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Pap Smear, HPV and HPV Vaccine

Pap Smear, HPV and HPV Vaccine. Peggy JB Scurry, MD, Ph.D. FACOG, FACS Assistant Professor & Chief of Gynecology Howard University Department of Obstetrics & Gynecology http://pscurrymd.scurtek.net National Medical Association Annual Conference August 2007. Objectives.

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Pap Smear, HPV and HPV Vaccine

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  1. Pap Smear, HPV and HPV Vaccine • Peggy JB Scurry, MD, Ph.D. FACOG, FACS • Assistant Professor & Chief of Gynecology • Howard University • Department of Obstetrics & Gynecology • http://pscurrymd.scurtek.net • National Medical Association Annual Conference • August 2007

  2. Objectives • After completing the lecture, participants should be able to: • Identify the risks of acquiring HPV infection • Describe the role of HPV in low-and high grade cervical lesions, cervical cancer and genital warts • Understand the appropriate clinical triage of patients with abnormal Pap smear results based on the Bethesda 2001 System and ACOG guidelines • Understand the efficacy of HPV DNA testing as an adjunct to conventional screening methods • Understand conservative management of abnormal pap smears for adolescents and menopausal women • Evaluate the new HPV Vaccine and counsel patients

  3. What are Common patient questions about HPV? • What is the difference between a Pap smear and an HPV test? • How do you get HPV? • How can I reduce the risk of getting HPV? • If I’m treated, can my partner reinfect me? • Does the diagnosis of HPV mean that my partner cheated? • Will I always have HPV? • How often should I be tested? • Is there a vaccine for HPV?

  4. Pap Smear Facts • More than 50 million Pap smears are performed on American women every year • With the use of Pap Smear screening programs, the incidence of cervical cancer has been reduced by 75% • False-negative reports are as high as 40% • One half of women who are diagnosed with cervical cancer have never had a Pap smear • An estimated 5 to 10% of Pap smears are interpreted as abnormal • ASCUS & LGSIL reports constitute over 95% of abnormal Pap smears

  5. Impact of the Bethesda System 2005

  6. Natural History of the Minimally Abnormal Pap Smear ASCUS LGSIL 53.8% 78.3% 18.2% 46.2% 3.4% Regress Persist Progress

  7. Comparison of ClassificationBethesda System Classic System Modified Pap

  8. Comparison of ClassificationSquamus Cell AbnormalitiesBethesda System Classic System Modified PAP

  9. Liquid Base Cytology • detection of cervical disease • Fewer cases of “obscuring features” and unsatisfactory test • More amenable to automation • Allows for reflex testing of residual fluid for High Risk HPV testing • Allows for chlamydia and GC testing from the liquid

  10. Why test for HPV? • It helps to clarify ambiguous cytology results and identifies persistent infection in women over 30 • HPV Testing, when combined with the Pap test, is more sensitive in determining the presence of disease than a pap test alone Manos MM. et al. JAMA. 1999:281:1605-1610. Clavel C. et al. Brit J Cancer. 2001:89:1616-1623.

  11. HPV • Nonenveloped double-stranded cicular DNA virus • Only effect epithelial cell • 100 types identified – species specific • 30-40 anogenital • 15-20 oncogenic types, including 16, 18, 31, 33, 35, 39, 45,51,52, 58 • HPV 16 (54%) and HPV 18 (13%) account for the majority of worldwide cervical cancers • Nononcogenic types include 6,11,40,42,43,44, • HPV 6 and 11 are most often associated with external anogenital warts HPV & Cervical Cancer, Merk Vaccine Div.,2005

  12. Education about HPV • HPV causes cervical cancer • 70% of women get HPV infections • Transmitted by skin to skin contact • HPV can remain dormant for years • Most HPV infections are usually transient & assymptomatic • HPV is not a disease, it is only a virus that may cause disease manifestations seen as CIN • While HPV is common, cancer is rare

  13. Education about HPV • About 70% of women of all ages will clear an HPV infection within 1 year • 90% of women will clear the infection within 2 yrs. • However, in adolescents (14-17yrs old) they required a longer time to clear, i.e. 12 mos and 3 yrs when compared to adults • This study found that only 3% of LGSIL progressed to high grade lesions by 36 mos. Lancet 2004:364:1678-83.

  14. HPV Epidemiology • HPV DNA has been found in 99.7% of cases of high-grade CIN and invasive cervical cancer • HPV detection is associated with a minimum 250X increased risk of HGSIL • HPV 16 is the most common cancer-associated HPV type:other types 18,31,33,35,39,51,52,56,58 • Persistent HPV infection produces chronic cervical dysplasia

  15. Pathogenesis of Cervical Cancer Persistent HPV Infection Cellular Dysregulation HPV Infection High-Grade CIN Immunologic Factors Invasive Cancer Co- carcinogens

  16. HPV Mode of Transmission • Sexual Intercourse • Non-penetrative Sexual activities • Perinatal transmission • Transmission through fomites • Early age of first intercourse • Multiple sex partners or partner with Msp • Smoke cigarettes • Oral Contraceptives

  17. Impact of Persistence of Oncogenic HPV Types • Persistent infection with high-risk HPV types is necessary for the development of CIN 3 • There is a strong relationship between persistent high-risk HPV infections (particularly with HPV 16 and `18) and SIL/HSIL incidence • Infections with high-risk types are more likely to persist than infections with low-risk types • A study of HPV persistence reported that HPV 16 infections persist longer than infections with other types • The persistence of high-risk types of HPV infections increases the risk of HSIL and is necessary for the development of CIN 3

  18. Why test only women 30 and older for HPV • HPV testing in women less than 30 is not effective due to high prevalence and transient infections • HPV prevalence decreases in women age 30 and older • Cervical cancer incidence increases for women age 30 and older Saslow D. et al. CANCER 52(6)342-362. Meikert PW. Et al. Int J Cancer. 1993.53.919-923.

  19. FDA Approval for HPV Testing • Two FDA- approved indications • Reflex testing ASCUS triage for women of any age with inconclusive Pap results • Primary adjunctive screening with a Pap test for women age 30 and older to detect the presence or absence of High-risk HPV

  20. HPV DNA Detection • Hybrid Capture 2 High-risk HPV Test • The Digene HPV Test • Commercially available, FDA approved • Two Probe mixing • High Risk – 16,18,31,33,35,39,45,51,52,56,58 • Low Risk – 6,11,42,43,44 • Sensitivity is about 5,000 copies of HPV-DNA

  21. Reflex HPV DNA Test Advantages • No need for patient to RTO for additional testing • Immediately inform patient of their risk status - reassurance if negative • Cost effective compared to other managements • More sensitive than cytology • More reproducible than cytology • Very high negative predictive value

  22. HPV FACTS • Most women will have HPV at some point, but very few will develop cervical cancer • Most HPV infections are temporary and go away on their own • Only HPV infections that do not go away over many years can lead to cervical cancer • While regular Pap tests have been successful in preventing many cervical cancers by finding cell changes early, some women at risk may be missed

  23. Management of Minimally Abnormal Pap • PAP nl cytology & (-) HPV = RS at 2- 3 yrs • PAP nl cytology & (+) HPV= Repeat 6-12 m • Risk of cervical cancer associated with extending the interval between cervical cancer screening (Women 30-64 yr) LESS Than 3 in 100,000 Excess risk of cervical cancer

  24. Management of Screen Positives • ASCUS may be managed by referral to immediate colposcopy, by repeat Pap smear, or by HPV testing. • Reflex HPV testing when ASCUS is derived from liquid based cytology has advantage • ASCUS (+) & HPV + Colposcopy • ASCUS (+) & HPV - Repeat Pap @ 12 mos

  25. Management of Screen Positives • Initial management of all other Pap abnormalities is by immediate referral to colposcopy • finding of atypical squamous cells cannot rule out high-grade (ASC-H), atypical glandular cells (AGC), LGSIL, and high-grade intraepithelial lesions (HGSIL)

  26. Adolescents & LGSIL • Best to be less aggressive with treatment • A large percentage of lesion regress spontaneously • Intervention treatment leads to: • *Increase risk of Preterm Labor • *Low birth weight infants • *Cervical Incompetence • *Detrimental to future fertility

  27. Management of Screen Positives • CIN 2/3 should usually be treated, both guidelines say. • The only exception is the adolescent with CIN 2, who may be followed with repeat cytology and colposcopy at 4 to 6 months if she is deemed reliable for follow-up, the colposcopy is adequate, and the endocervical sampling negative

  28. Management of Screen Positives • Women treated for CIN 2/3 can be monitored after treatment by cytology screening at 6 month intervals 3 or 4 times or by a single HPV test at 6 month, before returning to annual screening. • Any repeat abnormal Pap at the threshold of ASCUS or more advanced abnormality or a positive HPV test requires colposcopic evaluation

  29. Management of Screen Positives • An excisional procedure is required for abnormal findings, or an unsatisfactory colposcopy in non pregnant women referred for atypical glandular cells “favor neoplasia” (AGC-H), or adenocarcinoma in situ (AIS), or repeat atypical glandular cell “not otherwise specified: (AGC-NOS), or HGSIL. • The only exception is an adolescent with HGSIL cytology and a satisfactory and normal colposcopy and biopsy, who may be followed closely

  30. Genital Warts - Diagnosis • Diagnosis of genital warts are made by visual inspection • The use of HPV tests is not indicated for the routine diagnosis or management of visible genital warts • A genital warts diagnosis may be confirmed by biopsy, although biopsy is needed only in certain circumstances • HPV 6 and 11 are most often associated with nononcogenic types of external anogenital warts

  31. Genital Warts - Treatment • If left untreated, genital warts may resolve on their own, remain unchanged or increase in size or number • The primary goal of treating visible genital warts is removal for cosmetic reasons • In most patients, treatment can remove warts however, recurrences are frequent • Some patients may forego treatment as genital warts may resolve on their own

  32. Genital Warts - Treatment Regimens • A number of treatment options are available for visible genital warts • Factors which may influence the selection of treatment include patient preference, available resources, provider experience, the size, number, anatomic site, and morphology of warts and the cost, convenience, and adverse effects of treatment • Providers should have at least one patient-applied and one provider applied treatment

  33. Patient-Applied Treatments Podofilox 0.5% solution or gel Imiquimod 5% cream Provider-Applied Treatments Cryotherapy Podophyllin resin Trichloroacetic Acid or Bichloroacetic Acid 80%-90% Surgical Removal by electrosurgery Genital Warts - Recommended Treatment Regimens

  34. HPV Vaccines • HPV Vaccines will stop CIN 2/3 and cancer • The HPV 16 vaccine provided 100% protection against development of HPV 16 related CIN 2/3 during an average of 3.5 yrs of follow-up • Although the target is children, many women will want HPV vaccination – creating a “catch-up challenge for doctors

  35. The Digene HPV Test • Test for a panel of the 13 most common HPV types known to cause cervical cancer, but does not report of individual types • Digene is nearly ready to launch a 16, 18, 45 type-specific “reflex” test (to a positive Hybrid Capture 2 HPV panel) • Roche is preparing to get its type-specific Linear Array HPV test approved

  36. Quadrivalent 6,11,16,18 trial AKA Gardasil • The study reached an average of 3.5 years of follow-up • CIN 2/3 developed in 12 of the 750 women receiving placebo, in contrast to none of the 755 vaccine recipients • It may be that if an immune response has not been mounted, the vaccine may still have a positive effect for women already HPV 16 infected

  37. Quadrivalent HPV Vaccine • Protects against four HPV types (6,11,16,18) • These HPV types are responsible for 70% of cervical cancers & 90% of genital warts • The vaccine is admin thru a series of injections over a six month period (at 1,2 and 6 months) • Current studies indicate the vaccine is effective for at least five years (with 5 yr follow-up) • The private sector list price of the vaccine is $120 per dose (about $360 for the full series)

  38. Quadrivalent HPV Vaccine • Testing for HPV is currently not recommended before vaccination • Testing for HPV DNA would not identify past HPV infections, only current HPV infections • The vaccine is a preventive tool and is not a substitute for cancer screening • The quad HPV vaccine has been classified by the FDA as pregnancy category B • Its use in pregnancy is not recommended • Lactating women can receive the vaccine • It is not known whether vaccine Ag or Ab found in the vaccine are excreted in human milk

  39. Quadrivalent HPV Vaccine • Vaccination of women older than 26 yrs and males is currently under way. • The presence of immunosuppression is not a contraindication to the vaccine • However, the immune response may be smaller than in the immunocompetent patient • Women with previous HPV infection will benefit from protection against disease caused by the HPV vaccine genotypes with which they have not been infected

  40. Quadrivalent HPV Vaccine • Genital infection with low-risk types of HPV is associated with genital warts in men • Infection with high-risk types of HPV is associated preinvasive squamous lesions of the penis (penile intraepithelial neoplasm or PIN) and with penile cancer and anal intraepithelial neoplasia or AIN and with anal cancer

  41. Who will be vaccinated? • The primary target group for the HPV vaccine is young people from 9-26 yrs old & before sexual encounter • Many women already sexually active will likely want to be vaccinated

  42. Quadrivalent vaccine 100% - 99.7% effective! • The trial became center stage in the world media in early Oct. 2005, with headlines such as first anti-cancer vaccine 100% effective. • The results were truly astounding, as there were no CIN 2/3 cases in the Per Protocol group, among the 5,301 women vaccinated, in contrast to 21 cases in the 5,258 women who received the placebo

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