Is a delay in the introduction of human papillomavirus-based cervical screening affordable?

Objective It often takes considerable time for sufficient evidence to accumulate to support implementation of new methods in routine screening. Where national screening programmes are already effective, switching to a more sensitive screening test may not be a priority. Although risk associated with overly rapid implementation exists, postponement is also associated with a (to date unquantified) missed opportunity to prevent deaths. This risk tends not to be addressed where effective screening methods are already in use. We here estimate the monetary value of a one-year delay in replacing cytology cervical screening with human papillomavirus testing. Methods Using a previously validated model, we calculated the number of incident and fatal cervical cancers that would be diagnosed by 2030 in England, under the assumption that human papillomavirus testing replaces cytology in 2020 rather than 2019, and the monetary value of the quality-adjusted life years lost in preventable cases. Results A one-year delay in the implementation of human papillomavirus screening would miss the opportunity to prevent 581 cases of cervical cancer, and lead to a loss of 1595 quality-adjusted life years (3.5% discount rate) with a monetary value of £32 million (at £20,000 per quality-adjusted life year). Conclusion This is a measurable loss and should be considered in prioritising decision-making in screening.

1. We use individual-level data (from a population based case-control study of cervical cancer diagnosed between 2007 and 2012) A2 to obtain age-specific incidence rates in never-screened women. The numbers of cancers in the case-control study were weighted so that they matched, by calendar-year and age-group, cancer registration statistics between 2011-2015.
2. We estimated the relative risk for different birth cohorts from a modified age-periodcohort model.
3. Relative risks of cervical cancer by screening history were estimated using the casecontrol study. A2 The relative-effect of HPV-based screening compared with cytologybased screening was taken from the literature. 4. The relative risk of HPV vaccination was estimated from a microsimulation model. A3 The model was calibrated to the average age-specific cervical cancer rates in England between 2011 and 2015. The estimated yearly number of cancers diagnosed with cytology screening are an average of cancers diagnosed between 2020 and 2024 for women <60yrs and between 2020 and 2030 for women aged 60-79 (the benefit of HPV testing in 2019 on cancer will be realised between 1.5 and 11.5 years after the test is taken). (Table 1) To estimate the benefit of HPV testing relative to cytology, we use screening histories from the case control study A2 to estimate (by age group and FIGO stage) the proportion of women with a negative cytology test prior to diagnosis. We exclude cancers diagnosed within 18 months of a negative test because, for these cancers, it is probably too late to prevent the cancer by treating preinvasive disease. However, we include cancers diagnosed up to and including 1.5 years after the next screen (because by screening now we might be able to prevent those screen-detected on the next screen).
For women with cervical cancer, we calculated the proportion with a negative cytology test between 1.5 and 4.5 years prior to diagnosis if aged 25 to 49, and between 1.5 and 6.5 years if aged 50 to 59. For women aged 60 to 79, we looked at the proportion of with a negative test (at age 60 to 65) between 1.5 and 11.5 years prior to their diagnosis (Table 1). Not all the cancers diagnosed following a negative test would have been preventable had the test been HPV rather than cytology. We have previously estimated A4 that although 37.8% of cancers had a negative cytology in the appropriate window, only 23.9% (i.e. 63.2% of those with negative cytology) additional cancers would be prevented by primary HPV testing. The reduced efficacy is made up of: i) cancers that are both HPV and cytology negative; ii) cancers that will develop despite being HPV positive on screening; and iii) cancers that would have tested cytology positive will be HPV negative. To take this into account, we multiply the (age-and FIGO stage-specific) proportions of women with negative cytology by 0.632 (Table 1).

Appendix 2. Cancers prevented by HPV testing relative to cytology testingcomparison with published literature
Our group has previously estimated (in two separate publications) the reduction in cervical cancers with HPV primary testing relative to cytology. We use the same methodology in our papers but present slightly different results. Here we explain why they are different.
In the first manuscript published in 2017 A4 we estimated the reduction in cervical cancers at age 25 to 64 based on 2013 cancer incidence statistics, and report that they could be reduced by 487 (95% CI 394 to 563) cancers per calendar year or 3.4 (95% CI 2.8 to 4.0) per 100,000 women.
In the second manuscript published in 2018 A1  In this manuscript we estimate the reduction in cancers at age 25 to 79 up to 2030, and hence estimate 19 cancers more (n=581) in this manuscript than in the 2018 one.
There remains uncertainty regarding screening intervals and triage test to be used once HPV testing is implemented in England. If the intervals are extended so that there are additional interval cancers, then the benefit of early adoption in terms of cancers prevented could be lessened.

Vaccination
In England vaccination against HPV was introduced in 2008 for girls aged 12-13 as a free school-based programme, with catch-up for those aged 14-18. The youngest women receiving HPV primary testing in 2019 at age 25 will have been vaccinated against HPV 16/18 at the age of 14. Vaccination coverage at age 12 and 13 was 86%, at age 14 it was 69%, but only 40% at age 16 to 18. A5 The potential effect of the nonavalent vaccine has not been considered here, as none of the women screened in 2019 or 2020 will have benefited.
We have not accounted for the impact of herd immunity, but given how few women in the model would have benefited, its impact on test positivity rates and referral rates will be limited.
Cost to the health service The aim of this analysis was to quantify, in a scenario where a high-quality screening programme exists, the monetary value (in terms of QALYs) of delaying the implementation of HPV primary screening owing either to a late decision or a late implementation but does not discriminate between the two.
An earlier start of HPV screening needs to consider the differences in prices between HPV and cytology testing. While HPV testing used to be considerably more expensive than cytology, recently published literature suggests that after the initial investment needed to process the HPV samples in the laboratory the running costs of an HPV based screening programme are similar if not cheaper to that of cytology (even without extending the screening interval). A6,A7 It must be considered that HPV testing is associated with a high proportion of false positive tests than cytology. In the future, the increase in false positive results can be offset by more specific HPV assays and if the screening interval is increased the initial cost of switching to