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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
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
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


What are common patient questions about hpv
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?


Pap smear facts
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



Natural history of the minimally abnormal pap smear
Natural History of the Minimally Abnormal Pap Smear

ASCUS LGSIL

53.8% 78.3% 18.2%

46.2% 3.4%

Regress

Persist

Progress


Comparison of classification bethesda system classic system modified pap
Comparison of ClassificationBethesda System Classic System Modified Pap


Comparison of classification squamus cell abnormalities bethesda system classic system modified pap
Comparison of ClassificationSquamus Cell AbnormalitiesBethesda System Classic System Modified PAP


Liquid base cytology
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


Why test for hpv
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.


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


Education about hpv
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


Education about hpv1
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.


Hpv epidemiology
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


Pathogenesis of cervical cancer
Pathogenesis of Cervical Cancer

Persistent

HPV Infection

Cellular

Dysregulation

HPV Infection

High-Grade CIN

Immunologic

Factors

Invasive Cancer

Co- carcinogens


Hpv mode of transmission
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


Impact of persistence of oncogenic hpv types
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


Why test only women 30 and older for hpv
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.


Fda approval for hpv testing
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


Hpv dna detection
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


Reflex hpv dna test advantages
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


Hpv facts
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


Management of minimally abnormal pap
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


Management of screen positives
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


Management of screen positives1
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)


Adolescents lgsil
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


Management of screen positives2
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


Management of screen positives3
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


Management of screen positives4
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


Genital warts diagnosis
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


Genital warts treatment
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


Genital warts treatment regimens
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


Genital warts recommended treatment regimens

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


Hpv vaccines
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


The digene hpv test
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


Quadrivalent 6 11 16 18 trial aka gardasil
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


Quadrivalent hpv vaccine
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)


Quadrivalent hpv vaccine1
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


Quadrivalent hpv vaccine2
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


Quadrivalent hpv vaccine3
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


Who will be vaccinated
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


Quadrivalent vaccine 100 99 7 effective
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



Gardasil and cervarix vaccines
Gardasil and Cervarix vaccines

  • Now the challenge will be in getting the population vaccinated. Merck has its Gardasil Quadrivalent vaccine on the market

  • GlaxoSmithKline expects to put cervarix Bivalent HPV 16,18 vaccine on the market in late 2007


How hpv vaccine will and won t change practice
How HPV vaccine will and won’t change practice

  • We will continue screening long after the advent of multivalent HPV vaccines

  • To prevent the 30% of cancers linked to high-risk HPV types that are not in the vaccine

  • To protect the unvaccinated

  • To protect the previously HPV infected pt


Cervical screening will continue but will be more accurate and more efficient
Cervical screening will continue, but will be more accurate and more efficient

  • We are on the verge of reducing the risk of cervical cancer to close to zero, but it will take decades

  • Vaccinating young girls will not significantly reduce cervical cancer rates until these girls reach the median ages of microinvasive and invasive cervical cancer


Cervical cancer rates will depend on these factors
Cervical cancer rates will depend on these factors and more efficient

  • The extent of vaccination coverage

  • The number of high-risk HPV types in the vaccine

  • Whether vaccination provides multidecade protection or falls off with time

  • Whether the medical community and the public continue to diligently follow recommended screening guidelines


Fewer abnormal paps
Fewer abnormal Paps and more efficient

The vaccine will likely steadily decrease the rate of abnormal paps that are important, as an increasing proportion of women are vaccinated against the 2 most common types in high-grade CIN

Colposcopies and cervical treatment will decline in number with the proportion of the populated vaccinated


Specific testing
Specific testing and more efficient

  • Finding women with significant abnormalities may more and more be accomplished with the accuracy afforded by testing for specific HPV types known to be most at risk for CIN 3


Improving folate status protects against hpv
Improving folate status protects against HPV and more efficient

  • Improving folate status in women at risk of getting infected or already infected with high-risk HPV may help prevent cervical cancer.

  • It is reasonable to advise women with HPV that folate supplements may be helpful

  • Women with higher folate status were significantly less likely to be repeatedly HPV positive over a 2 year follow-up


Questions
Questions and more efficient

  • 1. The development of cervical cancer is thought to require which of the following?

    • a. Infection with any human papillomavirus

    • b. Persistent infection with select HPV types

    • c. Sustained immune deficiency

    • d. Prolonged use of oral contraceptives


Questions1
Questions and more efficient

  • 2. The 2001 Consensus Guidelines for women with cervical abnormality recommends which modality as the preferred approach to manage patients with an ASCUS Pap result?

    • A. Repeating the pap test times 2

    • B. Testing for high-risk types of HPV

    • C. Immediate coloposcopy

    • D. Follow closely


Questions2
Questions and more efficient

  • 3. The CDC estimates what percent of sexually active women will be infected with HPV by the age of 50.

    • A. 50%

    • B. 60

    • C. 70%

    • D. 80%


Questions3
Questions and more efficient

  • 4. Which of the following were associated with HPV vaccine acceptance among young women.

    • A. Knowledge about HPV and the vaccine

    • B. Belief that others would approve of vaccination

    • C. Perceived support from health care providers, partners

      and parents

      --D. All of the above.


Questions4
Questions and more efficient

  • 5. Ms. Smith claims she has been in a monogamous relationship for several years. She cannot understand why she has recently developed an uncomfortable cauliflower like lesion on the labia majora. She is concerned that her sex partner has been unfaithful recently. She believes that a positive HPV infection is an indication of infidelity. Ms. Smith’s belief is likely to be correct.

    A. True

    • False


Questions5
Questions and more efficient

  • 6. Among women, risk of acquiring HPV infection is most strongly associated with which of the following?

    A. Smoking

    B. Number of full-term pregnancies

    C. Number of life time sexual partners

    D. Immunosupression


Questions6
Questions and more efficient

  • 7. Most HPV infections resolve spontaneously and cause no symptoms.

    A. True

    B. False


Questions7
Questions and more efficient

  • 8. HPV 16 and 18 together cause what proportion of cervical cancers?

    A. 40%

    B. 50%

    C. 60%

    D. 70%


Questions8
Questions and more efficient

  • 9. What two HPV types are responsible for nearly 97% of genital warts?

    A. HPV 6 and 11

    B. HPV 31 and 35

    C. HPV 45 and 51

    D. HPV 16 and 18


Questions9
Questions and more efficient

  • 10. Sexually active young adults are known to be at the highest risk of contracting HPV infection. Prevalence is particularly high among 15 – 26 year old women. Therefore, all young women should be tested for the HPV infection.

    A. True

    B. False


Answers to questions
Answers to Questions and more efficient

  • 1. B 6. C

  • 2. B 7. A

  • 3. C 8. D

  • 4. D 9. A

  • 5. B 10. B


Answer these commonly asked questions for your patients
Answer these commonly asked questions for your patients and more efficient

  • What is the difference between a Pap smear and 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 treated?

  • Is there a vaccine for HPV?


New pap smear classification and hpv diagnosis and rx references
New Pap Smear Classification and HPV and more efficientDiagnosis and Rx References

  • ACOG Practice Bulletin, Number 61. Human papillomavirus. Washington, DC: American College of OB/GYN: April 2005.

  • ACOG Practice Bulletin, Number 45. Cervical cytology screening. Washington, DC: American College of OB/GYN;2003

  • ACOG Committee Opinion, Number 330.Evaluation and Management of Abnormal Cervical Cytology and Histology in the Adolescent.American College of OB?GYN;Obstet Gynecol 2006;107:963-8.


New pap smear classification and hpv diagnosis and rx references1
New Pap Smear Classification and HPV Diagnosis and Rx References

  • REFERENCES

  • APGO Educational Series, Advances in the Screening, Diagnosis, and treatment of Cervical Cancer:Assoc. of Professors of Gynecology and Obstetrics:20002

  • Clavel C, Masure M, Bory JP, et al. Human papillomavirus testing in primal screening for the detection of high-grade cervical lesions: a study of 793 women. Br J Cancer. 2001;89:1616-1623.

  • Cuzick J, Szarewski A, Cuble H, et al. Management of women who test positive for high –risk types of human papillomavirus: the HART study. Lan 2003;362:1871-1876.


New pap smear classification and hpv diagnosis rx references
New Pap Smear Classification and HPV Diagnosis & Rx References

  • Brown DR, Shew ML,Qadadri B, et al. Alongitudinal study of genital human pappillonavirus infections in a cohort of closely followed adolescent women. J Infect Dis.2005;191:182-92.

  • Franco, El, Harper DM. Vaccination against human papillomavirus infection: a new paradigm in cervical cancer control. Vaccine.2005;23:2388-2394


New pap smear classification hpv diagnosis rx references
New Pap Smear Classification HPV Diagnosis Rx References

  • Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10 year risk of cervical precancer and cancer in women with HPV type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Nat'l Cancer Inst. 2005;97:1072-1079.

  • Plyathilake CJ, Henao OL, Macaluso Mm et al. Folate is associated with the natural history of high risk human papillomaviruses Caner Res. 2004;64:8788-8793.


New pap smear classification and hpv diagnosis and rx references2
New Pap Smear Classification and HPV Diagnosis and Rx References

  • Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society guide for the early detection of cervical neoplasia and cancer. AC Cancer J. Clin. 2002;52:342-362.

  • Wright TC, Jr., Cox JT, Massad LS, Carlson J, Twiggs LB, Wilkinson EJ. 2003 consensus guidelines for the management of of women with cervical intraepithelial neoplasia. Am. J Obstet Gynecol. 2003;189:295-304.


New pap smear classification and hpv diagnosis and rx references3
New Pap Smear Classification and HPV Diagnosis and Rx References

  • Wright TC, Jr., Schiffman M, Solomon D, et al. Interim guidance of the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;103:304-309.

  • Wright, TC Jr, Schiffman M, Solomon D,et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;103:304-309


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