1. Clinical Use of HPV DNA Testing Thomas C. Wright, Jr. College of Physicians and Surgeons of Columbia University

2. Clinical Uses of HPV Testing Spectrum of HPV associated disease Clinical uses of HPV DNA testing Topics to be covered:

3. Anogenital HPV Infections Latent infection - no identifiable lesion Exophytic condylomas Low-grade and high-grade neoplasia Invasive cancers Cervix, vulva, anus, penis, head & neck, esophagus, conjunctiva Spectrum of clinical expression

4. Clinical Spectrum of Genital Infections Latent Infection Genital Warts

5. Clinical Spectrum of Genital Infections CIN 2,3 Invasive Cancer

6. Anogenital HPV Types High-risk types16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 Possible high-risk23, 53, 66, Low-risk types6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 Munoz et al. (2003) NEJM

7. Wright and Schiffman (2003) NEJM Natural History of HPV Infections

8. Clinical Uses of HPV Testing Spectrum of HPV associated disease Clinical uses of HPV DNA testing Topics to be covered:

9. HPV DNA Testing Management of ASC - US Secondary follow-up - abnormal Pap Follow-up post treatment Primary screening Potential clinical uses:

10. Atypical Squamous Cells - Undetermined Significance (ASC - US)

11. HPV Testing for Detecting CIN 2,3 in ASC Wright*1440.7854%0.6763% Manos*9950.8940%0.7639% Bergeron1110.8343%0.6732% Lin741.0053%-- -- Shlay2000.9331%-- -- Solomon*23240.9656%0.8558% HPV Testing Cytology Author No. Pts Sens Refer Sens. Refer *from liquid cytology

12. 2001 Consensus Guidelines All three standard modalities are considered safe and effective (A I) Because of costs, and patient convenience, "reflex" HPV testing is preferred if liquid- based cytology or co-collection available (A I) Management of ASC-US:

13. Management of ASC-US About 2.5 million ASC-US per year in U.S. 70% - 80% of these are liquid-based cytology specimens 70% - 80% of these get "reflex" HPV DNA testing and growing Status as of January 2004:

14. HPV DNA Testing Management of ASC - US Secondary follow-up - abnormal Pap Follow-up post treatment of CIN 2,3 Potential clinical uses:

15. HPV DNA Testing Management of ASC - US Secondary follow-up - abnormal Pap Follow-up post treatment Primary screening Potential clinical uses:

16. HPV Testing for Screening Who gets screened Testing method and with or without Pap Screening frequency Management of screen positives and negatives Questions to address:

17. Prevalence of HR HPV DNA Netherlands  ^ 13%10%2%2% Costa Rica  ^ 10% 6%3%3% Newfoundland  * 17%12% 5% 4% UK *^ 3%3%5% France  * 21%20%13%11% % HPV (+) by Age Country < 25 25-34 35-44 45+ * all women,  women without SIL, ^ by PCR,  by HC II

18. HPV by PCR CIN3 + 0 % 5 % 10 % 15 % 20 % 25 % 18- 19 20- 24 25- 29 30- 34 25- 29 20- 24 18- 19 35- 50 30- 34 35- 50 Kulasingham SL et al JAMA 2002;288:1749-57. Age-specific Prevalence of HPV and CIN 3 + in Planned Parenthood Study

19. HPV Testing for Screening Women 30 years and older FDA approval ACOG Practice Bulletin ACS Guidelines & NCI Workshop May change with increased data Age to initiate testing:

20. Primary Screening - Sensitivity: CIN 3+ StudyNo. Pap HPV Combo Portland10,03152 71 81 U.K.9,76190 94 98 Mexico6,11558 95 97 Costa Rica6,17682 94 97 South Africa2,92584 90 93 China1,93698100100 Baltimore1,04050100100 Germany7,59252 96100

21. Primary Screening - Specificity: CIN 3+ StudyNo. Pap HPV Combo Portland10,03198 92 91 U.K.9,76197 97 96 Mexico6,11599 94 93 Costa Rica6,17694 94 90 South Africa2,92586 80 76 China1,93676 83 68 Baltimore1,04098 96 96 Germany7,59299 96 95

22. HPV Testing for Screening Negativity for high-risk HPV identifies which women are at very low risk for having or developing CIN 2,3 over next 3 yrs Allows targeted screening Key advantage of using:

23. Predictive Value of HPV 20,817 women with adequate cytology at enrollment (1994-1996) Tested frozen CVL samples with HC II Follow-up was with cytology and "standard workup" of abnormals NCI - Kaiser Portland, OR cohort: Sherman (2003) JNCI

24. Development of CIN 3 on Follow-up HPV + Pap & HPV Neg

25. HPV Testing for Screening NCI, ASCCP, and ACS sponsored an experts' workshop to develop guidance for using HPV for screening. Meeting held February 2003 Interim Guidance: Wright et al. Obst. Gynecol. (2004)

26. NCI - ASCCP Interim Guidance HPV DNA as an Adjunct to Cytology HPV (-) ASC-US Both Negative Colposcopy Pap > LSIL Repeat Pap & HPV in 3 yrs in 12 mos HPV (+) ASC-US Results of HPV and Cytology

27. HPV Testing for Screening Will definitely produce some level of anxiety in almost all patients Concern was that clinicians would immediately perform colposcopy to rule out high-grade neoplasia Very expensive - overload the system Key issue is HPV (+) / Cytology (-)

29. Patient's comments when told about availability of HPV DNA testing for screening "Why the hell am I having a Pap smear every year if its not really finding out what we really need to find out? I would be really upset." Anhang et al. (2004) Cancer

30. Screening is all about risk. So what's the risk?

31. HPV (+) and Cytology (-) Clavel - France: 4.2% Cuzick - England: 2.8% Wright - South Africa:7.8% Risk for CIN 2+ at 6 mos:

32. HPV (+) and Cytology (-) Clavel - France: 10 of 10 CIN 2+ Cuzick - England: 9 of 9 CIN 2+ Wright - South Africa:13 of 14 CIN 2+ Repeat HPV (+) @ 6 mos:

33. HPV (+) and Cytology (-) Clavel - France: 40% Cuzick - England: 55% Wright - South Africa:60% Rates of HPV persistence - 6 mos:

34. Negative Cytology - HPV DNA Positive Repeat both Pap & HPV In 6 to 12 mos HPV (-) ASC-US High-risk HPV (+) Colposcopy Both Negative Pap > LSIL Repeat Pap & HPV in 12 mo. in 3 yrs

35. Clinical Uses of HPV Testing Spectrum of HPV associated disease Clinical uses of HPV DNA testing Topics to be covered: