Transcript HPV Testing and Cervical Screening in the UK

HPV Testing and Cervical
Screening in the UK
Alex Sargent
HPA Manchester
Human Papillomaviruses
• Mainly infect the anogenital tract ( approx 40 genotypes)
• Quite often asymptomatic
• LOW RISK (20 Types including types 6 and 11)
– Anogenital warts
– Very rarely found in cancers
• HIGH RISK (approx 14 types)
– Precursor lesions (CIN)
cervical cancer
– Most malignancies of the anogenital tract
99.7% of cervical cancers are
directly linked to previous
infection with a High Risk
HPV type
Walboomers et al 1999
High-risk HPV Prevalence (N=24,510)
45
40%
Percentage of HR HPV
40
35
30
28%
25
19%
20
15
12%
9%
10
8%
7%
6%
6%
55-59
60+
5
0
20-24
25-29
30-34
35-39
40-44
45-49
50-54
Age Group
Kitchener et al 2006
% of Type Specific HPV Prevalence
HR HPV Type by Cytology Grade
60
50
40
30
20
HPV 16
HPV 18
HPV 31
HPV 33
HPV 35
HPV 39
HPV 45
HPV 51
HPV 52
HPV 56
HPV 58
HPV 59
HPV 68
10
0
Normal
Borderline
Mild
Cytology Grade
Moderate
Severe or worse
MRI Involvement in HPV
• Malignant progression of laryngeal papilloma associated with human
papilloma virus type 6 (HPV-6) DNA. A P Zarod, J D Rutherford, and G
Corbitt. J Clin Pathol. 1988; 41: 280–283
• Anal human papillomavirus and anal cancer. Tilston P. J Clin Pathol. 1997;
50:625-34
• A study of anal intraepithelial neoplasia in HIV positive homosexual men.
Lacey HB, Wilson GE, Tilston P, Wilkins EG, Bailey AS, Corbitt G, Green PM.
Sex Transm Infect. 1999; 75:172-7
• Natural history of cervical human papillomavirus infection in women during
their first sexual relationship. Woodman CB, Collins S, Winter H, Bailey A,
Ellis J, Prior P, Yates M, Rollason TP, Young LS. Lancet. 2001; 357:1831-6
• More recent work has been our involvement
in the ARTISTIC Trial
• Designed to investigate the value of
incorporating HPV testing in to the English
cervical cancer screening programme
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Kitchener at al. Br J Cancer 2006; 95(1): 56-61
Sargent et al. Br J Cancer 2008; 98(10):1704-9
Kitchener et al Lancet Oncol. 2009;10(8):748.
Kitchener at al Health Technol Assess. 2009; 13(51):1-150, iii-iv
Sargent et al. J Clin Microbiol. 2010; 48(2), 554-8
Kitchener at al Eur J Cancer. 2011; 47(6):864-71
ARTISTIC Trial
Main findings
• Primary cervical screening with combined LBC and HPV
testing resulted in only a small reduction in the detection of
high grade disease at the next screening round compared to
LBC alone
• HPV testing, either for triage or as the initial screening test
triaged by cytology, would be cost effective with no loss of
sensitivity
• The screening interval could be increased from 3 to at least
6 years
• No significant adverse psychosocial effects were detected
NHS HPV Triage Pilot Studies
• Studies showed
• A reduction of inadequate smears (from 9% conventional cytology to
1-2% LBC)
• 46% (1680/3681) BNC & 83% (1507/1825) mild dyskaryosis were HPV
positive
• The rate of repeat smears fell by 74% (70% for BNC & 87% for mild)
• Rate of referral to colposcopy more than doubled (increased from
15%-44% for BNC & 37% - 80% for mild)
• Direct referral of HPV positive women to colposcopy may lead to
increased detection of CIN2+
Legood. BMJ 2006; 332:79-83
Moss. BMJ 2006; 332:83-85
Sentinel Sites project
Funded by the NHS Cervical Screening Programme
HPV Triage
• March 2008 -2011, 6 cytology centres (approx. 10% screening population
in England) acted as sentinel sites for HPV triage
• In the event of borderline or mild dyskaryosis cytology, residual material is
tested for HR HPV using the Hybrid Capture 2 test (≥2RLU/Co)
– HPV Positive women are referred to colposcopy
– HPV Negative women are returned to routine recall (HPV testing has a high NPV)
• Virology testing centralised in Manchester Virology lab and Bristol
Cytology lab
Sentinel Sites project
Test of cure
• In the event of an abnormal cytology report post-treatment, women are
referred for colposcopy (standard practice)
• In the event of a normal cytology report, residual material is tested for
high risk HPV by HC2 (≥2 RLU/Co)
• HPV negative women are referred for 3-year recall ( rather than annual
recall for 10 years) and HPV positive women referred for colposcopy
• HPV-directed referral strategy is of considerable benefit to women in
terms of reducing anxiety, uncertainty and the need for repeat smears, as
well as reducing work load in cytology
Kitchener et al. BJOG 2008; 115:1001-1007
Percentage HC2 positive for HR HPV
Types
HR HPV Positivity Rate by Referral Site
90
Cytology Lab A
80
Cytology Lab B
84
79
75
71
Cytology Lab C
70
60
50
46
40
31
30
20
15
16
12
10
0
TOC
TBO
Cytology Grade
TMIL
Improvements to the NHS CSP
• Increased identification of high grade CIN and increased specificity in
women undergoing HPV triage
• HPV triage offers immediate referral to colposcopy for those who may
have significant disease & rapid return to routine recall for women
unlikely to have significant disease due to high NPV of HPV testing
• HPV ToC offers rapid return to routine recall for treated women (approx.
80%)
• Reduced repeat testing will give rise to savings in primary care and
laboratories
HPV TESTING
NEW TECHNOLOGIES STUDY
Qiagen HC2 assay
• Clinically regarded as the “Gold Standard”
• Approved cervical specimens include Cytyc ThinPrep
PreservCyt® solution & SurePath preservative fluid
• Signal amplification DNA screening assay
• Targets 13 HR types
• Semi-automated system available
• No internal control for sample integrity
• Known issues regarding cross-reactivity
Qiagen Hybrid Capture 2 (HC2) Test
The Rapid Capture™ System
Courtesy of Digene
ALTERNATIVE HPV TESTS
Basic Methodologies
HPV Detection performed by molecular assays
- Signal Amplification (HC2 ; Cervista)
- Nucleic Acid Amplification (PCR ; TMA ; NASBA)
• Screening assays
– Designed to detect the group of High Risk HPV Genotypes
– Some assays also have limited genotyping capacity for types
16 and 18
• Genotyping assays
– Designed to Genotype the majority of the HPV types infecting
the Genital Tract-particularly the High Risk Genotypes
– Usually based on either a line blot assay format or micro-array
system
– As yet of questionable value in the cervical screening
programme
Some Commercial Screening Assays
Qiagen HC2
GenProbe APTIMA
Roche AMPLICOR
Roche Real Time
Abbott Real Time
Hologic Cervista
Norchip
Bio-Tools
Gen ID
Genomica
Clinical Validation
• In the case of HPV infections there is a big difference
between analytical sensitivity and clinical sensitivity
/specificity
• Meijer CJ et al have recently developed guidelines for
high-risk HPV test requirements for primary cervical
screening and validation guidelines for candidate HPV
assays
Int J Cancer 2009 Feb 1 124 (3) 516-20
Guidelines for HPV Testing
• The sensitivity of the candidate test for CIN2+ should
be at least 90%** of the sensitivity of the HC2 assay
to Detect Clinical Disease
• The specificity of the candidate test for CIN2+ should
be at least 98% of the specificity of the HC2 assay
**For our study the minimum sensitivity has been
raised to 95%
New Technologies Study
Aim
• To demonstrate non-inferiority of any new test relative to
Qiagen Hybrid Capture 2, in terms of both sensitivity and
specificity for detection of high grade disease (≥CIN2)
• To assess the clinical utility of the test for triage of low grade
cytology
• New tests were assessed at Bristol HPA and Manchester
HPA - 2500 SurePath LBC and 2500 ThinPrep LBC
Commercial Assays Under Evaluation
New Test
Surepath
Thinprep
Roche Cobas 4800


Abbott rt HPV
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Gen-probe HPV
APTIMA
++

Hologic Cervista
HPV
++ non-CE marked

Conclusions
• All assays so far have proved non-inferior to
the HC2 assay
– Genprobe (SurePath) and Hologic are still under
evaluation
• New tests are highly automated
• All assays have internal controls
• Abbott and Roche tests can simultaneously
detect and identify types 16 and 18
Possible Future
• Setting up of sentinel sites to pilot primary
HPV testing in cervical screening
• Use of self sampling to improve coverage of
the cervical screening programme
Acknowledgements
• Prof Henry Kitchener and the ARTISTIC Team
• Prof Julietta Patnick and members of the
NHSCSP
• Members of the Primary Screening Group
• Andrew Bailey and Staff in Virology,
Manchester Royal Infirmary