Don't leave the boys behind: Update on HPV – 2011

1. Don't leave the boys behind: Update on HPV – 2011 François Boucher MD, FRCPC

2. Objectives After this presentation, participants will be able to: • Recognize the different manifestations and complications of HPV. • Provide appropriate advice on HPV immunization to families of boys and girls. • Advocate to public health authorities on the merits of universal vaccination for HPV

3. N = 12 N = 60 The Human papillomavirus • DS DNA virus • Viral genome is episomal in the host cell • > 200 types • Classification according to • Tropism • Cutaneous • Mucosal (40 types) • Oncogenicity • High risk (15) • Low risk (12)

4. HPV genotypes • Tissue tropism • Cutaneous vs mucosal • Association with cancer • Oncogenic • Non-oncogenic • Unknown • 15 types known to be associated with cancer • HPV-16: 50% of cancers • HPV-18: 20% Neighbor joining phylogenetic tree of 106 PVs based on CPR region of L1 Park, SB. Lecture Notes in Computer Science. 2003. Vol. 2736.

5. Cumulative incidence of HPV infection among women sexually active and HPV negative at enrollment Winer RL et al Am J Epidemiol 2003;157:218–226

6. Estimated life-probability ofacquiring HPV & related morbidity in women • Genital HPV infection 75% • Genital condylomas ≥5% • Abnormal routine Pap test ≥35% • Invasive cervical cancer • Communities with routine Pap-testing <1% • Communities without routine Pap-testing ~3% • Other ano-genital cancers <1% • Anal cancers in men having sex with men ~3% • Proportion (~20%) of head/neck cancers <1%

7. 20 HPV16+ HPV18+ Onc HPV + 15 Onc HPV - 10 5 0 1 2 3 4 5 6 7 8 9 10 11 Cumulative incidence of cervical intraepithelial neoplasia grade 3 and cancer ( ≥ CIN3)over a 10-year period Cumulative incidence rate (%) Follow-up time (years) Khan MJ et al. JNCI 97:1072

8. HPV types associatedwith cervical lesions by grade Clinical Virology, 2nd edition, 2002, ASM press

9. Clinical diagnoses associatedwith oncogenic HPV • Cervix • Cervical intraepithelial neoplasia: CIN 1-2-3 • Adenocarcinoma in situ: AIS • Vulvovaginal cancers (VIN, VaIN) • 25-35% associated with HPV • Anal cancers • Rare, but increasing in incidence • 80-90% HPV • Penile cancers • 40% HPV • Neck/ENT cancers • 25-35% associated with HPV

10. Burden of HPV disease in men Heterosexual men • Prevalence of HPV infection estimated between 25% to 65% • HITCH study: 56% positive at study entry MSM • Overall prevalence is 57% • Most common type is HPV 16 • Infection independently associated with A) Receptive anal intercourse [OR 2] and B) 5+ sexual partners [OR 1.5] Chin-honget al, J. Infect dis. 2006

11. Prevalence of genital HPV infectionin males Giuliano AR, et al. Cancer Epidemiol Biomarkers. 2008

12. HPV infection in males

13. Anogenital warts in Men • Most common HPV manifestation in men • Prevalence in Canada (2004): • 165.2/100 000 in men • 128.4 in women • Peak prevalence age • 25-29 y.o. in men • 220-24 y.o. in women Kliewer EV et al. Sex Transm Dis 2009;36:380

14. Anal cancer: epidemiology • Uncommon, although increasing in incidence • 1.9% of all digestive system cancers; 5260 new cases diagnosed annually (USA) • Annual incidence: 2.04 (M) and 2.06 (F) per 100,000; higher in black men (1) • HIV-positive MSM have twice the incidence as that of HIV-negative MSM • In the HAART era, anal cancer incidence seems to increase (quadrupled compared to pre-HAART era in San Francisco study)(2) 1: Johnson, Cancer 2004 2: Chin-honget al, J. Infect dis. 2006

15. Anal and cervical cancer incidences compared • Cervical cancer incidence prior to cervical cytology screening: 40-50/100,0001 (1) • Cervical cancer currently: 8/100,000 • Anal cancer among HIV- MSM: up to 37/100,000 (2) • Anal cancer among HIV+ MSM: 137/100,000 person-years since 1996 (3) 1: Qualters JR et al. . MMWR 1992, 41:1-152: Daling JR et al. N Engl J Med 1987, 317:973–977 3: D’Souza G et al. J Acquir Immune Defic Syndr. 2008;48(4):491-499

16. Burden of disease in MSMHIV-positive

17. HPV Vaccines

18. HPV vaccines Gardasil™ (Merck) • Reassembled VLP protein L1 • Serotypes 6, 11, 16, 18 • Schedule: 0, 2 & 6 months • Approved: July 2006 Cervarix™ (GSK) • Reassembled VLP protein L1 • Serotypes 16, 18 • Schedule: 0, 1 & 6 months • Approved: February 2010

19. NACI recommendations 2007HPV vaccine • Females 9-13 years of age, as this is before the onset of sexual intercourse for most females in Canada, and the efficacy would be greatest • Females 14-26 years would benefit from the HPV vaccine, even if they are already sexually active, as they may not yet have HPV infection and are very unlikely to have been infected with all four HPV types in the vaccine. • Females 14-26 years who have had previous Pap abnormalities, including cervical cancer, or have had genital warts or known HPV infection would still benefit from the HPV vaccine.

20. Publicly fundedProvincial HPV vaccination programs http://www.phac-aspc.gc.ca/im/ptimprog-progimpt/table-1-eng.php

21. Justification for « off-label »extended schedule • Immune response to vaccine is strongest in younger girls • Data from BCCH affiliated Vaccine Evaluation Centre confirms two doses of HPV vaccine are protective due to a strong immune response in girls 9-13 years after two doses given at 0 & 6 months • Third dose to ensure sustained protection into sexually active years of life. • Girls who are known to have immune system defects associated with solid organ transplant, stem cell transplant, or HIV infection should receive HPV vaccine in the three dose schedule at 0, 2 and 6 months.

22. HPV vaccine coverage in Canada • Current coverage rates in Canada are considered suboptimal • Cultural & religious beliefs • Public perceptions • Vaccine program implementation • HPV vaccine uptake (2008-2009)(1): • Maritimes: 83% • QC: 84-87% (the first year…) • ON: 49% • AB-MB: 55% • BC: 66% 1: HPV vaccine can still be a tough sell. Times & Transcript, March 4, 2009 http://timestranscript.canadaeast.com/rss/article/591314

23. Population effectiveness • Australia public program since 2007 • 65-75% uptake • Incidence of AGW in women and men • 36 055 clients of the Melbourne Sexual Health Center, 2004-2008 • Decreased incidence in women ≈25%/heterosexual men ≈5% per quarter • Heterosexual couples study • www.mcgill.ca/hitchcohort/ • 322 couples • Decreased incidence of vaccine-type infections 22% vs 7% vaccinated vs unvaccinated 2009 ISTDR: Abstract OS2.9.02 EUROGIN 2010 Abstract No SS 4-6

24. So, should boys be vaccinated against HPV?

25. Cost of immunization programs in Canada over the years • 1993, boys & girls 0-15 y.o: • DPT (5 doses); D2T5 (1 ); OPV (4); Hib (3); MMR (1) • $83 • 2010, boys & girls 0-15 y.o: • DTaP-Polio-Hib (4 doses); DTaP-Polio (1); dTaP (1); PneumoC (3); MenC (1); MMR-V (1); MMR (1); HBV/HAV (2); Influenza (6-23 mo) (2 doses "primer" + 1) • $408 • …excluding HPV vaccine… • ≈50% conjugated pneumococcal vaccine

26. Cost of immunization programs in the USA • 2010, boys & girls 0-15 y.o: • 30 doses against 16 diseases (excluding Influenza) • $1450 for males, $1800 for females • HPV & meningo ≈ 25%

27. Vaccine efficacy in men Giuliano et al., NEJM 2011; 364(5):401

28. Prevention of HPV 6/11/16/18infection in men • 4065 males, aged 16-26 years • Per protocol efficacy: • 90.4% reduction in the incidence of HPV 6/11/16/18-related EGL • 89.4% reduction in condyloma/warts (6/11) • 85.6% reduction of persistent HPV 6/11/16/18 infection Giuliano et al., NEJM 2011; 364(5):401

29. Prevention of anal intraepithelial neoplasia (AIN) and anal cancer in MSM • 602/4065 males, aged 16-26 years • Per protocol efficacy: • 77.5% reduction in the incidence of HPV 6/11/16/18-related AIN and anal cancer • 74.9% reduction in high-grade AIN • 94.9% reduction of persistent HPV 6/11/16/18 infection Giuliano et al., NEJM 2011; 364(5):401

30. Cost-effectiveness of HPV vaccination • Vaccination of 12-year-old girls is cost-effective • Consistent across models • Estimates not sensitive to uncertainty in natural history and epidemiology of HPV • More uncertainty, less precision in cost-effectiveness estimates for: • Vaccination of adult women • Vaccination of males Kim JJ. NEJM, October 19, 2011 Chesson H. ACIP, October 10, 2010

31. Male HPV vaccination • Estimates of cost-effectiveness of male vaccination vary • Within one model when key assumptions are changed • Across different models due to differences in model structure and/or assumptions • Cost-effectiveness of male vaccination depends on health outcomes included • Most favorable scenario is when all potential health outcomes are included Chesson H. ACIP, October 10, 2010

32. Male HPV vaccination • Cost-effectiveness of male vaccination depends on vaccine coverage of females • Most favorable scenario for male vaccination is when coverage of females is low (1) • Male vaccination estimated to cost $26,000 (2) to $62,000 (3) per QALY when female coverage ≤ 50% 1: Brisson M, et al. J Infect Dis. 2011:204 (3): 372 2: Elbasha EH, Dasbach EJ. Vaccine 2010; 28(42): 6858 2: Kim JJ, Goldie SJ. BMJ 2009; 339:b3884

33. Male HPV vaccination • Improving vaccine coverage of females may be more cost-effective than male vaccination Even if outreach costs are incurred to increase coverage • HPV vaccination of MSM is likely to be a cost-effective intervention for the prevention of genital warts and anal cancer Kim (2010) found cost per QALY $15,000-$38,000 over range of assumptions about age at vaccination and prior exposure to HPV Kim JJ. Lancet Infectious Diseases, 2010; 10(12):845 - 852

34. HPV Immunization programs:Current issues • Duration of protection in women • At least five years, probably longer • Assess need for recall immunization • Duration of protection in males • Unknown • Importance of cross-protection among serotypes • Different population models are currently being evaluated for efectiveness & cost-benefit • Should vaccine valency be increased? If so, which types should be included?

35. Should pediatricians recommend HPV vaccination for boys? • Pro: • Safe, efficient and effective vaccine • Individual protection against AGW and cancers • Decreased burden of disease & transmission (evidence of herd immunity) • Principle of equity • Parents may ask for it… • Con: • Vaccine still very expensive • Cost-effectiveness still in doubt • Acceptance will be a challenge • Parents may oppose it… http://tinyurl.com/3apx7hh

36. Merci! François Boucher MD, FRCPC