The Usefulness of HPV Testing ?

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
ARTISTIC Trial HPV Prevalence by Age at
entryCourtesy of Dr Desai
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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

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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

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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
200092397-402
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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 99S7 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
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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 gt
• 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 gt 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
  gt 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
  Res200666(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 lt 30
• Everyone retrained
• Artistic gives a glimpse of this!

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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

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ARTISTIC TRIAL

• ARTISTIC has been extended to 6 years

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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 lt 30

44
Summary - HPV Testing

• Pity we couldnt 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 200633261-62
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Vaccination

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

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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

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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

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Vaccination

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

51
Prophylactic Vaccines

• Can you think of any potential problems?

52
Prophylactic Vaccines

• Problems?
• Everyone has to the vaccine
• Doesnt protect against all cancers so screening
  will have to continue

53
HPV types in Cervical Cancer
57.6
16
vaccine types
71.7
18
77.4
45
81.3
31
85.0
X
87.9
33
90.1
52
91.8
58
93.3
35
94.6
59
95.7
56
0
20
40
60
80
100
Proportion of cancers associated with HPV types
HPV 16/18 vaccine could prevent gt 70 of cervical
cancers
Munoz N, Bosch FX, et al. IARC Multicenter
Cervical Cancer Study Group. N Engl J Med 2003
348 51827.
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Prophylactic Vaccines

• Problems?
• What might happen to coverage
• Will have marked effect on the method of
  screening
• Some suggesting we will need HPV or automation

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Summary

• Screening as we know it is under considerable
  threat
• None of the modalities discussed however will
  remove need for screening
• Screening will continue but how and where?
• Money better spent on improving coverage?

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The Future ?

• Must make sure that new tests are brought into
  the cytology laboratory
• Often assumed that new tests such as hybrid
  capture and the molecular tests will be done in
  specialist or virology labs
• These labs are optimally staffed

57
The Future ?

• Since Cytology laboratories would have the staff
  and space we should take on these roles
• UK BMS staff with their strong generic training
  are well placed to adapt to such tests
• Ensure managers are aware of this

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Contact details

• Nick.dudding_at_sth.nhs.uk
• 0114 271 2538