The MANCHESTER and ARTISTIC COHORTS (HPV and Cervical Cancer)

INTRODUCTION

Human papillomavirus (HPV) infection is known to cause cervical cancer, but it is a relatively common infection, especially in young women, and usually clears without any symptoms or long-lasting effects. There are different strains (known as genotypes) of HPV, and some are more likely to cause pre-cancer or cancer than others. Until recently, cervical cancer screening has been done using a smear test (known as cytology), but the latest scientific evidence (including results from the ARTISTIC (A Randomised Trial In Screening To Improve Cytology) trial) points towards screening first for HPV infection (known as “HPV primary screening”). There are further improvements which could be made to the UK Cervical Screening Programme (CSP) now that the roll-out to primary HPV screening has been completed (in 2019). There is a balance which needs to be achieved between being able to detect most of the pre-cancers but without causing unnecessary anxiety in women with low risk of cancer. Women who test negative for HPV are at a very low risk of future cervical cancer. Even among women who test positive, there are many who will be at low risk, but conversely some may be at very high risk of already having pre-cancer, cancer or of developing cancer in the future. A second, or “triage” test is used to decide which of the HPV positive women are at highest risk and in need of referral for further tests. It is not sensible or cost-effective to refer every woman testing positive for HPV when infections are common particularly in young women and many infections are likely to clear on their own. The current guidelines say that women who are positive for HPV will only be referred if they also have some abnormal cells (seen from a cytology smear test done on the same sample). Referral for further investigation is via a colposcopy procedure which involves a closer look at the cervix with a microscope. This is usually carried out in an out-patient hospital clinic and takes about 20 minutes.

Screening policies vary across the world and women may be referred based on different criteria, for example in Australia women are referred based on HPV genotype as well as cytology. Long-term follow-up of cervical screening studies such as the Manchester Cohort Study and ARTISTIC Trials Cohort can provide evidence regarding the safest and most effective screening options. The UK National Screening Committee (UK NSC) uses this evidence to make recommendations to ministers in the 4 UK countries on all aspects of population screening. It ensures that screening provides more benefit than harm and at a reasonable cost to the NHS.

BACKGROUND TO THE SCREENING COHORTS

There are two cohorts who serve as the subjects for the data linkage requested in this agreement. The first cohort is the Manchester Study Cohort, and the second is the ARTISTIC Trial Cohort. Both cohorts have previously been merged as one for administrative purposes.

The MANCHESTER STUDY COHORT was recruited between 1987-1993 in collaboration with over 100 general practitioners and screening clinics in the Greater Manchester area who used the Christie Hospital cytology laboratory (now the Manchester Cytology Centre sited at Manchester Royal Infirmary). 78,062 cervical samples were collected from 61,564 women attending for routine cervical screening. There was no age restriction on the cohort of women. Participating practices and clinics covered a wide area in and around the city of Manchester and offered screening either in the context of well-woman clinics or in association with family planning services. The cohort for this follow-up study is restricted to the 49,549 women recruited between 1989-1993.

The study was approved by the local ethics committee. Verbal informed consent obtained when the smear was taken was deemed appropriate at the time. HPV tests in the laboratory were performed on stored samples after recruitment had ended, and no HPV results were reported either to the cytology laboratory or to the women.

At the time the Manchester Cohort was set up, HPV testing was not routine or cheap and so only a minority of samples were tested. The untested samples were stored until such a time as funding could cover the testing costs. NHS England has provided cancer registration data on the cohort. London School of Hygiene and Tropical Medicine (LSHTM) has been able to test the stored samples from the women who later developed cervical cancer and other cancers which may also be caused by HPV infection (vulva, vagina, anus and oesophagus). The results will be compared to a control group who do not have these cancers.

The second cohort under this agreement is from the women taking part in the ARTISTIC trial who were recruited between 2001-2004. Women aged 20-64 years undergoing routine screening were invited to be randomised to different screening strategies as part of the trial. The trial compared cytology with and without HPV testing among approximately 24,500 women - all in the same Manchester area. Over 60,000 HPV tests (Hybrid Capture 2 with full HPV typing of those testing positive) were performed on routinely collected cervical samples taken from baseline up to September 2009, when the initial trial ended. Women were followed to 2009 through the two local participating cytology laboratories for cytology and histology. The LSHTM have followed-up the cohort using data from NHS England based on their history of HPV infection and cytological abnormality, irrespective of their initial random allocation.

PURPOSE

The aims and the data collected on each cohort for the long-term follow-up of both cohorts are identical. The London School of Hygiene and Tropical Medicine will follow-up these unique cohorts in order to determine long-term risks associated with HPV infection. The data requested from NHS England (mortality and cancer registrations) is essential to achieve this aim of determining the risks.

This research can help the national screening committee decide whether changes to national screening policy are necessary. A balance must be achieved so that most of the women with abnormal cells are identified but unnecessary referral and anxiety for women are minimised. There are no other studies of women in England with such long follow-up. Health economists who build models to estimate which screening strategies are the most cost-effective rely on data from studies like these to give them information on how HPV behaves. Collecting further data will help make these models more accurate.

Questions this research aims to influence are:

(1) Is it safe to leave a longer interval between screening tests when a woman has a negative HPV test?

(2) What follow-up tests should be done in women who test positive for HPV? The study can evaluate cytology, genotyping (identifying the strain of HPV) or new testing methods.

(3) What age is it safe to stop screening? Future risks can be determined in women who tested negative for HPV at various ages.

DATA CONTROLLER AND PROCESSOR:

LSHTM are the sole data controller who also process the data.

The projects have received funding from Cancer Research UK (Manchester cohort) and the National Institute for Health Research (NIHR) (ARTISTIC cohort) - however these organisations are not involved in the processing of the personal data that NHS England will disseminate. The funders also do not exercise any control or decision-making capabilities about the use of the NHS England data in the outputs or study design.

There is involvement from University of Manchester (UoM) in the ARTISTIC Cohort follow-up: a consultant gynaecologist at the University is the clinical collaborator for this study and advises on interpretation of the data from a clinical perspective. There is also involvement from the Molecular Epidemiology Laboratory (MEL) at Queen Mary University London (QMUL) who store biological samples from the cohorts. Collaborators at UoM and QMUL do not advise on any data processing activities. Only the team at LSHTM (a medical statistician under the guidance of the Chief Investigator) have access to the data and are involved in making decisions regarding the collection and analysis of the data. UoM and QMUL are not involved in the controllership or processing of data that NHS England provides.

CONSENT AND LEGAL BASIS:

Verbal consent was sought when women were recruited to the Manchester cohort study (1988-1992) and written consent was sought when women were recruited to the ARTISTIC trial (2001-2004). The original consents are not being presented as the legal basis for this agreement. Neither consent was sufficient and specific enough in order to collect NHS England data in this agreement, therefore section 251 was required. Section 251 support remains in place to this date for both cohorts and subsequent studies.

The ethical approval for either cohort does not permit the woman to be contacted, so woman are not contacted directly about the progress of the study. The studies have a central web page from the LSHTM website - where details of recruitment, advances, and new publications are detailed. This will be updated as more publications and results are created. LSHTM also have a Facebook and Twitter account that regularly posts regarding recent trials and publications that the university have been involved in.

The linkage requested is necessary for the overall objective of the study and also for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller - 'attempting to establish and study the long term risk of cervical cancer and cervical pre-cancer following Human Papilloma Virus (HPV) infection'. This is in line with Article 6 (1)(E) of the General Data Protection Regulation (GDPR). Additionally, LSHTM are using Article 9(2)(J) of the General Data Protection Regulation - “processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject” to understand the long term risks of cancer following HPV infection, and if follow-up/screening services should be changed for those who test negative for HPV.

The retention of the data for 20 years is required for the long term follow-up. The ethics expires 20 years after the original application which is 01/10/2032. Close to this date an application for an extension will be made to align the studies as there is value in following these cohorts until death. Therefore end dates are essentially arbitrary as they will continue to be extended in line with the ARTISTIC ethics which will run to 31/07/2042.

The long-term cervical cancer risk following HPV infection will be estimated from the following:

1. Long-term follow-up of women in The Manchester Study and ARTISTIC trial cohort for whom HPV status was known at baseline

2. A case-control analysis comparing baseline HPV status in those developing cervical cancer during follow-up in The Manchester Study.

All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

Outputs to Scientific Community:

The results will be presented at the IPV and the Eurogin conferences. These are both international conferences which focus on carcinogenic HPV infection covering topics including epidemiology and strategies for cervical screening. Both meetings attract leading researchers from around the world and lead to new ideas and collaborations. Those informing on screening programmes around the world share their experiences. Attendance at these conferences enable the study team to reach those around the world and widen the impact of this research.

Data to 2015 from the ARTISTIC trial has been published (Gilham et al 2019, BJOG : an International Journal of Obstetrics & Gynaecology. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.15957) and was presented at the Eurogin conference in December 2019. Data from the Manchester cohort was presented at the virtual International Papillomavirus Conference (IPV) Conference in July 2020.

Researchers from LSHTM hope to attend conferences in person in 2023.

The results will also be published in peer-reviewed journals such as the European Journal of Cancer and the British Journal of Cancer. There have been delays because of the COVID pandemic, but LSHTM expect to submit papers with the long-term follow-up of both cohorts in the second half of 2022. The ARTISTIC cohort is funded by NIHR who will publish the final report in their HTA (Health Technology Assessment) peer-reviewed journal. This will be submitted for publication most likely towards the end of 2023.

Dissemination to policy makers:

The National Screening Committee who advise on policy changes to the NHS Cervical Screening Programme (NHSCSP) consider evidence published in scientific journals.

Dissemination to wider community:

The project team at LSHTM are aiming to disseminate the findings to the public through press releases, blogs, articles, conference presentations and annual event attendance. Information Officers based at Jo's Cervical Cancer Trust have agreed to work with the research team to produce some infographics, blogs and podcasts which are easily understood by a lay audience. These will be produced after each scientific paper has been accepted for publication. Charities, such as Jo’s Cervical Cancer Trust, do not have any access to record level data. Women tend to seek information from gynaecological charities primarily when they experience symptoms or have been diagnosed with cancer or pre-cancer, but charities also promote and give further information around cervical screening.

Social Media/Websites

The studies have a central web page from the LSHTM website - where details of recruitment, advances, and new publications are detailed. This will be updated as more publications and results are created. Infographics designed for lay audience in mind will be developed and uploaded. LSHTM Facebook and Twitter accounts are used regularly to publicise published results.

UPDATE UNDER V6: The following outputs have already been published:

- Cervical HPV infection and neoplasia in a large population-based cohort: the Manchester study. Peto et al. 2004.

Br J Cancer. https://dx.doi.org/10.1038%2Fsj.bjc.6602049

- Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort. Deacon et al. 2000. Br J Cancer. https://doi.org/10.1054/bjoc.2000.1523

- Triaging HPV positive women with normal cytology or low grade dyskaryosis: evidence from 10 year follow-up of the ARTISTIC trial cohort. Gilham et al. 2020. BJOG. https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.15957

- HPV testing compared with routine cytology in cervical screening: Long-term follow-up of ARTISTIC RCT. Gilham et al. 2019. Health Technol Assess. https://doi.org/10.3310/hta23280

- Longer screening intervals are recommended following a negative HPV test in primary cervical screening. Peto & Gilham. 2017.Evid Based Med. https://doi.org/10.1136/ebmed-2016-110625

- A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: Extended follow up in the ARTISTIC trial. Kitchener et al. 2011. Eur J Cancer. https://doi.org/10.1016/j.ejca.2011.01.008

- Sexual Behavior and HPV Infection in British Women, by Postal Questionnaires and Telephone Interviews. Almonte et al. 2011. J Med Virol. https://onlinelibrary.wiley.com/doi/10.1002/jmv.22085

- ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening. Kitchener et al. 2009. Health Technol Assess. https://doi.org/10.3310/hta13510

- Prevalence of type-specific HPV infection by age and grade of cervical cytology: data from the ARTISTIC trial. Sargent et al. 2008. Br J Cancer. https://doi.org/10.1038/sj.bjc.6604324

- HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial. Kitchener et al. 2006. Br J Cancer. https://doi.org/10.1038/sj.bjc.6603210

- The PapilloCheck® Assay for the Detection of High Grade Cervical Intraepithelial Neoplasia. Crosbie et al. 2015. J Clin Microbiol. https://journals.asm.org/doi/10.1128/JCM.01578-15

- Optimal threshold for a positive hybrid capture 2 test for detection of human papillomavirus: data from the ARTISTIC trial. Sargent et al. 2010. J Clin Microbiol. https://journals.asm.org/doi/10.1128/JCM.00896-09

The most recent publications in 2019 and 2020 were based on ARTISTIC data until the end of 2015. Publications based on updated data to 2020 have been delayed due to the pandemic but are expected in the second half of 2022.

The greatest change to the NHSCSP since its introduction in 1988 is the change from primary cytology screening (once known as smear tests) to primary HPV screening. The decision that led the NHS CSP (Cervical Screening Programme) to pilot primary HPV testing in England was based on data from the ARTISTIC cohort. At that time, the NHS Screening Committee considered evidence published in the scientific literature, particularly the full reports published in the HTA Journal. Following collaboration established at international conferences, the data was also used in a pooled analysis of the 4 major European clinical trials, which has led to many countries to change their national screening policies. The following 3 publications are cited on the NHSCSP website as evidence for the change in policy (Cervical screening: implementation guide for primary HPV screening - GOV.UK (www.gov.uk)):

- The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds. Kitchener et al. 2014. Health Technol Assess. https://doi.org/10.3310/hta18230

- Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Ronco et al. 2014. Lancet. https://doi.org/10.1016/S0140-6736(13)62218-7

- HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial. Kitchener et al. 2009. Lancet Oncol. https://doi.org/10.1016/S1470-2045(09)70156-1

The following yielded benefits have been achieved as a result of research papers being published. These have allowed for a greater understanding in this area of research.

(1) Data from the Manchester Cohort was the first English population-based study to estimate HPV prevalence by age, showing that HPV is much more prevalent in younger women. The sub-study on sexual behaviour contributed to the research at the time regarding the risk factors for HPV infection (e.g., a new sexual partner) and pre-cancer (e.g., longer time since last relationship which was a proxy for persistent infection).

(2) Other publications from the ARTISTIC Cohort have added to the understanding of the epidemiology of HPV and added evidence regarding the risks associated with certain screening results, for example shown lower risk following a negative HPV test compared to a negative cytology (smear) test, and higher risks following persistent HPV infection compared to new HPV infections.

(3) Publications from the ARTISTIC Cohort have added to the evidence on how two different HPV testing assays (Papillocheck and Hybrid Capture 2) perform (in terms of detecting HPV and cervical abnormalities) in routine screening.

INTRODUCTION

Human papillomavirus (HPV) infection is known to cause cervical cancer, but it is a relatively common infection, especially in young women, and usually clears without any symptoms or long-lasting effects. There are different strains (known as genotypes) of HPV, and some are more likely to cause pre-cancer or cancer than others. Until recently, cervical cancer screening has been done using a smear test (known as cytology), but the latest scientific evidence (including results from the ARTISTIC (A Randomised Trial In Screening To Improve Cytology) trial) points towards screening first for HPV infection (known as “HPV primary screening”). There are further improvements which could be made to the UK Cervical Screening Programme (CSP) now that the roll-out to primary HPV screening has been completed (in 2019). There is a balance which needs to be achieved between being able to detect most of the pre-cancers but without causing unnecessary anxiety in women with low risk of cancer. Women who test negative for HPV are at a very low risk of future cervical cancer. Even among women who test positive, there are many who will be at low risk, but conversely some may be at very high risk of already having pre-cancer, cancer or of developing cancer in the future. A second, or “triage” test is used to decide which of the HPV positive women are at highest risk and in need of referral for further tests. It is not sensible or cost-effective to refer every woman testing positive for HPV when infections are common particularly in young women and many infections are likely to clear on their own. The current guidelines say that women who are positive for HPV will only be referred if they also have some abnormal cells (seen from a cytology smear test done on the same sample). Referral for further investigation is via a colposcopy procedure which involves a closer look at the cervix with a microscope. This is usually carried out in an out-patient hospital clinic and takes about 20 minutes.

Screening policies vary across the world and women may be referred based on different criteria, for example in Australia women are referred based on HPV genotype as well as cytology. Long-term follow-up of cervical screening studies such as the Manchester Cohort Study and ARTISTIC Trials Cohort can provide evidence regarding the safest and most effective screening options. The UK National Screening Committee (UK NSC) uses this evidence to make recommendations to ministers in the 4 UK countries on all aspects of population screening. It ensures that screening provides more benefit than harm and at a reasonable cost to the NHS.

BACKGROUND TO THE SCREENING COHORTS

There are two cohorts who serve as the subjects for the data linkage requested in this agreement. The first cohort is the Manchester Study Cohort, and the second is the ARTISTIC Trial Cohort. Both cohorts have previously been merged as one for administrative purposes.

The MANCHESTER STUDY COHORT was recruited between 1987-1993 in collaboration with over 100 general practitioners and screening clinics in the Greater Manchester area who used the Christie Hospital cytology laboratory (now the Manchester Cytology Centre sited at Manchester Royal Infirmary). 78,062 cervical samples were collected from 61,564 women attending for routine cervical screening. There was no age restriction on the cohort of women. Participating practices and clinics covered a wide area in and around the city of Manchester and offered screening either in the context of well-woman clinics or in association with family planning services. The cohort for this follow-up study is restricted to the 49,549 women recruited between 1989-1993.

The study was approved by the local ethics committee. Verbal informed consent obtained when the smear was taken was deemed appropriate at the time. HPV tests in the laboratory were performed on stored samples after recruitment had ended, and no HPV results were reported either to the cytology laboratory or to the women.

At the time the Manchester Cohort was set up, HPV testing was not routine or cheap and so only a minority of samples were tested. The untested samples were stored until such a time as funding could cover the testing costs. NHS Digital has provided cancer registration data on the cohort. London School of Hygiene and Tropical Medicine (LSHTM) has been able to test the stored samples from the women who later developed cervical cancer and other cancers which may also be caused by HPV infection (vulva, vagina, anus and oesophagus). The results will be compared to a control group who do not have these cancers.

The second cohort under this agreement is from the women taking part in the ARTISTIC trial who were recruited between 2001-2004. Women aged 20-64 years undergoing routine screening were invited to be randomised to different screening strategies as part of the trial. The trial compared cytology with and without HPV testing among approximately 24,500 women - all in the same Manchester area. Over 60,000 HPV tests (Hybrid Capture 2 with full HPV typing of those testing positive) were performed on routinely collected cervical samples taken from baseline up to September 2009, when the initial trial ended. Women were followed to 2009 through the two local participating cytology laboratories for cytology and histology. The LSHTM have followed-up the cohort using data from NHS Digital based on their history of HPV infection and cytological abnormality, irrespective of their initial random allocation.

PURPOSE

The aims and the data collected on each cohort for the long-term follow-up of both cohorts are identical. The London School of Hygiene and Tropical Medicine will follow-up these unique cohorts in order to determine long-term risks associated with HPV infection. The data requested from NHS Digital (mortality and cancer registrations) is essential to achieve this aim of determining the risks.

This research can help the national screening committee decide whether changes to national screening policy are necessary. A balance must be achieved so that most of the women with abnormal cells are identified but unnecessary referral and anxiety for women are minimised. There are no other studies of women in England with such long follow-up. Health economists who build models to estimate which screening strategies are the most cost-effective rely on data from studies like these to give them information on how HPV behaves. Collecting further data will help make these models more accurate.

Questions this research aims to influence are:

(1) Is it safe to leave a longer interval between screening tests when a woman has a negative HPV test?

(2) What follow-up tests should be done in women who test positive for HPV? The study can evaluate cytology, genotyping (identifying the strain of HPV) or new testing methods.

(3) What age is it safe to stop screening? Future risks can be determined in women who tested negative for HPV at various ages.

DATA CONTROLLER AND PROCESSOR:

LSHTM are the sole data controller who also process the data.

The projects have received funding from Cancer Research UK (Manchester cohort) and the National Institute for Health Research (NIHR) (ARTISTIC cohort) - however these organisations are not involved in the processing of the personal data that NHS Digital will disseminate. The funders also do not exercise any control or decision-making capabilities about the use of the NHS Digital data in the outputs or study design.

There is involvement from University of Manchester (UoM) in the ARTISTIC Cohort follow-up: a consultant gynaecologist at the University is the clinical collaborator for this study and advises on interpretation of the data from a clinical perspective. There is also involvement from the Molecular Epidemiology Laboratory (MEL) at Queen Mary University London (QMUL) who store biological samples from the cohorts. Collaborators at UoM and QMUL do not advise on any data processing activities. Only the team at LSHTM (a medical statistician under the guidance of the Chief Investigator) have access to the data and are involved in making decisions regarding the collection and analysis of the data. UoM and QMUL are not involved in the controllership or processing of data that NHS Digital provides.

CONSENT AND LEGAL BASIS:

Verbal consent was sought when women were recruited to the Manchester cohort study (1988-1992) and written consent was sought when women were recruited to the ARTISTIC trial (2001-2004). The original consents are not being presented as the legal basis for this agreement. Neither consent was sufficient and specific enough in order to collect NHS Digital data in this agreement, therefore section 251 was required. Section 251 support remains in place to this date for both cohorts and subsequent studies.

The ethical approval for either cohort does not permit the woman to be contacted, so woman are not contacted directly about the progress of the study. The studies have a central web page from the LSHTM website - where details of recruitment, advances, and new publications are detailed. This will be updated as more publications and results are created. LSHTM also have a Facebook and Twitter account that regularly posts regarding recent trials and publications that the university have been involved in.

The linkage requested is necessary for the overall objective of the study and also for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller - 'attempting to establish and study the long term risk of cervical cancer and cervical pre-cancer following Human Papilloma Virus (HPV) infection'. This is in line with Article 6 (1)(E) of the General Data Protection Regulation (GDPR). Additionally, LSHTM are using Article 9(2)(J) of the General Data Protection Regulation - “processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject” to understand the long term risks of cancer following HPV infection, and if follow-up/screening services should be changed for those who test negative for HPV.

The retention of the data for 20 years is required for the long term follow-up. The ethics expires 20 years after the original application which is 01/10/2032. Close to this date an application for an extension will be made to align the studies as there is value in following these cohorts until death. Therefore end dates are essentially arbitrary as they will continue to be extended in line with the ARTISTIC ethics which will run to 31/07/2042.

The long-term cervical cancer risk following HPV infection will be estimated from the following:

1. Long-term follow-up of women in The Manchester Study and ARTISTIC trial cohort for whom HPV status was known at baseline

2. A case-control analysis comparing baseline HPV status in those developing cervical cancer during follow-up in The Manchester Study.

All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

Outputs to Scientific Community:

The results will be presented at the IPV and the Eurogin conferences. These are both international conferences which focus on carcinogenic HPV infection covering topics including epidemiology and strategies for cervical screening. Both meetings attract leading researchers from around the world and lead to new ideas and collaborations. Those informing on screening programmes around the world share their experiences. Attendance at these conferences enable the study team to reach those around the world and widen the impact of this research.

Data to 2015 from the ARTISTIC trial has been published (Gilham et al 2019, BJOG : an International Journal of Obstetrics & Gynaecology. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.15957) and was presented at the Eurogin conference in December 2019. Data from the Manchester cohort was presented at the virtual International Papillomavirus Conference (IPV) Conference in July 2020.

Researchers from LSHTM hope to attend conferences in person in 2023.

The results will also be published in peer-reviewed journals such as the European Journal of Cancer and the British Journal of Cancer. There have been delays because of the COVID pandemic, but LSHTM expect to submit papers with the long-term follow-up of both cohorts in the second half of 2022. The ARTISTIC cohort is funded by NIHR who will publish the final report in their HTA (Health Technology Assessment) peer-reviewed journal. This will be submitted for publication most likely towards the end of 2023.

Dissemination to policy makers:

The National Screening Committee who advise on policy changes to the NHS Cervical Screening Programme (NHSCSP) consider evidence published in scientific journals.

Dissemination to wider community:

The project team at LSHTM are aiming to disseminate the findings to the public through press releases, blogs, articles, conference presentations and annual event attendance. Information Officers based at Jo's Cervical Cancer Trust have agreed to work with the research team to produce some infographics, blogs and podcasts which are easily understood by a lay audience. These will be produced after each scientific paper has been accepted for publication. Charities, such as Jo’s Cervical Cancer Trust, do not have any access to record level data. Women tend to seek information from gynaecological charities primarily when they experience symptoms or have been diagnosed with cancer or pre-cancer, but charities also promote and give further information around cervical screening.

Social Media/Websites

The studies have a central web page from the LSHTM website - where details of recruitment, advances, and new publications are detailed. This will be updated as more publications and results are created. Infographics designed for lay audience in mind will be developed and uploaded. LSHTM Facebook and Twitter accounts are used regularly to publicise published results.

UPDATE UNDER V6: The following outputs have already been published:

- Cervical HPV infection and neoplasia in a large population-based cohort: the Manchester study. Peto et al. 2004.

Br J Cancer. https://dx.doi.org/10.1038%2Fsj.bjc.6602049

- Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort. Deacon et al. 2000. Br J Cancer. https://doi.org/10.1054/bjoc.2000.1523

- Triaging HPV positive women with normal cytology or low grade dyskaryosis: evidence from 10 year follow-up of the ARTISTIC trial cohort. Gilham et al. 2020. BJOG. https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.15957

- HPV testing compared with routine cytology in cervical screening: Long-term follow-up of ARTISTIC RCT. Gilham et al. 2019. Health Technol Assess. https://doi.org/10.3310/hta23280

- Longer screening intervals are recommended following a negative HPV test in primary cervical screening. Peto & Gilham. 2017.Evid Based Med. https://doi.org/10.1136/ebmed-2016-110625

- A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: Extended follow up in the ARTISTIC trial. Kitchener et al. 2011. Eur J Cancer. https://doi.org/10.1016/j.ejca.2011.01.008

- Sexual Behavior and HPV Infection in British Women, by Postal Questionnaires and Telephone Interviews. Almonte et al. 2011. J Med Virol. https://onlinelibrary.wiley.com/doi/10.1002/jmv.22085

- ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening. Kitchener et al. 2009. Health Technol Assess. https://doi.org/10.3310/hta13510

- Prevalence of type-specific HPV infection by age and grade of cervical cytology: data from the ARTISTIC trial. Sargent et al. 2008. Br J Cancer. https://doi.org/10.1038/sj.bjc.6604324

- HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial. Kitchener et al. 2006. Br J Cancer. https://doi.org/10.1038/sj.bjc.6603210

- The PapilloCheck® Assay for the Detection of High Grade Cervical Intraepithelial Neoplasia. Crosbie et al. 2015. J Clin Microbiol. https://journals.asm.org/doi/10.1128/JCM.01578-15

- Optimal threshold for a positive hybrid capture 2 test for detection of human papillomavirus: data from the ARTISTIC trial. Sargent et al. 2010. J Clin Microbiol. https://journals.asm.org/doi/10.1128/JCM.00896-09

The most recent publications in 2019 and 2020 were based on ARTISTIC data until the end of 2015. Publications based on updated data to 2020 have been delayed due to the pandemic but are expected in the second half of 2022.

The greatest change to the NHSCSP since its introduction in 1988 is the change from primary cytology screening (once known as smear tests) to primary HPV screening. The decision that led the NHS CSP (Cervical Screening Programme) to pilot primary HPV testing in England was based on data from the ARTISTIC cohort. At that time, the NHS Screening Committee considered evidence published in the scientific literature, particularly the full reports published in the HTA Journal. Following collaboration established at international conferences, the data was also used in a pooled analysis of the 4 major European clinical trials, which has led to many countries to change their national screening policies. The following 3 publications are cited on the NHSCSP website as evidence for the change in policy (Cervical screening: implementation guide for primary HPV screening - GOV.UK (www.gov.uk)):

- The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds. Kitchener et al. 2014. Health Technol Assess. https://doi.org/10.3310/hta18230

- Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Ronco et al. 2014. Lancet. https://doi.org/10.1016/S0140-6736(13)62218-7

- HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial. Kitchener et al. 2009. Lancet Oncol. https://doi.org/10.1016/S1470-2045(09)70156-1

The following yielded benefits have been achieved as a result of research papers being published. These have allowed for a greater understanding in this area of research.

(1) Data from the Manchester Cohort was the first English population-based study to estimate HPV prevalence by age, showing that HPV is much more prevalent in younger women. The sub-study on sexual behaviour contributed to the research at the time regarding the risk factors for HPV infection (e.g., a new sexual partner) and pre-cancer (e.g., longer time since last relationship which was a proxy for persistent infection).

(2) Other publications from the ARTISTIC Cohort have added to the understanding of the epidemiology of HPV and added evidence regarding the risks associated with certain screening results, for example shown lower risk following a negative HPV test compared to a negative cytology (smear) test, and higher risks following persistent HPV infection compared to new HPV infections.

(3) Publications from the ARTISTIC Cohort have added to the evidence on how two different HPV testing assays (Papillocheck and Hybrid Capture 2) perform (in terms of detecting HPV and cervical abnormalities) in routine screening.

Human papillomavirus (HPV) infection is known to cause cervical cancer, but it is a relatively common infection, especially in young women, which usually clears without any symptoms or long-lasting effects. There are different strains (known as genotypes) of HPV, and some are more likely to cause pre-cancer or cancer than others. Until recently, cervical cancer screening has been done using a smear test (known as cytology), but the latest scientific evidence (including results from the ARTISTIC trial) points towards screening first for HPV infection (known as “HPV primary screening”). National roll out of primary HPV testing within the UK Cervical Screening Programme is due to be completed by the end of December 2019. It is not sensible or cost-effective to refer a large number of women for further investigation when their infection is likely to clear on its own, so women who are positive for HPV will be only referred if they also have some abnormal cells (from their cytology test). Referral for further investigation is via a colposcopy procedure which involves a closer look at the cervix with a microscope. It is usually carried out in an out-patient hospital clinic and takes about 15-20 minutes. There is limited evidence on whether women with low-grade abnormal cells need to be referred to a colposcopy clinic straight away. It may be safe in some cases for the HPV test to be repeated instead. Cytology is not always the most efficient second test and screening studies such as the Manchester Cohort Study and ARTISTIC Trials Cohort can help policy makers decide what the best options are to save women being referred to colposcopy unnecessarily and to save money.

There are two cohorts who serve as the subjects for the data linkage requested in this agreement. The first cohort is the Manchester Study Cohort, and the second is the ARTISTIC Trial Cohort. Both cohorts will be merged as one as part of this agreement for ease of administrative purposes.

For background information on both the cohorts: Verbal consent was initially sought when women were recruited to the Manchester cohort study (1988-1992) and written consent was sought when women were recruited to the Artistic trial (2001-2004). Neither consent was sufficient and specific enough in order to flag the cohorts, therefore section 251 was required. Section 251 support remains in place to this date.

The linkage requested is necessary for the overall objective of the study and also for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller - 'attempting to establish and study the long term risk of cervical cancer and cervical pre-cancer following Human Papilloma Virus (HPV) infection'. This is in line with Article 6 (1)(E) of the General Data Protection Regulation. Additionally, LSHTM are using Article 9(2)(J) of the General Data Protection Regulation - “processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject” to understand the long term risks of cancer following HPV infection, and if follow-up/screening services should be changed for those who test negative for HPV.

HPV is the most common sexually transmitted disease but unfortunately most people do not know they are infected with the virus since the initial symptoms can be minor. London School of Hygiene and Tropical Medicine will follow-up these unique cohorts in order to determine long-term risks associated with HPV infection. The data requested (mortality and cancer information) and ultimately disseminated by NHS Digital will help to achieve this aim of determining the risks. HPV results from samples taken after recruitment linked to screening records and subsequent cancer incidence will help inform policy makers about how best HPV testing should be done.

Questions this research aims to influence are:

(1) Is it safe to leave a longer interval between screening tests when a woman has a negative HPV test?

(2) What follow-up tests should be done in women who test positive for HPV? The study can evaluate cytology, genotyping (identifying the strain of HPV) or new testing methods.

(3) What age is it safe to stop screening? Can a woman stop screening if she has tested negative for HPV when aged 50 years?

Methods - Recruitment to Both Cohorts

This agreement is to serve as an Amendment to an existing Data Sharing Agreement to join the two cohort studies (which have been under two separate reference numbers and data sharing agreements) and merge into 1 Data Sharing Agreement. The 2 studies are MR1355 (The Manchester Cohort Study) DARS-NIC-58603 & MR1016 (The ARTISTIC Trial Cohort Study) which is DARS-NIC-226323.

The MANCHESTER STUDY COHORT was recruited between 1987-1993 in collaboration with over 100 general practitioners and screening clinics in the Greater Manchester area who used the Christie Hospital cytology laboratory (now the Manchester Cytology Centre sited at Manchester Royal Infirmary). 78,062 cervical cell samples were collected from 61,564 women attending for routine cervical screening. There was no age restriction on the cohort of women. Participating practices and clinics covered a wide area in and around the city of Manchester, and offered screening either in the context of well-woman clinics or in association with family planning services.

The study was approved by the local ethics committee. Verbal informed consent obtained when the smear was taken was deemed appropriate at the time, as the clinical significance of HPV infection was not then known. However, verbal consent is not being presented as the legal basis for this agreement and is merely for background information. s251 support was subsequently sought and granted and serves as the legal basis for accessing patient identifiable information. s251 support is in place for both cohorts and subsequent studies. HPV tests/inspections were performed after recruitment had ended, and no HPV results were reported either to the cytology laboratory or to the women. The ethical approval does not permit the woman to continue to be contacted, so woman are not contacted directly about the progress of the study. The studies have a central web page from the LSHTM website - where details of recruitment, advances, and new publications are detailed. This will be updated as more publications and results are created. LSHTM also have a Twitter account, that regularly posts regarding recent trials and publications that the university have been involved in.

Samples taken before January 1989 were centrifuged and only the pellet was stored. Centrifugation is a technique which involves the application of centrifugal force (moving or tending to move away from a centre) to separate particles from a solution according to their size, shape, density, viscosity of the medium and rotor speed. This procedure entailed some loss of DNA and the possibility of contamination (due to the year it was carried out - technique was not as sophisticated). The cohort for this follow-up study is restricted to the 49,549 women recruited between 1989-1993.

At the time the Manchester Cohort was set up, HPV testing was not routine or cheap and so the study team tested only a minority of samples. The untested samples were stored until such a time as funding could cover the testing costs. Once the Manchester cohort is re-flagged at NHS Digital the study team will be able to see who has developed cervical cancer or cervical pre-cancer from the cancer registration data. LSTHM will then test the stored samples from these women and also a randomly selected control group to compare them. The control group are women in the cohort who do not have a cervical cancer registration. The primary aim is to study cervical cancer, however there is building scientific evidence showing that HPV may cause some cancers of the vulva, vagina, anus and oesophagus. LSHTM will also test original cervical samples from women who later developed these other cancers. The results will also be compared to the control group who do not have these cancers.

The second cohort for The ARTISTIC (A Randomised Trial In Screening To Improve Cytology) trial were consented between 2001-2004. The consent was then replaced by s251 support. Women aged 20-64 years undergoing routine screening were invited to be randomised to different screening strategies as part of the trial. The trail compared cytology with and without HPV testing among approximately 24,500 women - all in the same Manchester area. This project was an epidemiological follow-up based on their history of HPV infection and cytological abnormality, irrespective of their initial random allocation. Over 60,000 HPV tests (HC2 with full HPV typing of those testing positive) were performed on routinely collected LBC (liquid­based cytology) cervical samples taken from entry up to September 2009, when the initial trial ended.

Women were followed to 2009 through the two local participating cytology laboratories for cytology and histology.

The ARTISTIC trial originally reported after two rounds of primary cervical screening with human papillomavirus (HPV). ARTISTIC was a randomised trial of cervical cytology versus cervical cytology plus HPV testing,evaluated over two screening rounds, 3 years apart. Round 1 would detect prevalent disease and round 2 was a combination of incident and undetected disease from round 1.

The ARTISTIC study cohort was recalled for a third round of screening 3 years after Round 2 and 6 years following the participants initial enrolment to the study. Both arms of the original trial used a single protocol during Round 3. Between July 2007 and September 2009, 8873 women participated in Round 3; 6337 had been screened in Round 2 and 2536 had not been screened since Round 1.

The aims of the long term follow-up of this second cohort are identical to the first. There is a small overlap of about 2,000 women who were recruited to both studies. The technical specification has been drafted so that data is not provided twice for these women - rather a 'flag' will be created to show that they appear in both study cohorts.

London School of Hygiene and Tropical Medicine wishes to combine these cohorts into one study in order to streamline processing activities and analysis. The aims are the same and the data collected on each cohort are the same. LSHTM are the sole data controller and data processor for this project. The projects have received funding from Cancer Research UK and the National Institute for Health Research - however these organisations are not involved in the processing of the personal data that NHS Digital will disseminate.

The protocol for the ARTISTIC cohort states that there is involvement from University of Manchester - a doctor at the University is the clinical collaborator for this trial and therefore advises only on clinical issues - they do not advise on any data processing activities. The Clinical lead/collaborator was based at the university as that was the location of where the study cohort were recruited – therefore geographical proximity made them a clinical collaborator

Only the team at LSHTM (a medical statistician under the guidance of the Chief Investigator) have access to the data and are involved in making decisions regarding the collection and analysis of the data. . University of Manchester are not involved in the controllership or processing of data that NHS Digital provides.

Both projects initially received separate funding grants. The MANCHESTER Cohort received funding from Cancer Research UK, and the ARTISTIC Cohort received NIHR funding. The funders do not exercise any control or decision making capabilities about the use of the NHS Digital data in the outputs or study design.

The long-term cervical cancer risk following HPV infection will be estimated from the following:

1. Long-term follow-up of women in The Manchester Study and ARTISTIC trial cohort for whom HPV status was known at baseline

2. A case-control analysis comparing baseline HPV status in those developing cervical cancer during follow-up in The Manchester Study.

All outputs will be aggregate with small numbers suppression applied.

Outputs to Scientific Community:

Data to 2015 from the ARTISTIC trial has been published (Gilham et al 2019, BJOG. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.15957) and was presented at the Eurogin conference in December 2019. Data from the Manchester cohort was presented at the virtual IPV Conference in July 2020.

The results of the most latest follow-ups will be presented at the International Papillomavirus Conference (IPV) and the Eurogin conference. We hope to attend conferences in person in 2022 and 2023.

The results will also be published in peer-reviewed journals such as the European Journal of Cancer and the British Journal of Cancer. There have been delays to our plans because of the Covid pandemic, but expect to submit papers with the long term follow-up of both cohorts in the second half of 2021. The ARTISTIC cohort is funded by NIHR who will publish the final report in their HTA (Health Technology Assessment) peer-reviewed journal. This will be submitted for publication most likely in 2023.

Dissemination to policy makers:

The National Screening Committee who advise on policy changes to the NHS Cervical Screening Programme consider evidence published in scientific journals.

Dissemination to wider community:

The project team at LSHTM are aiming to work with Jo's Cervical Trust and/or the Eve Appeal, both cervical cancer charities, to disseminate work and findings to the public. This will be through report writing, conference presentations and annual event attendance. These charities do not have any access to record level data.

Social Media/Websites

The studies have a central web page from the LSHTM website - where details of recruitment, advances, and new publications are detailed. This will be updated as more publications and results are created. LSHTM Facebook and Twitter accounts are used regularly to publicise published results.

The following publications and resources have been created to date regarding data from these cohorts:

Triaging HPV positive women with normal cytology or low grade dyskaryosis: evidence from 10 year follow-up of the ARTISTIC trial cohort.

Gilham C, Sargent A, Peto J

2020

BJOG Jan;127(1):58-68

Long-term follow-up of ARTISTIC cervical screening trial cohort

Gilham C, Sargent A, Kitchener H, Peto J

2019

Health Technol Assess. Jun;23(28):1-44

Longer screening intervals are recommended following a negative HPV test in primary cervical screening

Peto J, Gilham C

2017

Evid Based Med. Jul 22; 22(5)

The PapilloCheck® Assay for the Detection of High Grade Cervical Intraepithelial Neoplasia

Crosbie EJ, Bailey A, Sargent A, Gilham C, Peto J, Kitchener HC

2015

J Clin Microbiol. Nov;53(11):3553-9

The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds

Kitchener H, Canfell K, Gilham C, Sargent A, Roberts C, Desai M, Peto J

2014

Health Technol Assess. Apr;18(23):1-196

Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials

Ronco G, Dillner J, Elfström KM, Tunesi S, Snijders PJ, Arbyn M, Kitchener H, Segnan N, Gilham C, Giorgi-Rossi P, Berkhof J, Peto J, Meijer CJ; the International HPV screening working group

2014

Lancet. Feb 8;383(9916):524-32

A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: Extended follow up in the ARTISTIC trial

Kitchener HC;Gilham C;Sargent A;Bailey A;Albrow R;Roberts C;Desai M;Mather J;Turner A;Moss S;Peto J

2011

Eur J Cancer. 2011. 47(6 ):864-871

Sexual Behavior and HPV Infection in British Women, by Postal Questionnaires and Telephone Interviews

Almonte M;dos Santos Silva I;Asare A;Gilham C;Sargent A;Bailey A;Turner A;Desai M;Kitchener HC;Peto J

2011

J Med Virol. 83(7 ):1238-1246

Optimal threshold for a positive hybrid capture 2 test for detection of human papillomavirus: data from the ARTISTIC trial

Sargent A, Bailey A, Turner A, Almonte M, Gilham C, Baysson H, Peto J, Roberts C, Thomson C, Desai M, Mather J, Kitchener H

2010

J Clin Microbiol. Feb;48(2):554-8

ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening

Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B, Sargent A, Roberts C, Desai M, Peto J; ARTISTIC Trial Study Group

2009

Health Technol Assess. Nov;13(51):1-150, iii-iv

HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial

Kitchener HC, Almonte M, Thomson C, Wheeler P, Sargent A, Stoykova B, Gilham C, Baysson H, Roberts C, Dowie R, Desai M, Mather J, Bailey A, Turner A, Moss S, Peto J

2009

Lancet Oncol. Jul;10(7):672-82

Prevalence of type-specific HPV infection by age and grade of cervical cytology: data from the ARTISTIC trial

Sargent A, Bailey A, Almonte M, Turner A, Thomson C, Peto J, Desai M, Mather J, Moss S, Roberts C, Kitchener HC; ARTISTIC Study Group

2008

Br J Cancer. May 20;98(10):1704-9

HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial

H C Kitchener, M Almonte, P Wheeler, M Desai, C Gilham, A Bailey, A Sargent, J Peto

2006

Br J Cancer Jul 3; 95(1): 56-61

Cervical HPV infection and neoplasia in a large population-based cohort: the Manchester study

Peto J, Gilham C, Deacon J, Taylor C, Evans C, Binns W, Haywood M, Elanko N, Coleman D, Yule R, Desai M

2004

Br J Cancer Aug 31; 91(5): 942-53

Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort

Deacon JM, Evans CD, Yule R, Desai M, Binns W, Taylor C, Peto J

2000

Br J Cancer 2000 Dec;83(11):1565-72

The National Screening Committee (NSC) makes recommendations for policy changes to the NHS Cervical Screening Programme (NHSCSP) based on published epidemiological and trial data. ARTISTIC is particularly informative to the NSC as it is the only cohort of women in the UK with long follow-up.

The aims of the screening programme are to identify and treat women at greatest risk of cancer and pre-cancer, but also minimise anxiety and over-treatment in women who have transient infections, which are likely to disappear on their own without treatment. Policy changes informed by the research are made to improve the efficiency of the programme in these respects. The greatest change to the NHSCSP is currently happening this year with the introduction of primary HPV screening. The decision that led to this change was based on a pooled analysis of the 4 major European clinical trials, one of which was ARTISTIC.

Despite rollout of the new programme, due to be complete by December 2019, there are still decisions to be made regarding the screening protocol. For this reason, the results from current work on the ARTISTIC and the MANCHESTER cohort will continue to influence policy and yield patient benefit.

Human papillomavirus (HPV) infection is known to cause cervical cancer, but it is a relatively common infection, especially in young women, which usually clears without any symptoms or long-lasting effects. There are different strains (known as genotypes) of HPV, and some are more likely to cause pre-cancer or cancer than others. Until recently, cervical cancer screening has been done using a smear test (known as cytology), but the latest scientific evidence (including results from the ARTISTIC trial) points towards screening first for HPV infection (known as “HPV primary screening”). National roll out of primary HPV testing within the UK Cervical Screening Programme is due to be completed by the end of December 2019. It is not sensible or cost-effective to refer a large number of women for further investigation when their infection is likely to clear on its own, so women who are positive for HPV will be only referred if they also have some abnormal cells (from their cytology test). Referral for further investigation is via a colposcopy procedure which involves a closer look at the cervix with a microscope. It is usually carried out in an out-patient hospital clinic and takes about 15-20 minutes. There is limited evidence on whether women with low-grade abnormal cells need to be referred to a colposcopy clinic straight away. It may be safe in some cases for the HPV test to be repeated instead. Cytology is not always the most efficient second test and screening studies such as the Manchester Cohort Study and ARTISTIC Trials Cohort can help policy makers decide what the best options are to save women being referred to colposcopy unnecessarily and to save money.

There are two cohorts who serve as the subjects for the data linkage requested in this agreement. The first cohort is the Manchester Study Cohort, and the second is the ARTISTIC Trial Cohort. Both cohorts will be merged as one as part of this agreement for ease of administrative purposes.

For background information on both the cohorts: Verbal consent was initially sought when women were recruited to the Manchester cohort study (1988-1992) and written consent was sought when women were recruited to the Artistic trial (2001-2004). Neither consent was sufficient and specific enough in order to flag the cohorts, therefore section 251 was required. Section 251 support remains in place to this date.

The linkage requested is necessary for the overall objective of the study and also for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller - 'attempting to establish and study the long term risk of cervical cancer and cervical pre-cancer following Human Papilloma Virus (HPV) infection'. This is in line with Article 6 (1)(E) of the General Data Protection Regulation. Additionally, LSHTM are using Article 9(2)(J) of the General Data Protection Regulation - “processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject” to understand the long term risks of cancer following HPV infection, and if follow-up/screening services should be changed for those who test negative for HPV.

HPV is the most common sexually transmitted disease but unfortunately most people do not know they are infected with the virus since the initial symptoms can be minor. London School of Hygiene and Tropical Medicine will follow-up these unique cohorts in order to determine long-term risks associated with HPV infection. The data requested (mortality and cancer information) and ultimately disseminated by NHS Digital will help to achieve this aim of determining the risks. HPV results from samples taken after recruitment linked to screening records and subsequent cancer incidence will help inform policy makers about how best HPV testing should be done.

Questions this research aims to influence are:

(1) Is it safe to leave a longer interval between screening tests when a woman has a negative HPV test?

(2) What follow-up tests should be done in women who test positive for HPV? The study can evaluate cytology, genotyping (identifying the strain of HPV) or new testing methods.

(3) What age is it safe to stop screening? Can a woman stop screening if she has tested negative for HPV when aged 50 years?

Methods - Recruitment to Both Cohorts

This agreement is to serve as an Amendment to an existing Data Sharing Agreement to join the two cohort studies (which have been under two separate reference numbers and data sharing agreements) and merge into 1 Data Sharing Agreement. The 2 studies are MR1355 (The Manchester Cohort Study) DARS-NIC-58603 & MR1016 (The ARTISTIC Trial Cohort Study) which is DARS-NIC-226323.

The MANCHESTER STUDY COHORT was recruited between 1987-1993 in collaboration with over 100 general practitioners and screening clinics in the Greater Manchester area who used the Christie Hospital cytology laboratory (now the Manchester Cytology Centre sited at Manchester Royal Infirmary). 78,062 cervical cell samples were collected from 61,564 women attending for routine cervical screening. There was no age restriction on the cohort of women. Participating practices and clinics covered a wide area in and around the city of Manchester, and offered screening either in the context of well-woman clinics or in association with family planning services.

The study was approved by the local ethics committee. Verbal informed consent obtained when the smear was taken was deemed appropriate at the time, as the clinical significance of HPV infection was not then known. However, verbal consent is not being presented as the legal basis for this agreement and is merely for background information. s251 support was subsequently sought and granted and serves as the legal basis for accessing patient identifiable information. s251 support is in place for both cohorts and subsequent studies. HPV tests/inspections were performed after recruitment had ended, and no HPV results were reported either to the cytology laboratory or to the women. The ethical approval does not permit the woman to continue to be contacted, so woman are not contacted directly about the progress of the study. The studies have a central web page from the LSHTM website - where details of recruitment, advances, and new publications are detailed. This will be updated as more publications and results are created. LSHTM also have a Twitter account, that regularly posts regarding recent trials and publications that the university have been involved in.

Samples taken before January 1989 were centrifuged and only the pellet was stored. Centrifugation is a technique which involves the application of centrifugal force (moving or tending to move away from a centre) to separate particles from a solution according to their size, shape, density, viscosity of the medium and rotor speed. This procedure entailed some loss of DNA and the possibility of contamination (due to the year it was carried out - technique was not as sophisticated). The cohort for this follow-up study is restricted to the 49,549 women recruited between 1989-1993.

At the time the Manchester Cohort was set up, HPV testing was not routine or cheap and so the study team tested only a minority of samples. The untested samples were stored until such a time as funding could cover the testing costs. Once the Manchester cohort is re-flagged at NHS Digital the study team will be able to see who has developed cervical cancer or cervical pre-cancer from the cancer registration data. LSTHM will then test the stored samples from these women and also a randomly selected control group to compare them. The control group are women in the cohort who do not have a cervical cancer registration. The primary aim is to study cervical cancer, however there is building scientific evidence showing that HPV may cause some cancers of the vulva, vagina, anus and oesophagus. LSHTM will also test original cervical samples from women who later developed these other cancers. The results will also be compared to the control group who do not have these cancers.

The second cohort for The ARTISTIC (A Randomised Trial In Screening To Improve Cytology) trial were consented between 2001-2004. The consent was then replaced by s251 support. Women aged 20-64 years undergoing routine screening were invited to be randomised to different screening strategies as part of the trial. The trail compared cytology with and without HPV testing among approximately 24,500 women - all in the same Manchester area. This project was an epidemiological follow-up based on their history of HPV infection and cytological abnormality, irrespective of their initial random allocation. Over 60,000 HPV tests (HC2 with full HPV typing of those testing positive) were performed on routinely collected LBC (liquid­based cytology) cervical samples taken from entry up to September 2009, when the initial trial ended.

Women were followed to 2009 through the two local participating cytology laboratories for cytology and histology.

The ARTISTIC trial originally reported after two rounds of primary cervical screening with human papillomavirus (HPV). ARTISTIC was a randomised trial of cervical cytology versus cervical cytology plus HPV testing,evaluated over two screening rounds, 3 years apart. Round 1 would detect prevalent disease and round 2 was a combination of incident and undetected disease from round 1.

The ARTISTIC study cohort was recalled for a third round of screening 3 years after Round 2 and 6 years following the participants initial enrolment to the study. Both arms of the original trial used a single protocol during Round 3. Between July 2007 and September 2009, 8873 women participated in Round 3; 6337 had been screened in Round 2 and 2536 had not been screened since Round 1.

The aims of the long term follow-up of this second cohort are identical to the first. There is a small overlap of about 2,000 women who were recruited to both studies. The technical specification has been drafted so that data is not provided twice for these women - rather a 'flag' will be created to show that they appear in both study cohorts.

London School of Hygiene and Tropical Medicine wishes to combine these cohorts into one study in order to streamline processing activities and analysis. The aims are the same and the data collected on each cohort are the same. LSHTM are the sole data controller and data processor for this project. The projects have received funding from Cancer Research UK and the National Institute for Health Research - however these organisations are not involved in the processing of the personal data that NHS Digital will disseminate.

The protocol for the ARTISTIC cohort states that there is involvement from University of Manchester - a doctor at the University is the clinical collaborator for this trial and therefore advises only on clinical issues - they do not advise on any data processing activities. The Clinical lead/collaborator was based at the university as that was the location of where the study cohort were recruited – therefore geographical proximity made them a clinical collaborator

Only the team at LSHTM (a medical statistician under the guidance of the Chief Investigator) have access to the data and are involved in making decisions regarding the collection and analysis of the data. . University of Manchester are not involved in the controllership or processing of data that NHS Digital provides.

Both projects initially received separate funding grants. The MANCHESTER Cohort received funding from Cancer Research UK, and the ARTISTIC Cohort received NIHR funding. The funders do not exercise any control or decision making capabilities about the use of the NHS Digital data in the outputs or study design.

The long-term cervical cancer risk following HPV infection will be estimated from the following:

1. Long-term follow-up of women in The Manchester Study and ARTISTIC trial cohort for whom HPV status was known at baseline

2. A case-control analysis comparing baseline HPV status in those developing cervical cancer during follow-up in The Manchester Study.

All outputs will be aggregate with small numbers suppression applied.

Outputs to Scientific Community:

The results will be presented at international HPV conferences including the International Papillomavirus Conference (IPV) and the Eurogin conference on HPV held every 18 months respectively. In the first instance, these include Eurogin December 2019 and IPV March 2020.

The results will also be published in peer-reviewed journals such as the European Journal of Cancer and the British Journal of Cancer. The first research papers concerning the case-control analysis of the Manchester cohort will be submitted to a peer-reviewed journal late 2019/early 2020.

Subsequent papers concerning aspects such as the cross-over between the two cohorts will be submitted in 2020 and 2021. The ARTISTIC cohort is funded by NIHR who will publish the final report in their HTA (Health Technology Assessment) peer-reviewed journal. This will be submitted late 2022 for publication most likely in 2023.

Projected publication dates still stand - most recently, data to 2015 from the ARTISTIC trial has recently been published (Gilham et al 2019, BJOG. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.15957) and was presented at the Eurogin conference in December 2019.

Dissemination to policy makers:

The National Screening Committee who advise on policy changes to the NHS Cervical Screening Programme will only consider evidence published in scientific journals.

Dissemination to wider community:

The project team at LSHTM are aiming to work with Jo's Cervical Trust and/or the Eve Appeal, both cervical cancer charities, to disseminate work and findings to the public. This will be through report writing, conference presentations and annual event attendance. These charities do not have any access to record level data.

The plan for larger scale engagement with the charities is still in the developmental stages, however meetings are ongoing to decide how to drive this message forward for 2020.

Social Media/Websites

The studies have a central web page from the LSHTM website - where details of recruitment, advances, and new publications are detailed. This will be updated as more publications and results are created. LSHTM also have a Twitter account, that regularly posts regarding recent trials and publications that the university have been involved in.

A report describing the 15 year follow-up of the ARTISTIC trial is currently in press (HTA journal). Additional papers centred on triage strategies and screening intervals are currently being prepared. The LSHTM is currently analysing data from the Manchester Study.

The following publications and resources have been created to date regarding data from these cohorts:

Long-term follow-up of ARTISTIC cervical screening trial cohort

Gilham C, Sargent A, Kitchener H, Peto J

2018

Health Technol Assess

Longer screening intervals are recommended following a negative HPV test in primary cervical screening

Peto J, Gilham C

2017

Evid Based Med. Jul 22; 22(5)

The PapilloCheck® Assay for the Detection of High Grade Cervical Intraepithelial Neoplasia

Crosbie EJ, Bailey A, Sargent A, Gilham C, Peto J, Kitchener HC

2015

J Clin Microbiol. Nov;53(11):3553-9

The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds

Kitchener H, Canfell K, Gilham C, Sargent A, Roberts C, Desai M, Peto J

2014

Health Technol Assess. Apr;18(23):1-196

Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials

Ronco G, Dillner J, Elfström KM, Tunesi S, Snijders PJ, Arbyn M, Kitchener H, Segnan N, Gilham C, Giorgi-Rossi P, Berkhof J, Peto J, Meijer CJ; the International HPV screening working group

2014

Lancet. Feb 8;383(9916):524-32

A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: Extended follow up in the ARTISTIC trial

Kitchener HC;Gilham C;Sargent A;Bailey A;Albrow R;Roberts C;Desai M;Mather J;Turner A;Moss S;Peto J

2011

Eur J Cancer. 2011. 47(6 ):864-871

Sexual Behavior and HPV Infection in British Women, by Postal Questionnaires and Telephone Interviews

Almonte M;dos Santos Silva I;Asare A;Gilham C;Sargent A;Bailey A;Turner A;Desai M;Kitchener HC;Peto J

2011

J Med Virol. 83(7 ):1238-1246

Optimal threshold for a positive hybrid capture 2 test for detection of human papillomavirus: data from the ARTISTIC trial

Sargent A, Bailey A, Turner A, Almonte M, Gilham C, Baysson H, Peto J, Roberts C, Thomson C, Desai M, Mather J, Kitchener H

2010

J Clin Microbiol. Feb;48(2):554-8

ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening

Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B, Sargent A, Roberts C, Desai M, Peto J; ARTISTIC Trial Study Group

2009

Health Technol Assess. Nov;13(51):1-150, iii-iv

HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial

Kitchener HC, Almonte M, Thomson C, Wheeler P, Sargent A, Stoykova B, Gilham C, Baysson H, Roberts C, Dowie R, Desai M, Mather J, Bailey A, Turner A, Moss S, Peto J

2009

Lancet Oncol. Jul;10(7):672-82

Prevalence of type-specific HPV infection by age and grade of cervical cytology: data from the ARTISTIC trial

Sargent A, Bailey A, Almonte M, Turner A, Thomson C, Peto J, Desai M, Mather J, Moss S, Roberts C, Kitchener HC; ARTISTIC Study Group

2008

Br J Cancer. May 20;98(10):1704-9

HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial

H C Kitchener, M Almonte, P Wheeler, M Desai, C Gilham, A Bailey, A Sargent, J Peto

2006

Br J Cancer Jul 3; 95(1): 56-61

Cervical HPV infection and neoplasia in a large population-based cohort: the Manchester study

Peto J, Gilham C, Deacon J, Taylor C, Evans C, Binns W, Haywood M, Elanko N, Coleman D, Yule R, Desai M

2004

Br J Cancer Aug 31; 91(5): 942-53

Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort

Deacon JM, Evans CD, Yule R, Desai M, Binns W, Taylor C, Peto J

2000

Br J Cancer 2000 Dec;83(11):1565-72

The National Screening Committee (NSC) makes recommendations for policy changes to the NHS Cervical Screening Programme (NHSCSP) based on published epidemiological and trial data. ARTISTIC is particularly informative to the NSC as it is the only cohort of women in the UK with long follow-up.

The aims of the screening programme are to identify and treat women at greatest risk of cancer and pre-cancer, but also minimise anxiety and over-treatment in women who have transient infections, which are likely to disappear on their own without treatment. Policy changes informed by the research are made to improve the efficiency of the programme in these respects. The greatest change to the NHSCSP is currently happening this year with the introduction of primary HPV screening. The decision that led to this change was based on a pooled analysis of the 4 major European clinical trials, one of which was ARTISTIC.

Despite rollout of the new programme, due to be complete by December 2019, there are still decisions to be made regarding the screening protocol. For this reason, the results from current work on the ARTISTIC and the MANCHESTER cohort will continue to influence policy and yield patient benefit.

Human papillomavirus (HPV) infection is known to cause cervical cancer, but it is a relatively common infection, especially in young women, which usually clears without any symptoms or long-lasting effects. There are different strains (known as genotypes) of HPV, and some are more likely to cause pre-cancer or cancer than others. Until recently, cervical cancer screening has been done using a smear test (known as cytology), but the latest scientific evidence (including results from the ARTISTIC trial) points towards screening first for HPV infection (known as “HPV primary screening”). National roll out of primary HPV testing within the UK Cervical Screening Programme is due to be completed by the end of December 2019. It is not sensible or cost-effective to refer a large number of women for further investigation when their infection is likely to clear on its own, so women who are positive for HPV will be only referred if they also have some abnormal cells (from their cytology test). Referral for further investigation is via a colposcopy procedure which involves a closer look at the cervix with a microscope. It is usually carried out in an out-patient hospital clinic and takes about 15-20 minutes. There is limited evidence on whether women with low-grade abnormal cells need to be referred to a colposcopy clinic straight away. It may be safe in some cases for the HPV test to be repeated instead. Cytology is not always the most efficient second test and screening studies such as the Manchester Cohort Study and ARTISTIC Trials Cohort can help policy makers decide what the best options are to save women being referred to colposcopy unnecessarily and to save money.

There are two cohorts who serve as the subjects for the data linkage requested in this agreement. The first cohort is the Manchester Study Cohort, and the second is the ARTISTIC Trial Cohort. Both cohorts will be merged as one as part of this agreement for ease of administrative purposes.

For background information on both the cohorts: Verbal consent was initially sought when women were recruited to the Manchester cohort study (1988-1992) and written consent was sought when women were recruited to the Artistic trial (2001-2004). Neither consent was sufficient and specific enough in order to flag the cohorts, therefore section 251 was required. Section 251 support remains in place to this date.

The linkage requested is necessary for the overall objective of the study and also for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller - 'attempting to establish and study the long term risk of cervical cancer and cervical pre-cancer following Human Papilloma Virus (HPV) infection'. This is in line with Article 6 (1)(E) of the General Data Protection Regulation. Additionally, LSHTM are using Article 9(2)(J) of the General Data Protection Regulation - “processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject” to understand the long term risks of cancer following HPV infection, and if follow-up/screening services should be changed for those who test negative for HPV.

HPV is the most common sexually transmitted disease but unfortunately most people do not know they are infected with the virus since the initial symptoms can be minor. London School of Hygiene and Tropical Medicine will follow-up these unique cohorts in order to determine long-term risks associated with HPV infection. The data requested (mortality and cancer information) and ultimately disseminated by NHS Digital will help to achieve this aim of determining the risks. HPV results from samples taken after recruitment linked to screening records and subsequent cancer incidence will help inform policy makers about how best HPV testing should be done.

Questions this research aims to influence are:

(1) Is it safe to leave a longer interval between screening tests when a woman has a negative HPV test?

(2) What follow-up tests should be done in women who test positive for HPV? The study can evaluate cytology, genotyping (identifying the strain of HPV) or new testing methods.

(3) What age is it safe to stop screening? Can a woman stop screening if she has tested negative for HPV when aged 50 years?

Methods - Recruitment to Both Cohorts

This agreement is to serve as an Amendment to an existing Data Sharing Agreement to join the two cohort studies (which have been under two separate reference numbers and data sharing agreements) and merge into 1 Data Sharing Agreement. The 2 studies are MR1355 (The Manchester Cohort Study) DARS-NIC-58603 & MR1016 (The ARTISTIC Trial Cohort Study) which is DARS-NIC-226323.

The MANCHESTER STUDY COHORT was recruited between 1987-1993 in collaboration with over 100 general practitioners and screening clinics in the Greater Manchester area who used the Christie Hospital cytology laboratory (now the Manchester Cytology Centre sited at Manchester Royal Infirmary). 78,062 cervical cell samples were collected from 61,564 women attending for routine cervical screening. There was no age restriction on the cohort of women. Participating practices and clinics covered a wide area in and around the city of Manchester, and offered screening either in the context of well-woman clinics or in association with family planning services.

The study was approved by the local ethics committee. Verbal informed consent obtained when the smear was taken was deemed appropriate at the time, as the clinical significance of HPV infection was not then known. However, verbal consent is not being presented as the legal basis for this agreement and is merely for background information. s251 support was subsequently sought and granted and serves as the legal basis for accessing patient identifiable information. s251 support is in place for both cohorts and subsequent studies. HPV tests/inspections were performed after recruitment had ended, and no HPV results were reported either to the cytology laboratory or to the women. The ethical approval does not permit the woman to continue to be contacted, so woman are not contacted directly about the progress of the study. The studies have a central web page from the LSHTM website - where details of recruitment, advances, and new publications are detailed. This will be updated as more publications and results are created. LSHTM also have a Twitter account, that regularly posts regarding recent trials and publications that the university have been involved in.

Samples taken before January 1989 were centrifuged and only the pellet was stored. Centrifugation is a technique which involves the application of centrifugal force (moving or tending to move away from a centre) to separate particles from a solution according to their size, shape, density, viscosity of the medium and rotor speed. This procedure entailed some loss of DNA and the possibility of contamination (due to the year it was carried out - technique was not as sophisticated). The cohort for this follow-up study is restricted to the 49,549 women recruited between 1989-1993.

At the time the Manchester Cohort was set up, HPV testing was not routine or cheap and so the study team tested only a minority of samples. The untested samples were stored until such a time as funding could cover the testing costs. Once the Manchester cohort is re-flagged at NHS Digital the study team will be able to see who has developed cervical cancer or cervical pre-cancer from the cancer registration data. LSTHM will then test the stored samples from these women and also a randomly selected control group to compare them. The control group are women in the cohort who do not have a cervical cancer registration. The primary aim is to study cervical cancer, however there is building scientific evidence showing that HPV may cause some cancers of the vulva, vagina, anus and oesophagus. LSHTM will also test original cervical samples from women who later developed these other cancers. The results will also be compared to the control group who do not have these cancers.

The second cohort for The ARTISTIC (A Randomised Trial In Screening To Improve Cytology) trial were consented between 2001-2004. The consent was then replaced by s251 support. Women aged 20-64 years undergoing routine screening were invited to be randomised to different screening strategies as part of the trial. The trail compared cytology with and without HPV testing among approximately 24,500 women - all in the same Manchester area. This project was an epidemiological follow-up based on their history of HPV infection and cytological abnormality, irrespective of their initial random allocation. Over 60,000 HPV tests (HC2 with full HPV typing of those testing positive) were performed on routinely collected LBC (liquid­based cytology) cervical samples taken from entry up to September 2009, when the initial trial ended.

Women were followed to 2009 through the two local participating cytology laboratories for cytology and histology.

The ARTISTIC trial originally reported after two rounds of primary cervical screening with human papillomavirus (HPV). ARTISTIC was a randomised trial of cervical cytology versus cervical cytology plus HPV testing,evaluated over two screening rounds, 3 years apart. Round 1 would detect prevalent disease and round 2 was a combination of incident and undetected disease from round 1.

The ARTISTIC study cohort was recalled for a third round of screening 3 years after Round 2 and 6 years following the participants initial enrolment to the study. Both arms of the original trial used a single protocol during Round 3. Between July 2007 and September 2009, 8873 women participated in Round 3; 6337 had been screened in Round 2 and 2536 had not been screened since Round 1.

The aims of the long term follow-up of this second cohort are identical to the first. There is a small overlap of about 2,000 women who were recruited to both studies. The technical specification has been drafted so that data is not provided twice for these women - rather a 'flag' will be created to show that they appear in both study cohorts.

London School of Hygiene and Tropical Medicine wishes to combine these cohorts into one study in order to streamline processing activities and analysis. The aims are the same and the data collected on each cohort are the same. LSHTM are the sole data controller and data processor for this project. The projects have received funding from Cancer Research UK and the National Institute for Health Research - however these organisations are not involved in the processing of the personal data that NHS Digital will disseminate.

The protocol for the ARTISTIC cohort states that there is involvement from University of Manchester - a doctor at the University is the clinical collaborator for this trial and therefore advises only on clinical issues - they do not advise on any data processing activities. The Clinical lead/collaborator was based at the university as that was the location of where the study cohort were recruited – therefore geographical proximity made them a clinical collaborator

Only the team at LSHTM (a medical statistician under the guidance of the Chief Investigator) have access to the data and are involved in making decisions regarding the collection and analysis of the data. . University of Manchester are not involved in the controllership or processing of data that NHS Digital provides.

Both projects initially received separate funding grants. The MANCHESTER Cohort received funding from Cancer Research UK, and the ARTISTIC Cohort received NIHR funding. The funders do not exercise any control or decision making capabilities about the use of the NHS Digital data in the outputs or study design.

The long-term cervical cancer risk following HPV infection will be estimated from the following:

1. Long-term follow-up of women in The Manchester Study and ARTISTIC trial cohort for whom HPV status was known at baseline

2. A case-control analysis comparing baseline HPV status in those developing cervical cancer during follow-up in The Manchester Study.

All outputs will be aggregate with small numbers suppression applied.

Outputs to Scientific Community:

The results will be presented at international HPV conferences including the International Papillomavirus Conference (IPV) and the Eurogin conference on HPV held every 18 months respectively. In the first instance, these include Eurogin December 2019 and IPV March 2020.

The results will also be published in peer-reviewed journals such as the European Journal of Cancer and the British Journal of Cancer. The first research papers concerning the case-control analysis of the Manchester cohort will be submitted to a peer-reviewed journal late 2019/early 2020.

Subsequent papers concerning aspects such as the cross-over between the two cohorts will be submitted in 2020 and 2021. The ARTISTIC cohort is funded by NIHR who will publish the final report in their HTA (Health Technology Assessment) peer-reviewed journal. This will be submitted late 2022 for publication most likely in 2023.

Projected publication dates still stand - most recently, data to 2015 from the ARTISTIC trial has recently been published (Gilham et al 2019, BJOG. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.15957) and was presented at the Eurogin conference in December 2019.

Dissemination to policy makers:

The National Screening Committee who advise on policy changes to the NHS Cervical Screening Programme will only consider evidence published in scientific journals.

Dissemination to wider community:

The project team at LSHTM are aiming to work with Jo's Cervical Trust and/or the Eve Appeal, both cervical cancer charities, to disseminate work and findings to the public. This will be through report writing, conference presentations and annual event attendance. These charities do not have any access to record level data.

The plan for larger scale engagement with the charities is still in the developmental stages, however meetings are ongoing to decide how to drive this message forward for 2020.

Social Media/Websites

The studies have a central web page from the LSHTM website - where details of recruitment, advances, and new publications are detailed. This will be updated as more publications and results are created. LSHTM also have a Twitter account, that regularly posts regarding recent trials and publications that the university have been involved in.

A report describing the 15 year follow-up of the ARTISTIC trial is currently in press (HTA journal). Additional papers centred on triage strategies and screening intervals are currently being prepared. The LSHTM is currently analysing data from the Manchester Study.

The following publications and resources have been created to date regarding data from these cohorts:

Long-term follow-up of ARTISTIC cervical screening trial cohort

Gilham C, Sargent A, Kitchener H, Peto J

2018

Health Technol Assess

Longer screening intervals are recommended following a negative HPV test in primary cervical screening

Peto J, Gilham C

2017

Evid Based Med. Jul 22; 22(5)

The PapilloCheck® Assay for the Detection of High Grade Cervical Intraepithelial Neoplasia

Crosbie EJ, Bailey A, Sargent A, Gilham C, Peto J, Kitchener HC

2015

J Clin Microbiol. Nov;53(11):3553-9

The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds

Kitchener H, Canfell K, Gilham C, Sargent A, Roberts C, Desai M, Peto J

2014

Health Technol Assess. Apr;18(23):1-196

Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials

Ronco G, Dillner J, Elfström KM, Tunesi S, Snijders PJ, Arbyn M, Kitchener H, Segnan N, Gilham C, Giorgi-Rossi P, Berkhof J, Peto J, Meijer CJ; the International HPV screening working group

2014

Lancet. Feb 8;383(9916):524-32

A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: Extended follow up in the ARTISTIC trial

Kitchener HC;Gilham C;Sargent A;Bailey A;Albrow R;Roberts C;Desai M;Mather J;Turner A;Moss S;Peto J

2011

Eur J Cancer. 2011. 47(6 ):864-871

Sexual Behavior and HPV Infection in British Women, by Postal Questionnaires and Telephone Interviews

Almonte M;dos Santos Silva I;Asare A;Gilham C;Sargent A;Bailey A;Turner A;Desai M;Kitchener HC;Peto J

2011

J Med Virol. 83(7 ):1238-1246

Optimal threshold for a positive hybrid capture 2 test for detection of human papillomavirus: data from the ARTISTIC trial

Sargent A, Bailey A, Turner A, Almonte M, Gilham C, Baysson H, Peto J, Roberts C, Thomson C, Desai M, Mather J, Kitchener H

2010

J Clin Microbiol. Feb;48(2):554-8

ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening

Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B, Sargent A, Roberts C, Desai M, Peto J; ARTISTIC Trial Study Group

2009

Health Technol Assess. Nov;13(51):1-150, iii-iv

HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial

Kitchener HC, Almonte M, Thomson C, Wheeler P, Sargent A, Stoykova B, Gilham C, Baysson H, Roberts C, Dowie R, Desai M, Mather J, Bailey A, Turner A, Moss S, Peto J

2009

Lancet Oncol. Jul;10(7):672-82

Prevalence of type-specific HPV infection by age and grade of cervical cytology: data from the ARTISTIC trial

Sargent A, Bailey A, Almonte M, Turner A, Thomson C, Peto J, Desai M, Mather J, Moss S, Roberts C, Kitchener HC; ARTISTIC Study Group

2008

Br J Cancer. May 20;98(10):1704-9

HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial

H C Kitchener, M Almonte, P Wheeler, M Desai, C Gilham, A Bailey, A Sargent, J Peto

2006

Br J Cancer Jul 3; 95(1): 56-61

Cervical HPV infection and neoplasia in a large population-based cohort: the Manchester study

Peto J, Gilham C, Deacon J, Taylor C, Evans C, Binns W, Haywood M, Elanko N, Coleman D, Yule R, Desai M

2004

Br J Cancer Aug 31; 91(5): 942-53

Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort

Deacon JM, Evans CD, Yule R, Desai M, Binns W, Taylor C, Peto J

2000

Br J Cancer 2000 Dec;83(11):1565-72

The National Screening Committee (NSC) makes recommendations for policy changes to the NHS Cervical Screening Programme (NHSCSP) based on published epidemiological and trial data. ARTISTIC is particularly informative to the NSC as it is the only cohort of women in the UK with long follow-up.

The aims of the screening programme are to identify and treat women at greatest risk of cancer and pre-cancer, but also minimise anxiety and over-treatment in women who have transient infections, which are likely to disappear on their own without treatment. Policy changes informed by the research are made to improve the efficiency of the programme in these respects. The greatest change to the NHSCSP is currently happening this year with the introduction of primary HPV screening. The decision that led to this change was based on a pooled analysis of the 4 major European clinical trials, one of which was ARTISTIC.

Despite rollout of the new programme, due to be complete by December 2019, there are still decisions to be made regarding the screening protocol. For this reason, the results from current work on the ARTISTIC and the MANCHESTER cohort will continue to influence policy and yield patient benefit.