1. Guidelines for Management of Human Papilloma Virus Lieutenant Commander Songhai Barclift, MD., USPHS HRSA/HIV/AIDS Bureau/Division of Service Systems 2010 USPHS Scientific and Training Symposium

2. Objectives Describe the epidemiology and pathology of HPV disease Describe the diagnosis and treatment of the most common HPV related diseases affecting humans Explain the latest efforts in the prevention of HPV disease Discuss the management of HPV related disease in pregnancy and HIV

3. 3 Virology of HPV Small nonenveloped virions Capsid composed of 2 structural proteins with icosahedral symmetry Single molecule of supercoiled, double- stranded, circular DNA about 8000 base pairs in length Phelps W, et al. Ann Intern Med. 1995;123:368-382. Reproduced with permission Shah KV. Sexually Transmitted Diseases. 2nd ed. New York: McGraw-Hill; 1990:425-431. Reproduced with permission Shah KV. Sexually Transmitted Diseases. 2nd ed. New York: McGraw-Hill; 1990:425-431.

4. Human Papilloma Virus Species-specific and tissue-specific Classified genotype encoding the capsid proteing L1 Induces both benign and malignant disease >100 genotypes identified – >40 genotypes infect the anogenital tract

5. Human Papilloma Virus Oncogenic HPV types: 16, 18, 31, 35, others – Type 16 accounts for 50% of cervical cancers and most noncervical cancers; HPV 18 accounts for 10- 15% of cervical cancers Types 6, 11, 40, 42, 53, and 54 associated with most external warts; types 6 and 11 seen in 90%

6. 6 HPV Subtypes by Relative Cancer Risk HPV Subtypes Cancer Risk 6, 11, 42, 43, 44, 54, 61, 70, 72, 81 Low to negligible 26, 53, and 66Probably high 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 High Muñoz N, et al. N Engl J Med. 2003;348:518-527.

7. HPV Disease: Epidemiology 80 percent of sexually active adults will acquire genital HPV before age 50 HPV infection common in US adolescent women prevalence 30-50 percent

8. 8 Epidemiology of Anogenital Human Papillomavirus (HPV) Koutsky L. Am J Med. 1997;102(5A):3-8. Estimated prevalence of HPV infection among men and women aged 15-49 years No infection Previous infection Asymptomatic infection Subclinical infection detected Anogenital warts No infection Previous infection Asymptomatic infection Subclinical infection detected Anogenital warts 10% 60% 25% 1% 4%

9. 9 Relative Risk of HPV 16 Infection: Age and Gender Stone KM, et al. J Infect Dis. 2002;186:1396-1402. Seroprevalence, % Age group, years 30 25 20 15 10 5 5 0 0 12-19 20-29 30-39 40-49 50-59 Women Men Women Men

10. Risk Factors for HPV Infection: Females – Adolescence – Multiple sex partners – Sex partners who have increased number of partners Males – Uncircumcised – Low condom use during sexual activity – High number of sexual partners

11. Transmission Primary route of anogenital infection is sexual intercourse Transmission requires skin to skin contact; penetration is not a prerequisite – Regular and consistent condom use achieves approximately 60% protection against infection

13. 13 Clinical Manifestations of Genital Warts Condylomata acuminata—female Flat cervical condylomata Keratotic flat wart Smooth papular wart Beutner KR, et al. Clin Infect Dis. 1998;27:796-806.

14. 14 Cases, %* Prepuce Glans Urethra Scrotum 100 90 80 70 60 50 40 30 20 10 0 0 Sites of Exophytic Anogenital Warts: Men Handsfield HH. Am J Med. 1997;102(5A):16-20. Importantly, individual patients may exhibit warts in multiple locations * These data reflect the percent of patients exhibiting warts in the specified regions. **Frequency may be higher in individuals practicing receptive anal sex. Perianal area** Penile shaft Penile shaft

15. 15 Sites of Exophytic Anogenital Warts: Women Cases, %* Handsfield HH. Am J Med. 1997;102(5A):16-20. *These data reflect the percent of patients exhibiting warts in the specified regions. Importantly, individual patients may exhibit warts in multiple locations *These data reflect the percent of patients exhibiting warts in the specified regions. Importantly, individual patients may exhibit warts in multiple locations Vulva Perianal area Vagina Cervix 100 90 80 70 60 50 40 30 20 10 0 0

16. 16 Differential Diagnosis of Genital Warts Normal anatomy (eg, pearly penile papules) Secondary syphilis Benign skin lesions (eg, benign nevi) Molluscum contagiosum Wiley DJ, et al. Clin Infect Dis. 2002;35(Suppl 2):S210-S224.

17. 17 Natural Course of Anogenital HPV Infection First Lesion Immune Response Regression INFECTIONINFECTION INFECTIONINFECTION Incubation (3 Weeks to 8 Months) Active Growth (Months) Active Growth (Months) Host Containment (Months to Years) Host Containment (Months to Years) Sustained Clinical Remission or Recurrent Disease Sustained Clinical Remission or Recurrent Disease Persistent Disease Lacey CJN. J Clin Virol. 2005;32(Suppl 1):S82-S90. Handsfield HH. Am J Med. 1997;102(5A):16-20. Lacey CJN. J Clin Virol. 2005;32(Suppl 1):S82-S90. Handsfield HH. Am J Med. 1997;102(5A):16-20.

18. 18 Gender-related Differences in the Diagnosis and Treatment of External Genital Warts: Males No age pattern in rates of HPV acquisition Few data available on natural course Anal lesions more likely in men who have sex with men Vaccination is a consideration Penile and anal cancer risk Likely location of lesions affected by circumcision Median time for clearance 5.9 months Palefsky JM. Dis Markers. 2007;23:261-272. Kiviat N, et al. J Infect Dis. 1990;162:358-361. Markowitz LE, et al. MMWR Recomm Rep. 2007;56(RR-2):1-24. Oriel JD. Brit J Vener Dis. 1971;47(1):1-13. Palefsky JM. Dis Markers. 2007;23:261-272. Kiviat N, et al. J Infect Dis. 1990;162:358-361. Markowitz LE, et al. MMWR Recomm Rep. 2007;56(RR-2):1-24. Oriel JD. Brit J Vener Dis. 1971;47(1):1-13.

19. 19 Gender-related Differences in the Diagnosis and Treatment of External Genital Warts: Females Lesions at multiple sites common Higher prevalence in adolescence Recommended for early vaccination Risk for cervical cancer Risk strongly driven by sexual behavior of male partner(s) Frega A, et al. Cancer Lett. 2003;196:127-134. Stone KM, et al. J Infect Dis. 2002;186:1396-1402. Markowitz LE, et al. MMWR Recomm Rep. 2007;56(RR-2):1-24. CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94. Burk RD, et al. J Infect Dis. 1996;174(4):679-689. Frega A, et al. Cancer Lett. 2003;196:127-134. Stone KM, et al. J Infect Dis. 2002;186:1396-1402. Markowitz LE, et al. MMWR Recomm Rep. 2007;56(RR-2):1-24. CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94. Burk RD, et al. J Infect Dis. 1996;174(4):679-689.

20. 20 Prevention Guidelines for Management of HPV Infection Markowitz LE, et al. MMWR Recomm Rep. 2007;56(RR-2):1-24. CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94. Markowitz LE, et al. MMWR Recomm Rep. 2007;56(RR-2):1-24. CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94. Screening Treatment

21. 21 HPV Vaccines Quadrivalent HPV vaccine—Gardasil ® approved for use in females aged 9-26 years (0,2 and 6 months) – Composed of virus-like particles (VLPs) from recombinant HPV 6, 11, 16, and 18 – Covers HPV subtypes responsible for 90% of genital warts Bivalent vaccine—Cervarix™ approved for use 10-25 (0,1 and 6) – Composed of VLPs assembled from recombinant HPV 16 and 18 L1 – Uses a different adjuvant than Gardasil Gardasil Prescribing Information, Merck, December 2007. Schmiedeskamp MR, et al. Ann Pharmacother. 2006;40:1344-1352. Gardasil Prescribing Information, Merck, December 2007. Schmiedeskamp MR, et al. Ann Pharmacother. 2006;40:1344-1352.

22. 22 HPV Vaccine in Men Quadrivalent vaccine shown to be effacacious in decreasing external lesions Quadrivalent vaccine shown to be effacacious in decreasing external lesions 2009 FDA approval for males 9-26 years 2009 FDA approval for males 9-26 years Direct benefit to reduce condyloma and penile intraepithelial neoplasia Direct benefit to reduce condyloma and penile intraepithelial neoplasia Indirect benefit to women Indirect benefit to women Questionable cost effectiveness Questionable cost effectiveness Gardasil Prescribing Information, Merck, December 2007. Schmiedeskamp MR, et al. Ann Pharmacother. 2006;40:1344-1352. Gardasil Prescribing Information, Merck, December 2007. Schmiedeskamp MR, et al. Ann Pharmacother. 2006;40:1344-1352. *As of December 2008.

23. 23 HPV Vaccine in Special Populations Pregnancy-limited information Pregnancy-limited information Category B Category B HIV HIV No specific recommendations or contraindications No specific recommendations or contraindications Gardasil Prescribing Information, Merck, December 2007. Schmiedeskamp MR, et al. Ann Pharmacother. 2006;40:1344-1352. Gardasil Prescribing Information, Merck, December 2007. Schmiedeskamp MR, et al. Ann Pharmacother. 2006;40:1344-1352...

24. 24 Guidelines for Management of HPV Infection CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94. Screening

25. 25 Guidelines for Management of HPV Infection Screening

26. 26 Guidelines for Management of HPV Infection CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94. Treatment

27. 27 Goals for the Treatment of External Genital Warts Left untreated, genital warts may resolve, remain unchanged, or increase in number Primary treatment goal is the eradication of visible warts and the induction of wart-free periods Additional goals for treatment include the potential to reduce – HPV infection – HPV infectivity CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94.

28. 28 Patient-applied Therapies Imiquimod Podofilox Aldara Prescribing Information, Graceway Pharmaceuticals; November 2007. Condylox ® 0.5% (podofilox gel) Prescribing Information. Watson Pharmaceuticals; November 2007. Aldara Prescribing Information, Graceway Pharmaceuticals; November 2007. Condylox ® 0.5% (podofilox gel) Prescribing Information. Watson Pharmaceuticals; November 2007.

29. 29 Provider-administered Therapies Cryotherapy Podophyllin resin TCA/BCA Surgical removal CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94. Lacey CJN, et al. J Clin Virol. 2005;32(Suppl 1):S82-S90. CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94. Lacey CJN, et al. J Clin Virol. 2005;32(Suppl 1):S82-S90.

30. 30 Alternative Therapies Used to Treat External Genital Warts Interferons Laser surgery CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94. Beutner KR, et al. Am J Med. 1997;102(5A):28-37. CDC, et al. MMWR Recomm Rep. 2006;55(RR-11):1-94. Beutner KR, et al. Am J Med. 1997;102(5A):28-37.

31. Contact SBarclift@hrsa.gov 301-443-0523