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The Usefulness of HPV Testing ?

The Usefulness of HPV Testing ?. Nick Dudding East Pennine Cytology Training Centre. Age-standardised incidence of invasive cervical cancer (total) and adenocarcinoma of the cervix. England and Wales 1971-2001. Cancer Trends: Office for National Statistics.

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The Usefulness of HPV Testing ?

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  1. The Usefulness of HPV Testing ? Nick Dudding East Pennine Cytology Training Centre

  2. Age-standardised incidence of invasive cervical cancer (total) and adenocarcinoma of the cervix. England and Wales 1971-2001 Cancer Trends: Office for National Statistics

  3. The cervical cancer epidemic that screening has prevented in the UK Peto et al. Lancet 2004; 364: 249

  4. Liquid Based Cytology • That was all before we started LBC which will have improved things even further

  5. The Future ? • Despite success of LBC still tremendous pressure for more change • HPV testing • Vaccination • Automated Screening • Molecular markers

  6. Why HPV Testing ? HPV is the principal cause of invasive cervical cancer and CIN Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. JMM Walboomers et al. J Pathol 1999; 189: 12-19 The causal relation between human papillomavirus and cervical cancer. FX Bosch et al. J Clin Path 2002; 55: 244-265

  7. Biology of HPV • Persistence, type and (? viral load) are the important risk factors for CIN • High risk HPV types and infection with • Multiple HPV types increase risk

  8. Biology of HPV High risk types; 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 6, 73, 82 Munoz et al. NEJM 2003; 348: 518

  9. Biology of HPV • HPV infection very common in sexually active young women • Prevalence drops in women over 30 years • Median duration of new infection 8 – 14 months • 40% persistent at 12 – 24 months

  10. 45.0% 39.9% 40.0% 35.0% 30.0% 27.9% 25.0% HPV infection 20.0% 18.5% 15.0% 12.2% 9.2% 10.0% 8.2% 7.3% 6.0% 6.0% 5.0% 76 1027 722 682 480 313 118 222 173 2575 2591 3680 3934 3397 2720 2382 1972 1259 0.0% 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 Age ARTISTIC Trial HPV Prevalence by Age at entryCourtesy of Dr Desai

  11. HPV in Cervical Screening • What are the potential advantages of HPV testing that with regards to cervical screening ?

  12. HPV in Cervical Screening • Negative predictive value of high risk HPV is very high • A woman not infected with high risk HPV is at almost no risk of developing cervical cancer in next ten years • It has a high sensitivity • Most women with high grade CIN will be identified by HPV testing

  13. HPV in Cervical Screening • Many HPV positive women will NOT have high grade disease • They have an infection !!! • Positive predictive value of high risk HPV is low • Lower specificity than cytology • More limited utility in under 30,s where prevalence is higher

  14. HPV in Cervical Screening • How might we use it in cervical screening ?

  15. HPV in Cervical Screening • Triage of low-grade samples • Follow-up after treatment • Primary screening

  16. HPV in Cervical Screening • How might we test ? • PCR based Tests • HCII

  17. HC II • Easy to do - Simple kit • Identifies if any of 13 high risk types are present • Highly consistent & reproducible • Cant give info on individual types • Important since 16 carries far more risk • Needs to be batched to be cost effective

  18. Triage of low-grade samples Borderline or mild dyskaryosis HPV Test + - Refer Repeat / routine

  19. Triage of low grade samples • Speed up referral • Reduce number of re-tests • Return women to normal recall earlier • Avoid referral for those that don't need it

  20. Triage of low-grade samples Positive HPV test more sensitive than repeat cytology in triage of women with low grade smear abnormality: Kaiser-Permanente Study ALTS (ASCUS/LSIL Triage Study) Manos. JAMA 1999; 281: 1605 Koutsky et al. JNCI 2000;92:397-402

  21. Triage of low-grade samples • Abandoned triage of mild dyskaryosis ! • For ASCUS (BNC) cases • One HPV test is as sensitive as serial cytology, taken every 6 months over two years

  22. Triage of low-grade samples • Supported by a Met analysis carried out by Arbyn • Triage more sensitive than repeat cytology for ASCUS (BNC) • Not useful in triage of mild dys Arbyn: 2005 Gynae Oncol 99:S7 – S11

  23. HPV triage in UK ? • NHS LBC pilots • 45% BNC & 82% Mild were HPV positive • Reduced rate of repeat smears • 52% – 86% • Increase in rates of referral to colposcopy • 64% – 138% Legood. BMJ 2006; 332: 79-83 Moss. BMJ 2006; 332: 83-85

  24. HPV triage in UK ? • Cost effective under current UK screening protocols • Appropriate management strategies would need to be developed Legood. BMJ 2006; 332: 79-83 Moss. BMJ 2006; 332: 83-85

  25. TOMBOLA • Trial Of Management of Borderline and Other Low grade Abnormal smears • Based on conventional samples • Expected to report anytime now • First indications NOT as positive as one might have expected

  26. TOMBOLA • BSCC 2007 • 34% of women with BNC HPV positive • 61% of women with mild dys HPV positive • A single HPV test insufficient to warrant colposcopy • No compelling economic reason to adopt Triage

  27. Sentinel sites • NHSCSP has started rolling out HPV triage via sentinel sites • Just started • 6 centres • Sheffield, Norfolk & Norwich, Bristol, Manchester, Liverpool and Northwick park • Using HC II • HPV testing carried out in Manchester

  28. Sentinel protocol • BNC / Mild dys & HPV positive • refer • At Colp • High grade CIN = treat • CIN I / neg colp / mild dys > cytology again at 6 months

  29. Summary - Triage • We await results with interest • Efficacy of triage for BNC is almost certain • Less certain for mild • ? Refer HPV positive women straight away or repeat again in 6 or 12 months • To look closely at cost effectiveness • Particularly the link with 14 day turnaround • Will LBC increase performance of cytology ?

  30. Follow up after Treatment • Currently women with excised / treated CIN II / III are followed by annual smears for 10 years

  31. Follow up after Treatment • Also being investigated by the Sentinel sites • HPV and cytology at 6 months • If negative = routine recall • If HPV & cytology positive > colposcopy • If only one positive, another cytology test in 6 months.

  32. Summary - Follow up after Treatment • Within UK programme seems to carry enormous benefits

  33. Primary Screening by HPV Testing • Sensitivity of HPV testing is higher than cytology, • Direct referral for colposcopy of all women aged > 30 who are HPV positive in one screening round would detect almost all high-grade CIN and invasive cancer (Meijer 2000)

  34. Primary Screening by HPV Testing • Remember however that many of these women do not have HG disease at that time • Just a viral infection that might regress • 10 year risk of CIN III with HPV +ve test • 13.6% in younger women • 21% in older women (Kjear et al. Cancer Res:2006;66(21):10630-6) • Increase referrals to colposcopy • Sacrifice specificity for sensitivity ?

  35. HART study(HPV in Addition to Routine Testing) • HPV testing could be used for primary screening in women older than 30 years, with cytology used to triage HPV-positive women. • HPV-positive women with normal or borderline cytology could be managed by repeat testing after 12 months. Cuzick et al. Lancet 2003; 362: 1871-1876

  36. Primary Screening by HPV Testing • POBOSCAM Oct 2007 Lancet • Naucler – Sweden NEJM Oct 2007 • Both compared conventional Pap smears to HPV testing by PCR • Both suggested that you detect CIN III earlier • Can safely extend screening interval to six years!

  37. Primary Screening by HPV Testing • Both detect high grade CIN earlier • Could be detecting some CIN II / III that might have regressed (esp CIN II) • Might need a better test that can separate regressive from progressive HPV infections might be needed Khan et al. J Natl Cancer Inst 2005; 97: 1072-0

  38. Primary Screening by HPV Testing • Both do not take into account the vast difference between conventional & LBC samples • Do not take into account women aged < 30 • Everyone retrained • Artistic gives a glimpse of this!

  39. ARTISTIC TRIAL • A Randomised Trial In Screening To Improve Cytology • 25,000 women (20 – 65) in Manchester • Investigating potential of primary screening • Doing a cost benefit analysis • Expecting full results anytime now • First results NOT as good as expected

  40. ARTISTIC TRIAL • Preliminary data suggests that liquid based cytology plus HPV is NOT more sensitive over 2 screening rounds than cytology alone

  41. ARTISTIC TRIAL • High grade dyskaryosis rates over study period • Revealed arm (effect of HPV + Cyto) • 1.9% - 0.37% • Concealed arm (effect of LBC only) • 1.6% - 0.33%

  42. ARTISTIC TRIAL • ARTISTIC has been extended to 6 years

  43. Summary - HPV Testing • Offers potential • Might add cost so will have to do the cost benefit analyses • Appropriate management strategies • Will have to decide which way to test • PCR v Hybrid capture • Improve specificty of HPV testing by using techniques that home in on individual types • Work out how to deal with those aged < 30

  44. Summary - HPV Testing • Pity we couldn’t let LBC bed in • None of big studies compare with LBC and ARTISTIC gives a glimpse of what might have been achieved • Need to look at impact on laboratories & 14 day turnaround • Automation could make HPV testing less competitive

  45. Summary - HPV Testing • CONCERNS • A lack of knowledge in the general public • Could money be better spent on coverage ?

  46. HPV Testing • “Excessive or misguided use of HPV testing will increase costs without adding benefit” • “Like most revolutionary technologies, HPV testing must be managed wisely to do good rather than harm” Mark Schiffman. BMJ 2006;332:61-62

  47. Vaccination • Currently two on the market • Gardasil (Merck) – protects against • HPV 16, 18; 6, 11 • Cervarix (GSK) – protects against • HPV 16,18

  48. Vaccination • In UK should start this September • Start at 12, 2 year opt in up to 18 • In UK expect decision on which soon • As of October 2007 • Gardisal licensed in 80 countries • Cervarix in 30

  49. Vaccination • It will cost around £250 for the three doses needed. • Gardisal also protects against 6 & 11 and will thus reduce the problems caused by genital warts • GSK has a stronger adjuvant and possibly better cross protection • ? HPV types 45, 31 & 52

  50. Vaccination • Politically driven decision • Add massive cost • Screening will have to continue

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