1. HPV and Infectious Disease HHD 2015 HHD 2015 Joel Palefsky, M.D. Professor of Medicine UCSF

2. Infectious Virus Particle of HPV 1,2 Capsid proteins: L1L2 Viral DNA Viral exterior Viral interior 1. Baker TS, et al. Biophys J. 1991;60:1445–1456. 2. Chen XS, et al. Mol Cell. 2000;5:557–567.

5. Estimated Annual Burden of HPV-Related Diagnoses in the United States 1 million new cases of genital warts 3 1.4 million new cases of low-grade cervical dysplasia (CIN 1) 2 330,000 new cases of high-grade cervical dysplasia (CIN 2/3) 2 9,710 new cases of cervical cancer 1 1. American Cancer Society. Cancer Facts and Figures 2006. Atlanta, Ga: American Cancer Society; 2006:4. 2. Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med. 2003;127:946–949. 3. Fleischer AB, Parrish CA, Glenn R, Feldman SR. Condylomata acuminata (genital warts): Patient demographics and treating physicians. Sex Transm Dis. 2001;28:643–647. 3,700 deaths estimated in 2006 1

6. Oncogenic HPV types  16, 18, 31, 33, 35  39, 45, 51, 52, 56, 58, 70

7. Non- oncogenic HPV types  HPV 6, 11- genital warts  HPV 1, 2 and 4- plantar and palmar warts

8. HPV Infection and Productive Life Cycle Adapted from Doorbar J. J Clin Virol. 2005;32S:S7–S15. Virus introduced through microabrasion Viral DNA replication Virion assembly Infectious virions shed Virus infection Late HPV protein production L1 & L2 Early HPV protein production E1, E2, E4, E5, E6, & E7

10. p53 E6-AP E6 E6 leads to degradation of p53 Ubiquitin X

11. E7 RB E2F E7 RB E2F Cell Cycle Binding of E7 to RB releases E2F

13. E1 and E2  E1 is responsible for coordinating the division of the viral DNA with that of cell division  E2 has many functions  Works with E1  Regulates expression of E6 and E7

16. E4 and E5  E4 is found in the cytoplasm, is associated with the cell cytoskeleton  ? Leads to collapse and ?effect on infectivity?  E5 works with E6 and E7 to increase malignant transformation  Leads to reduced turnover of EGF receptors on cell surface

17. E5 and EGF E5 EGF

18. 2-tiered system: LSIL & HSIL Precancer Infection Reflects HPV biology and clinical management

19. Schiffman, MH. J Natl Cancer Inst. 1992; 84:394-98 HPV infection Low-grade CIN High-grade CIN Cervical cancer

20. HPV testing for screening Cervical cytology has limited sensitivity Cervical cytology has limited sensitivity HPV testing is now approved for primary cervical screening in women over age 25 years HPV testing is now approved for primary cervical screening in women over age 25 years Can increase the screening interval in women who test negative Can increase the screening interval in women who test negative

21. Risk factors for development of HPV-associated lesions  Sexual activity  Younger age  Smoking  Other sexually transmitted diseases, especially chlamydia trachomatis  Immune suppression  HPV strain variant  Genetic background

22. Incidence of oropharynx and cervical cancers Chaturvedi A et al. J Clin Oncol 2011; 29: 4294-4301 22

23. Incidence of HPV-positive and HPV-negative oropharynx cancers Chaturvedi A et al. J Clin Oncol 2011; 29: 4294-4301 23

24. Penile cancer  About 40% of cases are HPV- related Associated mortality of 41% 2 Associated mortality of 41% 2  Survival is  2 years without treatment. 3  Patients often seek treatment late. 3  Treatment is associated with substantial psychological and sexual dysfunction 4 Image used with permission from Alex Ferenczy, MD. 1. Hernandez BY et al. Cancer. 2008;113(suppl 10):2883–2891. 2. Rippentrop JM et al. Cancer. 2004;101: 1357–1363; 3. Misra S et al. Lancet Oncol. 2004;5:240–247. 4. Maddineni S et al. BMC Urology. 2009;9:8. 24

28. 28 Anal and cervical cancer incidence Cervical cancer prior to cervical cytology screening: 40-50/100,000 Cervical cancer currently: 8/100,000 Anal cancer among HIV- MSM: up to 37/100,000

29. Anal cancer rates in North American AIDS Cohort Collaboration on Research and Design) (NA-ACCORD) 1996-2007 Incidence/100,000 (85% CI) Incidence/100,000 (85% CI) HIV-infected HIV-infected MSM131 (109-157) MSM131 (109-157) MSW 46 (25-77) MSW 46 (25-77) Women 30 (17-50) Women 30 (17-50) Silverberg M et al. CID, e-pub Jan 2012

30. 30 Prevalence of AIN among MSM Population-based data Chin-Hong et al. Ann Int Med. 2008;149;300-6. Prevalence, % HIV-positive participants HIV-negative participants All participants

31. Anal and cervical HPV infection in HIV-positive women Palefsky JM et al. J Infect Dis. 2001;183:383-391.

32. San Francisco Giants 2010, 2012 and 2014 World Series Champions

33. Treatment of condyloma/warts  Expectant- many will resolve spontaneously  Patient-applied therapies  Podophyllotoxin (Condylox™) gel applied 3 days on/4 days off  Imiquimod (Aldara ™) cream applied 3 times/week  Sinecatechin (Veregen™) cream applied 3 times daily until clearance

34. Treatment of condyloma/warts  Clinician-applied therapies  Liquid nitrogen  80% trichloroacetic acid  Surgical excision  Laser  Thermocoagulation/infrared coagulation  Loop electrosurgical excision procedure (LEEP)  Intralesional interferon

35. Treatment of low-grade lesions  Most clinicians would follow carefully without treatment since many resolve spontaneously

36. Treatment of cervical high-grade lesions  Loop electroexcision procedure  Cryotherapy  Surgical cone biopsy  Laser

39. The nonavalent HPV vaccine Schiller J. Lancet Oncol 2015;16(5):e217-25

42. Quadrivalent vaccine in males: efficacy against HPV 6/11/16/18-related external genital lesions (HM+MSM) 1 Related Cases n=1,394n=1,404 0 10 20 30 40 50 HPV 6-, 11-, 16-, or 18-Related External Genital Lesions Quadrivalent vaccine Placebo 3 32 90.6% Reduction (70, 98) 1 Giuliano A, Palefsky J et al. NEJM 2011 Feb 3;364(5):401-11 Per-Protocol Efficacy Population 42

44. Quadrivalent vaccine in males: efficacy against HPV 6/11/16/18-related AIN and anal cancer in MSM 1 Related Cases n=194n=208 0 10 20 30 40 50 HPV 6-, 11-, 16-, or 18-Related AIN and Anal Cancer Quadrivalent vaccine Placebo 5 24 77.5% Reduction (40, 93) Per-Protocol Efficacy Population n = number of subjects who have at least 1 follow-up visit after month 7. 1 Palefsky J, Giuliano et al. NEJM 2011, 365: 1576-85 44

45. The nonavalent HPV vaccine MMWR / March 27, 2015 / Vol. 64 / No. 11

46. ACIP recommendations for HPV vaccine in women 9vHPV, 4vHPV or 2vHPV can be used for: 9vHPV, 4vHPV or 2vHPV can be used for: routine vaccination of females aged 11 or 12 routine vaccination of females aged 11 or 12 females through age 26 years who have not been vaccinated previously or who have not completed the 3-dose series females through age 26 years who have not been vaccinated previously or who have not completed the 3-dose series If providers do not know or do not have available the HPV vaccine product previously administered, or are in settings transitioning to 9vHPV, any available HPV vaccine product may be used to continue or complete the series for females for protection against HPV 16 and 18 If providers do not know or do not have available the HPV vaccine product previously administered, or are in settings transitioning to 9vHPV, any available HPV vaccine product may be used to continue or complete the series for females for protection against HPV 16 and 18

47. HPV vaccination of men  Vaccine approved for routine use in boys and men age 9-21 years to prevent HPV 6/11- related genital warts and anal HPV infection, AIN and anal cancer due to vaccine types  Approved for routine use in MSM and HIV+ men age 22-26 years

48. s s Ali et al, BMJ 2013

49. HPV prevalence in the pre- and post-HPV vaccination eras Markowitz L et al. JID 2013; 208: 383-93

50. Conclusions  Vaccines are effective to prevent cervical and vulvovaginal HPV infection and associated disease due to vaccine types  Vaccine prevents anal HPV infection and AIN in boys and men due to the types most commonly found in anal cancer  Secondary prevention for those already infected with HPV

51. The future  Implementation of vaccine in developing countries  Two-dose vs. three dose

52. International research program Joel Palefsky, M.D., Program director www.ddcf.org Joel.palefsky@ucsf.edu 415-476-1574