Crisis in US Health Care Failure of Primary HPV related Cancer Prevention. Learning Objectives. 4. Encourage the use the HPV vaccine

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1 Crisis in US Health Care Failure of Primary HPV related Cancer Prevention Daron G. Ferris, MD Professor Department of Obstetrics and Gynecology Georgia Regents University Cancer Center Georgia Regents University Augusta, Georgia USA Learning Objectives After this presentation, if you really listen and stay awake, you might be able to: 1. Discuss the burden of HPV and HPV vaccination data 2. Describe the reasons for and implications of HPV vaccination failure in the US 3. Utilize the 9-valent HPV vaccine 4. Encourage the use the HPV vaccine to prevent potentially lethal anogenital neoplasias Conflicts of Interest Relevant to Presentation Merck GSK

Cervical Cancer 24 year old woman, US Army No Children No Pap test for 4 years Cervical

women have cervical cancer Incidence: 510,000 new cases each year 80% in developing

Southcentral 39,648 Central America 67,078 Asia Southeast Asia Africa 49,025 1,077 South

deaths (288,000 annually) Estimated individual loss of life: 25.

2 Cervical Cancer 24 year old woman, US Army No Children No Pap test for 4 years Cervical Cancer: Worldwide Prevalence, Incidence, and Mortality Estimates Prevalence: 2,274,000 women have cervical cancer Incidence: 510,000 new cases each year 80% in developing countries 14,845 United States/ 64,928 51,266 Canada Europe Eastern Asia 151,297 21,596 Southcentral 39,648 Central America 67,078 Asia Southeast Asia Africa 49,025 1,077 South America Australia/ New Zealand Mortality: Second leading cause of female cancer-related deaths (288,000 annually) Estimated individual loss of life: 25.9 years (Breast Cancer: 19 years, Ovarian Cancer: 17.4 years) HPV Associated Cervical Cancer Rates by State, United States,

Estimated annual burden (new cases) of HPV related disease in the United States

Genital HPV Incidence and Prevalence HPV peak prevalence age 15-25 years HPV presence

presence after age 40 is likely persistent and expressed Persistence of oncogenic HPV

Vaginal HPV Cervical Cancer HPV Risk Factors Age at first intercourse Number of sexual

co-existing microorganisms Human Touching others Infection From Time of First Sexual

3 Estimated annual burden (new cases) of HPV related disease in the United States genital warts 1 million. Genital HPV Incidence and Prevalence HPV peak prevalence age years HPV presence declines with age Approximately 80% of people will contract HPV (ubiquitous) HPV presence after age 40 is likely persistent and expressed Persistence of oncogenic HPV is a major risk factor for cancer Most infections latent or subclinical Subclinical Vaginal HPV Cervical Cancer HPV Risk Factors Age at first intercourse Number of sexual partners Tobacco use Oral contraceptive pills Dietary factors Immunosuppression Other co-existing microorganisms Human Touching others Infection From Time of First Sexual Intercourse Cumulative Incidence of HPV Infection Months Since First Intercourse HIV+ with HSV and HPV

Biology of HPV Small double stranded DNA virus Over 100 types identified;

L1 and L2 are capsid proteins E6 and E7 are the oncogenic gene products Bind p53

E6 E6AP DNA Damage p53 Ionizing radiation UV irradiation E6 mutagens p21 cyclin

Genes MN S DNA synthesis Cell cycle progression G2 Blood Vessel Proliferation

HPV- Infected Normal Cervix Cervix Pre Cancer Cervical Cancer Infection

Regulation Resistance to Apoptosis Increased Genetic Instability Cell

Upregulation of Viral Oncogenes Increased Chromosomal Abnormalities Activation of

4 Biology of HPV Small double stranded DNA virus Over 100 types identified; approximately 30 types infect the genital tract Divided into late and early genes L1 and L2 are capsid proteins E6 and E7 are the oncogenic gene products Bind p53 and retinoblastoma proteins (tumor suppressor gene products) Prevents Apoptosis E6 E6AP DNA Damage p53 Ionizing radiation UV irradiation E6 mutagens p21 cyclin cdk Increased Cell Proliferation E7 E2F Rb E2F Transactivation of G1 Cellular Genes MN S DNA synthesis Cell cycle progression G2 Blood Vessel Proliferation Natural History of Cervical Carcinogenesis HPV HPV Persistence HPV Integration HPV- Infected Normal Cervix Cervix Pre Cancer Cervical Cancer Infection Progression Invasion Clearance CIN 1 Regression CIN 3 Loss of Cell Cycle Regulation Resistance to Apoptosis Increased Genetic Instability Cell Proliferation Sequestration of Tumor Suppressor Proteins HPV Integration Upregulation of Viral Oncogenes Increased Chromosomal Abnormalities Activation of Telomerase Ferris, DG, et al. Modern Colposcopy, Textbook and Atlas HPV Acquisition Ferris, DG, et al. Modern Colposcopy, Textbook and Atlas

5 HPV Productive Expression Condylomata in a drug abuser Cervical condyloma in 15 year old girl Outlet obstruction from Condyloma Ferris, DG, et al. Modern Colposcopy, Textbook and Atlas 28 yo GRU patient HIV+ Buschke Lowenstein 19 Sept yo GRU patient HIV+ Buschke Lowenstein Recurrence Wife HIV+, Hx CIN 3 2 conizations 2014

6 Genital HPV Epithelial Tropism- HIV positive woman Cervical Intraepithelial Neoplasia 3 Vaginal Condyloma Vulvar Condyloma Ferris, DG, et al. Modern Colposcopy, Textbook and Atlas Perianal intraepithelial neoplasia 3 HPV Persistence Ferris, DG, et al. Modern Colposcopy, Textbook and Atlas HPV Infection in Men Penile Warts Penile Cancer Penile Pre-cancer Anal Warts Anal Pre-cancer Anal Cancer Recurrent Respiratory Papillomatosis Bronchiolar HPV Head and Neck Cancer

Cancer Head and Neck Cancer Vulvar warts

development of cervical lesion - 22 to 25

Guanacaste study Normal Cervix CIN3 Total

9 Million Follow up of Abnormal Pap Tests

7 HPV Infection in Women Cervical Warts Cervical Pre-cancer Cervical Cancer Vaginal Warts Vaginal Pre-cancer Vaginal Cancer Oral Warts Anal warts Anal Pre-cancer Anal Cancer Head and Neck Cancer Vulvar warts Vulvar Pre-cancer Vulvar Cancer Rapid development of cervical lesion - 22 to 25 yr old woman - Normal to CIN 3 - NCI Guanacaste study Normal Cervix CIN3 Total Cost Burden of HPV in the United States (2000) General Population Persons Years of Age $ 3.6 Billion $ Million $ Million $ 2.7 Billion $ Million $ Million Follow up of Abnormal Pap Tests and Treatment of CIN Treatment of Invasive Cervical Cancer Treatment of External Anogenital Warts 1. Chesson HW, Blandford JM, Gift TL, Tao G, Irwin KL. Perspect Sex Reprod Health. 2004;36:11 19.

8 Preventable situation So you mean if my daughter had received the Gardasil shots, she probably would not be having this surgery today? Mother of 21 yo woman - GRU Cancer Center August 2013 CIN3 Loop Conization HPV Infection Genital Warts Cervical Pre-cancer Cervical Cancer Before 2006 But this is Secondary Cervical Cancer Prevention fraught with problems Ferris, DG, et al. Modern Colposcopy, Textbook and Atlas Primary HPV-related Cancer Prevention Anogenital Pre-cancer Anogenital Cancer HPV L 1 VLP Vaccine Anogenital Warts RRP HPV Infection

The most effective way to prevent HPV related cancer Orphan girls from the Sacred Valley of Peru receive HPV vaccine

16, 18 Types 16, 18 Females: Anal, cervical, vaginal and vulvar precancer and cancer; Genital warts Males: Anal

in males Pregnancy Hypersensitivity to yeast Contraindications Pregnancy Hypersensitivity to latex (latex only

9 The most effective way to prevent HPV related cancer Orphan girls from the Sacred Valley of Peru receive HPV vaccine Quadrivalent/HPV4 (Gardasil) HPV Vaccines Name Bivalent/HPV2 (Cervarix) Merck Manufacturer GlaxoSmithKline 6, 11, 16, 18 Types 16, 18 Females: Anal, cervical, vaginal and vulvar precancer and cancer; Genital warts Males: Anal precancer and cancer; Genital warts Indications Females: Cervical precancer and cancer Males: Not approved for use in males Pregnancy Hypersensitivity to yeast Contraindications Pregnancy Hypersensitivity to latex (latex only contained in pre filled syringes, not single dose vials) 3 dose series: 0, 2, 6 months Schedule (IM) 3 dose series: 0, 1, 6 months

The Washington Post December 28, 2013 Brady Dennis Five pressing health priorities in 2014 As head of the Centers for Disease Control and Prevention, Thomas Frieden oversees an agency with the

From fighting foodborne illness outbreaks and influenza epidemics to educating people about the risks of obesity and smoking, the CDC s work touches every corner of public health.

10 The Washington Post December 28, 2013 Brady Dennis Five pressing health priorities in 2014 As head of the Centers for Disease Control and Prevention, Thomas Frieden oversees an agency with the sprawling mission of reining in diseases in the United States and across the globe. From fighting foodborne illness outbreaks and influenza epidemics to educating people about the risks of obesity and smoking, the CDC s work touches every corner of public health. Given that broad range of responsibilities, we asked Frieden about what he considers the top public health priorities for Below are five areas he said deserve special attention, and why each is important. His comments have been edited for length:. 1. Increasing human papilloma virus (HPV) vaccinations. The bottom line here this is an anti cancer vaccine. Usually, when we introduce a new vaccine, we expect the uptake will be gradual and will increase by about 10 percent per year. HPV has stalled. We re at 30 percent, and it didn t increase at all last year. The country of Rwanda is at 85 percent. If we were at 85 percent, then 4,400 girls alive today would not get cervical cancer in their lifetimes. But because we re not, they will. International uptake HPV vaccine 3 doses Australia UK Canada Netherlands USA Brotherton, Lancet 2011; Cuzick BJC 2010; Ogilvie et al., 2010; Marc et al., 2010, NIS Teen 2011

Estimated vaccination coverage with selected vaccines and doses among adolescents aged 13 17

Vaccination Coverage if Missed Opportunities were Eliminated: Adolescents 13 17 Years, NIS Teen

encounter when some but not all ACIP recommended vaccines are given HPV 1: receipt of at least

gov/vaccines/stats surv/nis/nis 2011 released.

11 Estimated vaccination coverage with selected vaccines and doses among adolescents aged years, by survey year National Immunization Survey Teen, US, Actual and Achievable Vaccination Coverage if Missed Opportunities were Eliminated: Adolescents Years, NIS Teen 2011 Among girls unvaccinated for HPV, 78% had a missed opportunity Missed opportunity: encounter when some but not all ACIP recommended vaccines are given HPV 1: receipt of at least one dose of HPV 2011 NIS Teen available at surv/nis/nis 2011 released.htm#nisteen HPV Vaccine Acceptance Problem Vaccine Developed Vaccine Available Vaccine Administered Disease Incidence Decreased Individual Issues Family/ Parent Issues Cultural Issues Provider Issues

12 Opportunities for Improvement: Health Care Provider Issues Knowledge of vaccines Administrative and organizational strategies Strong recommendations to patients Nichol KL. Cleve Clin J Med. 2006;73: FUTURE I Quadrivalent HPV Vaccine Trial Median follow-up of 36 months 5455 women randomized Aged 16 to 24 years Not pregnant No prior abnormal Pap smears No more than 4 male sex partners Virgins were enrolled if seeking contraception Allergy to vaccine components HPV 6/11/16/18 L1 20/40/40/20mg/doses VLP 20/40/40/20 µg/doses (PP n=2723) IM injections Day 0 Month 2 Month 6 Placebo 225 Placebo µg aluminum adjuvant/dose 225 µg aluminum (PP adjuvant/dose n=2732) Primary end points HPV 6-, 11-, 16-, 18-related CIN/AIS/cancer Genital warts Vulvovaginal neoplasia Liquid-based cytology External genitalia/cervical HPV tests HPV serology Colposcopy: algorithm-based Pathology panel Follow-up every 6 months for 48 months Garland SM et al. N Engl J Med 2007;356: Per Protocol and MITT Vaccine Efficacy Future I Quadrivalent HPV Vaccine Trial Vaccine Placebo Per Protocol n Cases Rate n Cases Rate Efficacy 95% CI > CIN % (94-100) Genital warts, 2261 VAIN/VIN MITT % (94-100) > CIN < % (92-100) Genital warts, VAIN/VIN % (87-99) PP = 3 doses, Sero neg D1, HPV DNA neg to respective HPV types D1 to Mo 7 MITT = >1 dose, HPV DNA neg to respective HPV types D1 Garland SM et al. N Engl J Med 2007;356: Rate = Cases/100 subject years at risk

FUTURE II Quadrivalent HPV Vaccine Trial Median follow-up of 36 months 12,167 women randomized Aged 15 to 26 years Not pregnant No prior abnormal Pap smears No more than 4 male sex partners Virgins

(PP n=6080) Primary end point HPV 6-, 11-, 16-, 18-related CIN/AIS/cancer Liquid-based cytology External genitalia/cervical HPV tests HPV serology Colposcopy: algorithm-based Pathology panel

13 FUTURE II Quadrivalent HPV Vaccine Trial Median follow-up of 36 months 12,167 women randomized Aged 15 to 26 years Not pregnant No prior abnormal Pap smears No more than 4 male sex partners Virgins were enrolled if seeking contraception Allergy to vaccine components HPV 6/11/16/18 L1 VLP 20/40/40/20 µg/doses (PP n=6087) IM injections Day 0 Month 2 Month 6 Placebo 225 µg aluminum adjuvant/dose (PP n=6080) Primary end point HPV 6-, 11-, 16-, 18-related CIN/AIS/cancer Liquid-based cytology External genitalia/cervical HPV tests HPV serology Colposcopy: algorithm-based Pathology panel Follow-up every 12 months for 48 months Future II Study group, et al. N Engl J Med 2007;356: FUTURE II: Quadrivalent HPV Vaccine: Prevention of CIN 2/3 and AIS Per Protocol 98% efficacy Modified ITT 95% efficacy Number of cases P< P< n= n= Placebo Future II Study group, et al. N Engl J Med 2007;356: Vaccine FDA Indications for Quadrivalent HPV Vaccine

Safety Vaccine related Adverse Experiences Injection site (1

(Aluminum) (N=3,470) Placebo (Saline) (N=320) Pain 83.9% 75.

14 Safety Vaccine related Adverse Experiences Injection site (1 to 5 days post-vaccination) HPV Vaccine (N=5,088) Placebo (Aluminum) (N=3,470) Placebo (Saline) (N=320) Pain 83.9% 75.4% 48.6% Swelling 25.4% 15.8% 7.3% Erythema 24.6% 18.4% 12.1% Pruritus 3.1% 2.8% 0.6% Systemic adverse event (1 to 15 days postvaccination) GARDASIL (N=5,088) Placebo (N=3,790) Fever 10.3% 8.6%

9 valent HPV vaccine (Gardasil 9) 9 valent HPV vaccine includes five more oncogenic HPV types (31, 33, 45, 52, 58) in addition to the four original HPV types (6, 11, 16, 18) in Gardasil Phase III

15 9 valent HPV vaccine (Gardasil 9) 9 valent HPV vaccine includes five more oncogenic HPV types (31, 33, 45, 52, 58) in addition to the four original HPV types (6, 11, 16, 18) in Gardasil Phase III study evaluated the efficacy, safety and immunogenicity of 9 V (n=7,099) compared with Gardasil (n=7,105) in year old females Primary efficacy received all three doses of vaccine, not infected with relevant HPV types at enrollment and remained free of infection with relevant HPV types through Month 7 (per protocol population) 96.7 % reduction (95% CI; 80.9, 99.8) in the combined incidence of highgrade cervical/vulvar/vaginal intraepithelial neoplasia caused by HPV types 31, 33, 45, 52, 58 (1 case in 9 V vs. 30 cases in Gardasil) 97.1 % reduction (95% CI; 91.8, 99.2) in the combined incidence of cervical/vulvar/vaginal neoplasia of any grade caused by HPV types 31, 33, 45, 52, 58 (3 cases in 9 V vs. 103 cases in Gardasil) Immunogenicity 9 valent vaccine GMTs and seroconversion rates were non inferior to Gardasil Safety profile similar (90.8% 9 V vs 85.1% Gardasil injection site AEs) Joura E, et al Eurogin 2013 Most important factor in parent s decision to vaccinate their children Health Care Provider Recommendation JAMA Pediatrics 2014 Simple Message Strongly recommend HPV vaccine Almost everyone gets HPV HPV causes cancers in women and men HPV vaccine is for cancer prevention

Realization that you will die from a vaccine

initial impact of Cervical Cancer Thanks Please

16 Realization that you will die from a vaccine preventable disease The face of Cervical Cancer 23 year old woman with 5 year old boy She died 6 months after day of diagnosis (photos above) The initial impact of Cervical Cancer Thanks Please prevent cancer! VACCINATE Gracias dferris@gru.edu Preguntas? Questions?

An update on the Human Papillomavirus Vaccines. I have no financial conflicts of interest. Case 1. Objectives 10/26/2016

An update on the Human Papillomavirus Vaccines Karen Smith-McCune Professor, UCSF Department of Obstetrics, Gynecology and Reproductive Sciences John Kerner Endowed Chair I have no financial conflicts