HPV testing in the management of colposcopy patients

Transcription

1 RCN Colposcopy Conference 5 th November 2011 HPV testing in the management of colposcopy patients Theresa Freeman-Wang MRCOG Consultant Gynaecologist Whittington Hospital, London

2 Necessary but NOT sufficient...

3 Molecular Pathology Model of Cervical Cancer X Wright and Schiffman, NEJM, 2003

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7 The burden of HPV disease 1,2 Physical morbidity (including increased obstetric risk) and mortality Psychosocial anxiety of a positive Pap test anger, depression, disgust, self-blame impaired coping, family, work impact on intimate relationships, sexual dysfunction Economic 1. Frazer et al, 2006; 2. Farnsworth et al, 2003

8 Estimated World Burden of HPV-Related Disease and Diagnoses Cervical cancer: million in High-grade precancerous lesions: 10 million 2 Low-grade cervical lesions: 30 million 2 Genital warts: 30 million 3 HPV infection without detectable abnormalities: 300 million 2 1. Parkin DM, Bray F, Ferlay J, Pisani P. CA Cancer J Clin. 2005;55: World Health Organization. Geneva, Switzerland: World Health Organization; 1999: World Health Organization. WHO Office of Information. WHO Features. 1990;152:1 6.

9 6 1 1 High-Risk Low-Risk 16 18

10 % of Cancers Incremental aetiologic contributions of HPV types: importance of genotype 16 & X

11 CUMULATIVE INCIDENCE RATE OF CIN3 KHAN ET AL. J NATL CANCER INST 2005 The cumulative incidence of CIN 3+ in 13,229 women over a ten year period by single HPV test result at enrolment 25% 20% 15% HPV16 POSITIVE HPV18 POSITIVE HPVPOSITIVE non HPV16/18 HPV NEGATIVE 70% of cancers 50% of pre-cancers 10% 5% Non-informative for 10 years 0% FOLLOW-UP TIME (MONTHS)

12 HPV prevalence with LGT and non-lgt cancers (IARC monograph) Site HPV+ve % HPV 16% Vulval Vagina Penis Anal canal Oropharynx Larynx

13 Statistical measures Sensitivity the proportion of true positives that are correctly identified by the test TP/TP+FN Specificity the proportion of true negatives that are correctly identified by the test TN/TN+FP Positive Predictive Value=TP/TP+FP

14 HPV testing- The Gold Standard: Hybrid Capture II (HC2) Pooled sensitivity for CIN % Pooled sensitivity for CIN % Pooled specificity for CIN % 14% more sensitive than cytology if LSIL cytology, NO difference bet HC2 and cytology for detection of CIN2+

15 HPV testing the pros and cons HPV testing is more reproducible and sensitive than cytology but only slightly less specific sensitivity 96% vs 53%; specificity 90% vs 96% BUT. Detection of HPV positive women with transient infections and no or regressing lesions Need to prevent over-referral and colposcopy SO? Use of genotyping and biological markers

16 How,Who and When to use HPV-DNA Testing 1. Primary screening for cervical neoplasia 2. In triage of minimally abnormal and inconclusive smears Borderline / mild (5-7%) 3. As a test of cure

17 1. Use of HPV DNA test As a primary screening

18 Canadian Cervical Cancer Screening Trial (CCCaST) 10,456 women yrs of age seeking screening in Montreal or St. Johns Had BOTH digene HPV Test & conventional cytology Women positive on either test had colposcopy Mayrand et al. New Engl J Med 2007

19 Comparison of HPV DNA to Pap N Eng J Med, 2007: Canadian Cervical Cancer Screening Trial (CCCaST) 100% 90% 94.6% Missed CIN % 96.8% 80% 70% 60% 50% 55.4% 40% 30% 20% 10% 0% Sensitivity HPV DNA Sensitivity Pap 95% CI: % CI: P=0.01 Specificity HPV DNA 95% CI: Specificity Pap 95% CI: P<0.001 N Eng J Med 2007; 357: 1,579-88

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21 2. Use of HPV DNA test Triage of Borderline/mildly dyskaryotic smears

22 HPV in management of low grade abnormalities HPV+ve and ASCUS=LSIL biologically HPV-ve and ASCUS is relatively safe histology ASCUS HPV- ASCUS HPV+ LSIL all CIN2& CIN AJOG 2003

23 LSIL(CIN 1): ALTS summary points CIN 3 is found in about 15% CIN 2 is found in about 10% CIN 2 may regress Colposcopy sensitivity for detection of CIN 3 is only 50-70% 83% tested positive for high-risk HPV The majority had repeat abnormal Pap The ALTS Group. Management of women with LSIL. AJOG 2003

24 BNA Colposcopy Cumulative loss to follow up of 25% pos 6 mths Repeat Pap 12 mths Repeat Pap 18 mths Repeat Pap 24 mths neg neg neg neg Screening Pap

25 BNA Immediate HR HPV Colposcopy Loss to follow up 10% pos neg Screening Pap Cycle

26 3.Use of HPV DNA test Test of cure after treatment of cervical pre-cancer

27 Current Post-Treatment Management Visit 1 4-6months Cytology, Colposcopy (HPV DNA) Subsequent visits 12 monthly Cytology Colposcopy? (HPV DNA) Annual screening for up to 10 years before return to normal recall

28 Test of Cure (TOC) If cytology negative/ HPV 6 months risk of CIN2+ over next 2 years was <0.5%. Returning to normal recall would prevent 10 annual cytology tests. Could save up to 400,000 cytology tests/ year. Women who are cytology positive or HPV positive at 6 months post treatment to be colposcoped.

29 HPV Triage-Implementation

30 HPV Sentinel Sites Triage Presentation

31 HPV Sentinel 1 FIRST BORDERLINE Sites Implementation or FIRST MILD Project DYSKARYOSIS 2 High grade or persistent low HPV Triage and Test of Cure Protocol grade cytology with treated For women aged years CIN, no HPV test HPV -ve HPV +ve COLPOSCOPY No repeat cytology negative colposcopy no biopsy or biopsy with no CIN CIN1 CIN2/3 No treatment TREATMENT 3 Cytology at 12 months with or without colposcopy (local preference) Cytology at 6 months Normal Abnormal Routine 3 or 5 year recall (depending on age <50 or 50) HPV -ve 4 3 year recall HPV +ve COLPOSCOPY Cytology follow up according to national guidelines

32 HPV implementation 1 10million over two years for England Expect 16 million per year savings after two years National guidance was issued in August ews-leaflets.html

33 HPV Implementation 2 Local call and recall computer software has been adapted to incorporate HPV results. Invitation and result letters are being revised to include information on HPV and test results, where HPV testing is performed. Women are frequently confused by the term wart virus, so best avoided. Using the term HPV positive can arouse concern and may be confused with HIV positive. Result letters will indicate that high-risk HPV has been detected. HPV triage and test of cure presentation August 2011

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35 Karin Denton- Bristol X5 increase in colposcopy/ week including private sector and consultant clinics After two years: inc 10% on baseline 3 cases cancer in Borderline group

36 To reduce the impact on colposcopy services First year: implementation of HPV triage is limited to women having their first occurrence of borderline nuclear changes or mild dyskaryosis; Test of cure is limited to newly treated women. Second year: implementation of HPV triage is extended to all borderline and mild samples and test of cure to all women on annual follow up following treatment for CIN. HPV triage and test of cure presentation August 2011

37 Cost of HPV implementation Projected from sentinel site project: per samples i.e. 2 per sample in 1 st year 1 per sample in 2 nd year To include: HPV test, transport, reporting, colposcopy, staffing, biopsies etc.

38 HPV technologies DNA based detection assays Hybrid Capture II 13 HPV types Qiagen* (Cervista HPV 14 HPV types Hologic) DNA based Genotyping assays Cobas 4800 Roche RealTime High Risk HPV Abbott Diagnostics RNA based detection assay APTIMA E7 mrna Genprobe * Gold standard

39 John Tidy - Sheffield Negative colposcopy: 3-10% risk of CIN 3 over next 3 years Sheffield : 3.1%-CIN3; 3.6%-CIN 2 NPV for colposcopy 98-99% 128 additional colposcopies per samples screened Test of cure: 25.7% tx failure; 7.3% CIN 3 Normal cytology, HPV pos 10.1%- (6.3% CIN 3)

40 CIN 2+ in Colposcopy negative/ HPV positive low grade smear abnormalities R Kelly, P Walker, H Kitchener, S Moss BJOG 2011 May 31, doi: /j x women with HPV pos, BNA/mild and negative colposcopy Cumulative rate CIN 2+ at 3 yrs 4.4% J Berkof et al Cancer Epidemiol Biomarkers Prev 2006;15(7): If HR-HPV, normal cytology, 18/12 risk CIN 3+ =6% If HR-HPV, BNA cytology, 18/12 risk CIN 3+ =20% If HPV 16 pos normal cytology, 18/12 risk CIN 3+ =14% If HPV 16 pos BNA cytology, 18/12 risk CIN 3+ =37%

41 Of 436 women declared CIN free, 26 (6%) developed HG-CIN at follow up. We suggest additional screening at an interval of less than three years should be offered to women with a negative colposcopy or No CIN on biopsy

42 Guidance on Explaining HPV Triage to Women

43 Explaining HPV Triage to Women We cannot know when an individual woman became infected. We cannot know from whom this infection was transmitted. High risk HPV does not cause genital warts and wart associated types do not cause CIN. HPV infection cannot be treated, only CIN. HPV vaccination will help prevent HPV infection/cin in the future. HPV Sentinel Sites Triage Presentation

44 Explaining HPV A positive HPV test does not mean their current partner has been unfaithful HPV is very common. Many women will acquire it when they become sexually active. Most women will clear an HPV infection, approx 90%

45 Explaining HPV HPV is usually cleared by the immune system. Having HPV is not a marker for sexual behaviors, infidelity or timing of infection.

46 Explaining HPV Cervical cancer should be considered a very rare complication of a very common virus.

47 HPV testing- Self sampling HPV may improve coverage with self testing 26.6% returned self collected HPV sample vs 16.4% who went for smear after repeat invitation GOK et al BMJ 340 Mar11-1p1040

48 Current problems with commercial self tests... Lack of counselling Lack of understanding of HPV positive result?who responsible for acting on results In England women not eligible for NHS colposcopy so who would pay Dr Thom asks further 15 for GP consultation

49 Misuses of HPV testing... Repeat testing in mild dyskaryosis Routine testing in high grade dyskaryosis Testing too early post treatment /Repeat testing too frequently Testing the male partner outside of a clinical trial Prior to offering vaccination

50 Importance of individual HPV types Use of genotyping

51 Managing HPV (+) Women Potential use of genotyping assays: Use of type-specific assays to determine specific type of "high-risk" HPV present Goal is to identify women at highest risk for having CIN 2+ and getting them in for immediate colposcopy

52 HPV 16 Commonest in cancer and CIN2+ Most persistent type Highest PPV for Cancer and CIN2+ Higher risk sign More aggressive management

53 Castle P et al J Natl Cancer Inst 2005;97: Risk for CIN 3+ 35% 25% HPV 16 positive 32.5 % 39.5 % 15% Any high-risk HPV(+) other than HPV % 8.4% 9.5% 0.0% ASC-US LSIL ASC-US LSIL

54 Risk with Specific (GENO)Types Type Cancers Controls O.R. HPV 16 53% 3.0% 434 HPV 18 11% 1.0% 248 HPV 45 4% 0.5% 197 HPV 31 3% 0.6% 123 HPV 52 2% 0.2% 200 HPV 33 2% 0.2% 373 Munoz et al. (2003) NEJM

55 Screening Post vaccination Schiffman et al NEJM Nov 2005

56 Proposal for Screening women with HPV followed by direct triage on reflex cytology and HPV genotyping (FROM MEIJER 2007) Test positive HPV Test negative reflex Cytology triage(6%) screen 6 years (94%) cyto: normal (4.2%) Cyto: abnormal (1.8%) HPV genotyping gynaecologist HPV 16,18,31,33,45 pos Repeat HPV test and cytology after 2 years HPV pos non-16,18,31,33,45 After 3 years only cytology HPV or cyto: pos gynaecologist If pos gynaecologist both neg routine screen If neg routine screen

57 The emerging role of HPV in the 21 st Century... move to HPV-based cervical cancer prevention strategies Longer screening intervals Strategies to avoid over-treatment HPV-positive women who do not have obvious long-term persistence of HPV or treatable lesions at the time of initial evaluation. Probably the greatest potential for reduction in cervical cancer rates from HPV screening is in low-resource regions that can implement infrequent rounds of low-cost HPV testing and treatment. Schiffman M et al JNCI.103(5):368-83, 2011 Mar 2.

58 26-30 May, 2014 Queen Elizabeth II Conference Centre, London, UK LOOK FORWARD TO SEEING YOU IN LONDON

59 Cervical disease in women, HPV and Men Penile HPV infection in husbands of cervical cancer cases: 73% HPV positive Partners of 42 women with CIN,69% of penile biopsies HPV pos Range 30-64% in Finnish, Mexican, Danish and Swedish studies Campion MJ et al. Lancet 1985;1(8435): Dunne EF et al. J Infect Dis2006;194(8): Simon P et al. Eur J Obs,Gyn & Repro Biol. 2010;153(1):8-11

60 HPV and Men >95% of HPV detection: Penile shaft, coronal sulcus, scrotum, glans penis (including prepuce in uncircumcised) Not prevalent in semen or urethra HPV infection reduced by: Circumcision Condoms No association with age Less likely to have persistence (6%) A.R. Giuliano et al. / Vaccine 26S (2008) K17 K28

61 See you in London

62 Screening success... Screen coverage -at least 70% of the targeted population should be screened at least once in a lifetime, Reproducible, sensitive and specific screening assays and diagnostic tests for the detection CIN 3 Provision of effective treatment Quality assurance of the programme Gravitt PE et al. Int J Ca 129(3):517-27, 2011 Aug 1.

63 Cost Effectiveness of Screening with and without HPV vaccination depends on Continued Screening Diane Harper Lack of continued screening even with vaccination increases cervical cancer incidence. NOW 2 2. Lack of continued screening even with vaccination increases the ICER of vaccination. 3. If HPV vaccine duration is only 15 years, and lack of continued screening occurs, there is no benefit of HPV vaccination for the mass population. Berkhof J et al. Modeling the influence of screening uptake on the future incidence of cervical cancer and the cost-effectiveness of HPV vaccination. HPV Conference Montreal 2010.

64 Post vaccination: Target populations Vaccinated year olds who were not sexually active before vaccination Vaccinated year olds who were sexually active but had not been exposed to high risk HPVs Vaccinated year olds who were sexually active, were exposed to HPV, made their own antibodies Vaccinated year olds who were sexually active, did acquire high risk HPVs, didn t make antibodies

65 Post vaccination: Target populations year olds who could have been vaccinated but were not year olds who started vaccination but did not complete the course year olds who were not offered vaccination >18 year olds from, for example Australia who were vaccinated

66 Older women and HPV... Most women of this age will have a cervix that has undergone metaplasia. If they have been exposed to an HPV infection, most will have already cleared it with their natural immunity...