1. HPV and Pap Guidelines Jennifer Johnson MD

2. Objectives 1. Define the new PAP guidelines. 2. Identify the historical trends and new evidence resulting in the guidelines for PAP screening. 3. Describe the immunization recommendations for HPV

3. Cervical cancer screening High quality screening with cytology has markedly reduced mortality from SCC of cervix Since its introduction in mid 20 th century, cervical cancer now ranks 14 th in cancer deaths Protection from cervical cancer is primary goal – Preventing all cervical cancer is unrealistic

4. Statistics In 2011 – 12,109 women diagnosed with cervical cancer – 4,092 women died from cervical cancer www.cdc.gov

5. Cervical cancer screening About half of cervical cancer in US is in women never screened Screening interval should be chosen so the development of invasive cancer is highly unlikely before the next screen – On average takes 10-13 years from CIN2,3 to cervical cancer

6. Harms from screening Anxiety STI diagnosis Discomfort Bleeding Increased risk of pregnancy complications

7. Guidelines Preventing all cervical cancer is unrealistic Detection of CIN3 is goal of screening Increased colposcopies is a surrogate for harms of screening

8. Background It is understood that persistent infection with high risk HPV is necessary for the development of cervical cancer – Case series have shown that nearly 100% of cervical cancer cases test positive for HPV

9. HPV HPV 16 is most carcinogenic – 55-60% HPV 18 is next most carcinogenic – 10-15% 10 other types cause remaining 25-35% of cervical cancers

10. Screening Should begin at 21 Women younger than 21 years should not be screened regardless of sexual initiation or other related risks – These are not recommendations for patients with cervical cancer, HIV, immunocompromised or exposed to DES – Based on very low incidence of cancer and lack of data that screening is effective in this group Only 0.1% of cases of cervical cancer occur before 20 years

11. Rationale HPV infection is acquired by young women shortly after initiation of vaginal intercourse Nearly all are cleared within 1-2 years Although cancer is rare, neoplasia is not Earlier onset of screening may result in increased anxiety, morbidity, and expense – Screening may not prevent cancer in this age group – Incidence of cervical cancer in this age group has not changed with screening

12. Prevention for adolescents Adolescent prevention programs should focus on HPV vaccination access to appropriate health care Initiation of reproductive health care should not be dependent on cervical cancer screening. – Strategies for prevention include HPV vaccination and counseling about safe sex practices

13. Methods Age 21-29 cervical cytology alone – HPV testing is not recommended because of high prevalence of infection but low risk of cervical cancer

14. Rationale age 21-29 Few studies addressing length between screening Annual screening – Slightly greater cancer reduction, but results in twice the number of colposcopies – Risk of HSIL/cancer 3 years after negative pap is not significantly higher than risk after 1 year

15. Rationale Annual incidence of cervical cancer in women 21-24 is 1.4/100,000 55,000 tests must be obtained for every cervical cancer diagnosed in this age group Because of low risk, this allows for observation of minor cytologic abnormalities Massad et al. 2012 ASCCP Consensus Guidelines Conference

16. Screening Women aged 30-65 co-testing with cytology and HPV testing every 5 years is preferred – If screening with cytology alone it should be performed every 3 years

17. Rationale age 30-65 Cytology alone – Limited evidence does not support screening interval longer than 3 years HPV co-testing – Increased detection of CIN 3 – Increase in diagnostic lead time with co testing leads to lower risk following a negative screen – 5 year interval produces similar or lower cancer risk – HPV testing also enhances identification of women with adenocarcinoma of cervix

18. Screening

19. When to stop screening Age 65 With adequate prior screening and no CIN 2+ in last 20 years Adequate negative screening – 3 consecutive negative paps – Or 2 consecutive negative HPV co tests within previous 10 years

20. When to stop screening Screening should not resume for any reason, even if new partner – Low risk of progression to cancer in this age group

21. Common management issues ASCUS negative HPV Negative cytology and positive HPV

22. ASCUS negative HPV Very low risk of CIN 3 Recommend to continue with routine screening as indicated for age

23. Negative cytology and positive HPV Repeat co-testing in 12 months OR Immediate HPV genotype for 16/18 and if positive be referred for colposcopy

24. Specific populations Women with – HIV – Immunocompromised (such as solid organ transplants) – Exposed to DES – Previously treated for CIN 2, CIN3, or cancer

25. Women with HIV CDC recommends cervical cytology screening twice in the first year after diagnosis and annually after Should be initiated at the age of diagnosis even if younger than 21

26. Immunocompromised Cytology has been typically performed Annual screening at age 21 is reasonable

27. History of CIN 2 or higher Have 2.8 fold increase risk of invasive disease for up to 20 years Should undergo routine age based screening for 20 years even if past age 65

28. Hysterectomy Women who have hysterectomy with removal of cervix and have no history of CIN 2 or higher. Screening should be discontinued and not restarted for any reason Primary vaginal cancer is the rarest of gynecologic cancers Women should continue to be screened if they have had total hysterectomy and history of CIN2 or higher in past 20 years or cervical cancer ever. – Cytology every 3 years for 20 years post treatment is reasonable

29. Progression to cancer CIN 1 is a manifestation of acute infection and has high rate of regression CIN 2 is a mix of low grade and high grade lesions CIN 3 and AIS are cancer precursors Progression to cancer is slow Because of the risk of cancer in untreated patients the threshold for treatment is CIN 2 + except in special populations

30. Unsatisfactory Cytology With unsatisfactory cytology and no or unknown HPV tests, repeat cytology in 2-4 months is recommended In women with HPV positive co-test result, repeat cytology in 2-4 months or colposcopy is acceptable Colposcopy is recommended for women with 2 consecutive unsatisfactory cytology results

31. Absent or insufficient transformation zone component With negative cytology – Women age 21-29 Routine screening HPV testing is unacceptable – Women age 30 or older HPV testing is preferred Repeat cytology testing in 3 years is acceptable

32. HPV Human papillomavirus Most common sexually transmitted infection in US Numerous genotypes High risk-includes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 Types 16 and 18 are most commonly isolated types in cervical cancer

33. HPV Factors that determine which will persist are not well understood Genotype is the most important determinant of persistence and progression

34. HPV vaccine Persistent HPV infections cause almost all cancers of the cervix 3 vaccines – Quadrivalent (Gardasil) 6, 11, 16, 18 – 9-valent (Gardasil 9) 6, 11, 16, 18, 31, 33, 45, 52, 58 – Bivalent vaccine (Cevarix) 16, 18

35. HPV vaccine CDC and ACOG recommend routine vaccination with HPV for girls and boys Target age is 11-12 years All 3 vaccines are given in a three dose series with a schedule of 0, 1-2 months, and 6 months Series does not need to be restarted if there is a delay in administration of the second or third dose

36. HPV Vaccine Despite the benefits, only approximately 1/3 of girls in the recommended age groups have received all three vaccines Compared with other vaccines, HPV vaccination rates in US are unacceptably low Not associated with an earlier onset of sexual activity or an increased incidence of STIs

37. Timing of vaccination HPV vaccination is recommended at the target age of 11-12 to help reduce risk of anogenital cancer and genital warts All 3 vaccines are recommended for females age 9-26 The quadrivalent and nanovalent vaccines are recommended for males aged 9-26 Earlier vaccination is preferred because the vaccines are most effective before onset of sexual activity

38. Vaccine safety According to Vaccine Adverse Events Reporting System – More than 60 million doses of HPV vaccine have been given and there is no data to suggest any severe adverse effects or adverse reactions linked to vaccination – Nanovalent vaccine had higher rate of injection swelling and erythema than quadrivalent vaccine

39. Vaccine safety Should advise patients to expect discomfort after vaccination and that it is not a cause of concern Anyone who has had a life threatening allergic reaction to a previous dose or component should not get the vaccine Individuals with a moderate or severe illness should wait until illness improves before receiving vaccine

40. Special populations HPV vaccination in pregnancy is not recommended, but routine pregnancy testing before vaccination is not recommended as well The presence of immunosuppression is not a contraindication to HPV vaccination

41. Vaccination efforts High rates of vaccination will reduce HPV related disease in US According to CDC, if HPV vaccination coverage increases to 80%, it is estimated an additional 53,000 cases of cervical cancer could be prevented during the lifetime of those younger than 12 years For every year that coverage does not increase an additional 4400 women will develop cervical cancer

42. Screening after vaccination Should be screened according to the same guidelines as women who have not been vaccinated

43. Primary HPV screening In 2011 the guidelines for cervical screening were updated At that time primary hrHPV testing alone was not recommended In April 2014 the FDA approved labeling to include primary hrHPV screening for women 25 years and older Journal of Lower Genital Tract Disease

44. Primary HPV screening The FDA approval does not include recommendations for applying hrHPV screening

45. HPV screening Women under age 25 should continue to follow current guidelines that recommend cytology alone beginning at age 21. Women with a negative primary HPV test result should not be retested again for three years – Same screening interval recommended under current guidelines for a normal cytology test result.

46. HPV screening An HPV test positive for HPV 16 and 18, two types associated with a higher risk of future disease, should be followed with colposcopy A test that is positive for HPV types other than 16 and 18 should be followed by reflex cytology testing

47. QUESTIONS