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1 dr mario sideri Presentation Transcript

  • 1. HPV NATURAL HISTORY AND HPV TESTING Mario Sideri Unità Ginecologia Preventiva Istituto Europeo di Oncologia, Milano Italian HPV Study Group (IHSG)
  • 2. What’s new? In the last 30 years the causal association between HPV infection and cervical cancer has been demonstrated papillomavirus
  • 3. The Nobel Prize in Physiology or Medicine 2008 Harald Zur Hausen for his discovery of human Papilloma viruses causing cervical cancer
  • 4. Vaccination Population at risk (screening) Detection & Intervention (pre-cancer elimination) OLD STRATEGYNEW STRATEGY
  • 5. Papillomavirus is known from decades. However only in the recent years we have recognized the wide diffusion and the benign meaning of HPV infection What is HPV?
  • 6. Human Papillomavirus
  • 7.  Papillomavirus are species specific viruses  HPV are very common viruses and are present in almost all the species of mammalians and birds  More than 100 HPV types have been described in humans  Human PV infect the skin and mucous membranes where they can cause typical benign proliferations as warts and papillomas Papillomavirus De Villiers et al., Virology (2004)
  • 8.  HPV infection causes in some instances microproliferations not visible with the naked eye  HPV tends to prersist for long periods of time, often as latent infection  Some HPV associated lesions can evolve into malignant neoplasia Papillomavirus De Villiers et al., Virology (2004)
  • 9. HPV Infection Langerhans cells Dendritic cells Dermis Micro-wound Epidermis Draining lymphatics Basement membrane CD 16
  • 10.  90% of young women acquires the virus with the beginning of sexual intercourses  Most of them become negative after 6-18 months of transient infection  Only about 10% of young women become persistently infected with HPV for a longer period of time HPV natural history
  • 11.  less than 30% of persitently infected women develops a CIN lesion  the vast majority of CIN clears spontaneously  some CIN persist, but even most of persistent CIN3 will never become cancer HPV natural history
  • 12. In this way, the almost ubiquitary HPV infection, very rarely ends up into cervical cancer. Conversely, the association of HPV infection with cervical cancer offers unique opportunities of cancer prevention HPV and Cervical Cancer
  • 13.  553 college students (mean age 19)  HPV test and pap smear every 4 months for 5 years  mean follow up 41.2 months HPV natural history: Seattle Study Winer et al., Am J Epidemiol (2003)
  • 14.  19.7% was HPV DNA positive at enrollment  During two years follow up 39% of women negative at enrollment became HPV DNA positive  High risk HPV were found more frequently, types 16,18,51,56,33,35,39 Winer et al., Am J Epidemiol (2003) HPV natural history: Seattle Study
  • 15. Winer et al., Am J Epidemiol (2003)
  • 16.  60 adolescents (14-17) were followed for a mean time of 26 months  Every three months were evaluated for HPV infection  In addition a weekly self sampling for HPV was performed for a time lenght up to 15 weeks Brown et al., J Infect Dis (2005) HPV natural history: Adolescent study
  • 17. Timing HPV overall HPV oncogenic Enrollment 28% 22% Last visit 40% 37% At least once* 82% 77% Brown et al., J Infect Dis (2005) * At least two positive samples HPV natural history: Adolescent study
  • 18. Only 3 girls were always negative to vaginal HPV testing  All referred to be virgins Brown et al., J Infect Dis (2005) HPV natural history: Adolescent study
  • 19.  HPV detectability rarely persist for more than 24 months  in more than 90% of the cases HPV becomes undetectable within 24 months HPV Natural history
  • 20. Detectable HPV Author Age 6 12 24 __________________________________ Woodman 20 24 4 <1 Mosicki 20 50 30 10 Ho 20 30 9 % persistent HPV infection in months
  • 21.  persistent HPV infection may cause the development of invasive cervical cancer in 10 to 15 years  many known and unknown co-factors are responsible for cancer develpoment HPV Natural history
  • 22.  20.817 women with neagtive cytology at baseline  HPV test at enrollement  Follow up for 10 years; endpoint CIN2-3 development Natural history of HPV oncogenesis Portland study Kahn et al., JNCI (2005)
  • 23. 0% 5% 10% 15% 20% 25% 0,0 4,5 15,0 27,0 39,0 51,0 63,0 75,0 87,0 99,0 111,0 119,5 Follow-Up Time (months) CumulativeIncidenceRateof≥CIN3 HPV16 + HPV18 + HPV + HPV+/ HPV16- /18- HPV - Kahn et al., JNCI (2005) CIN3 develpoment during follow up in relation to HPV status
  • 24. ALL HPV 16 Rodriguez et al., Proceedings of 24th International HPV Conference and Clinical Workshop, China 2007. Abstract
  • 25.  HPV persistent infection can cause the development of invasive cervical cancer in 10 to 15 years  many co-factors are involved in the process of cancer development Natural history of HPV infection
  • 26. Few studies addressed in longitudinal studies HPV status in sex couples HPV: what we know in sex couples?
  • 27. ….In our current study, less than half of the couples exhibited perfect HPV- type specific concordance. More than one third of couples had complete discordance…..
  • 28. Multivariate regression analysis. Reporting a new sex partner or the same sex partner or no sex partner was not significantly associated with the risk of infection reappearance.
  • 29. HPV Clearance
  • 30. HPV re-infection (redection)
  • 31. HPV infection is very common and is not a disease pre-cancer is a rare event cancer is an exceptional event HPV: what we now know
  • 32. HPV infection is very rarely associated to cancer development However HPV is necessary for cancer develpoment HPV and Cervical Cancer
  • 33. Cervical cancer screening • Pap smear as primary screening test • Identification of CIN3 • Elimination of CIN3 through excisional conservative surgery The historical strategy
  • 34. Screening aim To identify and eliminate this lesion
  • 35. Vaccination Population at risk (screening) Detection & Intervention (pre-cancer elimination) USUAL STRATEGYNEW STRATEGY
  • 36. Cervical cancer screening • Testing the population for the causative agent of cervical cancer • Testing aimed to identifcation of CIN3 • Testing not aimed to detect infection HPV TESTING
  • 37. Cervical cancer screening PROOF of PRINCIPLE HPV TESTING
  • 38. CERVICAL CANCER SCREENING IN INDIA N = 131.476 Four arms randomized study: •Control •VIA •Pap smear •HPV test HPV test Pap smear VIA Control
  • 39. Cervical cancer screening known limitations of cytology screening PAP SMEAR
  • 40. 30 40 50 60 70 80 90 100 1971 1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 8 9 10 11 12 13 14 15 16 17 18 Incidence/100000 ScreeningCoverage(%) Cervical cancer screening Start of organised screening
  • 41. Never pap smear 162 62% Pos. pap & adequate follow-up 29 11% False negative pap 37 14% Previous abnormal smear* 34 13% TOTAL 262 100% Screening “failures” italian data Amadori A. Int J Gynecol Cancer 1998 262 invasive cancer cases, TR Romagna and Toscana (1986-93). * Repeat smear not done, colposcopy not done, colposcopy done late, negative colposcopies, negative biopsies, CIN3 diagnosed with no further action.
  • 42. Cause, n (%) Kaiser study1 Swedish study2 No recent screen 464 (56%) 789 (64%) Cytology detection failure 263 (32%) 300 (24%) Failure of follow-up of abnormal cytology 106 (13%) 91 (7%) Screening history of women with invasive cervical carcinoma 1. Leyden WA, et al. J Natl Cancer Inst 2005; 97:675683; 2. Andrae B, et al. J Natl Cancer Inst 2008; 100:622629.
  • 43. Results of the NTCC study (Nuove Tecnologie per lo Screening del Cancro Cervicale)
  • 44. Setting: population based screening programme Prospective randomized study on new screening test Accrual phase: March 2002 to December 2004 94,370 women aged 25–60 years were randomized Arm A 47,001 = conventional cytology Arm B 47,369 = HPV testing (HC2) Two screening rounds were completed (6 years) METHODS
  • 45. Women were divided into two different age groups: • 25 to 34 • 35 to 60 METHODS
  • 46. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. METHODS
  • 47. Relative detection (HPV vs cytology) was: • 2·00 for CIN2 • 2·08 for CIN3 • 2·03 for CIN2 and 3 RESULTS: first round, 35-60 yrs Meaning: HPV test detects 2 times more CIN 2-3 than pap In other words the pap smear is negative in 50% of CIN2-3
  • 48. Relative detection (HPV vs cytology) was: • 2·00 for CIN2 • 2·08 for CIN3 • 2·03 for CIN2 and 3 RESULTS: first round, 35-60 yrs Question: Are these “new” CIN2-3 clinically relevant? Go to the second round…
  • 49. RESULTS: second round, 35-60 yrs Meaning: In the HPV group the CIN2-3 were identified earlier than in the cytology arm the relative detection (HPV vs cytology) was • 0·54 for CIN2, • 0·48 for CIN3 • 0·51 for CIN2 and 3
  • 50. RESULTS: second round, 35-60 yrs Question: Which is the clincal value of the “anticipated” diagnosis? the relative detection (HPV vs cytology) was • 0·54 for CIN2, • 0·48 for CIN3 • 0·51 for CIN2 and 3
  • 51. RESULTS: 35-60 yrs Question: Which is the clincal value of the “anticipated” diagnosis? It is safe to increase the intervals between two screens. But what about the invasive cancers?
  • 52. First Round 6 8 0.61 Second Round 0 7 0.016 Total 6 15 0.052 HPV test pap smear P value RESULTS: 35-60 yrs Number of invasive cancers Meaning: Follow up of untreated CIN2-3 carries the risk of cancer development
  • 53. First Round 6 8 0.61 Second Round 0 7 0.016 Total 6 15 0.052 HPV test pap smear P value RESULTS: 35-60 yrs Number of invasive cancers Clinical consequences of the study: Stop pap smear screening and switch to HPV testing
  • 54. Relative detection (HPV vs cytology) round one • 2·00 for CIN2 • 2·08 for CIN3 • 2·03 for CIN2 and 3 together. Relative detection (HPV vs cytology) at round two • 0·54 for CIN2 • 0·48 for CIN3 • 0·51 for CIN2 and 3 together. RESULTS: 35-60 yrs HPV testing: •Reassure more than 90% of negative women (negative is negative; interval increase) •Offer better protection against cancer
  • 55. RESULTS: 25-34 yrs What about the young women, aged 25 to 34? Same results or different situation?
  • 56. RESULTS: 25-34 yrs The relative detection (HPV vs cytology) was: Round 1 • 3·91 for CIN3 and AIS Round two • 0·20 for CIN3 and AIS. Meaning: Four times more CIN3 and AIS detected by HPV testing Five times less CIN3 and AIS in the subsequent round (more evident effect in young women than in older)
  • 57. First Round 1 1 1.00 Second Round 0 2 0.50 Total 1 3 0.37 HPV test pap smear P value RESULTS: 25-34 yrs Number of invasive cancers Clinical consequences of the study: Some considerations….
  • 58. RESULTS: 25-34 yrs The relative detection (HPV vs cytology) was: Round 1 • 3·91 for CIN3 and AIS Round two • 0·20 for CIN3 and AIS. Considerations: Double number of lesions in the whole period (overdiagnosis-overtreatment)
  • 59. First Round 1 1 1.00 Second Round 0 2 0.50 Total 1 3 0.37 HPV test pap smear P value RESULTS: 25-34 yrs Number of invasive cancers Clinical consequences of the data 25-34 yrs: The increment in cancer detection is counter balanced by an increase in diagnosis and treatment of clinically non relevant (regressing?) CIN2-3
  • 60. First Round 7 9 0.62 Second Round 0 9 0.004 Total 7 18 0.028 HPV test pap smear P value RESULTS: 25-60 yrs Number of invasive cancers The total figures of cancer reduction is still impressive; this figure prompted GISCi to start the long and difficult process to abandon pap smear as primary screening test because it is unethical to continue with pap smear screening
  • 61. HPV TEST: Which optimal use? • HPV test has an high NPV • HPV test is ideally suited to reassure the negative HPV individuals and to increase intervals between two subsequent screens • at any age HPV negative test is reassuring
  • 62. There are no scientific doubt that HPV test should be used as primary screening test. Implementation is still a problem where pap smear screening system is in place CONCLUSIONS It is a Copernican revolution… Copernicus was placed under investigation…..
  • 63. 1940’ TECHNOLOGY
  • 64. THANK YOU FOR YOUR ATTENTION! Mario Sideri Unità Ginecologia Preventiva Istituto Europeo di Oncologia, Milano Italian HPV Study Group (IHSG)