The HPV Vaccine:
A Clinical Update
Karen Soren, MD
Director, Adolescent Medicine
Associate Clinical Professor, Pediatrics & Public Health
College of Physicians and Surgeons
Columbia University Medical Center
Learning Objectives
•
To review the epidemiology and clinical
significance of infection with human
papillomavirus (HPV)
•
To discuss recommendations for vaccination
with HPV vaccine in girls, young adult women
and males
•
To discuss controversies involving the HPV
vaccine with respect to parental acceptance,
state mandates, side effects and use in males
Human Papillomavirus (HPV)
Double-stranded DNA virus
Infects human epithelial cells
>200 different strains of the virus
– 30-40 anogenital
– 15-20 oncogenic
Genital warts, cervical dysplasia
not-reportable, so prevalence
data incomplete
Considered the most common
sexually transmitted infection in
the United States
Image: Merck
Epidemiology of HPV Infection
• 10% worldwide prevalence (highest in Africa)
• 20 million in US currently infected with anogenital strain
• 5.5 million/yr in US acquire new genital HPV infection
• 3/4 of infections occur in 15 - 24 year olds
• Among women 14-59, overall HPV prevalence – 27%
• Almost 40% of sexually active 14-19 year old girls and 50%
of sexually active 20-24 year olds infected
• Prospective study of female college students: 26% infected
at baseline; of those who were negative, 43% acquired
HPV infection over 3 years
NHANES data 2003-2004
Dunne et al, JAMA 2007
Bierman et al, NEJM 1998
CDC (MMWR) 2007
Human Papilloma Virus- Natural History
• Over half of sexually active women & men infected with
HPV at some point in their lives
• Most HPV infections are asymptomatic and transient
(~91% resolve without treatment in 2 years)
• Reactivation or re-infection possible
• In some individuals, HPV infections result in genital warts or
Pap test abnormalities
• Persistence of HPV infection (with high-risk subtypes)
associated with a variety of anogenital cancers
HPV and Cervical Cancer
HPV present in virtually all cervical
cancers (70-99%)
Infection is generally indicated by
the detection of HPV DNA
HPV 16, 18, 31 and 45 account for
80% of cervical cancers ( with HPV
16 - 54%, HPV 18 -13%)
Screening programs effective where
they are well-implemented
Image: CDC.gov
HPV and Cervical Cancer
US Statistics:
– In 2009, estimated 11,270 new cases of invasive
cervical cancer with 4,070 deaths
– Median age of diagnosis – 48 years
– Prevalence greatest in minority women
(Hispanics> African Americans> Caucasians)
National Cancer Institute, 2010 update
SEER (Surveillance, Epidemiology, and End Results) data, NCI, 2007
Cancer Types, Other Than Cervical Cancer, Attributable to HPV
100
Estimated, %
80
Estimated percentage of cancer cases attributable to HPV
70
60
50
50
50
40
20
20
0
Anal
Vulvar
Vaginal
Penile
Oropharyngeal
Cancer Type
González Intxaurraga MA et al. Acta Dermatovenerol. 2002;11:1–8.
(From Merck)
HPV and Anogenital Warts
• HPV 6 and 11 responsible for >90% of anogenital warts
• In 2006, ~ 420,000 reported cases of genital warts in US
• Prevalence: 1.5% - 13%
• Topical /surgical therapies available
• Treatment can be painful and embarrassing
• Up to 1/3 of genital warts may regress spontaneously
within 3 months
• Recurrence rates vary greatly
• Significant psychological burden
Genital Warts
Cincinnati STD/HIV Prevention Training Center, at CDC. gov
Not all genital bumps are warts…
Pearly Penile Papules
From CDC.gov
Scenario 1
• You offer the HPV vaccine to a 14 year old
patient who you are seeing for a regular
check-up. Her mother tells you that she is
concerned that if you give the vaccine, her
daughter will interpret that as permission to
become sexually active. She also feels that
the vaccine is still too new and may have
serious side effects.
Scenario 2
• A sexually active 16 year old girl requests the
HPV vaccine while seeing you in order to get
birth control. Her mother does not know she is
here today and is unaware of her daughter's
sexual activity or use of contraception. Can you
give her the vaccine without informing the
parent?
Scenario 3
• A 17 year old boy asks about the vaccine
against genital warts and wants to know if
you recommend it. His mother looks horrified
– she says she thought that the vaccine was
for girls only and was primarily a vaccine that
protected against cervical cancer.
Common Parental Questions and Concerns
• How safe is the vaccine? What are the
side effects?
• If I vaccinate my child, is she more likely to
become sexually active?
• When should she get this vaccine – isn’t it
better to wait until she is older?
• Is my child allowed to get the HPV vaccine
without my permission?
More Questions…
• If someone is currently infected with HPV, will
the vaccine treat it?
• What happens if you cannot come back on time
for the second and third injections?
• Will a woman still need Pap screening if she is
vaccinated against the HPV virus?
• Should boys be vaccinated against HPV? What
is a permissive recommendation?
HPV Vaccine
Gardasil® (Merck)
– FDA approved 6/06
– Quadrivalent vaccine (HPV4)
– Uses virus-like particles, recombinant L1 capsid
proteins of individual HPV types
– Adjuvant – aluminum hydrophosphate sulfate
– Protects against HPV 6, 11 (75-90% genital warts)
and 16,18 (70% cervical cancer)
– Indicated for girls and women 9 - 26 years of age
– Schedule: 0, 2 and 6 months
– Protection demonstrated for at least 5 years
HPV Vaccine
Cervarix ® (GlaxoSmithKline)
– FDA approved in 10/09
– Bivalent vaccine (HPV2)
– Uses virus-like particles, recombinant L1 capsid proteins
of individual HPV types
– Uses novel proprietary aluminum- based adjuvant
– Protects against HPV 16 and 18
– Indicated for women 10-25 (26 by ACIP)
– Schedule: 0, 1 and 6 months
– Protection demonstrated for at least 6.4 years
HPV Vaccine Efficacy- HPV4 (Gardasil)
Clinical trials demonstrated:
– 98% efficacy in preventing cervical pre-cancers caused
by targeted HPV types in women uninfected at baseline
– Girls who have not already been infected with any of the
4 sub-types of HPV get the most benefit from vaccine
(44% efficacy in all women irrespective of baseline HPV
status)
– Vaccine nearly 100% efficacious in preventing vulvar/
vaginal pre-cancers and genital warts caused by targeted
HPV types
– May offer cross-protection against HPV type 31
Future II Study Group, NEJM, 2007
HPV Vaccine Efficacy- HPV2 (Cervarix)
Clinical trials demonstrated:
– Vaccine may be more immunogenic than HPV4 with
higher post-vaccination antibody titers
– Efficacy 96-98% in prevention of cervical pre-cancers
– Efficacy 30% in all vaccinated women, irrespective of
baseline HPV status
– Vaccine only targets 2 strains (16 and 18) so not
effective in preventing genital warts
– Appears to offer cross-protection against other HPV
sub-types (31, 45, 52)
Paavonen, Lancet 2007 and 2009
Gardasil vs Cervarix
– Cervarix appears to induce higher antibody titers against
HPV 16 and 18 than Gardasil
– Both vaccines appear to offer cross-protection against
other HPV types, but Cervarix may offer more
– Gardasil also offers protection against genital warts (HPV
types 6,11)
– Gardasil has demonstrated vulvar/vaginal cancer
protection
– Gardasil approved for use in males
– Small cost difference between 2 vaccines
• CDC vaccine price list- private sector cost per dose:
Gardasil $130.27
Cervarix $128.75
Einstein et al. Hum Vaccines 2009
Bonnanni et al, Vaccine 2009
Paavonen et al, Lancet 2009
Medeiros et al, Int J Gynecol Cancer 2009
Recommendations: National Organizations
• ACIP and ACOG recommend use of vaccine in females
ages 9-26 years (either quadrivalent or bivalent)
• ACIP, AAP, AAFP, SAM support routine vaccination of
11-12 year-old girls
• All support catch-up vaccination for females 13-26 yrs
not previously vaccinated or who have not completed full
vaccine series
ACIP - Advisory Committee on Immunization Practices
ACOG- American College of Obstetricians and Gynecologists
AAP- American Academy of Pediatrics
AAFP- American Academy of Family Physicians
SAM- Society for Adolescent Medicine
Recommendations: National Organizations
• Vaccine most effective if given before 1st sexual contact
• Females who have equivocal or abnormal Pap tests,
positive HPV tests, or genital warts can receive HPV
vaccine
• Vaccine recipients should be advised that data do not
indicate that the vaccine will have any therapeutic effect
on existing HPV infection, cervical lesions, or genital
warts
• Vaccination can provide protection against infection with
vaccine HPV types not already acquired
If a teen or young woman is already sexually
active, or infected with HPV…
No therapeutic effect demonstrated on alreadypresent HPV infection or associated disease
However, vaccine still recommended – can
protect against other sub-types of virus, or reinfection
HPV Vaccine
• Both vaccines (HPV4 and HPV2) – administered as a
series of 3 intramuscular injections over a 6-month period
at 0, 1-2, and 6 months
• Costs range: $120 - $150 per dose (HPV 2 may be slightly
less expensive)
• Covered by Vaccines for Children Program
• Most insurance plans and managed care plans cover
recommended vaccines
• No change in Pap smear recommendations
Vaccine Scheduling Issues
What happens if the teen is late for the second
and/or third vaccine – do you restart the
series?
–Do not restart - recommendations similar to
those for other childhood vaccines
–Resume vaccination when teen re-presents
for care
Vaccine Scheduling Issues
What is the minimal interval allowable between
injections – can you give the shots earlier if you
worry that the teen is poorly adherent to
appointment visits?
–Minimal interval between injection 1 and 2 is four
weeks
–Minimal interval between injection 2 and 3 is
12 weeks and between 1 and 3 is 24 weeks
Safety and Side Effects of Vaccine
• In clinical trials- adverse events similar in
vaccine and placebo groups (HPV4)
– Headache (28%)
– Dizziness (11%)
– Syncope (11%)
– Fever (13%)
– Nausea (7%)
– Injection site pain (2.2%)- higher in injection group
• Similar profile for HPV2, more injection site
symptoms
FDA.gov
Slade et al, JAMA 2009
Einstein et al. Hum Vaccines 2009
VAERS (Vaccine Adverse Events Reporting System)
associated with HPV4, through 12/08:
•
54 reports / 100,000 doses distributed (12,242 reports)
•
Distribution of adverse effects per 100,000 doses:
–
–
–
–
–
–
–
–
–
–
8.2 cases syncope
7.5 local site reactions
6.8 dizziness
5.0 nausea
4.1 headache
3.1 hypersensitivity
2.6 urticaria
0.2 venous thrombotic event, autoimmune disorder, Guillain-Barre syndrome
0.1 anaphylaxis, death
<0.05 transverse myelitis, pancreatitis, motor neuron disease
•
Most side effects not greater than background rates
•
Disproportionate reporting of syncope and venous thrombosis
Slade et al, JAMA 2009
VAERS associated with HPV4, through 1/2010:
• 28 million doses of Gardasil (HPV4) administered in US
• 15,829 reports
– 92% considered not serious
• Most common – local reaction/soreness at injection site
• Included fainting, headache, nausea, fever
• Falls after fainting potentially serious
– 8% considered serious adverse events
• Guillain Barre (many reports not verified, incidence not greater than
background rate)
• Blood clots – 90% in girls with other risk factors (birth control pills,
smoking, obesity)
• Deaths (49 reported, 28 confirmed – most with other causes)
From cdc.gov/vaccinesafety
HPV Vaccine and Pregnancy
• No studies yet on safety of vaccine during
pregnancy
• Currently, vaccine not recommended for
pregnant women (Category B)
• Those who are inadvertently vaccinated while
pregnant should enroll in prenatal care and
enroll in registry manufacturer is compiling to
collect information on pregnancy outcomes
HPV Vaccine and Males:
• In 10/09, Gardasil® (HPV4) – FDA approved for use in
males
• ACIP then issued provisional permissive recommendation
for vaccination of males
• HPV4 can be administered to males 9-26 to prevent
genital warts
• Doctors and clinics can administer Gardasil to males at
their discretion (optional vs routine vaccination)
• Estimate that there are 250,000 new cases of genital warts
per year in US men
HPV Vaccine and Males:
• CDC in process of examining efficacy of vaccine in
preventing HPV-related male cancers
• Vaccine efficacy data against anal pre-cancers among men
who have sex with men presented 2/10 to ACIP
• Overall efficacy of HPV4 - 75% against AIN 2 or worse from
HPV types 6,11,16,18
• Efficacy against AIN 2/3 from HPV 16/18 is 87%
• New evidence that HPV infection may increase acquisition
of HIV infection in males in Kenya; vaccination encouraged
AIN- anal intraepithelial neoplasia, data presented to ACIP
J Inf Dis, 2010
HPV Vaccine and Males:
• Vaccine most effective if given prior to sexual contact
• Unclear if vaccination to prevent partner infection is costeffective
• CDC panel recommended covering the costs of Gardasil
for boys ages 9 through 18 who are beneficiaries of the
federal Vaccines for Children program, which pays for
vaccinations for uninsured children, those enrolled in
Medicaid, or who meet other criteria
HPV Vaccine and Adult Women
• Placebo-controlled randomized trial of HPV4 underway
– 38,000 women (ages 24-34, 35-45)
– Excluded women with h/o LEEP, biopsy-proven cervical
HPV, vulva/ vaginal pre-cancers, h/o genital warts
– At enrollment, 1/3 positive for exposure to >1 vaccine type
– So far (>3 yrs): good vaccine efficacy (overall 89%)
against persistent infection, dysplasia, and genital warts
– Efficacy better in younger women
– Cost effectiveness of vaccine decreases as age increases
– FDA decision pending
LEEP- Loop Electrosurgical Excision Procedures
Data – presented to ACIP 2/10
Parental Acceptance of Vaccines
• ~ 35 million US adolescents don't receive all recommended
vaccines despite national recommendations
• Also -unique barriers to acceptance of vaccine targeted
toward preadolescents that prevents a sexually transmitted
infection
• HPV coverage rates:
– Nationally: 37% (25% - private patients) receive 1st vaccine
– Nationally: 11-18% patients complete series
– In NYC: 48% eligible girls- receive 1st vaccine
CDC 2010 National STI Conference
Parental Acceptance
• Studies demonstrate parents have high level of
interest in HPV vaccine; are willing to have their
children vaccinated
• Important factors for parental acceptability
– Vaccine efficacy
– Disease severity
– Physician recommendation
• Physician skills in describing vaccines to
adolescents/preadolescents and their parents and
discussing sexuality – key for acceptance
Zimet GD. J Adolesc Health. 2005;37:S17–S23.
Short MB et al. Curr Opin Pediatr. 2006;18:53–57.
Mays RM et al. Soc Sci Med. 2004;58:1405–1413.
Promoting Administration of HPV Vaccine
• If parent concerned about promoting risky sexual
behavior…
– Note that there are no data that link vaccination with
earlier sexual activity
– Emphasize that vaccine most effective prior to sexual
activity and potential exposure to HPV
– Titers appear higher if vaccinated earlier
• Emphasize:
– Cancer prevention, link between HPV and cervical
cancer
– Universal recommendations
– Efficacy of the vaccine
Need for Consent
• In most states, routine vaccinations can only be
given to children under the age of 18 with parental
consent
• IN NY, HPV vaccine administration requires
parental consent if given to minors, although some
organizations for adolescent reproductive rights
argue legal uncertainty
Should States Mandate HPV Vaccination?
• 2006: Michigan senate enacted legislation to mandate
vaccine for entrance to 6th grade – but legislation not
enacted
• 2007: Texas governor issued order that girls be
vaccinated against HPV; revoked by legislature
• As of February 2010, 17 state have proposed HPVrelated legislation or resolutions
• American Academy of Pediatrics not yet advocating
mandatory HPV vaccination
Summary
• HPV is the most common STI in adolescents and is
directly linked to anogenital warts and cervical cancer
• To date, HPV vaccine is safe and highly efficacious in
preventing precursors to cervical cancer
• Routine vaccination of 11-12 year-old girls is supported
by the CDC, ACIP and AAP, with catch-up for women
through age 26
• Males can now be offered vaccination with Gardasil
• Parents are generally accepting of this vaccine,
especially if counseled correctly