A systematic review was carried out to assess the available evidence on cost-effectiveness for primary HPV screening as part of an organised screening
programme for the prevention of cervical cancer. Consistent evidence was found that cervical screening programmes using primary HPV screening are cost-effective and potentially cost saving when compared with programmes using primary cytology screening. The studies identified were not considered applicable to CervicalCheck and or the Irish healthcare system because of differences in the cervical screening programmes and healthcare delivery costs. Therefore, an economic model specific to the Irish setting was required due to the lack of applicable published
cost-effectiveness evidence from another setting.
A decision analysis model was built to compare the total net costs and benefits associated with different HPV-based screening strategies for the prevention of cervical cancer compared with the current CervicalCheck strategy of primary liquid-based cytology (LBC) screening followed by triage with HPV. A Markov model structure based on the natural history of cervical cancer was developed. Model
parameters were derived from CervicalCheck, Irish datasets, peer-reviewed literature
xxii and expert opinion. Costs and benefits were assessed from the perspective of the publicly-funded health and social care system. Effectiveness was measured as quality-adjusted life years (QALYs) gained for each of the potential screening
strategies. The difference in QALY gains is the most valid way to compare the overall effectiveness of the alternative strategies rather than the relative number of cancer cases and cancer deaths. QALYs take into account differences in the quantity and quality of life and, and so capture, for example, differences in the stage at which a cancer is diagnosed. Both quantity and quality of life may differ substantially for those diagnosed with earlier stage disease (stage 1 disease confined to the cervix) versus advanced disease that has spread to other parts of the body (stage IV).
QALYs also take into account any difference in the duration of survival of those who die from cervical cancer. QALYs also account for harms due to screening, including overdiagnosis. Overdiagnosis may lead to a loss of quality of life due to increased surveillance of CIN 1 (potentially increasing stress and anxiety) and unnecessary treatment of CIN 2 and CIN 3 lesions. QALY estimates are discounted to reflect society’s preference for benefits to be realised sooner and undesirable effects to be realised further into the future.
This HTA considered 32 different screening strategies, including different primary screening tests (HPV or LBC), triage tests, screening intervals, and screening exit ages. Triage consisted of a single test, sequential testing or co-testing. Triage tests consisted of liquid-based cytology (LBC); partial genotyping for HPV 16 and 18; and dual staining for p16INK4a/Ki-67. The prevalence of HPV infection is higher in women under the age of 30 years than it is in women aged 30 years and older. This may reduce the clinical effectiveness of primary HPV screening in this age group.
Therefore, one alternative age-based strategy was considered: primary liquid-based cytology (LBC) screening with HPV triage in women under the age of 30 years with primary HPV screening with liquid-based cytology triage in women aged 30 years and over. Finally, given recommendations from the International Agency for
Research on Cancer that cervical screening should be considered for all women aged 25 to 65 years when resources permit, all of the proposed strategies also considered extending the upper age limit from 60 to 65 years. All strategies were considered for both unvaccinated and vaccinated cohorts of women. Conventional cytology was not considered because CervicalCheck has used liquid-based cytology (LBC) since its establishment in 2008.
The model was used to predict the financial cost, number of lifetime screens,
referrals to colposcopy, cervical cancer cases, cervical cancer deaths, QALYs and life-years gained (LYG) for each of the 32 proposed strategies in unvaccinated and vaccinated cohorts. Incremental cost effectiveness ratios (ICERs) were calculated for each strategy. The total net costs and benefits associated with each of these
Health Technology Assessment (HTA) of human papillomavirus testing as the primary screening method for prevention of cervical cancer
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xxiii screening strategies were determined by modelling one year’s cohort from age 25 years to end of life.
For the cohort of women who have not been vaccinated against HPV 16 and 18 (the unvaccinated cohort), CervicalCheck’s current strategy was more costly and either less or equally effective, when compared with all other options (apart from
extending the current strategy to age 65 and primary HPV screening followed by triage comprising co-testing with partial genotyping and p16INK4a/Ki-67 with screening extended to age 65). Similarly, for the cohort of women who have been vaccinated against HPV 16 and 18, CervicalCheck’s current strategy was less effective and more costlycompared with all other strategies (apart from extending the current strategy to age 65 years).
For the unvaccinated cohort, given willingness-to-pay thresholds in the range of
€20,000 to €45,000 per QALY, primary HPV screening with liquid-based cytology triage at five-yearly intervals from age 25 to 60 years was found to be cost-effective with an ICER of €29,788 per QALY gained. While this strategy provides comparable clinical effectiveness to current screening practice, a number of other strategies were found to be more effective, and would also lead to a reduction in costs compared with current practice.
For all strategies, extending the screening age to 65 years decreases both the number of cervical cancer cases and cervical cancer deaths. However, as these benefits occur far into the future, the effect of discounting means that the number of QALYS gained is small. Although more effective, the incremental benefit of extending the screening age is small relative to their incremental cost. As such, this would not be considered cost-effective when compared with primary HPV screening with liquid-based cytology triage at five-yearly intervals from age 25 to 60 years. Using the willingness-to–pay threshold based on QALYs allows for comparison to be made across the entire health service and identifies when interventions can be considered good value for money. Applying the willingness-to-pay threshold to guide the choice regarding the optimal strategy ensures that where the health gains are small,
relative to the increase in costs, this is highlighted and consideration can be given to redistributing resources to elsewhere within the health system to maximise the benefit for the entire population.
Two subgroup analyses were conducted at the request of the Expert Advisory Group.
The first considered extending the screening exit age from 60 to 65 years in a cohort who have not had the benefit of lifetime access to CervicalCheck from the age of 25 years (that is, for women who were 50 years old when CervicalCheck commenced in 2008). This analysis confirmed that extending the upper screening age limit from age 60 to age 65 years provides a clinical benefit, but is not cost-effective under
xxiv willingness-to-pay thresholds in the range of €20,000 to €45,000 per QALY,
irrespective of when access to organised screening starts (25 or 50 years). Given their historic underscreening, it may be considered appropriate to extend screening to age 65 years for these women for ethical reasons. However, to ensure the benefits of this additional screening round are maximised, a targeted campaign to encourage uptake in those over 60 years of age would be necessary given the lower uptake rate of screening in older women.
The second subgroup analysis considered how best to screen women under the age of 30 years not vaccinated for HPV 16 and 18, in the context of primary HPV
screening followed by liquid-based cytology triage at five-yearly intervals being adopted from age 30 years. These women have a high prevalence of both HPV infection and cervical abnormalities, and five-yearly screening may lead to an increased risk of interval cancers within this subgroup. However, infection is also more likely to clear spontaneously within this age group, and in the absence of persistent infection, cytological abnormalities will typically regress.
The optimal screening strategy for this subgroup of unvaccinated women under the age of 30 years was found to be primary HPV screening followed by liquid-based cytology triage at five-yearly intervals from age 25 to age 60 years. Providing three-yearly screening for those aged under 30 (that is, adding one more screening round) increases the effectiveness of this strategy, but also increases its cost. With an ICER of €48,501 per QALY, this would not be considered cost-effective under willingness-to-pay thresholds in the range of €20,000 to €45,000 per QALY. If three-yearly screening to age 30 is adopted for clinical reasons, ongoing evaluation and monitoring of its effectiveness will be required, taking into consideration the proportion of the population vaccinated against HPV and the prevalence of HPV infection.
Furthermore questions still remain as to the optimal surveillance for unvaccinated women aged less than 30 years who screen positive for HPV, but negative on liquid-based cytology triage. Two alternative referral pathways were considered in this subgroup analysis. In the first, women who were HPV positive at 12 months were referred directly to colposcopy and in the second, women were only referred to colposcopy if they tested positive on partial genotyping test for HPV 16 or HPV 18 at 12 months. Both referral pathways lead to similar clinical outcomes and costs. The requirement for a positive partial genotyping test would reduce the number of colposcopy referrals in this age group, but lead to repeated annual screening and thus potentially high levels of anxiety for some women. The efficacy of screening in this cohort will therefore require ongoing evaluation.
Health Technology Assessment (HTA) of human papillomavirus testing as the primary screening method for prevention of cervical cancer
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xxv For the cohort of women who have been vaccinated against HPV 16 and 18, none of the modelled strategies were considered cost-effective when compared with no screening at a willingness-to-pay threshold of €45,000 per QALY. The strategy with the lowest ICER of €58,745 per QALY was primary HPV screening with liquid-based cytology triage at five-yearly intervals from age 25 to 60 years. Given that
CervicalCheck was only established in 2008 and is thus relatively new, extending beyond five-yearly screening was considered to be unacceptable at this point, so longer screening intervals were not included in the model. There is uncertainty about how women who have been vaccinated against HPV 16 and 18 will progress through the precancerous states from infection with HPV to invasive cervical cancer. It was assumed that when compared with unvaccinated women, the risk of developing cervical cancer is 70% lower in women who have been vaccinated against HPV 16 and 18. This was very influential on the number of cervical cancer cases predicted by the model and whether or not the modelled strategies were cost-effective. While screening strategies with longer intervals than those modelled may be more
appropriate for women who have been vaccinated against HPV 16 and 18, a policy of continued screening at five-yearly intervals may be reasonable until further long-term data emerge on the development of cervical cancer in these women.
The budget impact analysis was conducted from the perspective of the publicly-funded health and social care system. The budget impact analysis, over an eight-year period from 2018 to 2025, of switching from the current strategy to primary HPV screening with liquid-based cytology triage at five-yearly intervals from 25 to 60 years estimated a net saving of up to €3 million for the CervicalCheck population who have been vaccinated against HPV 16 and 18, €32 million for the CervicalCheck population who have not been vaccinated against HPV 16 and 18 and up to €35 million for the entire CervicalCheck population.