1. HPV testing as a Primary screening tool in England Dr Karin Denton

3. HPV or Cytology? Long running debate HART study – Cytology reported to have low sensitivity – BUT pan-european study – UK was always better than mean – Conventional cytology

4. ARTISTIC TRIAL A Randomised Trial In Screening To Improve Cytology A Randomised Trial In Screening To Improve Cytology Funded by HTA Funded by HTA Set up to evaluate the effectiveness of HPV testing in primary cervical screening (Manchester) Set up to evaluate the effectiveness of HPV testing in primary cervical screening (Manchester)

5. ARTISTIC TRIAL 24, 510 women 24, 510 women LBC & HPV test for HR HPV regardless of cytology result LBC & HPV test for HR HPV regardless of cytology result

6. HPV prevalence by age

7. ARTISTIC A combination of LBC & HPV testing over 2 screening rounds is NOT more sensitive than cytology alone A combination of LBC & HPV testing over 2 screening rounds is NOT more sensitive than cytology alone However by the third round, HPV primary screening with cytology triage more sensitive, ie longer duration of protection However by the third round, HPV primary screening with cytology triage more sensitive, ie longer duration of protection

8. Round 3 Artistic outcomes BaselineCumulative outcomeRate Cytology negativeCIN2+1.4% HPV-CIN2+0.9% CIN3+0.3% HPV16/18+CIN2+38% CIN3+25.8% Non 16 /18 HPV+CIN2+9.8% CIN 3+4.9%

9. What does Artistic tell us? HPV primary screening is more sensitive over 3 screening rounds than cytology + HPV triage A high proportion of women are HPV positive HPV positivity has low specificity for CIN2+

10. What does Artistic NOT tell us How good is cytology at improving specificity – Cytology reporting was blind to HPV result

11. Implications of changing to primary HPV screening A change to HPV primary screening with cytology triage would have many practical implications Essential not to undermine a very successful screening programme Pilot methodology has been very helpful in implementing other major changes including LBC and HPV triage and TOC

12. A successful programme

13. NHS CSP pilot of HPV primary screening? Steering group established 3 Subgroups established – Laboratory issues – Clinical algorithms – Cost effectiveness Much preparatory work has been done Pilot requires ministerial approval ?

14. Proposed Pilot of HPV primary screening 6 sites nationally including Bristol Convert a proportion of women to new protocol Propose to convert – several GP practices from multiple PCT’s – Whole PCT’s Full training would be given to sample takers Information leaflets and letters for women would be available No change to patient experience – same sample etc

15. Risks/Challenges Clinical algorithm – before and after referral to colposcopy – Must be evidence based, usable despite complexity Which HPV test? IT issues Effect on colposcopy

16. Algorithm

17. 3 HR-HPV Test HR-HPV -ve HR-HPV +ve Cytology triage Routine recall 3y(25-49) 5y(≥50) Cytology normal Cytology abnormal – borderline or worse Screen in 2 years # HR-HPV -ve HR-HPV +ve Routine recall 3y(25-49) 5y(≥50)* Colposcopy referral Cytology normalCytology abnormal – borderline or worse Colposcopy referralScreen in 2 years HR-HPV -ve HR-HPV +ve Routine recall 3y(25-49) 5y(≥50)* Colposcopy referral All women aged 25-64 on routine call/recall and early recall Draft

18. Index test HR-HPV +ve/cytology ≤low grade <40yrs DRAFT Colposcopy Examination Inadequate Abnormal Normal and adequate No biopsy or biopsy <CIN1 ≥CIN2CIN1 Negative biopsy Abnormal Biopsy CIN1+ Discussion at MDT within 2m Treat † Recall in 12m Index test HR-HPV +ve/ cytology ≤low grade Index test HR-HPV +ve/cytology ≥high grade Discussion at MDT within 2m Discharge to 3y recall HR-HPV -veHR-HPV +ve † Option of colposcopy at clinicians discretion Reflex cytology and/or 12m follow up Index HR-HPV +ve/cytology ≥high grade or ≥40yrs Repeat colposcopy in 12m LLETZ Draft

19. Which HPV test? NHS CSP undertook an evaluation leading to a national contract process with NHS Procurement 4 technologies approved with both LBC platforms – HC2 – Genprobe – Abbott – Roche 1 evaluation not yet complete – Cervista (TP)

20. All tests have been evaluated as at least equivalent to HC2 HPV primary screening would need to be done from same menu No new entrants for at least 3 years

21. IT issues Exeter system designed in 1988! Creaking under the strain Significant modifications already in progress to accommodate HPV triage and TOC and changes to terminology Changes for HPV primary screening are bigger Need to accommodate results with no cytology Can be done but new system would be better

22. Effect on colposcopy

23. How good will we be at this? In ARTISTIC, cytologists were blind to HPV result Overcalling has potential to cause great harm by unnecessary referral to colposcopy and undermine cost effectiveness

24. Sensitivity/ Specificity HPV is more sensitive but less specific than cytology Need to maintain both sensitivity and specificity Focus on Sensitivity. HPV + cyto negative - ? Role for genotyping Specificity. HPV+ cyto borderline - ? Role for molecular markers eg p16

25. Sensitivity/specificity HPV is more sensitive but less specific than cytology Need to maintain both sensitivity and specificity Focus on Sensitivity. HPV + cyto negative - ? Role for genotyping Specificity. HPV+ cyto borderline - ? Role for molecular markers eg p16

26. CintecPlus

27. Mild dyskaryosis

28. Severe dyskaryosis

29. How long?? Duration of pilot. – At least one screening round including time for colp referral and histology – 4 years Decision to implement – At least 1 year Implementation – At least 2 years

30. Screening interval Currently 3 years age 25-49, 5 years age 50-65 Good evidence that HPV primary screening gives longer duration of protection Interval is likely to be extended Recall date is set at the time of the index test and cannot be retrospectively extended

31. HPV Vaccine HPV vaccine offered to all 12 year olds from 2008 Catch up programme to cover all 13-18 year olds up to by 2010 How effective has it been?

32. Insert vaccine data

33. However, peak age of CIN 3 is 25-34, therefore maximal effect not felt until around 2025 At that point 50% reduction in high grade dyskaryosis is forecast

34. Future development? Self sampling?

35. Many variables... High grade rates will drop gradually due to – HPV triage – Vaccine effects – Long term protection offered by HPV primary screening Implications for quality assurance and working practices

36. Lab staffing In an HPV primary screening model, HPV test will replace the primary screen Much less requirement for primary screeners – ? 80% less Requirement for checkers and consultants unchanged New skill set required – confidence in reporting HPV positive, cytology negative result

37. South West 2012

38. South West 2014

39. Lab reconfiguration A lab serving population yielding 35 000 samples today with HPV triage and TOC 3 consultants – aprox 1.5 wte 3 seniors/checkers – 3 wte 8 screeners 2500 HPV tests 400 high grade cytology 1500 low grade cytology A Lab serving the same population with HPV primary screening in a vaccinated population 3 consultants - <1 wte Seniors/checkers - ? 1.5 wte ?0 screeners Staff to do HPV testing ? 20 000 HPV tests Maybe as low as 100 high grade cytology ?effect on low grade rate

40. SW HPV primary screening ?

41. Conclusion There is strong evidence that HPV primary screening could improve the sensitivity of cervical screening Many practical issues need resolving Pilot methodology If successful, screening programme will change dramatically