1. Human Papillomavirus and HPV Vaccine
Charlene Graves, M.D.
Medical Director, Immunization Program, ISDH
(317)
October 2007

2. HPV (Human Papillomavirus) Disease
Infection
Cancer
Virus is species-specific
HPV types are usually body site-specific
Skin-to-skin transmission of infection

3. HPV – The Most Common STI
In the U.S., 6.2 million people are newly infected each year
Estimated that 80%+ of sexually active women will have acquired genital HPV by age 50
What about men? Heterosexual men – prevalence of HPV infection was 20%+ (influence of sampling site and how specimens are collected)

4. HPV Background Small DNA virus
Inserts into human DNA by process termed INTEGRATION
HPV on skin and mucosal surfaces
Not in body fluids (different from Hepatitis B virus)
RESIDENTIAL infection – basal epithelium of skin, inactive there. Some trigger then promotes viral replication, ascends to top layer

5. Immunology of HPV
Shielded from the host immune response because resides in the skin epithelium
Not all infected persons have antibodies
One study showed that 54%-69% of infected women had antibodies

6. HPV Characteristics > 100 types identified 40+ are anogenital
Oncogenic types
16, 18: 70% of cervic. CA
Non-oncogenic types
6, 11 for genital warts
90% of genital warts

7. Laboratory Testing for HPV
Cannot culture for HPV
DNA assays vary in sensitivity and type specificity
Digene Hybrid Capture 2 (HC2) High-Risk DNA Test approved by the FDA for use in women
Serologies only for research – VLP-based enzyme immunoassays.

8. HPV DNA Testing - NOT A. for men
B. to check for HPV in genital warts/other STIs
C. to check for HPV in partners of B
D. to check for HPV in partners of women with pre-cancerous lesions
E. to check for HPV in pregnant women

9. Oncogenic Types re Cervical Cancer
Most significant risk factor in etiology of cervical cancer
Prevalence of HPV DNA in cervical cancers worldwide = 99.7%
Specific oncogenic HPV types detected in 63%-97% of invasive cervical cancer cases worldwide
Types 6 & ll in 80% of anal cancers and 40% of vulvar cancers

10. Impact of HPV in Adolescents & Young Adults in the U.S.
74% of infections in year olds (1 in 4 of all in that age group)
Lifetime risk for sexually active men and women is at least 50%
Estimated lifetime risk for genital warts is about 10%
Other anogenital cancers
Also oropharyngeal cancers

11. ACS & ACOG Guidelines for Cervical Cancer Screening in Adolescents
Should begin about 3 years after onset of intercourse but no later than 21 years of age
May start earlier - based on time course in progression of CIN and unpredictable F/U in young women
Pap smear screening each year (or every 2 years if liquid based) to age 30

12. Burden of Disease – Cervical Cancer in the U.S.
50%+ of sexually active persons will acquire a genital HPV in their lifetime
U.S. – about 12,200 cases and 4,100 deaths in 2003
U.S. – 300,000 cases of high-grade dysplasia
Indiana – about 1,000 women newly diagnosed, 300+ deaths

13. Cervical Cancer - Worldwide
2nd leading cause of female cancer-related deaths (1 in 20)
288,000 deaths each year
510,000 NEW cases each year

14. U.S. - Progress in Cervical Cancer
75% decline in rates since Pap testing introduced in U.S.
83% of women had Pap test within the past 3 years
Over 50% of cervical CA cases in women who rarely/never have Pap test
Projected cases for 2006: 9,700 new, 3,700 deaths

15. Invasive Cervical Cancer
Natural History of HPV Infection and Potential Progression to Cervical Cancer1
0–1 Year
0–5 Years
1–20 Years
Initial HPV Infection
Continuing Infection
CIN 2/3
Invasive Cervical Cancer
CIN 1
Cleared HPV Infection
1. Pinto AP, Crum CP. Clin Obstet Gynecol. 2000;43:352–362.

16. HPV Transmission and Acquisition
Nonsexual routes
Rare mother to newborn
Hypothesized –fomites, clothing
Sexual contact
Through sexual intercourse
Genital-genital, manual-genital, oral-genital not as common modes of transmission
Condom use may reduce risk, but it is not fully protective

17. Study of female college students (N=603)
Infection From Time of First Sexual Intercourse
Study of female college students (N=603)
Months Since First Intercourse
Cumulative Incidence of
HPV Infection
From Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226, by permission of Oxford University Press.

18. Natural History - HPV Clearance
Women years of age – 80% of HPV infections are transient
Study of 608 college women – 70% of new infections cleared within 1 year, 90% within 2 years
Certain HPV types are more likely to persist (e.g., types 16 & 18)

19. Treatment of HPV Infection
Cannot be DIRECTLY treated
Only HPV-associated lesions can be treated
Options: cryotherapy, electrocautery, laser therapy, and surgical excision
Genital warts – topical agents
Treatment might reduce infectiousness

20. HPV Persistence
Persistent infection: Detection of same HPV type 2 or more times over several months to 1 year
Crucial for development of cervical pre-cancer and cancer
Other factors
Age >/= 30 years
Infection with multiple HPV types
Immune suppression

21. HPV Vaccine Strategies
Vaccinate before onset of sexual activity
Vaccinate both males and females
Immune response strongest at youngest ages
Unknowns:
What antibody titers are protective
How long protection will last
Getting vaccine to women rarely tested for cervical cancer

22. Sexual Activity Factors re HPV
Infections acquired soon after sexual activity begins
16 months later – 40% infected
YBRSS (2003) sexual activity:
7% by age 13
1/3 by 9th grade
2/3 by high school graduation

23. Gardisil (Merck) FDA licensed on June 8, 2006
Quadrivalent vaccine (types 6, 11, 16, 18). $300-$500 cost for series
Licensed for females 9–26 years
Nearly 100% efficacy for warts, Pap changes, infection
Intramuscular injections –at starting age, then 2 months & 6 months later

24. More on Gardisil re ACIP
Review of data from clinical trials – 11,000 females age 9-26 years
Review of cost effectiveness studies
Plans for post-licensure safety monitoring
ACIP recommendations for use of vaccine as of June 29, 2006

25. ACIP Recommendations
Routine immunization of females years of age
“Catch-up” for females years not previously vaccinated
Ideally, vaccinate before sexual activity
Pap test, HPV DNA, HPV antibody NOT recommended before vaccination
No change in cervical cancer screening recommendations

26. Vaccine Safety No serious adverse events in clinical trials
VAERS – local reactions, fainting
Guillain-Barre Syndrome – 3 reports, not out of proportion
5 million doses distributed as of June 2007

27. Vaccine Unknowns Immune memory appears strong Need for booster shots?
Cross-reactivity to protect against other HPV types
Safety in pregnancy – registry maintained by Merck

28. Special Situations: Already HPV Infected
Vaccination still of some benefit to prevent acquisition of some HPV types
If known genital warts, abnormal Pap or HPV DNA +, vaccination recommended
Vaccine will NOT protect from disease related to HPV types involved in current infection
Vaccine will not affect existing cervical lesions or infections (it is not therapeutic)

29. Cervarix (GSK) Not yet FDA licensed – submit late 2006
IM dosing -at starting age, then 1 and 6 months later
Bivalent vaccine (types 16, 18)
Tested in year olds
Prevented Pap smear changes in 68%

31. Indiana Legislation re HPV
Senate Bill 327 of 2007 introduced by Senator Connie Lawson
Initially, mandated vaccine for all 6th grade girls
Revised to mandate education for all 6th grade girls
ISDH role – develop educational information

32. Indiana Legislation, continued
Also a parent response form to be returned to the school (starts 2008)
Responses available:
Plan to have vaccinated
Do not plan to have vaccinated
Choose not to answer the question
In 2008, aggregate reporting of data to ISDH

33. Vaccine Availability Vaccines for Children (VFC)
Private health insurance
Title X Clinics
If had been mandated for all 6th grade girls, $2.67 million of state funding would have been needed

34. Questions?