HPV and the Future of Cervical Screening John Tidy, Professor of Gynaecological Oncology Chair, National Colposcopy QA Committee, Sheffield
What is HPV? Small ds DNA virus Over 140 genotypes described Restricted infection Only certain types of HPV can infected certain tissues HPVs 1 and 2 affect skin of hand and foot HPVs 6,11,16 and 18 infect genital and oral mucosa
What is HPV? Cannot be cultured in the laboratory Detected only tests for HPV DNA or RNA 80% of people become infected with HPV after on set of sexual activity HPV is transmitted by intimate contact Most people eradicate HPV infection but can take over 13 months Persistence of HPV infection linked to the development of cervical neoplasia
HPV Vaccination Now using Gardasil (HPV 6,11,16 &18) From September 2014 2 doses, at least 6 months apart Year 8 (12-13 year old girls) Uptake 2013/14 287,757 girls Dose 1 89.5% (84.3 95.4%) Dose 2 87.2% (78.2 93.4%) All 3 doses 79.7% (58.1 88.2%)
HPV Vaccination Recent results from a 9-valent HPV vaccine HPVs 6,11,16,18,31,33,45,52 and 58 HPV 31,33,45,52 and 58 related disease 0.1 per 1000 person years in 9-valent group 1.6 per 1000 person years in HPV 6,11,16 and 18 group Adverse events related to injection site more common in 9-valent group Joura et al 2015
Effect of HPV Vaccination Data from Scotland Still commence screening from age 20 Commenced HPV vaccination in 2008 School based (80%) and catch-up (30%) Linked data sets from screening programme and colposcopy records fro women aged 20-21 in 2008-2011 Reduction in rates of CIN for vaccinated population CIN3 RR 0.45, CIN2 RR 0.5, CIN1 RR 0.7 Pollock et al 2014
How is HPV testing used in the current English Cervical Screening Programme Utilise the high sensitivity and negative predictive value of HPV testing In excess of 98% of all high grade cervical neoplasia (CIN2+) and invasive cancers contain high risk HPV (HR-HPV) The absence of HR-HPV predicts the absence of cervical neoplasia
Two stage evaluation of HR-HPV testing Evaluation within an effective organised quality assured national screening programme HR-HPV testing for triage of low grade dyskaryosis (borderline, mild) Test of cure 6 months after treatment for CIN HR-HPV testing as primary screen with reflex cytology
Why use HR-HPV testing in triage of low grade cytology Increased detection of high grade CIN leading to earlier treatment and early discharge Early return of women with low grade cytology who were HR-HPV negative to routine recall Early return of women with low grade cytology and are HR-HPV positive but have a negative satisfactory colposcopy to routine recall
Why use HR-HPV testing in triage of low grade cytology Cost effectiveness Despite increased costs of HR-HPV testing and temporary increase in colposcopy workload there are savings made from reducing community based cytology follow up samples Cost effectiveness for triage of mild dyskaryosis may appear not be significant for an individual laboratory but will be effective for the NHSCSP
Rationale for HPV Sentinel Site Study Insufficient data from LBC/HPV triage pilots Need to assess HR-HPV testing as part of test of cure Comparative data between Thinprep and Surepath LBC systems Using residuum for HR-HPV testing Establish cut off for HR-HPV testing by HC2 Used 2RLU as positive and NOT 1RLU
Rationale for HPV Sentinel Site Six centres Study Manchester, Liverpool, Sheffield, Norwich, Northwick Park and Bristol Four centres Thinprep Manchester, Norwich, Northwick Park and Bristol Three centres Surepath Manchester, Liverpool, Sheffield, Two centre for HPV testing Manchester and Bristol
BORDERLINE or MILD DYSKARYOSIS Moderate dyskaryosis or worse with treated CIN HPV -ve HPV +ve COLPOSCOPY No repeat cytology BORDERLINE/MILD with negative colposcopy, no biopsy or biopsy with no CIN CIN1 CIN2/3 No treatment TREATMENT Cytology at 12 months with or without colposcopy Cytology only at 6 months Normal, borderline, mild Moderate, severe HPV ve HPV +ve Routine 3 or 5 year recall (depending on age <50 or 50) 3 year recall COLPOSCOPY Treat or, if normal, cytology follow up according to national
Results from the Sentinel Site Study
Sentinel sites HR-HPV +ve (%) rates by cytology and age Borderline Mild Total Age group N=6507 N=3544 N=10051 25-34 N=5324 35-49 N=3912 50-64 N=815 Total N=10051 68.6% 89.2% 77.2% 41.9% 77.0% 52.0% 31.0% 66.5% 40.2% 53.7% 83.9% 64.4%
Percentage 80 70 60 50 40 30 20 10 0 HR-HPV positivity in borderline cytology and PPV for high grade CIN A B C D E F Study site Borderline HPV% Borderline PPV CIN2+ Borderline PPV CIN3+ Av. CIN3 6.7%
Percentage HR-HPV positivity in mild cytology and PPV for high grade CIN 100 90 80 70 60 50 40 30 20 10 0 Mild HPV% Mild PPV CIN2+ Mild PPV CIN3+ Av. CIN3 5.4% A B C D E F Study site
Use of HPV as a Test of Cure The absence of HPV 6 months treatment in women with negative or low grade cytology predicts the absence of residual disease Women can be discharged to 3 yearly recall The presence of HPV 6 months treatment in women with negative or low grade cytology increases the detection of residual disease
Detection of CIN in Test of Cure overall data PPV to detect CIN CIN2+ CIN3+ Abnormal cytology 13.3% 8.1% Normal cytology / HPV+ 2.7% 0.4% The incidence of CIN in the normal cytology/hpv + group is very low Discharge this group to routine recall
Summary HR-HPV triage reduces the need for follow up cytology in Borderline 3.8% of all smears (127,367) Mild dyskaryosis 2.2% of all smears (74,757) Must have three negative samples before returning to routine recall Borderline HR-HPV ve 46.3% Mild dyskaryosis HR-HPV ve 16.1%
Summary HR-HPV triage allows early diagnosis and treatment of high grade CIN and early return of women without CIN to routine recall Borderline CIN 2+ 9.3 21.5% Colp neg +/- neg Bx 45.53% Mild dyskaryosis CIN 2+ 9.1-30% Colp neg +/- neg Bx 37.10%
Summary Addition of HR-HPV for test of cure allows women who have been treated for CIN to return to routine recall so avoid need for 7 extra cytology samples (10 annual 3x3 yearly recall) 80.6% of all women treated for CIN will be cytology negative / HR-HPV negative so can be returned to routine recall
HPV testing as a Primary Screen Increased sensitivity of HPV testing may increase disease detection The absence of HPV may allow screening interval to be increased Screening with cytology may not be fit for purpose in a vaccinated population with low prevalence of disease
English NHS Cervical Screening Programme HPV Primary Screening Sentinel Site Study Coverage of 140,000 screened women Commenced mid April 2013 Invitations sent out Roll out at each of the sites over the following 6 weeks Extensive web based information and training packages for primary care
Primary HPV Screening Assessment of HPV genotyping Assessment of CINTEC plus Assessment of colposcopic performance by HPV genotyping
Primary HPV Screening 6 sites all previously part of sentinel site study Local models for conversion to primary HPV screening are variable Single PCT or GP practices across PCTs Bristol Liverpool Manchester Norfolk and Norwich Northwick Park Sheffield
Primary HPV Screening Different HPV technologies will be used at each site Roche Norfolk and Norwich, Sheffield Genprobe Bristol,Liverpool Abbot Manchester, Northwick Park Comparison studies between HC2 and other technologies At least 400 samples dual tested Good agreement between HC2 and other technologies
HPV Primary Screening Algorithm Pilot Year 1 All women aged 25-64 on routine call/recall and early recall HR-HPV Test HR-HPV -ve Routine recall 3y(25-49) 5y( 50)* HR-HPV +ve Cytology triage Cytology normal # Cytology abnormal borderline or worse Re-screen in 12m Colposcopy referral HR-HPV -ve HR-HPV +ve Routine recall 3y(25-49) 5y( 50)* Cytology normal # Cytology abnormal borderline or worse Notes Inadequate tests at any screening episode in the pathway will be repeated in 3 months. Three inadequate tests in a row will lead to a colposcopy referral. Women in follow up for cgin, SMILE or microinvasive carcinoma at a pilot site will be given annual HPV testing (instead of cytology) for 10 years. *Routine recall to be extended to 6 years (subject to approval) for all age groups entering pilot in year 2. #HPV16/18 recorded where available. Final Version 1.0 February 2013 Re-screen in 12m HR-HPV -ve Routine recall 3y(25-49) 5y( 50)* Colposcopy referral HR-HPV +ve # Colposcopy referral
HPV Primary Screening Pilot Colposcopy Management Recommendations Colposcopy Examination Inadequate Normal and adequate Abnormal Index test HR- HPV +ve/cytology low grade <40yrs Index HR-HPV +ve/cytology high grade or 40yrs No biopsy or biopsy <CIN1 Abnormal Biopsy CIN1+ CIN1 CIN2 Negative biopsy Repeat colposcopy in 12m LLETZ Index test HR-HPV +ve/ cytology low grade Index test HR-HPV +ve/cytology high grade Recall in 12m Manage according to national guidance Discussion at MDT within 2m Discharge to 3y recall Discussion at MDT within 2m HR-HPV -ve HR-HPV +ve Version 1.1 December 2012 3y recall Cytology negative 12m recall Cytology abnormal Refer to colposcopy
The story so far Sheffield May 2013 Norfolk and Norwich May 2013 Liverpool July 2013 Manchester July 2013 Bristol September 2013
The story so far HPV positivity rate 10.7 15.0% HPV positive / negative cytology rate 62.8 70.0% Referral to colposcopy rate 4.0 4.7%
Conclusions Evaluation of primary HR-HPV testing with reflex cytology has commenced HR-HPV positivity rates are as expected Better rates of HR-HPV positive/cytology negative compared with ARTISTIC Referral rates to colposcopy unchanged at 4% of the screened population Referral rates may increase due to persistence of HPV infection