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.

The latest scientific evidence (including results from the ARTISTIC trial) shows that screening for HPV infection as a first test (known as “primary HPV screening”) is better than screening for abnormal cytology with a “smear” test. The NHS Cervical Screening Programme rolled out primary HPV testing across England in 2019. The adopted policy is likely to be continually reviewed in order to make further improvements.

The disadvantage of primary HPV testing is that more women, particularly young women, will test positive for HPV including many with normal cytology. It is not sensible to refer a large number of women for further tests when their infection is likely to clear on its own and so a second test has to be used to identify the women who are at highest risk (called a triage test). 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. At the moment women who are positive for HPV will be referred only if they also have some abnormal cells (from a cytology test).

The NHS currently uses an HPV test which can separately identify HPV 16 and HPV 18, but this is not used in clinical practice. Women with HPV16 in particular, have a much higher risk of pre-cancer and cancer and so it makes sense to use this information in the screening programme. It is possible to analyse HPV samples to identify the actual types (genotypes) of HPV present. The 13 high-risk types can only be individually identified using specialist laboratory tests within a research study.

HPV infections that come and go are harmless but infections that persist put women at higher risk of developing disease in the future. Young women in particular may acquire an infection which clears and then acquire another infection at a later date. This means that they could test positive for HPV at two time points which might appear that they have a long-lasting infection when in fact they have two transient infections. This happens more often than you might think because about 30% of women aged 25-29 and 15% of women aged 30-39 are positive for HPV at any point in time. Genotyping can help establish whether the same HPV type is present at the two time points (persistent), or whether there are two separate infections (“type-swap”)

ARTISTIC: A Randomised Trial In Screening To Improve Cytology

Between July 2001 and October 2003, women aged 20-64 years attending for routine cervical screening (NHS programme) in Greater Manchester were invited to participate in the trial. In total, 24,510 participants had a cervical sample collected for liquid based cytology and HPV testing, and were randomly allocated in a ratio of 3:1 to have the HPV result revealed and acted upon, or concealed and further management based on cytology alone. Management of women with abnormal cytology was identical on both arms and in line with the national guidance for the English Cervical Screening Programme (NHS CSP 2004). Women in the revealed arm with negative cytology who tested HPV positive were invited for repeat HPV testing at 12 months and if still positive could choose between immediate colposcopy or a repeat HPV test at 24 months and colposcopy if still positive.

The cohort was followed beyond the original protocol for a third screening round. During this study extension, the ethics committee required that HPV results were linked to anonymised data, so women on both randomised arms were managed on the basis of cytology according to national guidelines. HPV results in round 3 were ignored until March 2008, when the Manchester Cytology Centre became one of six Sentinel Sites for HPV triage in England. The aim of the Sentinel Sites project was to evaluate the roll-out of HPV triage of low grade cytological abnormalities. Therefore, women with borderline and mild dyskaryosis cytology who tested HPV positive were referred to colposcopy, whilst those who were negative were returned to routine recall.

The Manchester Study

Between 1987 and 1993, 61,564 women attending for routine cervical screening in the Greater Manchester area agreed to take part in the study. There was no age restriction.  After the routine cervical smear was taken, a second sample was collected for the research study. The samples were frozen for long-term storage.

HPV testing was carried out between 1990 and 1996 on a random sample of 7,278 of the women in the cohort, and on selected cases diagnosed with pre-cancer. HPV tests were performed after recruitment had ended, and no HPV results were reported either to the cytology laboratory or to the women. At this time, the clinical significance of HPV infection was not known. Results from this project were published in 2004.

Long-term follow-up of ARTISTIC and Manchester Study cervical screening cohorts

Women were followed through local cytology laboratories for cytology and histology to 2009 for the ARTISTIC study and to 1998 for the Manchester Study.

We are now undertaking complete cytological follow-up by linkage to NHS cervical screening call-recall records for both cohorts to include women who have moved from the Manchester area. The cohorts are also being followed-up for CIN3 and cancer incidence and mortality by linkage to the NHS Central Register.

Only the highest degree of pre-cancer, CIN3, is registered nationally (along with cancers) but women with CIN2 and CIN3 are usually treated the same. This means that it is useful to count both CIN2 and CIN3 when analysing the data since for practical purposes they will be treated the same by a doctor. We are extending the ARTISTIC follow-up to 2021 by obtaining histology results from local laboratories from 2009 to 2021. These laboratories still process samples for around 90% of the women in the study. This means that we will get diagnoses of CIN2 for this period of time, as well as CIN3. There are roughly equal numbers of each, so we shall double the number of diagnoses which will make our calculations more precise.

In addition to collecting additional data on CIN2+ diagnoses from the ARTISTIC cohort, we are also collecting further screening samples from these women and to test them again for HPV. About 10,000 HPV tests among ARTISTIC women will be done over the 5 year period between 2018 and 2022 in the Manchester Cytology Centre which covers the Greater Manchester area. These samples already tested for HPV as part of routine screening will be then genotyped if positive, and all stored for future research.

We are also linking the 2000 women who participated in both the ARTISTIC and Manchester studies and to relate HPV results taken at these 2 time points around 10 years apart.

Objectives of long-term follow-up of both study cohorts

Our research can help the national screening committee decide on the best options to reduce the number of women being referred unnecessarily. 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 ours to give them information on how HPV behaves. Collecting further data will help make these models more accurate.

Our research questions include:

1. Is it safe to leave a longer interval between screening tests when a woman has a negative HPV test?
2. What age is it safe to stop screening? Does a woman have to be tested in her sixties if she has tested negative for HPV in her fifties?
3. What follow-up (triage) tests should be done in women who test positive for HPV?
4. Is a longer screening interval also safe for women who have had treatment (such as LLETZ) for CIN2 or CIN3?

Nested case-control study of incident cases of CIN3 and cervical cancer

The Manchester Cohort have been linked to national cancer registration data to identify those diagnosed with HPV-related cancers and cervical pre-cancer. We will compare HPV status (in 1989-1993) and cervical screening histories in approximately 100 women who subsequently developed cervical cancer against a set of 300 control women. 

Data Processing

These studies are lead by Professor Julian Peto and analysed by Clare Gilham, statistician. We are following these cohorts passively, there is no contact with the women and therefore their screening and care is not affected by this study. This means that we are not undertaking any decision-making (including automated decision-making) at an individual level, but we are analysing the data as a whole to influence national policy change. All data files: original study data, cervical screening records, histology data, cancer and death registrations are linked using NHS numbers. Every woman has a unique study number which is used in our study database. Along with study number, the data stored are: date of birth, date and result of smear tests, HPV test results, cervical histology results (biopsy results), cancer registrations (date of registration, cancer type), death registrations with date and causes of death. No names or addresses are stored in this master data file. It is kept on secure password-protected computers at LSHTM and can only be accessed by the study statistician. NHS numbers, names and addresses were sent securely to NHS Digital for linkage to cancer registration and mortality data. Our processing activities have been approved by an ethics committee, we have Section 251 approval from the Confidentiality Advisory Group and further permission from ONS and NHS Digital to use cancer and death registration data. The statistical analyses of the data produces tabular or graphical results where no member of the studies could be identified. Anonymous data will only be shared with other researchers with prior permission from NHS Digital. Data will be stored for at least 20 years because this is an on-going study which will continue to provide valuable data for years to come. Those who have requested national data opt-out have been removed from the study data by NHS Digital. If you participated in either the Manchester Study (1988-93) or ARTISTIC Trial (2001-04) and wish to find out more, or wish to opt out of your data being used for this purpose, please e-mail clare.gilham@lshtm.ac.uk. The legal basis for processing of data according to GPDR are article 6(1)(e) task in the public interest and article 9(2)(j) scientific research. If you have any questions in relation to the LSHTM’s processing of your personal data or your rights as an individual, please read the LSHTM Data Protection Policy or to contact the Data Protection Officer.