Learning Objectives. What is HPV? Incidence in the U.S. 5/22/2013. Human papillomavirus Infections

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Human papillomavirus Infections Anne Rompalo, MD, ScM Professor of Medicine Learning Objectives By the end of the presentation the participants will be able to: Describe the role of persistent HPV

recommended guidelines should not be applied. (exceptions to the screening guidelines) What is HPV?

1 Human papillomavirus Infections Anne Rompalo, MD, ScM Professor of Medicine Learning Objectives By the end of the presentation the participants will be able to: Describe the role of persistent HPV infection in the development of cervical cancer Discuss the cervical cancer screening recommendations of the USPSTF, ACOG and the American Cancer society Describe the clinical situations when the recommended guidelines should not be applied. (exceptions to the screening guidelines) What is HPV? What is HPV? Pathogenesis Double stranded DNA virus that belongs to the Papovaviridae family Genital types have specific tropism (affinity) for genital skin and mucosa HPV infects stratified squamous epithelium and stimulates cellular proliferation Affected cells display a broad spectrum of changes ranging from benign hyperplasia to dysplasia to invasive carcinoma. 3 4 Epidemiology Incidence in the U.S. Genital HPV is one of the most common STDs. Estimated 20 million people currently have a detectable genital HPV infection. A recent estimate suggests 80% of women will have acquired genital HPV by the age of 50. Percent infected Most women become infected with HPV soon after beginning intercourse Months from first intercourse 5 Winer RL et al. Am J Epidemiol Feb 1;157(3):

HPV GENOTYPES HPV types are divided into 2 groups based on their association with cervical cancer: Epidemiology Low risk types associated with genital warts and mild Pap test abnormalities Low Risk

cervical cancer High Risk HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 Precancer cervical changes Cervical/penile cancer Anal and other cancers 7 1. Cox.

2 HPV GENOTYPES HPV types are divided into 2 groups based on their association with cervical cancer: Epidemiology Low risk types associated with genital warts and mild Pap test abnormalities Low Risk Common HPV Types HPV Types HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 Lead to: Benign cervical changes Genital warts High risk types associated with mild to severe Pap test abnormalities and cervical cancer High Risk HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 Precancer cervical changes Cervical/penile cancer Anal and other cancers 7 1. Cox. Baillière s Clin Obstet Gynaecol. 1995;9:1. 2. Munoz et al. N Engl J Med. 2003;348:518. Natural History of HPV Most genital HPV infections are transient, asymptomatic, or subclinical, and have no clinical consequences in immunocompetent individuals. The incubation period is unclear. The median duration of new cervical infections is 8 months but varies by type. 90% of women clear in 2 years. Gradual development of an effective immune response is the likely mechanism for HPV DNA clearance. Most women with high risk HPV have normal Pap test results and never develop precancerous cell changes. Pathogenesis Natural History of HPV Pathogenesis Persistent infection is infection that is not cleared by the immune system and is characterized by persistently detectable HPV DNA. HPV infection that persists is the most important factor for precancerous cervical cell changes and cervical cancer. Most women with persistent HPV infection do not develop cervical cancer precursors or cervical cancer Stages of Cancer Progression Epidemiology Transmission of Genital HPV Predominantly associated with sexual activity Can occur from asymptomatic and subclinical patients Infectivity after treatment of genital warts or cervical cell abnormalities is unknown Wright & Schiffman, NEJM

3 Risk Factors for Women Young age Sexual behavior Risk increases with increasing lifetime number of male sex partners Early age of first sexual intercourse Sexual behavior of male sex partners risk increases for women whose sex partners had multiple sex partners Epidemiology Risk Factors for Men Greater lifetime number of sex partners Greater number of recent sex partners Being uncircumcised Epidemiology Immune status HPV more likely to be detected in immune suppressed women and Sequelae In most cases, genital HPV infection is transient and has no clinical manifestations or sequelae. Clinical manifestations of genital HPV infection include: Genital warts Cervical cell abnormalities Anogenital squamous cell cancers HPV Associated Cancer US Site Total Cancers # Cases Attributable to HPV (%) Cervix 11,150 11,150 (100) Penis 1, (40) Vulva/Vagina 5,630 2,252 (40) Anus 4,650 4,185 (90) Airway 24,540 6,380 (26) TOTAL 47,250 24,479 (12) 15 American Cancer Society. Cancer Facts and Figures. 2007; Parkin DM. Vaccine Diagnosis of Genital Warts Diagnosis is usually made by visual inspection with bright light. Diagnosis can be confirmed by biopsy when: Diagnosis is uncertain Patient is immunocompromised Warts are pigmented, indurated, or fixed Lesions do not respond or worsen with standard treatment There is persistent ulceration or bleeding Diagnosis Genital Warts: Symptoms Genital warts usually cause no symptoms other than the warts themselves. Vulvar warts dyspareunia, pruritis, burning discomfort Penile warts occasional itching Urethral meatal warts occasional hematuria or impairment of urinary stream Vaginal warts usually asymptomatic; occasional discharge/bleeding, obstruction of birth canal (secondary to increased wart growth during pregnancy) Perianal warts usually asymptomatic; pain, bleeding on defecation, itching Most patients have fewer than 10 genital warts, with total wart area of cm

Genital Warts: Appearance Condylomata acuminata Cauliflower like appearance Skin colored, pink, or hyperpigmented May be keratotic on skin; generally non keratinized on mucosal surfaces Smooth

4 Genital Warts: Appearance Condylomata acuminata Cauliflower like appearance Skin colored, pink, or hyperpigmented May be keratotic on skin; generally non keratinized on mucosal surfaces Smooth papules Usually dome shaped and skin colored Flat papules Macular to slightly raised Flesh colored, with smooth surface More commonly found on internal structures (i.e., cervix), but also occur on external genitalia Keratotic warts Thick horny layer that can resemble common warts or seborrheic keratosis 19 Perianal Warts Source: Seattle STD/HIV Prevention Training Center at the University of Washington/ UW HSCER Slide Bank 20 Vulvar Warts Penile Warts Source: Reprinted with permission of Gordon D. Davis, MD. 21 Source: Cincinnati STD/HIV Prevention Training Center 22 Differential Diagnosis of Genital Warts Other infections Diagnosis Condylomata lata tend to be smoother, moist, more rounded, and darkfield positive for Treponema pallidum Molluscum contagiosum papules with central dimple, caused by a pox virus; rarely involves mucosal surfaces Differential Diagnosis of Genital Warts Acquired dermatologic conditions Seborrheic keratosis Lichen planus Fibroepithelial polyp, adenoma Melanocytic nevus Neoplastic lesions Normal anatomic variants Pink pearly penile papules Vestibular papillae (micropapillomatosis labialis) Skin tags (acrochordons) Diagnosis

Frequency of spontaneous regression is unclear.

General Treatment of Genital Warts Management Primary goal is removal of symptomatic warts.

5 Warts or Not??? Genital Warts: Duration May regress spontaneously or persist with or without proliferation. Frequency of spontaneous regression is unclear. Persistence of infection occurs, but frequency and duration are unknown. Recurrences after treatment are common. General Treatment of Genital Warts Management Primary goal is removal of symptomatic warts. If left untreated, genital warts may regress spontaneously or persist with or without proliferation. In most patients, treatment can induce wart free periods. Currently available therapies may reduce, but probably do not eradicate infectivity. Effect of current treatment on future transmission is unclear

6 General Treatment of Genital Warts Management Treatment Regimens Management No evidence that presence of genital warts or their treatment is associated with development of cervical cancer. Some patients may choose to forgo treatment and await spontaneous resolution. Consider screening persons with newly diagnosed genital warts for other STD (e.g., chlamydia, gonorrhea, HIV, syphilis). Patient applied and provider administered therapies are available. Providers should be knowledgeable about and have available at least 1 patient applied and 1 provideradministered treatment. Choice of treatment should be guided by: The preference of the patient The available resources The experience of the healthcare provider Management Recurrence Up to 2/3 of patients will experience recurrences of warts within 6 12 weeks of therapy; after 6 months most patients have clearance. If persistent after 3 months, or if there is poor response to treatment, consider biopsy to exclude a premalignant or neoplastic condition, especially in an immunocompromised person. Treatment modality should be changed if patient has not improved substantially after 3 provideradministered treatments or if warts do not completely clear after 6 treatments. Partner Management for Patients with Genital Warts Sex partner examination is not necessary. Prevention Providing treatment solely for the purpose of preventing future transmission cannot be recommended. The counseling of sex partners provides an opportunity for these partners to: Learn about the implications of having a partner who has genital warts and about the potential for future disease transmission. Receive STD and Pap screening if necessary Anogenital Squamous Cell Cancers HPV infection is causally associated with cervical cancer and probably other anogenital squamous cell cancers (e.g., anal, penile, vulvar, vaginal). Over 99% of cervical cancers have HPV DNA detected within the tumor. Persistent infection with a high risk HPV type is necessary but not sufficient for the development of cervical cancer. 35 HPV Prevalence (%) Women with HR HPV Are at Risk of Developing Cervical Cancer High Risk HPV Types (hc2) Cancer Sellors et al. CMAJ. 2003;168:421. Age (Years) 2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, Cancer Incidence per 100,000 6

Cervical Cell Abnormalities Usually subclinical Detected by Pap test, colposcopy, or biopsy Usually caused by high risk HPV types Most of the time high risk HPV types do not cause any abnormalities.

Often regress spontaneously without treatment Diagnosis of Cervical Cell Abnormalities Cytology (Pap test) Useful screening test to detect cervical dysplasia Diagnosis Provides indirect evidence of

7 Cervical Cell Abnormalities Usually subclinical Detected by Pap test, colposcopy, or biopsy Usually caused by high risk HPV types Most of the time high risk HPV types do not cause any abnormalities. Most women infected with high risk HPV types have normal Pap test results. Often regress spontaneously without treatment Diagnosis of Cervical Cell Abnormalities Cytology (Pap test) Useful screening test to detect cervical dysplasia Diagnosis Provides indirect evidence of HPV because it detects squamous epithelial cell changes that are almost always due to HPV Obtaining the Pap Smear Normal Cervix Bethesda System ACOG Pap Screening Guidelines First Screen Age of 21 Women up to age 30 Every three years Women age 30 and older 3 negative results on Pap tests - rescreen with cytology every 3 years OR Cytology + HR HPV test. If both are negative, rescreen in 5 years. Any patient with a history of high grade dysplasia must do annual screening x 20yrs 7

When to start American Cancer Society & USPSTF 2012 Annual?

extend q 5 years No HPV co test < 30 years Stop >65 years or total hysterectomy

Abnormalities Indication for colposcopy is guided by physical exam or Pap test

Current guidelines define adequate screening as three consecutive negative

cessation of screening, with the most recent test performed within 5 years

8 When to start American Cancer Society & USPSTF 2012 Annual? Screening Methods and Intervals Age 21 No Cytology: 21 65: q 3 years 30 65: Can extend q 5 years No HPV co test < 30 years Stop >65 years or total hysterectomy If vaccinated No change in recommendations Diagnosis Diagnosis of Cervical Cell Abnormalities Indication for colposcopy is guided by physical exam or Pap test findings with or without HPV DNA test findings. Current guidelines define adequate screening as three consecutive negative cytology results or two consecutive negative co tests within 10 years before cessation of screening, with the most recent test performed within 5 years Indications for cervical biopsy include: Visible exophytic lesions on the cervix Pap test with ASCUS, +HRHPV LGSIL or greater 44 Colposcopy Colposcopy of Cervix 8

9 Cervical Intraepithelial Neoplasia Dysplasia Natural History Biopsy Regress Persist Progress to CIN 3 Progress to Cancer CIN1 57% 32% 11% <1% CIN2 43% 35% 22% 5% CIN3 32% 56% N/A 12% Ostor AG. Int J Gyn Path LEEP: Loop Electrical Excision Procedure Cone Biopsy Cone Biopsy 9

HPV VACCINE Gardasil (Merck) The HPV Vaccine Protects against types 16, 18, 6, 11 FDA approved for use in males and females 9 26 years of age Prevents HPV infection; doesn t treat existing infection

HPV Type Distribution in Women with Squamous Cervical Cancer 4% 4% Others 21% HPV 16 15% 56% HPV 18 HPV 45 HPV 31 Additional Vaccinations The cervical cancer vaccination is given over 3 visits.

Today Vaccination 1 Month 2 Vaccination 2 Month 6 Vaccination 3 Vaccination Complete Follow up Pap tests 1. Clifford GM. Cancer Epidemiol Biomarkers Prev. 2005;14:1157-1164. 2. Munoz N et al. NEJM.

10 HPV VACCINE Gardasil (Merck) The HPV Vaccine Protects against types 16, 18, 6, 11 FDA approved for use in males and females 9 26 years of age Prevents HPV infection; doesn t treat existing infection Virus like particles (VLP) Highly effective Safe, few serious adverse side effects Requires 3 injections Expensive ($360 + administrative fees) Smith, RA et al. Cancer. 2003;53(1): HPV Type Distribution in Women with Squamous Cervical Cancer 4% 4% Others 21% HPV 16 15% 56% HPV 18 HPV 45 HPV 31 Additional Vaccinations The cervical cancer vaccination is given over 3 visits. Today, then in about 2 months and then in about 4 months. It is not known at this time whether booster shots will be needed. Today Vaccination 1 Month 2 Vaccination 2 Month 6 Vaccination 3 Vaccination Complete Follow up Pap tests 1. Clifford GM. Cancer Epidemiol Biomarkers Prev. 2005;14: Munoz N et al. NEJM. 2003; 348(6): HPV Vaccine Important Considerations Vaccine is most effective before first sexual intercourse less effective in sexually active women Pap Test Still Necessary Normal Pap smear HPV testing before vaccine not recommended Vaccine is not a treatment for current HPV infection, genital warts, or pre cancer Abnormal Pap smear Human Papillomavirus Vaccination. ACOG Committee Opinion No ; 108:

11 Patient Counseling and Education Patient Counseling and Education The Nature of HPV Infection Genital HPV infection is common in sexually active adults. Incubation period is variable, and it is often difficult to determine the source of infection. Natural history of HPV infection is usually benign: Low risk genital HPV types are associated with mild Pap test abnormalities and genital warts. High risk types are associated with mild to severe Pap test abnormalities and, rarely, cancers of the cervix, vulva, anus, and penis. Most women infected with high risk HPV types have no Pap test abnormalities and do not develop cervical cancer. Genital warts have a high recurrence rate after treatment Counseling Women with HPV Remind your patient that: Most women will have HPV at some point There is no way of knowing how long HPV has been present Having HPV is not a sign of infidelity Counseling Women with HPV Most women who have HPV do not develop abnormal cells of cancer Women who have HPV in their cells a long time are at greater risk for developing abnormal cells or cancer Patient Counseling and Education Transmission Issues Determining source of infection is usually difficult. Recurrences usually are not re infection. Transmission risk to current and future partners is unclear. Abstinence and long term mutual monogamy with an uninfected partner are the most effective options to prevent transmission. Likelihood of transmission and duration of infectivity with or without treatment are unknown. Value of disclosing a past diagnosis of genital HPV infection to future partners is unclear, although candid discussions about past STD should be encouraged. 65 Risk Reduction Patient Counseling and Education Assess patient s behavior change potential. Develop individualized risk reduction plans with the patient for lasting results. Discuss prevention strategies such as abstinence, mutual monogamy with an uninfected partner, condoms, limiting number of sex partners, etc. While the effect of condoms in preventing HPV infection is unknown, condom use has been associated with lower rates of genital warts and cervical cancer, both HPV associated diseases. HPV infections can occur in male and female genital areas that are not covered by a latex condom, as well as in areas that are covered

12 HPV Awareness: National Cancer Institute Survey WHAT IS YOUR HPV IQ? NCI sponsored random telephone interview of adults All women (3,500) asked about HPV Only 38% had never heard of human papillomavirus or HPV Of these, only 47% were aware that HPV causes cervical cancer NCI Website What percent of sexuallay active adults are infected with genital HPV during their lifetime? 10% 25% 40% 50% All of the following are true about transmission of genital HPV, except Transmission is associated with sexual activity Transmission via fomites has been documented Transmission can occur from asymptomatic and subclinical patients Transmission most likely requires contact with viable HPV and microtrauma of skin/mucous membranes The HPV types accounting for more than half of genital cancers are 6 and 11 6 and and and 16 Which is the most important risk factor associated with development of cervical precancer/cancer? Older age High risk HPV types Persistence of HPV infection Immunodeficiency

13 If left untreated, visible warts may Resolve on their own Remain unchanged Most genital HPV infections are transient and have no clinical manifestations or sequelae True False Increase in size and number All of the above Patient counseling and education should cover The nature of HPV infection Transmission issues Risk reduction All of the above All of the following are appropriate patient education messages about the nature of HPV infection except: Genital HPV is a viral infection which is one of the most common STDs High risk HPV types are associated with external genital warts Genital warts have a high recurrence rate after treatment The majority of women with hi risk HPV types do not develop cervical cancer Which of the following is correct about partner management for patients diagnosed with genital warts? Sex partner examination is not necessary because no data indicate that reinfection plays a role in recurrences Providing treatment solely for the purpose of preventing future transmission cannot be recommended because the value of treatment in reducing infectivity is not known The counseling of sex partners provides an opportunity for partners to learn about genital warts/transmission and to obtain STD and pap screening All of the above The presence of genital warts is an indication for Change in Pap test frequency Cervical colposcopy Both of the above Neither of the above

14 You have a new FP patient that is 18 years old and has been sexually active for 3 years. She has never had a Pap test. What do you recommend for Pap screening? Do a Pap smear today and q year. Do a Pap smear today and every other year. Do a Pap smear at age 21 years old and q year. Do a Pap smear at age 21 and every three years. Your FP patient is 29 years old. Her last Pap smear was normal 1 year ago. She was treated for moderate dysplasia with cryosurgery 5 years ago. When is her next pap due? Today and every other year. Next year and every other year. Today and every year. Next year and then every three years

Human Papilloma Viruses HPV Testing and Treatment of STDs

Human Papilloma Viruses HPV Testing and Treatment of STDs New York State Collaborative Efforts in Medical Evaluations of Child and Adolescent Sexual Offenses. Child and Adolescent Sexual Offense Post-Assault