|Cost-effectiveness of human papillomavirus testing after treatment for cervical intraepithelial neoplasia
|Coupe V M, Berkhof J, Verheijen R H, Meijer C J
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
The study examined several strategies for follow-up after treatment for high-grade cervical intraepithelial neoplasia (CIN). The strategies included the current pattern of care in the Netherlands, three strategies with two recalls (A strategies), one variant with loop excision of the transformation zone (LLETZ treatment), and two strategies with only one recall (B strategies). The strategies were as follows.
Current strategy: repeat cytological testing with Papanicolaou (Pap) smears at 6, 12 and 24 months after treatment.
A1: human papillomavirus (HPV) and cytological testing at 6 and 24 months.
A2: only HPV testing at 6 and 24 months.
A3: a mixed strategy with HPV testing at 6 months and both cytological and HPV testing at 24 months.
See-and-treat: at 6 months, a positive colposcopic result is immediately followed by LLETZ treatment without histological verification.
B1: both HPV and cytological testing at 6 months.
B2: both HPV and cytological testing at 12 months.
Economic study type
The study population comprised a hypothetical cohort of women treated for high-grade CIN (2/3).
The setting was secondary care. The economic study was carried out in the Netherlands.
Dates to which data relate
The effectiveness data were derived from studies published between 2001 and 2006. The costs and some resource use data were obtained from studies published in 1992 and 2006, as well as from 2000 tariffs. The price year was 2004.
Source of effectiveness data
The clinical data used in the decision model were transition probabilities across health states (both progression and regression rates were considered) and test characteristics (sensitivity and specificity).
A Markov model was developed to simulate the natural history of HPV infections and cervical abnormalities in women treated for CIN2/3. A key assumption of the model was that CIN2/3 is preceded by a high-risk HPV infection. Women moved across the seven health states of the model in cycles of 6 months. The time horizon of the model was 5 years. The health states and transition patterns were described extensively. The structure of the model was reported graphically.
Sources searched to identify primary studies
Transition probabilities across health states (natural history) were mainly obtained from three Dutch studies that followed up cohorts of women receiving CIN treatment. Cytology accuracy was also obtained from a Dutch population-based screening cohort study. Limited information on the other sources of data was given.
Methods used to judge relevance and validity, and for extracting data
It was not stated whether a review of the literature was undertaken. Therefore, it is possible that the primary studies might have been identified selectively. The authors selected Dutch analyses, where possible, to be representative of their study population. No information on the methods used to combine the estimates was given.
Measure of benefits used in the economic analysis
Several model outputs were considered, such as
missed CIN2/3 or cancer cases as a percentage of the total number treated;
the number-needed-to-treat (NNT);
the mean duration until detection of post-treatment CIN;
the colposcopy rate for women without post-treatment CIN; and
the mean number of repeat smears.
The number of missed post-treatment CIN cases was considered to be the main benefit measure. The number of repeat smears and the colposcopy rate for women without post-treatment CIN2/3 were used to represent patient burden. No discounting was necessary.
The analysis of the costs was carried out from a societal perspective. It included the direct medical costs associated with conventional cytology, HPV testing and the treatment of recurrent CIN2/3 or early stage cervical cancer. The costs associated with travelling were also considered. Some assumptions were made for some resource use. For example, for the costs of treatment for persistent or recurrent CIN, it was assumed that 75% of the women were treated by LLETZ and 25% by cone biopsy. A breakdown of the cost items was not given and the costs were generally reported as macro-categories. The unit costs were obtained from Dutch studies and from the Dutch Handbook for Economic Evaluations. Discounting was relevant, as 5-year costs were considered, and an annual rate of 3% was used. The price year was 2004.
Statistical analysis of costs
The costs appear to have been treated deterministically.
In accordance with the societal perspective adopted, productivity costs were considered. No information on the approach used to calculate these costs was given.
A deterministic univariate sensitivity analysis was performed to assess the robustness of the proportion of missed post-treatment CIN2/3 cases and average discounted 5-year costs per woman with regard to changes in:
the performance of HPV testing (analytical sensitivity 90 to 99% and specificity 97 to 100%);
the performance of conventional cytological testing (sensitivity for CIN2/3 of 60 to 80% and specificity of 90 to 99%);
the laboratory costs of HPV testing (EUR 20 to EUR 40);
the costs of treating CIN2/3 (EUR 500 to EUR 1,100);
the costs of treating invasive cervical cancer (EUR 3,000 to EUR 9,000); and
the specificity of colposcopy without histological verification before treatment used in the see-and-treat strategy (60 to 90%).
Estimated benefits used in the economic analysis
The missed CIN2/3 or cancer (percentage of total number treated) was 0.69 with the current strategy, 0.17 with A1, 0.21 with A2, 0.18 with A3, 0.17 with see-and-treat, 0.47 with B1 and 0.42 with B2.
The NNT with respect to the current strategy was 192 with A1, 208 with A2, 196 with A3, 192 with see-and-treat, 455 with B1 and 370 with B2.
The mean duration until detection of post-treatment CIN was 8.2 months with the current strategy, 5.7 months with A1, 6.3 months with A2, 6.3 months with A3, 5.6 months with see-and-treat, 5.5 months with B1 and 10.7 months with B2.
The rate of colposcopy for women without post-treatment CIN was 16% with the current strategy, 25% with A1, 13% with A2, 16% with A3, 22% with see-and-treat, 19% with B1 and 8% with B2.
The mean number of repeat smears was 3.42 with the current strategy, 2.46 with A1, 2.32 with A2, 2.37 with A3, 2.28 with see-and-treat, 1.35 with B1 and 1.21 with B2.
The overall cost per women was EUR 472 with the current strategy, EUR 478 with A1, EUR 386 with A2, EUR 423 with A3, EUR 465 with see-and-treat, EUR 328 with B1 and EUR 281 with B2.
Synthesis of costs and benefits
The costs and benefits were not formally combined as cost-effectiveness ratios, although some graphical results were provided. In general, all strategies that included HPV testing were preferred to the current strategy since they were more effective in reducing missed cases and less costly (except for A1 which was slightly more costly). The reduction in costs was mainly due to fewer repeat smears.
The simultaneous evaluation of costs and benefits (effectiveness and patient burden) suggested that strategies with HPV testing at 6 months and either combined testing at 24 months (A2) or HPV testing at 24 months (A3) were particularly interesting, as they led to a lower proportion of missed CIN2/3 cases, a lower colposcopy rate for women without post-treatment CIN, fewer repeat smears, and lower discounted costs per woman compared with the current strategy. A1 and B1 were extendedly dominated by other strategies.
The sensitivity analysis showed that variations in model inputs did not substantially alter the results of the study, although the magnitude of the cost-savings was sensitive to the specificity of cytology.
High-risk human papillomavirus (HPV) testing for monitoring women treated for high-grade cervical intraepithelial neoplasia (CIN) was cost-effective in comparison with current patterns of care in the Netherlands. The highest detection rate of post-treatment CIN was found for the strategies of combined testing (cytology and HPV testing) at 6 and 24 months, at a relatively low cost.
CRD COMMENTARY - Selection of comparators
The rationale for the choice of the comparators was clear since the study aimed to cover all possible follow-up strategies after CIN treatment, including the current pattern of care. You should decide whether they are valid comparators in your own setting.
Validity of estimate of measure of effectiveness
It was unclear whether a systematic review of the literature was undertaken to identify the primary studies, as the methods and conduct of the review were not reported. Little information on the design and other characteristics of the primary studies was given. The authors selected Dutch studies in order to model the natural history of disease in a way that was representative of the epidemiological characteristics of their patient population. Also, the use of longitudinal studies to model the natural history of the disease appears to have been appropriate. However, the approach used to combine the primary studies was not described. Sensitivity analyses were performed to take variability and uncertainty around key model clinical inputs into account, but these factors were not varied simultaneously.
Validity of estimate of measure of benefit
The benefit measures used in the analysis were specific to the disease considered in the study. They are not comparable with the benefits of other health care interventions. However, these intermediate end points are typical of diagnostic interventions.
Validity of estimate of costs
The analysis of the costs was consistent with the perspective of the study, as both the direct and indirect costs were included. However, there were few details of the sources of the direct costs and resource use and no information on the indirect costs. The authors justified the omission of some categories of costs, which should not have affected the conclusions of the analysis. A breakdown of the cost items was not given, and some costs were presented only as macro-categories. Thus, it would not be possible to replicate the analysis in other settings. Statistical analyses of the costs were not carried out but some key cost estimates were varied in the sensitivity analysis. The price year was reported, which will simplify reflation exercises in other time periods.
The authors did not compare their findings with those from other studies. They also did not explicitly address the issue of the generalisability of the study results to other settings. However, the extensive use of sensitivity analysis enhanced the external validity of the study and the results were generally robust to variations in the parameters investigated. The use of multivariate sensitivity analyses would have been more appropriate as a means of handling the issue of uncertainty in key clinical and economic model parameters.
Implications of the study
The study results support the use of HPV testing for the management of women after treatment for CIN2/3. The authors stated that the current findings should be confirmed in a prospective clinical trial.
Coupe V M, Berkhof J, Verheijen R H, Meijer C J. Cost-effectiveness of human papillomavirus testing after treatment for cervical intraepithelial neoplasia. BJOG. An International Journal of Obstetrics and Gynaecology 2007; 114(4): 416-424
Other publications of related interest
Because readers are likely to encounter and assess individual publications, NHS EED abstracts reflect the original publication as it is written, as a stand-alone paper. Where NHS EED abstractors are able to identify positively that a publication is significantly linked to or informed by other publications, these will be referenced in the text of the abstract and their bibliographic details recorded here for information.
Nobbenhuis MA,Meijer CJ, van den Brule AJ, et al. Addition of high-risk HPV testing improves the current guidelines on follow-up after treatment for cervical intraepithelial neoplasia. Br J Cancer 2001;84:796-801.
Wright TC Jr, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004;103:304-9.
Paraskevaidis E, Arbyn M, Sotiriadis A, et al. The role of HPV DNA testing in the follow-up period after treatment for CIN: a systematic review of the literature. Cancer Treat Rev 2004;30:205-11.
Subject indexing assigned by NLM
Cervical Intraepithelial Neoplasia /economics /virology; Colposcopy /economics; Cost-Benefit Analysis; Female; Humans; Markov Chains; Models, Biological; Netherlands; Papillomavirus Infections /economics; Risk Factors; Uterine Cervical Neoplasms /economics /virology
Date bibliographic record published
Date abstract record published