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HPV and Infectious Disease HHD 2015 Joel Palefsky, M.D. Professor of Medicine UCSF Infectious Virus Particle of HPV1,2 Capsid proteins: L1 L2 Viral DNA Viral exterior 1. Baker TS, et al. Biophys J. 1991;60:1445–1456. 2. Chen XS, et al. Mol Cell. 2000;5:557–567. Viral interior Estimated Annual Burden of HPV-Related Diagnoses in the United States 9,710 new cases of cervical cancer1 3,700 deaths estimated in 20061 330,000 new cases of high-grade cervical dysplasia (CIN 2/3)2 1.4 million new cases of low-grade cervical dysplasia (CIN 1)2 1 million new cases of genital warts3 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. Oncogenic HPV types 16, 18, 31, 33, 35 39, 45, 51, 52, 56, 58, 70 Non- oncogenic HPV types HPV 6, 11- genital warts HPV 1, 2 and 4- plantar and palmar warts HPV Infection and Productive Life Cycle Virus introduced through microabrasion Infectious virions shed Virion assembly Viral DNA replication Late HPV protein production L1 & L2 Virus infection Early HPV protein production E1, E2, E4, E5, E6, & E7 Adapted from Doorbar J. J Clin Virol. 2005;32S:S7–S15. E6 leads to degradation of p53 p53 E6-AP X Ubiquitin E6 Ubiquitin Binding of E7 to RB releases E2F E2F E7 RB RB E7 Cell Cycle E2F 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 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 E5 and EGF EGF EGF EGF EGF EGF E5 EGF EGF EGF EGF EGF EGF EGF EGF 2-tiered system: LSIL & HSIL Reflects HPV biology and clinical management Infection Precancer HPV infection Low-grade CIN High-grade CIN Cervical cancer Schiffman, MH. J Natl Cancer Inst. 1992; 84:394-98 HPV testing for screening • • • Cervical cytology has limited sensitivity 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 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 Incidence of oropharynx and cervical cancers Chaturvedi A et al. J Clin Oncol 2011; 29: 4294-4301 22 Incidence of HPV-positive and HPV-negative oropharynx cancers Chaturvedi A et al. J Clin Oncol 2011; 29: 4294-4301 23 Penile cancer About 40% of cases are HPVrelated • 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 dysfunction4 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 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 28 Anal cancer rates in North American AIDS Cohort Collaboration on Research and Design) (NA-ACCORD) 1996-2007 Incidence/100,000 (85% CI) •HIV-infected • • • MSM MSW Women 131 (109-157) 46 (25-77) 30 (17-50) Silverberg M et al. CID, e-pub Jan 2012 Prevalence of AIN among MSM Prevalence, % Population-based data All participants HIV-negative participants HIV-positive participants Chin-Hong et al. Ann Int Med. 2008;149;300-6. 30 Anal and cervical HPV infection in HIV-positive women 90 80 70 60 50 40 30 20 10 0 Anal Cervical HIV- HIV+ CD4 HIV+ CD4 HIV+ CD4 <200 200-500 >500 Palefsky JM et al. J Infect Dis. 2001;183:383-391. San Francisco Giants 2010, 2012 and 2014 World Series Champions 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 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 Treatment of low-grade lesions Most clinicians would follow carefully without treatment since many resolve spontaneously Treatment of cervical high-grade lesions Loop electroexcision procedure Cryotherapy Surgical cone biopsy Laser The nonavalent HPV vaccine Schiller J. Lancet Oncol 2015;16(5):e217-25 Quadrivalent vaccine in males: efficacy against HPV 6/11/16/18-related external genital lesions (HM+MSM)1 Per-Protocol Efficacy Population 50 Related Cases 40 Quadrivalent vaccine 90.6% Reduction (70, 98) Placebo 32 30 20 10 3 0 n=1,394 n=1,404 HPV 6-, 11-, 16-, or 18-Related External Genital Lesions 1Giuliano A, Palefsky J et al. NEJM 2011 Feb 3;364(5):401-11 42 Quadrivalent vaccine in males: efficacy against HPV 6/11/16/18-related AIN and anal cancer in MSM1 Per-Protocol Efficacy Population 50 Quadrivalent vaccine Placebo Related Cases 40 30 77.5% Reduction (40, 93) 24 20 10 5 0 n=194 n=208 HPV 6-, 11-, 16-, or 18-Related AIN and Anal Cancer n = number of subjects who have at least 1 follow-up visit after month 7. 1Palefsky J, Giuliano et al. NEJM 2011, 365: 1576-85 44 The nonavalent HPV vaccine MMWR / March 27, 2015 / Vol. 64 / No. 11 ACIP recommendations for HPV vaccine in women • 9vHPV, 4vHPV or 2vHPV can be used for: • • • 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 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 HPV vaccination of men Vaccine approved for routine use in boys and men age 9-21 years to prevent HPV 6/11related 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 s Ali et al, BMJ 2013 HPV prevalence in the pre- and post-HPV vaccination eras Markowitz L et al. JID 2013; 208: 383-93 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 The future Implementation of vaccine in developing countries Two-dose vs. three dose International research program Joel Palefsky, M.D., Program director www.ddcf.org [email protected] 415-476-1574