Cervical screening in the UK: cytology to primary HPV testing

The NHS has pledged to reduce the cervical cancer incidence rate below the WHO elimination target of 4 per 100,000 by 2040. This will be achieved in birth cohorts born since 1990 who have been offered vaccination, but the incidence rate is likely to remain high among older women unless screening performance can be improved. In 2019, primary HPV testing was introduced in the UK but questions remain on how to effectively manage women with persistent HPV infection.

The overarching aim of the portfolio of work is to understand the natural history of HPV infection and to inform NHS screening policy. The objectives are to: 1. Discuss how mortality and incidence rates are impacted by changes in screening policy, hence informing age at starting and stopping screening 2. Describe the natural history of HPV and progression to CIN3 and cancer in terms of HPV prevalence, persistence, acquisition and redetection 3. Investigate the effect of sensitivity of HPV testing in relation to screening intervals 4. Evaluate HPV genotyping and HPV DNA methylation as options for triaging HPV positive women

The first paper in the portfolio showed the considerable decline in cervical cancer mortality since the organised Cervical Screening Programme was introduced by the NHS in 1988. We estimated that, without screening, the UK would have had one of the highest cervical cancer rates in the world. An updated analysis of the age birth cohort trends shows mortality rates have increased after age 65 when cytology screening stops, implying that these cohorts are likely to benefit from being offered at least one catch-up HPV test in their 70s. In addition, women born from 1984-1990, who were not invited for screening until age 25 and were not routinely offered vaccination as teenagers, have experienced higher cervical cancer incidence and mortality in their late 20s than previous birth cohorts.

The remaining five research papers in the portfolio concern the analysis of long-term follow-up data from two cohorts of women attending cervical screening in Greater Manchester. We showed a higher sensitivity of HPV testing than cytology screening for identifying risk of disease. The low long-term cancer risk following a single negative HPV test at the baseline of the ARTISTIC cohort indicated that screening intervals can be extended to at least 5 years as supported by the National Screening Committee. New HPV infections are common and mostly transient, so an effective triage test is required to prevent low-risk women being referred unnecessarily to colposcopy. We have shown that the cytology triage protocol currently in use by the NHS CSP is too conservative. Our analysis suggests that the National Screening Committee should explore partial genotyping as an alternative triage option, as has been adopted in other countries.

Abnormal cytology is currently the triage method in the UK for identifying those with prevalent disease, but in the future, this is likely to be replaced by HPV genotyping and molecular markers such as DNA methylation which can also be used on self-taken samples. Methylation is currently not sensitive or specific enough to safely return HPV positive women to routine recall, but may instead be used to reassure those who are not recalled immediately for retesting.Over the coming years, cervical cancer will become so rare among vaccinated cohorts that it will not be cost effective to screen all women at the current rate, so to remain effective screening should depend on vaccination status.