HPV - From Warts to Cancer

12/26/217 HPV Infection Immunizing for Cancer Prevention Paul J Carson, MD, FACP Professor, Dept. of Public Health North Dakota State University Epidemiology and Pathology HPV Genotypes and Their Disease Associations HPV Epidemiology Mucosal/Genital sites of infection Cutaneous sites of infection ~ 8 types 79 million persons infected in U.S. with 14 million new infections per year 5-7% of sexually active adults infected by age 5 High risk (oncogenic) 16, 18, 31, 33, 45, 52, 58, 35, 39, 51, 56, 59, 68 Cervical, anogenital, and OP cancers, CIS and ACIS Low risk (non-oncogenic) 6, 11 Genital warts, Laryngeal papillomas, Low grade cervical dz Common hand and foot warts 9% women will clear by 2 years, 1% will have prolonged infection 45% of men age 18-59 are infected (NHANES 213-14), infxn much more likely to persist Han et al. JAMA Onc 217 Contrast HPV Incidence with Other Common STIs Cumulative Incidence of HPV Infection in College Women After Time from 1 st Intercourse Source: CDC 1

12/26/217 HPV Prevalence Common in Females Prior to Vaccine, Especially in Early 2s Cumulative Incidence of Genital HPV Infection in Male University Students, 23-26 Prevalence, % 6 Low-risk HPV* 5 High-risk HPV* 4 3 2 1 14 19 2 24 25 29 3 39 4 49 5 59 Age National Health and Nutrition Examination Survey, 23-26 HPV Prevalence Among Males Age 18-59: NHANES 213-14 HPV - From Warts to Cancer HPV Prevalence (%) 5 45 4 35 3 25 2 15 1 5 Normal Cervix CIN I CIN II Any HPV High Risk HPV 9v vaccine strain of HPV Oral Oncogenic HPV CIN III CIN III Invasive Cancer Chaturvedi, Cancer Res 215. Han, JAMA Oncol 217. Estimated Average Annual Number of Cancers Attributable to HPV By Anatomic Site - U.S., 28-212 HPV Vaccine - Not Just for Girls 18, 16, 14, 12, 1, 8, 6, 4, 2, 83% males One will get HPV Infection, and will be just as likely to develop a cancer as a female 9v Vaccine Type Non HPV or Non Vaccine Type Viens, MMWR 216. 2

12/26/217 HPV, Oral Cancer, and Men Incidence of HPV(+) vs HPV(-) Tonsillar Cancer in Sweden HPV associated OP 5x > men than women) Appears to be associated with oral sexual behavior and number of lifetime partners 22x Increased Risk for OP Cancer in Men Estimated 7.1 million men with oral oncogenic HPV infection in U.S. 7x HPV-16 Other Oncogenic HPV Chaturvedi, Cancer Res 215. D Souza, JID 29. D Souza, JID 216. Agalliu, JAMA Oncol 216. Estimated Annual Burden of HPV- Related Diagnoses in the United States HPV Will Affect Far More of Your Patients than Meningococcal Infection and Hib Combined Vaginal cancer ~2,2 1,2 4, 35, 38,795 Vulvar cancer Anal cancer ~2,115 1,2 ~6,35 1,2,a 3, 25, Pre-Vaccine Era Annual Incidence Cervical cancer ~12,34 1,2 High-grade cervical dysplasia ~28,5 2,3 Genital warts ~5, 1,, 2,4,a Low-grade cervical dysplasia ~1.1 million 2,3 Case counts for HPV-related diagnoses relate to approximately 4 HPV types, not just HPV 6, 11, 16, and 18. Includes cases in both men and women 2, 15, 1, 5, 3, 15, Meningococcal Infection Invasive Hib HPV Related Cancers Lifetime Risk of HPV-Related Pathology Event Risk of Cervical HPV Infection CIN 1 CIN 2/3 or AIS Cervical Cancer Without Pap Testing With Pap Testing Risk of Genital Warts (Men and Women) Risk of Oral HPV Infection Risk (Ratio) 1 in 2 1 in 6 1 in 25 1 in 31 1 in 123 1 in 8 1 in 2 The Vaccine CDC Fact Sheet, May-24. Ho et al. NEJM 1998. American Cancer Society: Cancer Facts and Figures 25. CIN = Cervical Intraepithelial Neoplasia; AIS = Adenocarcinoma in situ. 3

12/26/217 Prophylactic HPV Vaccines: L1 Virus-like Particles (VLPs) Non-infectious Produce higher levels of Abs than natural infection HPV Vaccine: What Does it Cover Valency Year Licensed Strains covered Prevents Quadrivalent 26 6, 11, 16, 18 7% Cervical Cancers 9% Genital Warts Bivalent 27 16, 18 7% Cervical Cancers 9-Valent 214 6, 11, 16, 18, 31, 33, 45, 52, 58 9% Cervical Cancers 9% Genital Warts HPV-Associated Cancers by Serotypes in 9-Valent Vaccine Cancer Type 16, 18 31, 33, 45, 52, 58 Total Covered Cervical 66-7% 15-2% 81-9% Vaginal 55% 18% 73% Vulvar 49% 14% 63% Anal (M) 79% 4% 83% Anal (F) 8% 11% 91% Penile 48% 9% 57% Oropharyngeal (M) 63% 4% 67% Oropharyngeal (F) 51% 9% 6% HPV Vaccine: Who Gets it and When HPV Vaccination Timeline Females Males Earliest dose 9 9 Recommended 1 st dose 11 12 11-12 Catch-up Period 13 26 13 21 Permissive -- Up to 26 2 doses: if start before 15 th b-day (, 6-12 mo, ok if > 5 mos) Schedule Special populations: Pregnancy: not recommended limited data Pre-existing cervical abnormality: recommended Immunosuppressed: 3 doses for severe immunosuppression 3 doses (, 1-2, 6 mo) if started on or after 15 b-day or if immunosuppressed 6 months months If started prior to 15 th birthday 7 months Dobson, JAMA 213 4

12/26/217 Efficacy of the quadrivalent vaccine against clinical endpoints among women aged 16-26 in per protocol efficacy population Vaccine Efficacy Clinical endpoint Vaccine No. of women No. of cases Placebo No. of women No. of cases HPV 16/18-related CIN 2/3 OR AIS 8,847 8,46 53 HPV 6/11/16/18-related VIN 2/3 7,897 7,899 8 Vaccine efficacy % (95% CI) 1% (92.9, 1) 1% (41.4, 1) HPV 6/11/16/18-related ValN 2/3 7,897 7,899 5 HPV 6/11/16/18-related genital warts (condyloma) 7,897 1 7,899 91 1% (<, 1) 98.9% (93.7, 1) Average duration of follow up was 3. - 3.5 years http://www.who.int/bulletin/volumes/85/9/6-38414-table-t3.html Falling Rates of Oncogenic HPV in 16-18 yo Sexually Active Females in England HPV Vaccination Impact on Genital Warts in Young Australian Men and Women HPV 16/18 Prevalence (%) 2 18 16 14 12 1 8 6 4 2 28 21-211 212-213 (pre-immunization) (2-3 yrs post-immunization) (4-5 yrs post-immunization) Herd immunity seen for males BMJ (Ali et al., 213) Evidence for Herd Protection from HPV Vaccine 4vHPV Infection among sexually active women age 14-24 in three eras: Percent Prevalence 2 18.8 18 16.9 16 14 12 Unvaccinated women Vaccinated women 11.8 1 8 7.1 6 4 1.9 2 Pre-vaccine Era Early-vaccine Era Recent-vaccine Era 23-26 27-21 211-214 Vaccine Coverage Oliver S. CDC Epidemic Intelligence Service Conference, 217. 5

12/26/217 North Dakota and U.S. Adolescent (Age 13-17) HPV Vaccination Rates (215 NIS) North Dakota Adolescent (13-17) Immunization Rates (NIS) % Vaccinated 8 7 6 5 4 3 2 1 HPV1-Female HPV3-Female HPV1-Male HPV3-Male U.S. North Dakota 1 9 8 7 6 5 4 3 2 1 Healthy People 22 Goal for HPV3 Tdap MCV4 Female 1 dose HPV Female 3 doses HPV Male 1 dose HPV Male 3 doses HPV Actual and Potentially Achievable Vaccination Coverage with >1 Dose HPV in 13 yo Girls if Missed Opportunities Eliminated Barriers to Vaccination MMWR July 215 Parental Attitudes Towards HPV Vaccination 6 5 54 % 4 3 2 23 32 1 Mandating vaccine is a bad idea Vaccine might cause lasting health problems Vaccine being pushed to make money for drug companies Calo et al. Cancer Epi, Biomarkers & Prevent, 216 6

12/26/217 Reasons Parents Don t Vaccinate Against HPV Top five reasons for not vaccinating adolescents with human papillomavirus (HPV) vaccine* - National Immunization Survey-Teen, United States, 213 Parents of girls Parents of boys Reason % (95% CI) Reason % (95% CI) Lack of knowledge 15.5 (13.-18.5) Not recommended 22.8 (2.6-25.) Not needed or necessary 14.7 (12.5-17.3) Not needed or necessary 17.9 (15.9-2.1) Safety concern/side effects 14.2 (11.8-16.8) Lack of knowledge 15.5 (13.7-17.6) Not recommended 13. (1.8-15.5) Not sexually active 7.7 (6.4-9.2) Not sexually active 11.3 (9.1-13.9) Safety concern/side effects 6.9 (5.6-8.5) *Analysis limited to parents reporting that they were not likely to seek HPV vaccination for their teen in the next 12 months or were unsure of their HPV vaccination plans. Quality of Physician Communication About HPV Vaccine 1:2 Women Graduating from College Will Acquire HPV, Can You Guess Which One? National survey of 776 pediatricians and family physicians 1 Up to 27% do not strongly endorse 26% do not recommend at age 11-12 for girls and 39% do not for boys Only 51% usually recommended same-day vaccination 59% used a risk-based approach to recommend HPV vaccine 1/3 of FPs reported little or no confidence in pre-licensure vaccine safety studies 2 5% Only 4% of 928 respondents of a national sample of Peds/FPs/Obs reported always recommending HPV vaccine to female patients age 11-12 yo, 55% for 13-17 yo 3 Gilkey MB. Cancer Epi Biomarkers Prev 215 O Leary ST. Prev Med 213 Vadaparampil ST. Am J Prev Med 214 HPV Vaccine -What Are the Concerns? Why give it so young? Does it tacitly approve/promote premarital or promiscuous sex? Safety Concerns 7

12/26/217 HPV Vaccine -What Are the Concerns? Why give it so young? Does it tacitly approve/promote premarital sex? Safety Concerns Rationale for Vaccinating Appropriate 11- or 12-Year-Olds (continued) 1 A national survey of adolescents and young adults age 15 24 years (N=1552) focused on their sexual health knowledge, attitudes, and experiences; these data reflect 114 participants who reported an initial sexual intercourse encounter. HPV=human papillomavirus. 1. Hoff T et al. National Survey of Adolescents and Young Adults: Sexual Health Knowledge, Attitudes and Experiences. Henry J. Kaiser Family Foundation; 23. Adapted by the author(s) from " National Survey of Adolescents and Young Adults: Sexual Health Knowledge, Attitudes and Experiences, (#3218), The Henry J. Kaiser Family Foundation, May 23. This information was reprinted with permission from the Henry J. Kaiser Family Foundation. Younger Vaccinees Mount Better Antibody Responses HPV Vaccine -What Are the Concerns? Plots of month 7 humoral responses in females to component human papillomavirus (HPV) vaccine types, by age at enrolment. 25 2 15 GMT 1mo after 3 rd Dose of HPV-2 2.2x Why give it so young? Does it tacitly approve/promote premarital sex? Safety Concerns 1 1.7x 5 9-14 y.o. 15-25 y.o. Anti HPV-16 Anti HPV-18 Anna R. Giuliano et al. J Infect Dis. 27;196:1153-1162 8

12/26/217 Subsequent Sexual Behavior in Vaccinated vs Unvaccinated Females HPV Vaccine -What Are the Concerns? Author / Yr N Country Measured Outcome Group difference Why give it so young? Does it tacitly approve/promote premarital sex? Anupam 215 28,111 USA Incidence of STIs No difference Hansen 214 41,786 Denmark, Norway, Sweden Smith 214 26,493 Canada Bednarczyk 212 1,398 USA Age at first intercourse, Number of sexual partners Incidence of STIs and Pregnancy in adolescent girls pre and post HPV introduction Pregnancy, Contraception counseling, STI infx/counseling No difference No difference No difference Safety Concerns HPV Vaccine Safety From June 26-March 216, ~ 9 million doses of HPV vaccine given in U.S., > 2 million doses worldwide Clinical licensure trials: Increased incidence of sore arm, lightheadedness VAERS: 33,945 reports filed, 92% not serious, 7% serious. Fainting, dizziness, nausea, headache, fever, hives, localized pain most common 96 deaths no pattern and no connection to vaccine found Post-Licensure Safety Trials for HPV Vaccination Author / Year N Country Slade, 29 12,424 U.S. Type of Study Case Report Analysis Klein, 212 189,625 U.S. Cohort Measured Outcome VAERS Severe Adverse Events Emergency department visits and hospitalizations Group Difference Increased Syncope and DVT Increased syncope and local skin infections, no SAEs Scheller, 214 1,613,798 Denmark Case-Control Incidence rate of venous thromboembolism No difference Arnheim- Denmark, 997,585 Dahlström, 213 Sweden Cohort Incidence of autoimmune dz, neurological, and thromboembolic events No difference Chao, 211 189,629 U.S. Cohort Incidence of autoimmune conditions No difference Huygen, 215 18,391 Worldwide Scheller, 215 3,983,824 Denmark Sweden Case Report Analysis Mølbak, 216 164,226 Denmark Case-Control Complex Regional Pain Syndrome No association Case-Control Multiple sclerosis No difference Pre-vaccination care-seeking in females reporting SAEs Increased OR - 2.1 Strategies to Improve HPV Vaccine Acceptance What can we do to Improve? Three pronged communication approach based on the best evidence to date: 1. Announce 2. EASE the main concern 3. Recommend 9

12/26/217 How You Frame the Question Study Cross-sectional observational study of pediatrician-parent discussions at well-child visits around topic of vaccination Study described to providers and parents only in general terms re: communication Vaccination Today?? Parents assessed on prior survey for degree of vaccine hesitancy, over-sampled vaccine-hesitant parents Video camera recorded the encounter in the pediatrician s exam room Communications experts assessed the manner in which conversation was initiated Opel D. Pediatrics 213 Adolescent Vaccination Uptake by Communication Style Summary: Framing the Question and Pursuit Presume Acceptance 74% Pursue Pursue 12% 2% = 88% accept 5% offer mitigated plan 7% reject immunization ** 1 9 ** * * p <.5 ** p <.1 8 ** 7 Participate Acceptance Pursue 4% = 21% 25% accept 42% offer mitigated plan 33% resist immunization 6 5 4 3 Participate Acceptance Acquiesce 4% % = 4% accept 13% offer mitigated plan 83% resist immunization 2 1 Tdap Opel D. Pediatrics 213 Announcements Meng Informed Shared HPV Efficient Moss JL. Soc Sci & Med 216 Improving HPV Vaccine Acceptance Announcements vs Conversation Conversation 16 % Increase at 6 mos vs 14 N = 29 clinics, 17,173 children p =.2 12 1 8 6 4 2 Control Conversation Announcements Brewer et al. Pediatrics 216. 1

12/26/217 Normalize HPV Vaccination: Sandwich Between the Routine Vaccines Announce Example Tdap HPV I see here that Michael just turned 11. Because he s 11, Michael is due for meningitis, HPV, and Tdap vaccines. We ll give those at the end of today s visit. Now that Michael is 12, there are three vaccines we give to kids his age. Today, he ll get meningitis, HPV, and Tdap vaccines. Meningococcus EASE the Main Concern Example: EASE the Main Concern Elicit main concern about the vaccine Ask the parent to be specific, is this the main concern? Acknowledge the main concern Important to say you understand why they have this concern Share your commitment You and the parent are together on wanting what is best for the child, show how you keep up to date on information needed for child s care Educate on what research shows in every day language to address concern Elicit. What s your main concern about HPV vaccine? I think we can wait until Bianca is a little older, don t you? Acknowledge. I get it, Bianca is young, I can see why you may be worried that she isn t ready for HPV vaccine. Share your commitment. The safety and necessity of these vaccines is something I take very seriously in my practice. Because preventive care for kids Bianca s age is important to me, I keep up-to-date on vaccine studies and I follow CDC guidelines for vaccination. Educate on what research shows. Children Bianca s age should get HPV vaccine because younger children develop better protection. We want her to get the vaccine far before she is exposed to an infection that could lead to cancer. HPV vaccine is cancer prevention. Make a Strong Recommendation, Emphasize Benefits of Vaccination On Schedule I highly recommend getting this vaccine today, my kids are vaccinated One of only 2 vaccines we have that prevent cancer! If vaccination done at 11-12 yo visit, only 2 doses (one less shot, one less clinic visit)! If done at younger age, much better vaccine response and likelihood of protection! Our boys need this as much as our girls? Possibility of non-sexual transmission, or future infected spouse 11

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