Service Development
Title:
Division:
Lead Officer:
Background:
National Reference Laboratory for HPV
testing related to National Immunisation
Programme
and
Small Scale Laboratory for HPV testing
related to Test of Cure in High Grade
Cervical Disease (CIN2+)
Health Protection Scotland
and
National Services Division
Jane Spence, Project
Manager, National HPV
Programme
And
Isobel Gavin, Project
Manager, NSD
Bid Ref No:
Date:
Project Sponsor:
14 January
2008
Martin Donaghy, Medical
Director, HPS
And
Carol Colquhoun, National
Screening Co-ordinator,
NSD
There have recently emerged two substantive and evidence-based indications for the early
introduction of Human Papilloma Virus testing in Scotland: for surveillance purposes in
respect of the imminent introduction of an HPV immunisation programme and as test of
cure in the treatment of high grade cervical disease.
No established (i.e. mainstream funded) laboratory provision exists in Scotland although
the south east of Scotland regional virus laboratory run by Professor Heather Cubie has
considerable experience in HPV testing.
The present joint application covers both proposed developments in recognition that the
preferred solution is a single virus laboratory discharging diagnostic and reference functions
although it is recognised that the responsibility for advising on funding the two service
elements will rest with different advisory bodies, the Reference Laboratory Working Group
and the National Advisory Group for Breast and Cervical Screening. It is hoped that this
joint submission will afford both parties a fuller understanding of the synergies likely to
accrue from the two initiatives being taken forward together.
The information presented in each section below is shown, where appropriate, separately
for an immunisation surveillance service (A) and for a “test of cure” diagnostic service (B).
A. Immunisation Surveillance Service
From September 2008, HPV vaccination will be included in the national immunisation
schedule in Scotland, targeted at females aged 12 to 13 years with a catch up campaign
targeted at females up to but not including 18 years. Two vaccines have been licensed; the
decision on which will be used in the national programme is likely to be announced in
February 2008. A quadrivalent vaccine, Gardasil, has been developed by Sanofi Pasteur. It
offers protection against HPV types 6, 11 (causative agents of over 90% of genital warts)
and 16 and 18 (implicated in approximately 70% of cervical cancers). A second vaccine,
Cervarix, has been developed by GSK to protect against types 16 and 18. The decision on
which vaccine will be made in May 2008.
The introduction of a vaccine against HPV may over time necessitate the reorganisation of
the cervical screening programme to reflect changes in the prevalence of HPV in this
population. A system for monitoring HPV and HPV related disease in the Scottish
population would provide data to inform what will be the optimum mix of vaccination,
screening and HPV testing required to reduce the incidence of cervical cancer.
HPS is leading the national project to introduce the HPV immunisation programme in
Scotland which is estimated to cost between £65-70 million over the 3 year period 20082011. As with all national immunisation programmes, there is a need to assess its
effectiveness. At its meeting in October 2007, the Joint Committee on Vaccination and
Immunisation endorsed a programme to evaluate the HPV Immunisation programme which
has the following objectives:

To evaluate the effect of the HPV vaccination programme on HPV-related i)
cervical disease, ii) genital warts, and iii) the frequency of vaccine-type and nonvaccine-type HPV infections in women of vaccinated age and in males and
females not eligible for HPV vaccination;

To measure vaccine effectiveness against vaccine-type HPV infections and HPVrelated diseases, and

To investigate risk factors and mechanisms of vaccine failure.
HPS is developing the Scottish arm of this programme including a baseline study of HPV
prevalence in Scottish males and females aged 11 to 18 years. It is composed of the
following elements (further information is provided in the attached paper.):
1.
Surveillance of overall and type specific HPV prevalence in males and females in the
birth cohorts invited for routine or catch-up HPV Immunisation by:
a.
Determining overall and type-specific HPV prevalence in a representative sample
of females from cohorts who have been invited for HPV immunisation and are
attending for their first and second cervical screening appointments.
b.
Determining HPV prevalence and type-specific prevalence in sentinel populations
likely to include a high proportion of females who are not or are unlikely to attend
cervical screening
c.
Determining overall and type-specific HPV prevalence in males
2.
Surveillance of type specific HPV prevalence in those diagnosed with Cervical
Intraepithelial Neoplasia (CIN) 1, 2, 3) by the Scottish Cervical Screening Programme.
3.
Enhanced Surveillance of Genital Warts – dependent on the choice of vaccine.
4.
Enhanced Surveillance of non cervical, anogenital carcinoma (prevalence, type
specific prevalence and incidence) by the Scottish Cancer Registry.
The levels of ongoing immunity provided by the vaccine will need to be monitored in order
to inform the organisation of the immunisation schedule against HPV and to identify the
need for a booster. In this regard, discussions have taken place with one of the two
pharmaceutical companies for the introduction of a Phase IV post licensing study in
Scotland. In parallel with the Phase IV Study, a group of Scottish researchers have been in
discussions with the Chief Scientist’s Office of the Scottish Government to obtain a
research programme grant to fund a number of studies on key questions on HPV covering
testing, immunisation, primary care and cervical screening. There is considerable overlap
between evaluating the impact of the HPV immunisation programme and the CSO
proposal.
Core to the achievement of these objectives is the provision of a National Reference
Laboratory to type HPV isolates detected in liquid cytology (from cervical screening), urine
(sentinel surveillance) and biopsy tissues (cancer registry). Discussions with the Scottish
Clinical Virology Group have indicated that only one laboratory is required to carry out both
the initial HPV testing and typing of such specimens - Specialist Virology Centre at the
Royal Infirmary of Edinburgh led by Drs. Heather Cubie and Kate Cuschieri both of whom
have considerable expertise and experience in HPV virology and are collaborating closely
with HPS in the national programme.
B. Cervical disease test of cure
For women treated at colposcopy for high grade cervical disease (CIN2+) there is now
clear evidence to show that the use of HPV testing, preferably in conjunction with cytology,
will identify at an early stage which women are likely to show residual/recurrent disease
after treatment. A sub group of the National Advisory Group on Breast and Cervical
Screening has considered the benefits and disbenefits of this intervention and considered
the way that HPV status influences decision making by colposcopists.
Early studies suggested that high risk HPV DNA detection was more sensitive than and at
least as specific as cytology for predicting recurrence of CIN in women treated for high
grade CIN. These studies led to the conclusion that the intensity of monitoring of women
2
post treatment could be reduced in those women who were HPV negative and cytology was
within normal limits. These studies led to the setting up of a number of country specific
studies which are beginning to be published. Early results support carrying out both
cytology and HPV testing at the same time in post treatment women.
Aberdeen has participated in a three centre test of cure study, along with Manchester and
London, and has recruited approximately 970 women after treatment of high grade CIN.
Most of the study women are at three year follow up and it was hoped the study would be
complete in 2007 but it is, as yet, still unpublished. Edinburgh is also participating in a
smaller (100 women) test of cure study, the design of which varies slightly from Aberdeen’s.
Cervical screening is undergone by well women without symptoms therefore it is important
that there is good quality evidence about the benefits and potential harm of any proposed
change in protocol for diagnosis or treatment. Mechanisms would have to be put in place
to monitor the impact of a potential introduction of a HPV test of cure and, if there was
uncertainty about benefit and disbenefit, this uncertainty would have to be conveyed to the
women affected. Accurate and balanced information for women is essential to enable them
to make an informed choice. Evidence from a report to the Department of Health on the
evaluation of HPV/LBC pilot studies showed that women with a non routine smear who
tested positive for HPV had high anxiety levels immediately post testing. It is advisable
therefore that any introduction of the HPV test of cure is supported by information on the
meaning of the test result, the meaning of the HPV status, the absolute risk of cancer and
the prevalence of HPV infection. The Aberdeen study includes formulation of information
for women.
Cost effectiveness of the test of cure also has to be considered. It is estimated that there
would be a reduced follow-up cost as a result of a return to routine screening instead of
annual follow up at colposcopy. In comparison there is the additional cost of HPV testing,
an estimate of which is detailed at the end of this document. It is also acknowledged that
there would be reduced time and travel costs for women, although this factor is more
difficult to cost. There are also benefits to be gained from minimising follow-up as some
women do not attend for all of their annual smears post treatment.
The Scottish Cervical Screening Programme currently follows NHS Cervical Screening
Programmes’ guidelines for follow-up, with the exception of the duration (5 years in
Scotland as opposed to 10 in England). Under this protocol, follow-up should start at 6
months and cytology alone is currently recommended. Initial 6 month smears are generally
carried out in a colposcopy clinic and further follow up smears are carried out either in
colposcopy or primary care, depending on the result of the 6 month smear. Women treated
for high grade disease (CIN2+) require 6 and 12 month follow-up cytology and annual
smears for 5 years before returning to 3 yearly smears.
The introduction of “test-of-cure” would be based on cervical examination and “smear”taking in a primary care setting at 6, 12 and 24 months post treatment only in the majority of
women. Those women, who are HPV free at 24 months (approx 88%), would then revert to
a routine 3-year cervical screening cycle. This would result in a cost saving for primary
care within NHS Boards.
Some situations are more complex, for example, for a woman with persistent low grade
smears or an unexplained moderate smear and normal colposcopy, high grade CIN. This
is more likely to pose a clinical dilemma if she wishes to retain her fertility. In such
situations, further testing for HPV genotype or for HPV RNA may provide useful information
to help guide the need for further cervical excision and in some cases hysterectomy.
It is argued there is sufficient evidence of benefit of the introduction of a test of cure post
treatment to facilitate reduction in intensive follow-up of women referred to colposcopy
Aim and
Objectives:
A. Immunisation Surveillance Service
To provide an HPV testing and genotyping service for Scotland which will facilitate
evaluating the impact of the routine and catch-up HPV immunisation programme on HPV
infection and HPV related disease in the Scottish population by providing information on:

trends in the type-specific prevalence of HPV in the Scottish population especially
those to whom immunisation is being offered, in those with CIN 1, 2 and 3 and in
3
anogenital cancers;

the prevalence of vaccine and non-vaccine HPV genotypes in both males and
females in those who are at higher risk of cervical cancer and who may not take up
either vaccination or screening;

HPV types associated with probable vaccine failures and resultant breakthrough
infections.
B. Cervical disease test of cure
To provide an HPV testing [and genotyping for a proportion of women] service for Scotland
which will permit post-colposcopy lesion ablation HPV testing at 6 and 12 months post
treatment in order to evaluate the effectiveness of treatment and “test of cure”. Through
this clinical mechanism to:

reduce anxiety for women who have undergone treatment;

reduce the frequency and overall number of post-treatment pelvic examinations and
smear examinations and;

return the majority of women to routine 3 year screening earlier than current practice
permits.
A. Immunisation Surveillance
Service:
September 2008
Planned Start
Date:
Scope:
Deliverables/
Outputs:
B. Cervical disease test of
cure:
April 2009. Proceeded by a
500-1000 sample pilot in
2008/09
Required Finish
Date:
On-going
IN SCOPE
OUT OF SCOPE
National Surveillance of HPV Infection and
HPV related disease;
On-going research related to the above.
Research related to the long-term
effectiveness of specific pharmaceutical
products;
Requests for testing on individual patients
requesting HPV immunisation outside of the
national programme.
Requests for testing on individual patients
for the clinical diagnosis of HPV associated
cancers
A. Immunisation Surveillance Service






HPV testing and genotyping to detect types 16, 18 and other high risk genotypes
associated with cervical cancer in liquid cytology, urine and tissue biopsy specimens
taken as part of the National surveillance Programme (estimated to be ;
HPV testing and genotyping to detect types 6 and 11 in samples taken from genital
warts cases (dependent on decision on vaccine for National programme);
Specialist virological support and expert advice to assist interpretation of results from
these tests;
Provision of internal quality control;
On-going research and development relevant to the National HPV Immunisation
Programme;
Liaison with HPA and other UK and European HPV laboratories.
4
B. Cervical disease test of cure




HPV testing post colposcopy lesion ablation to monitor the success of treatment of
high grade cervical disease;
Specialist virological support and expert advice to assist interpretation of results
from these tests;
Contain HPV testing within a specialised laboratory with infrastructure,
accreditation and quality control
Ongoing research and development relevant to the Scottish Cervical Screening
Programme
A. Immunisation Surveillance Service
Functions:
1.
Testing methods
In common with all microbial nucleic acid tests, HPV detection methods are continually
evolving and improving through use of novel viral and cellular markers of HPV infection.
Commercial HPV screening assays are available from Digene Corporation and Roche
Molecular Diagnostics. HPV typing assays are available from Roche Molecular Diagnostics,
Norchip and Innogenetics and the range of commercial assays is expanding to include type
specific, generic and real-time PCR, qualitative and quantitative assays. The Edinburgh
team has produced its own assays, has carried out comparisons with the available
commercial tests and has worked with several companies in their development. We are
experienced in selecting the appropriate test(s) for particular situations, for example in
distinguishing type specific persistence from sequential transmission of different HPV types
and in assessing the risk of significant disease by detecting activity of viral cancer genes
The number of tests is being estimated currently. For these purposes being set at
7,000 per year.
2. Specialist virological support and expert advice
Expertise in HPV technology and application has developed over many years in Edinburgh,
through grant funding, the NHS Executive, Lothian Health and collaborations with
diagnostic companies. The team is led by Dr Heather Cubie who is internationally
recognised as an expert in the field and her clinical and interpretative skills will be available.
There are also two highly experienced staff: Dr Kate Cuschieri, a Grade B Clinical Scientist,
who would have day to day responsibility for delivery of the service, has been involved in
HPV research for 5 years and Mrs Catherine Moore who is a BMS2 and has been involved
in HPV research since 1998.
B. Cervical disease test of cure
1.
Testing Methods
As for surveillance, it is cheaper to carry out a screening test first. The Hybrid capture 2 test
(hc2) is the only CE marked and FDA approved screening test currently on the market.
There is some argument that it is unnecessary to genotype within test of cure, as any
woman who remains high risk HPV positive should be watched carefully. Estimated
numbers would be 1000 samples to be genotyped at 6 months and 500 at 12 months. A
compromise would be to do HPV screening only at 6 months but type (sequential samples)
from individuals who were positive at 6 and 12 months. This would significantly reduce the
costs of genotyping.
The estimate is that around 5,000+ women may have treatment for high-grade cervical
lesions per annum and will be reassessed at 6 and 12 month thereafter. The laboratory
could therefore expect to receive 10,000 samples for HPV testing from the whole of
Scotland in a full year and would expect around 12% of samples to be positive (10-15% at
6 months) and 5-10% at 12 months (provisional data).
2.
Specialist virological support and expert advice
As for Immunisation Surveillance Service above
5
ESTIMATED COSTS 2009/10 : SCSP ONLY
ITEM:
STAFF COSTS
NON STAFF COSTS
REVENUE:
£
Notes / Assumptions:
85,109
202,500
Total: 287,609
£
Total Revenue Bid: 287,609
CAPITAL:
£
NOTES:
NOTES:
Total Capital Bid:
‘Split Funding’
Stakeholders:
It is proposed that total costs will be apportioned to the Scottish Cervical
Screening Programme and Health Protection Scotland.
Scottish Government Health and Wellbeing Directorate
Health Scotland
HPV Specialist Virologists
ISD
Breast and Cervical Screening National Advisory Group
NHS Boards
NHS National Services Scotland
Constraints:
Resources
Resource / Skills
Requirements:
See above
Workforce /
Facilities Impact:
Governance:
The project will be overseen by the HPV Steering Group, which will submit a report to NSS
and SEHD as the publicly accountable bodies.
ACCEPTED BY:
Development
Leads:
Signature:
Date:
Signature:
Date:
SUPPORTED BY:
Signature:
NSS Director:
Date:
6