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# Cost effectiveness of human papillomavirus test of cure after treatment for cervical intraepithelial neoplasia in England: economic analysis from NHS Sentinel Sites Study

BMJ 2012; 345 (Published 01 November 2012) Cite this as: BMJ 2012;345:e7086
1. Rosa Legood, lecturer in decision modelling1,
2. Megan Smith, program manager, cancer modelling2,
3. Jie-Bin Lew, senior research programmer2,
4. Robert Walker, senior research programmer2,
5. Sue Moss, professor of cancer epidemiology3,
6. Henry Kitchener, chair of gynaecological oncology4,
7. Julietta Patnick, director at NHS cancer screening programmes5,
8. Karen Canfell, associate professor and cancer modelling program leader26
1. 1Health Services Research and Policy Unit, London School of Hygiene and Tropical Medicine, London WC1 9HS, UK
2. 2Cancer Research Division, Cancer Council NSW, Woolloomooloo, NSW 2011, Australia
3. 3Centre for Cancer Prevention, Queen Mary University of London, Wolfson Institute of Preventive Medicine, London EC1M 6BQ
4. 4School of Cancer and Enabling Sciences, University of Manchester, St Mary’s Hospital, Manchester M13 9WL, UK
5. 5NHS Cancer Screening Programme, Sheffield S10 3TH, UK
6. 6School of Public Health, University of Sydney, Australia
1. Correspondence to: R Legood rosa.legood{at}lshtm.ac.uk
• Accepted 6 October 2012

## Abstract

Objectives To evaluate the cost effectiveness of human papillomavirus testing after treatment for cervical intraepithelial neoplasia (CIN).

Design Economic analysis using a Markov modelling approach to combine cost and epidemiological data from the NHS Sentinel Sites Study with data from previous studies of post-treatment recurrence rates.

Setting English NHS Cervical Cancer Screening Programme.

Interventions Management guidelines after treatment of CIN involving annual cytology follow-up for 10 years, compared with alternative protocols using the human papillomavirus test to reduce the amount of post-treatment surveillance.

Main outcome measures Cases of underlying CIN3+ averted at 10 years and costs per 1000 women treated.

### Sensitivity analysis

Figure 2 shows the results of a sensitivity analysis for the cost per additional case of underlying CIN3+ averted for each of the human papillomavirus strategies. The findings were most sensitive to assumptions about the assumed level of compliance with follow-up recommendations and the cost of collecting follow-up test samples (that is, whether this was done in the community or by a specialist in a hospital setting); in the case of the sentinel sites protocol, the results were also somewhat sensitive to the assumed test characteristics of HC2. Post-treatment management using the sentinel sites protocol became more attractive when the cost of collecting follow-up test samples was assumed to be higher (that is, assuming that they were collected by a specialist in a hospital setting), as human papillomavirus strategies would involve fewer visits overall. However, this strategy became less attractive when HC2 was assumed to be less specific; it also became slightly less attractive when the proportion of the cohort treated for CIN1 was higher, as this group have fewer visits under cytology only follow-up. Assumptions about the test characteristics of cytology and colposcopy had relatively smaller effects.

Fig 2 Effect of various model assumptions on cost per additional residual recurrent cervical intraepithelial neoplasia (CIN) 3+ case averted, compared with cytology only follow-up. HPV=human papillomavirus; LBC=liquid based cytology. *Under perfect compliance assumptions, this strategy was predicted to result in more underlying CIN3+ at 10 years than cytology only follow-up, so cost per underlying case of CIN3+ averted should be interpreted as cost per underlying case of CIN3+ averted by cytology only follow-up compared with HPV testing strategy. †Population composition (age structure and proportion treated for CIN1 v CIN2+) was varied to reflect different post-treatment populations observed in HPV Sentinel Sites Study and in a recent study of post-treatment management.2 Baseline analyses reflected HPV sentinel sites population, in which 63% of treated women were younger than 35 years and 10% of women were treated for CIN1 and the remainder for CIN2+. The “younger” population had a higher proportion of treated women aged <35 years (73%), consistent with that observed in a previous study2; the “more CIN1” population had a higher proportion of women treated for CIN1 (23.6%), consistent with that observed in a previous study.2 ‡Sensitivity and specificity varied within feasible range. §Effect on outcomes was too small to show substantial variation in this depiction. ¶Negative values indicate that strategy prevents more cases and is cost saving compared with cytology only follow-up

The overall findings of the evaluation were sensitive to assumptions about compliance with follow-up visits to the extent that they altered the relative ranking of the strategies. If we assumed perfect compliance, we found cytology only follow-up to be comparatively more effective, with fewer cases of underlying CIN3+ at 10 years than for either of the human papillomavirus testing strategies. However, the associated costs were also considerably increased; and although assuming perfect compliance also increased costs for the strategies involving human papillomavirus testing, this occurred to a lesser extent (table 3). When we compared the relative costs and outcomes of the two human papillomavirus strategies, the extended human papillomavirus follow-up protocol had similar efficacy to the sentinel sites protocol but was associated with higher costs under the scenarios examined in sensitivity analysis.

Table 3

Sensitivity analysis: predicted outcomes and resource use over 10 years, per 1000 women treated if perfect compliance with recommendations is assumed

View this table:

## Discussion

This evaluation was informed by comprehensive and detailed use of epidemiological and cost data from the NHS Cervical Cancer Screening Programme Sentinel Sites Study and other observational studies, plus data from the screening programme in England. We found that the early use of human papillomavirus testing after treatment averts more cases of CIN3+ and is also cost saving compared with cytology only follow-up, because it seems to be more effective at the early identification of women who are at risk of recurrent disease in the future. The findings also indicate that the capacity of annual cytology to prevent CIN3+ in women previously treated for CIN depends on a very high level of compliance with annual visits. This is likely to explain, in part, the difference between our findings and those of a previous evaluation, which assumed perfect compliance with follow-up recommendations.5 We also found that human papillomavirus testing according to the sentinel sites protocol results in fewer colposcopies over 10 years than does cytology only follow-up, and a higher proportion of colposcopies resulted in re-treatment. This is potentially an important reduction in the burden of follow-up on women, as well as on the health system. It also indicates that the colposcopies done under this strategy are better targeted at women who will benefit from them. As a result of the successful implementation of the sentinel sites and this cost effectiveness analysis, the human papillomavirus test of cure is now being implemented nationally in England, so the cytology only protocol is no longer current practice.

When we assessed the relative effects and costs of alternative human papillomavirus based strategies, we found that once-only cytology and human papillomavirus testing at six months after treatment is predicted to have comparable effectiveness to a strategy involving three rounds of repeat testing; in addition, the once-only cytology and human papillomavirus based testing strategy was found to be less costly. This finding may be relevant to other settings, especially in countries that have implemented extended human papillomavirus testing protocols. For example, the national screening programmes in Australia and New Zealand have introduced recommendations involving repeated rounds of human papillomavirus and cytology testing after treatment, in which women are required to have negative results in both tests for two consecutive years before they are discharged back to routine screening.24 25 These recommendations were originally based, in part, on cost minimisation (rather than cost effectiveness) analysis comparing extended human papillomavirus testing with previous recommendations in those settings, which was annual cytological follow-up until the age of 70. To our knowledge, the comparative cost effectiveness of simplified human papillomavirus test based strategies compared with extended test protocols has not been examined in these settings and is a potential subject for future cost effectiveness analyses.

Follow-up testing at six months post-treatment could also be further streamlined to involve only human papillomavirus testing without cytology. Studies of longitudinal outcomes after primary human papillomavirus testing in the general population show that cumulative rates of CIN3+ in human papillomavirus negative women are very similar to rates in the group of women who are both human papillomavirus and cytology negative over several years of follow-up,26 implying that adjunctive testing with both tests is relatively inefficient compared with using human papillomavirus testing alone. However, further data on the comparative performance of human papillomavirus testing alone versus combined with cytological screening are needed in the post-treatment setting. We were not able to evaluate human papillomavirus testing as a standalone test in this evaluation, because the data used came from studies in which human papillomavirus testing was done at six months only when cytology was negative.

The high negative predictive value of post-treatment management involving human papillomavirus testing and cytology at six, 12, and 24 months has recently been reported to be maintained over five years.27 Longer term follow-up data from the Sentinel Sites Study will further enable the validity of the observable model predictions (such as rates of colposcopy and re-treatments) to be assessed. Our evaluation of the cost effectiveness of human papillomavirus as a test of cure over a period of 10 years represents a modelled extrapolation of data obtained from studies with shorter follow-up periods. Therefore, although our findings support the implementation of human papillomavirus based strategies for post-treatment management, a need remains for ongoing monitoring and evaluation of the long term safety of these strategies.

### Conclusion

We found that the human papillomavirus test of cure according to the sentinel sites protocol is a more effective and less costly strategy than annual cytological follow-up over 10 years. The findings of this analysis suggest that a single round of cytology and human papillomavirus testing six months after treatment effectively identifies women at future risk of serious recurrent cervical disease. The results support the full scale implementation within the NHS Cervical Cancer Screening Programme of human papillomavirus testing as a test of cure after treatment for CIN.

#### What is already known on this topic

• Results of previous studies are inconsistent about whether human papillomavirus (HPV) testing as a test of cure after treatment for cervical intraepithelial neoplasia (CIN) is cost effective

• If realistic assumptions are made about women’s compliance with follow-up recommendations, HPV testing is likely to be more effective and cost less than strategies based on annual cytological follow-up of women treated for CIN

## Notes

Cite this as: BMJ 2102;345:e7086

## Footnotes

• Contributors: RL, KC, and MS designed the study. MS, RW, J-BL, and KC implemented the model in TreeAge. RL and SM provided epidemiological support and data analysis. RL, KC, MS, and J-BL drafted the initial manuscript. All authors were responsible for redrafting the final manuscript.

• Funding: The study was funded by the NHS Cancer Screening Programme. The analyses and decision to publish were independent of the funders.

• Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: RL, SM, MS, RW, J-BL, and KC were funded by the NHS Cancer Screening Programme to do this work. KC is involved in configuring a new trial of cervical screening in Australia which will involve support from several manufacturers.

• Ethical approval: Not needed.

• Data sharing: Further details are available in the web technical appendix.

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