Human Papilloma Virus (HPV)

• HPV testing
• Our answers to questions asked about HPV infection
• TOMBOLA study
• ARTISTIC trial
• HPV pilots
• HPV pilot protocol
• Fact sheets
• Evaluation of HPV triage

HPV testing

There are over 100 subtypes of Human Papilloma Virus (HPV). Most do not cause significant disease in humans. However, some subtypes, notably types 16 and 18, 31 and 33, have been confirmed as agents which cause cervical cancer. 'High risk' HPV types have been found to be present in close to 100% of all cervical cancers. Research has indicated that women with a mild or borderline smear result who have no evidence of high risk HPV infection are very unlikely to develop cervical cancer. HPV testing has therefore been proposed as a means of distinguishing women in this group who have a higher risk of developing cervical cancer from those who have very low risk. A Health Technology Assessment (HTA) review concluded that HPV testing could not currently be recommended for primary screening without further research. Current evidence does, however, support limited introduction of the test in order to improve the management of women with smears showing borderline nuclear change or mild dyskaryosis.

HPV testing can help to identify those women with borderline nuclear change or mild dyskaryosis who do not require immediate referral for colposcopy. There is, however, still some uncertainty about the negative predictive value of the test in the presence of persistent mild dyskaryosis and the safety associated with reduced surveillance. This particular aspect of HPV screening is being carefully evaluated in pilot studies. Viewed overall, however, it seems likely that the introduction of HPV testing for triage of women with smears showing borderline nuclear change or mild dyskaryosis could reduce referral to colposcopy and repeat smears. It would therefore reduce anxiety for some women and be cost effective for the NHS.

Our answers to questions asked about HPV infection

How long might a woman have had the infection?

The virus might have been present for some time before its detection. Some people come across the virus and never show its presence, developing a kind of immunity. In others it can remain in the body without harm for considerable periods of time or be quickly dealt with by the immune system.

Is there any treatment?

There is no reliable treatment to get rid of the virus, but since in most women it disappears spontaneously over time, a "wait and see policy" is the usual management.

Can men be tested for HPV?

At present there is no reliable test to demonstrate the presence of the virus in men.

Can men be treated?

This is unnecessary (just as it is in women) unless the virus develops into clinical warts (growths), which project above the surrounding skin.

For more details about HPV and cervical cancer, see The Aetiology of Cervical Cancer

TOMBOLA study

This study was set up to determine the most appropriate way to deal with HPV positive results and associated psychological issues. The MRC funded Trial of Management of Borderline and other Low grade Abnormal smears (TOMBOLA), started recruitment of women in December 1999 and was a seven year multi-centre trial run from Dundee, Aberdeen and Nottingham. The aim of the trial was to:

• determine whether a policy of cytological surveillance or initial colposcopy is the more efficient and effective policy for further investigation and clinical management in women with mild or borderline cervical dyskaryosis.
• determine whether, following colposcopic examination of women with mild or borderline dyskaryosis, immediate large loop excision of the transformation zone (LLETZ) or biopsy and recall for LLETZ, is the more effective and efficient method of treatment.
• evaluate the contribution of HPV testing to the effectiveness and efficiency of the existing procedures for management of women with mild or borderline dyskaryosis.

The study population comprised 10,000 women between the ages of 20 and 59 from the Tayside, Grampian and Nottingham areas that had:

• an index borderline smear followed by another smear, six months later, which showed either borderline or mild dyskaryosis;
• an index smear classified as mildly dyskaryotic

The TOMBOLA trial is expected to produce its main report in 2007.

For details of its early findings see;
Psychological effects of a low-grade abnormal cervical smear test result: anxiety and associated factors
British Journal of Cancer (2006) 94, 1253-1262.

ARTISTIC trial

Professor Henry Kitchener is leading a trial investigating HPV as a primary screening test. The trial, enttitled ARTISTIC (A Randomised Trial of HPV Testing in Primary Cervical Screening) is taking place in Manchester, Stockport, Wigan & Leigh and Salford & Trafford, and began in June 2001.

The trial should

• Provide clear evidence on the costs, medical effects and psychosocial impact of adding HPV testing to cervical cytology
• Provide an estimate of the effectiveness and costs of HPV as a stand-alone test
• Determine the contribution of HPV detection to the cervical screening programme, particularly to sensitivity, specificity and inadequate smears
• Address methodological issues in HPV testing

The study population comprises 25,000 women aged 20-64 who are attending general practices for routine cervical screening and who consent to having an HPV test.

HPV pilots

These pilots are designed to evaluate a number of issues associated with introducing HPV testing into the cervical screening programme as triage for smears showing borderline nuclear change and mild dyskaryosis. The issues being examined include:

1. The extent to which HPV testing in women with low grade cytological changes reduces the need for colposcopy

2. The positive predictive value of the HPV test in women with low grade smear abnormalities and the negative predictive value for women with persistent mild dyskaryosis.

3. The public acceptability of HPV testing as part of the screening programme. This needs to be seen as a component of an improved cervical screening test and not a "sexually transmitted disease test" . The anxiety of patients returned to normal recall after a negative HPV test despite an earlier abnormal smear is being monitored as well as the anxiety caused to patients whose HPV test is positive and followed by immediate referral for colposcopy.

4. An assessment of the prevalence of HPV infection in the UK population with low-grade abnormalities and the impact of the introduction of testing on a laboratory.

The two new technologies of HPV testing and Liquid Based Cytology (LBC) form a natural link in that the use of liquid based specimens allows an HPV test to be performed at a later date in the laboratory without the patient being required to provide a second sample. HPV and LBC were both piloted and assessed at the same pilot sites. These were:

• Norfolk and Norwich Hospital
• Southmead Hospital, North Bristol NHS Trust
• Royal Victoria Infirmary, Newcastle

The sites were selected through a competitive process according to criteria which included size of service, quality assurance standards and current performance.

HPV pilot protocol

The HPV pilot essentially replaces assessment of low-grade abnormalities by colposcopy with assessment by HPV testing. Women whose index smear shows borderline nuclear change or mild dyskaryosis also have material tested for high-risk HPV types. If HPV positive, they are referred immediately to colposcopy.

If the test shows they are HPV negative, then they will have a repeat smear in 6 months time, as now, and a second HPV test. If the apparent abnormality has either persisted as mild dyskaryosis or progressed to a high-grade smear (a very unlikely occurrence) or the women are now found to be HPV positive, they are then referred for colposcopy. If the abnormality had regressed or is no worse than borderline nuclear change and the woman is HPV negative on both occasions then she will be discharged back to routine screening.

Two of the pilot sites (Bristol and Norwich) are now using a slightly revised HPV triage protocol. Women who test positive for HPV following a low-grade smear are only referred to colposcopy immediately if they are aged 35 or over when their smear is taken. Younger women are asked to return for a repeat smear and HPV test in six months and the referral is made on the basis of this second test. This is because older women with HPV are more likely to need treatment than younger women with HPV. HPV negative women are managed in the same way as the original pilot protocol.

Fact sheets

Evaluation of HPV triage

Here is the final report of the independent evaluation of the LBC/HPV pilot. The evaluation was commissioned by the Policy Research Programme of the Department of Health.

Evaluation of HPV/LBC Cervical Screening Pilot Studies (PDF 1.48Mb)