Pediatrics Grand Rounds 12 February 2010
University of Texas Health Science Center at San Antonio
Human Papillomavirus (HPV) Human Papillomavirus (HPV) Disease and Prevention Pediatric Grand Rounds San Antonio 12 February 2010 Nonenveloped encapsulated doubledouble-stranded small DNA virus
33
Pediatrics Grand Rounds 12 February 2010
¾ Lifetime risk
for sexually active men and women is > 50% ¾ By 50 years of age > 80% of women will have acquired genital HPV infection ¾ Estimated annual incidence: ~6 million ¾ Estimated prevalence: ~20 million ¾ In sexually active individuals 15– 15–24 years of age ~9 million are currently infected
Genital HPV Infection Risk Factors RISK FACTOR Young age (20(20-29 years)
WOMEN MEN
Number of sexual partners (lifetime) Uncircumcised (man/male partner) Early age of sexual dé début Partner sexual behavior Smoking Oral contraceptive use
9 9 9 9 9 9 9
9 9 9
Risk of Acquiring HPV After First Intercourse in Female Adolescents 70
Cumulative risk of cervical HPV infection in female adolescents with only 1 sexual partner
60 Cumulative Risk of HPV (%)
Genital HPV Prevalence and Incidence in U.S.A.
University of Texas Health Science Center at San Antonio
60% INFECTED BY 5-YEARS
50 40 30 20
35% INFECTED BY 18-MONTHS
10 0 0
12
24
36
48
60
Time Since First Intercourse (Months) From Collins S, Mazloomzadeh S, Winter H, et al. High incidence of cervical human papillomavirus infection in women during their first sexual relationship. Br J Obstet Gynaecol. 2002;109:96–98. Reprinted with the permission of the Royal College of Obstetricians and Gynaecologists.
Pediatrics Grand Rounds 12 February 2010
University of Texas Health Science Center at San Antonio
2008 Nobel Prize in Medicine
Harald zur Hausen, DSc, MD [Professor Emeritus] Recent Chairman and Scientific Director German Cancer Research Centre Heidelberg, Germany
Why Are We Concerned About HPV?
Most Common HPV Types in Cervical Cancer: Cumulative Prevalence (Squamous Cell Carcinoma)1 HPV 16
Because HPV is…
HPV 18
HPV 45
HPV 31
HPV 33
54.0
HPV 16
…a necessary causative agent in cervical cancer1 67.7
HPV 16+18
One of the most common sexually transmitted infections (STI) in the United States today2
73.1
HPV 16+18+45
76.9
HPV 16+18+45+31 HPV 16+18+45+31+33
80.3 0
1. Bosch FX, Lorincz A, Muñoz N, Meijer CJLM, Shah KV. J Clin Pathol. 2002;55:244−265. 2. Centers for Disease Control and Prevention. Genital HPV Infection Fact Sheet. Rockville, Md: CDC National Prevention Information Network; 2004.
20
40 60 Cumulative Prevalence (%)
1. Bosch FX, de Sanjosé S. J Natl Cancer Inst Monogr. 2003;31:3–13.
80
100
Pediatrics Grand Rounds 12 February 2010
University of Texas Health Science Center at San Antonio
Risk of Cervical Lesions and Cancer in Women Exposed to HPV at a Young Age1 Relative risks for CIN and invasive cancer increase with decreasing age of first sexual intercourse
Relative Risk Estimates*
7 6 5 4
Age at First Intercourse (Years) ≥23 or Never 18–22 ~6-FOLD INCREASE ≤17
~3-FOLD INCREASE
3 2 1 0 CIN (n=206)
Invasive Cervical Cancer (n=327)
*Mantle-Haenszel estimates adjusted for age only 1. La Vecchia C, Franceschi S, DeCarli A, et al. Cancer. 1986;58:935–941.
Pediatrics Grand Rounds 12 February 2010
University of Texas Health Science Center at San Antonio
Cervical Cancer Mortality in the US and Prevalence of High-Risk HPV 30
Peak HPV infection occurs in young adults
Prevalence of High-Risk HPV1,* Cervical cancer deaths2,†
25 Cervical cancer deaths peak in midlife
330,000 new cases of highhigh-grade cervical dysplasia2
15 10
1 million new cases of genital warts3
5 0 15-19
20–24
25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
Age Group, Years *Population-based prevalence of cervicovaginal HPV in the United States based on self-collected vaginal swabs among females participating in the National Health and Nutrition Examination Survey (NHANES) 2003-2004.1 †Age
3,700 estimated deaths1 9,710 new cases of cervical cancer1
20 Percentage
Estimated Annual Burden of HPV-Related Diagnoses in the United States, 2006
distribution of all cervical cancer deaths between 1935 and 2000 in the United States.2
1. Adapted from Dunne EF et al. JAMA. 2007;297:813–819. 2. Adapted with permission from Insinga RP. Womens Health Issues. 2006;16:236–242.
1.4 million new cases of lowlow-grade cervical dysplasia (CIN 1)2 CIN = cervical intraepithelial neoplasia. 1. American Cancer Society. Cancer Facts and Figures 2006. Atlanta, Ga: American Cancer Society; 2006:4. 2. Schiffman M et al. Arch Pathol Lab Med. 2003;127:946–949. 3. Fleischer AB et al. Sex Transm Dis. 2001;28:643–647.
Pediatrics Grand Rounds 12 February 2010
University of Texas Health Science Center at San Antonio
Why Are We Concerned About HPV?
Genital Warts: An Important Healthcare Issue Estimated number of new cases per year in the United States1:
1 million
Because HPV is… A necessary causative agent in cervical cancer1 …one of the most common sexually transmitted infections (STI) in the United States today2
Estimated number of sexually active adults with clinically visible genital warts2:
1 in 100 Estimated number of people who will develop genital warts in their lifetime3:
1 in 10 Estimates include both males and females 1. Bosch FX, Lorincz A, Muñoz N, Meijer CJLM, Shah KV. J Clin Pathol. 2002;55:244−265. 2. Centers for Disease Control and Prevention. Genital HPV Infection Fact Sheet. Rockville, Md: CDC National Prevention Information Network; 2004.
New Claims Per 100,000 Person-Years at Risk
Incidence of New Claims for Genital Warts in Young Adults 350
Female Male
300 250 200 150 100 50 0 15–19
20–29
30–39
40–49
50–59
Age (Years) From Koshiol JE, St. Laurent SA, Pimeta JM. Rate and predictors of new genital warts claims and genital warts-related healthcare utilization among privately insured patients in the United States Sex Transm Dis. 2004;31:748–752. Reprinted with permission from Lippincott Williams and Wilkins.
1. Fleischer AB et al. Sex Transm Dis. 2001;28:643–647. 2. Koutsky L. Am J Med. 1997;102:3–8. 3. Franco EL et al. In: Franco EL, Monsonego J, eds. New Developments in Cervical Screening and Prevention. Blackwell Science; 1997:14–22.
Pediatrics Grand Rounds 12 February 2010
University of Texas Health Science Center at San Antonio
ACIP Recommendations [MMWR 2007. 56(RR56(RR-2):12):1-24 (23 March 2007)] ¾ Routine immunization of girls 1111-12 years old ¾ CatchCatch-up vaccination for unun-/incompletely
immunized females 1313-26 years old ¾ Second dose 22-months and third dose 66months following first dose ¾ Concomitant immunizations at same visit ¾ No change in current cervical cancer screening recommendations ¾ Can immunize women with: abnormal Pap smear; lactation; immunodeficiency
ACIP Provisional Recommendations [Females and Males/1 December 2009]
Cervical Cancer Mortality in the US and Prevalence of High-Risk HPV 30
Peak HPV infection occurs in young adults
Prevalence of High-Risk HPV1,* Cervical cancer deaths2,†
25 Before This Occurs Percentage
20
To Reduce This
Cervical cancer deaths peak in midlife
Vaccination with the quadrivalent HPV vaccine for prevention of cervical cancers and precancers, and genital warts
15 10
The quadrivalent vaccine has also been demonstrated to protect against vulvar and vaginal cancers and precancers
Immunize Here 5 11-12
0 15-19
20–24
25–29
Vaccination with either the bivalent HPV vaccine or the quadrivalent vaccine for prevention of cervical cancers and precancers
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
Age Group, Years *Population-based prevalence of cervicovaginal HPV in the United States based on self-collected vaginal swabs among females participating in the National Health and Nutrition Examination Survey (NHANES) 2003-2004.1 †
Age distribution of all cervical cancer deaths between 1935 and 2000 in the United States.2
1. Adapted from Dunne EF et al. JAMA. 2007;297:813–819. 2. Adapted with permission from Insinga RP. Womens Health Issues. 2006;16:236–242.
The 33-dose series of quadrivalent HPV vaccine may be given to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts Ideally, vaccine should be administered before potential exposure exposure to HPV through sexual contact
Pediatrics Grand Rounds 12 February 2010
University of Texas Health Science Center at San Antonio
GARDASIL® (Quadrivalent Human Papillomavirus [HPV Types 6, 11, 16, 18] Recombinant Vaccine)
GARDASIL® (Quadrivalent Human Papillomavirus [HPV Types 6, 11, 16, 18] Recombinant Vaccine)
GARDASIL®: The First Cervical Cancer Vaccine in the United States
• VLPs are produced in Saccharomyces cerevisiae — The L1 proteins self-assemble into VLPs. — Purified VLPs are adsorbed on aluminium-containing adjuvant. — The adjuvant is amorphous aluminum hydroxyphosphate sulfate (225 µg per dose).
Ph II–P005 Proof of Principle 16- to 23-year-old women
5,000 3,000 Serum cRIA GMT, mMU/mL
• Quadrivalent human papillomavirus 6/11/16/18 L1 virus-like particle (VLP) vaccine
GARDASIL® Maintained Type-Specific, Neutralizing Antibody Responses1 GARDASIL (Per Protocol) Per-Protocol Placebo
1,000 The duration of protection of GARDASIL is unknown beyond 48 months.
100
10 Vaccination
• Each 0.5-mL dose contains HPV Types 6/11/16/18 (20/40/40/20 µg L1 protein, respectively)
1 0
7
684
684
12 663
18 649
30 609
42 533
48 481
680
680
661
638
604
532
489
Months Since Enrollment Number of Subjects
*Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL. GMT = Geometric mean titer; cRIA = Competitive radioimmunoassay. 1. Adapted from Mao C, Koutsky LA, Ault KA, et al. Obstet Gynecol. 2006;107:18–27.
GARDASIL® (Quadrivalent Human Papillomavirus [HPV Types 6, 11, 16, 18] Recombinant Vaccine)
Populations Used to Evaluate GARDASIL® Subject age: 16-26 years old Sero (+) and/or PCR (+) to the relevant vaccine HPV type at day 1
PPE Population Excluded
MITTMITT-3 [All]
Sero ((-) and/or PCR ((-) to the Relevant Vaccine HPV Type at Day 1
Included
Included
Included
Sero (+) and/or PCR (+) to the Relevant Vaccine HPV Type at Day 1
EXCLUDED
INCLUDED
PCR (+) to the Relevant Vaccine HPV Type During the Vaccination Phase
Included
Included
Day 1 (+) to nonnon-vaccine HPV type
Included
Included
Day 1 Pap ≥ASCUS
Included
Included
Protocol Violators/< 3 doses
Included
Included
After Day 30
After Day 30
Excluded
Included
Protocol violators
Excluded
Included
Case counting
PPE = Per-protocol efficacy.
General Populations [MITT] Used to Evaluate GARDASIL®1 MITTMITT-2 [Naï [Naïve]
General Population Impact
PCR (+) to the relevant vaccine HPV type during the vaccination phase
