Human Papillomavirus and HPV Vaccine Charlene Graves, M.D. Medical Director, Immunization Program, ISDH Chgraves@isdh.in.gov (317) 233-7164 October 2007

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

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)

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

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

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

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.

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

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

Impact of HPV in Adolescents & Young Adults in the U.S. 74% of infections in 15-24 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

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

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

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

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

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.

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

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.

Natural History - HPV Clearance Women 15-25 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)

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

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

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

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

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

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

ACIP Recommendations Routine immunization of females 11-12 years of age “Catch-up” for females 13-26 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

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

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

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)

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 15-25 year olds Prevented Pap smear changes in 68%

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

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

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

Questions?