HPV efficacy in men for UCAYA

1. HPV Vaccine for Men:
Analysis of Efficacy
Mike Guyton, MD
Assistant Clinical Professor/Academic
Faculty in General Pediatrics

3. Objectives
• Present some quick facts about HPV to empower
Doctor/Patient discussion and education
• Discuss and analyze an example of the current
literature
• Generate discussion on validity of the data analysis
• Discuss ways to engage the controversy surrounding
HPV vaccination

4. HPV: Quick Facts
• HPV has been associated with cancers of both men and
women
– Cervical (~100%), Oropharyngeal SCC (~60%), Penile,
Vaginal/Vulvar, and Anal
• The probability that a sexually active male will get a new
genital HPV infection (12 month period) is 0.29-0.39
• However, there is a difference in immune response that is
seen in men and women
– HPV Seropositivity: 17.9% F vs. 7.9% M
• The quadrivalent HPV vaccine has been shown to be
efficacious in preventing persistent infection and genital
disease in females
– Active against types 6, 11, 16, 18

5. Current Recommendations
• Gardasil is the HPV vaccine used at CPM
• Females: Routine vaccination at 11 or 12yo or 13-
26yo if no previous vaccination
• Males: Routine vaccination at 11 or 12yo or 13-26yo
if no previous vaccination (10/2011)

6. 2010 National Health Interview Study
• Annual Household Survey, conducted by a branch of the
CDC
• 1741 men aged 18-26 years
– Interviews conducted 3-14 months after licensure of the vaccine
for men
• Only 54% of participants at the time had heard of HPV, and
only 35% had heard of HPV vaccination
• Only 1.1% of those interviewed had initiated HPV
vaccination, and ~0.1% had completed vaccination series
• Studies showed that a doctor’s recommendation was a key
determinant of HPV vaccination
– Men who had higher MD contacts had greater awareness

7. What about Us?
76%
21%
3%
Gardasil Series Administration (Males and
Females); 2012
1 Dose
2 Doses
3 Doses
0
10
20
30
40
50
60
70
80
90
100
11 12 13 14 15 16 17 18
Gardasil Administration By Age for
Females and Males; 2012
Females
Males

9. The Study

10. The Study
• Randomized, Placebo-controlled, Double-Blind Trial
– Gold Standard for clinical trials
– Minimizes allocation bias,; only differences in outcome are those
intrinsic to the treatments being compared
• 4065 boys/men aged 16-26 years
– 3463 heterosexual, 602 with male sex partners
– Hetero: 1-5 female partners; MSM: 1-5 male or female partners
• 18 countries Included
• Study was conducted between September 2004 and August 2008
• Exclusion Criteria:
– Clinically detectable anogenital warts/genital lesions suggestive of
infection with non-HPV STI’s
– History of the above findings

11. Study Objectives
• Primary Objective:
– Show that the quadrivalent HPV vaccine decreased the incidence of genital
lesions associated with HPV-6, 11, 16, 18 (compared to placebo)
• Secondary Objective:
– Show that the vaccine decreased the incidence of persistent HPV infection of
the above types and the detection of DNA associated with these types at any
time (compared to placebo)
• Additional Objective:
– Assessment of Vaccine Safety

12. Which is Which
Condyloma Accuminata Condyloma Lata

13. Methods: Study Design
• 2 main populations examined
– Intention-to-Treat: Subjects who received 1+ doses of
vaccine/placebo and returned for follow up (represents
general population of unvaccinated boys/men)
– Per-Protocol: Subjects who were seronegative on D1 and
PCR-negative from D1-M7 for HPV vaccine type/types
• Subjects randomly assigned to receive HPV vaccine vs.
placebo
– Ratio was 1:1
– Given at Day 1, month 2, and month 6
• Series of detailed anogenital examinations and biopsies
were completed

14. Methods: Endpoints
• Primary endpoint:
– +/- external genital lesions associated with HPV serotypes 6/11/16/18
– Penile, Perianal, or Perineal intraepithelial neoplasia (PIN)
– Penile, Perianal, or Perineal cancer
• Persistent Infection
– Defined as detection of the same HPV type in an anogenital swab or biopsy
collected on 2+ consecutive occasaions
– Interval of at least 6 months between visits

15. Methods: Analysis
• Fixed Event Design was used to measure endpoints
– “the design of the study is fixed before the main stage of data collection and
analysis takes place”
– Typically theory driven, based on assumptions; in this case, the assumption is
that the true efficacy of the vaccine is 80%.
• By estimating efficacy, the researchers could determine
the number of patients/cases needed to generate
enough power to meet a certain goal
• i.e, when at least 32 cases satisfied the primary end
point, analysis was conducted

17. Results: Efficacy
• Overall Sero-Conversion
– 97.4% of vaccinated subjects for HPV-6, 11, 16, 18
– 0.9% with no seroconversion
– 1.5% with seroconversion to ¾ HPV subtypes
• Genital Lesions:
– ITT Population:
• 36 vs 89 external lesions seen (vaccine vs. placebo); efficacy of
60.2%
• 65.5% efficacy against lesions of HPV-6,11, 16, 18 (significant
related to 6 and 11)
• Against Condyloma Accuminata: 67.2% (HPV-6 and HPV-11)
• Efficacy against PIN was no observed

18. Results: Efficacy
– Genital Lesions
• PP Population:
– 6 vs 36 external lesions seen (vaccine vs. placebo);
efficacy 83.8%
– 90.4% efficacy against lesions of HPV-6, 11, 16, and 18
– No lesions associated with HPV-16 or HPV-18 vaccine
group, with some seen in the placebo group
– Against Condyloma Acuminata: 89.4%
– 3 cases of PIN grade 1 or worse seen in placebo group

20. Results: Efficacy
• Persistent Infection
– ITT: observed efficacy of 47.8% (significant reduction)
– PP: observed efficacy of 85.6%

23. Results: Safety
• Overall, 69% vs 64% in the vaccine/study group reported
adverse events
– Injection site pain was more common in the vaccine group
– Increase in oral temperature
– Interestingly, more people died if they received the placebo vs the HPV
vaccine
• 14% of both Vaccine and Placebo groups reported Vaccine-
Related Systemic Adverse Events

25. Conclusions from the study
• Point Blank: Its beneficial to get the HPV vaccine
if you are a dude and want to prevent genital
warts due to HPV-6, 11, 16, or 18
• The vaccine may not be 100% effective
– There were 3 cases condyloma accuminata observed
among vaccine recipients in the per-protocol group
– Could be true vaccine failure vs error on part of study
• There are lower rates of adverse events (injection
site and serious) for guys vs girls
– Greater muscle mass
– Reluctance to report

26. Limitations
• Narrow Age Range of the subjects
– Only 16-26 years of age
• Short follow up period
– Median follow up ~ 3 years
• Subjects had no more than 5 lifetime sexual
partners
– Average man has been reported to have anywhere
from 7-9 sexual partners in their lifetime,
depending on the source

27. Great Data, but…..
• Why don’t we have amazing rates of vaccinations for
males across the board, like we see with women?
– Less cost effective to many countries; instead focus on
boosting female vaccination for herd immunity benefits
• Several Barriers to vaccination identified
– Cost of vaccine to the uninsured
– Need to get a series of 3 shots
– Time needed for adequete provider/patient interaction
• Acceptability overall is low as a result
– 50.4 on a 100 point scale among 8360 men across 22
studies
– 55-100% acceptabiity among women in similar studies

28. Approaching the HPV controversy with parents
• Approach 1: Use the data as a defense
– Remember, HPV vaccination was shown to be 60-90% effective!!
• Approach 2: Shift focus to the cancer prevention role rather than
the STD prevention role of vaccination
– Mention male specific cancers and current rise in these cancers
– Challenge the belief that HPV vaccination is not relevant for men
• Approach 3: Make it personal
– Discussion about future marriage partner
• Approach 4: Introduce the topic of vaccination at an earlier WCC
or visit.
– Gives parents time to assimilate safety information, conduct their own
research, as well generate thought out questions to ask the provider

29. Useful Sites
• Merck Vaccine Patient Assistance Program
– http://www.merck.com/merckhelps/vaccines/
• Center for Disease Control
– http://www.cdc.gov
• American Sexual Health Association
– http://www.ashasexualhealth.org/std-sti/hpv.html
• Society for Adolescent Health and Medicine
– http://www.adolescenthealth.org

30. References
• Giuliano, Anna Ph.D., Palefsky, Joel MD, et al. Efficacy of
Quadrivalent HPV Vaccine against HPV Infection and Disease in
Males. The New England Journal of Medicine. Vol 364, No. 5. 401-
411; 2/2011
• Lu, Peng-jun MD, Williams, Walter MD et al. Human
Papillomavirus Vaccine Initiation and Awareness: U.S. Young Men in
the 2010 National Health Interview Survey. American Journal of
Preventative Medicine. Vol 44, No. 4. 330-338; 4/2013
• Newman, Peter, Logie, Carmen, et al. HPV Vaccine Aceptability
among men: a systematic review and meta-analysis. Sexually
Transmitted Infections 2013. Vol 89. 568-574; 7/2013
• http://www.uptodate.com
• http://www.cdc.gov