1. 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

2. 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

3. 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

4. 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 year olds
Among women 14-59, overall HPV prevalence – 27%
Almost 40% of sexually active year old girls and 50% of sexually active 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
Bierman et al, NEJM 1998
Dunne et al, JAMA 2007
CDC (MMWR) 2007

5. 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
Approximately

6. 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 %, HPV %)
Screening programs effective where they are well-implemented
Image: CDC.gov

7. 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

8. Cancer Types, Other Than Cervical Cancer, Attributable to HPV
Estimated percentage of cancer cases attributable to HPV
Cancer Type
González Intxaurraga MA et al. Acta Dermatovenerol. 2002;11:1–8. (From Merck)

9. 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

10. Genital Warts
Cincinnati STD/HIV Prevention Training Center, at CDC. gov

11. Not all genital bumps are warts…
Pearly Penile Papules
From CDC.gov

12. 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.

13. 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?

14. 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.

15. 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?

16. 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?

17. 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 years of age
Schedule: 0, 2 and 6 months
Protection demonstrated for at least 5 years

18. 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 (26 by ACIP)
Schedule: 0, 1 and 6 months
Protection demonstrated for at least 6.4 years

19. 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

20. 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

21. 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 $ Cervarix $128.75
Einstein et al. Hum Vaccines 2009
Paavonen et al, Lancet 2009
Medeiros et al, Int J Gynecol Cancer 2009
Bonnanni et al, Vaccine 2009

22. 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 year-old girls
All support catch-up vaccination for females 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

23. 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

24. If a teen or young woman is already sexually active, or infected with HPV…
No therapeutic effect demonstrated on already- present HPV infection or associated disease
However, vaccine still recommended – can protect against other sub-types of virus, or re- infection

25. 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

26. 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

27. 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 weeks and between 1 and 3 is 24 weeks

28. 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
Einstein et al. Hum Vaccines 2009
Slade et al, JAMA 2009

29. 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

30. 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

31. 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

32. 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

33. 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

34. HPV Vaccine and Males:
Vaccine most effective if given prior to sexual contact
Unclear if vaccination to prevent partner infection is cost- effective
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

35. 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

36. 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

37. 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.

38. 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

39. 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

40. 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 HPV- related legislation or resolutions
American Academy of Pediatrics not yet advocating mandatory HPV vaccination

41. 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 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