Board Fam Pract. 20051813-19 4.
Keane MT et al. Vaccine. 2005232486-2493.
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The Most Effective Time to Vaccinate Is Before
Exposure
Behavior reported in an independent study
100
Suggests minimal exposureto HPV at 9 to
11years of age
80
Cohorts That Have Had Intercourse ()
60
40
40
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20
7
2
14-15
16-17
12-13
11
Age at First Intercourse (years)
In an analysis of 1552 adolescents and young
adults, the subset (n1014) featured in this
chart reported having engaged in sexual
intercourse. Centers for Disease Control and
Prevention. MMWR. 200251(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.
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Case Study
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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

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HPV vaccination should be recommended to this
patient, as the prevalence of HPV disease peaks
at what age among women?
?
KEY QUESTION

• 10 to 14 years
• 15 to 19 years
• 20 to 24 years
• 25 to 29 years

Use your keypad to vote now!
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Prevalence of Genital Warts in Females Peaks
Before Age 25
Genital Wart Prevalence in Individuals lt35 Years
of Age in Private Health Plans
N3,664,686 n5095 cases of genital warts
Adapted from Insinga RP et al. Clin Infect Dis.
2003361397-1403.
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Is this womans sexual history relevant to her
eligibility to receive HPV vaccination?
?
DECISION POINT

• Yes
• No
• Unsure

Use your keypad to vote now!
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While the Prevalence of HPV Infection After
Sexual Debut Is High, the Infection Rate for Any
Specific Type Is Lower
(n94)
Female college students
Cumulative Incidence of HPV Infection
Months Since First Intercourse
Not all HPV 6/11 specimens were individually
tested for HPV 6 and HPV 11. Types 31, 45, 51,
52, 55, 58, 56, 33, 35, 39, 40, 42, 53, 54.
Adapted from Winer RL et al. Am J Epidemiol.
2003157218-226.
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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

AAPAmerican Academy of Pediatrics ACHAAmerican
College Health Association SAMSociety for
Adolescent Medicine.Winer RL et al. Am J
Epidemiol. 2003157218-226 CDC and National
Foundation for Infectious Diseases news
conference. Washington, DC January 23, 2008.
Anne Schuchat, MD, Assistant Surgeon General,
United States Public Health Service Director,
National Center for Immunization and Respiratory
Diseases, CDC. Michael N. Oxman, MD, Professor,
University of California, San Francisco Staff
Physician, Infectious Disease Section, VA Medical
Center, San Diego. Kristin Nichol, MD, MPH,
Chief of Medicine, Minneapolis VA Medical Center
Professor of Medicine and Vice Chair, Department
of Medicine, University of Minnesota.
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Q A
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PCE Takeaways
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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

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In what percentage of your eligible patients do
you plan to offer HPV vaccination?
?
KEY QUESTION

• 0-10
• 11-25
• 26-50
• 51-75
• 76-100

Use your keypad to vote now!
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2008
Symposia Series 2

• Embassy Suites Raleigh-Durham/Research Triangle
• Cary, North Carolina
• June 21, 2008

52