Abstract
Objective: Human papillomavirus (HPV) infections can lead to cervical intraepithelial neoplasia (CIN) lesions, cervical cancer (CC) and genital warts (GWs). This study intended to assess the annual cost of CC, CIN and GW management in Belgium.
Method: A retrospective study using a Belgian Hospital Disease Database (for yearly hospital cost of CC and GW patients) and a clinical expert survey were performed to assess the medical management of CC, CIN and GW patients. Belgian official sources were used to estimate the annual costs of management of CC, CIN and GW patients both from a healthcare payer perspectives (HCPP) and a societal perspective.
Results: Based on the 667 patients diagnosed annually in Belgium with CC and an annual cost per patient of €9,716, the total annual cost of CC is €6.5 million (HCPP). The 10,495 estimated CIN 1, 2 and 3 patients led to an annual cost of €1.97 million (HCPP). The 7,989 estimated annual number of diagnosed GW patients led to an estimated annual cost of €2.53 million (HCPP).
Conclusion: HPV-related diseases represent an important burden on Belgian society, especially when considering that the estimates in this study are probably underestimations, as the management costs of other HPV-related diseases (vulvar, vaginal, penile, oropharyngeal (pre-) cancers, recurrent respiratory papillomatosis etc.) are not included in this analysis.
Introduction
Throughout the 27 member states of the European Union, 34,300 women are diagnosed with cervical cancer (CC) annually, resulting in approximately 16,300 deathsCitation1, and another 688,000 patients* are diagnosed with genital warts (GWs)Citation2. In Belgium, 667 new cases of invasive CC are diagnosed each year, and one-third of these cases will lead to deathCitation3,Citation4. Infections with oncogenic human papilloma virus (HPV) are a necessary cause of CC, and certain non-oncogenic HPV cause GWsCitation5,Citation6. HPV is widespread and affects at least 70% of sexually active adults (male and female) during their lifetimeCitation7.
Given the natural history of oncogenic HPV infection (which usually evolves from low-grade to high-grade lesions and then to cancer), it is possible to prevent cases of CC by detecting pre-cancerous lesions, also called cervical intraepithelial neoplasia (CIN), and treating them effectively. Thanks to the implementation of screening programmes, the incidence of CC in Europe has been declining over the past 30 years, leading to a decrease (ranging between 30 and 80%) in associated mortalityCitation8,Citation9. In Belgium, screening is essentially opportunistic and often performed at yearly intervals. A scheme promoting the recommended one cervical smear every 3 years for women aged 25–64 years was set up in the Flemish Region aloneCitation10. However, according to Arbyn and Van OyenCitation11, coverage of the Belgian female population is similar in all regions (i.e. 57% in Flanders, 61% in the Walloon Region and 58% in the Capital Region (Brussels)).
The incidence of GWs, which are clinically visible manifestations of certain non-oncogenic HPV types, most commonly with HPV types 6 and 11Citation5, is currently increasing throughout EuropeCitation12 and it is estimated that 1% of the sexually active population in the US has clinically apparent GWsCitation13. A recent published study on GW burden in four Nordic countries reported that 10% of women experience GWs before the age of 45, with an increasing occurrence in younger cohortsCitation14. Current treatments for GWs are long and painful, and frequent relapses may occurCitation15,Citation16.
CC screening and treatment of HPV-related diseases represent a high burden on public health and the healthcare budget. For example, screening activities and treatment of HPV-related diseases (including cervical dysplasia, CC and GWs) in the UK represent a cost of £208 million per year from the National Health Service (NHS) perspectiveCitation17, and an average €276 million per year from the healthcare payer perspective in FranceCitation18–20.
The prophylactic quadrivalent HPV vaccine (Gardasil®†) was licensed in Europe in September 2006. It is currently indicated for the prevention of CC, high-grade cervical dysplasia, high-grade vulvar dysplasia and external GWs caused by HPV types 6, 11, 16 and 18. To estimate the potential benefits of a HPV vaccination programme, health authorities are interested in the economic burden associated with HPV-related diseases.
The cost of HPV screening in Belgium has already been calculated and reported by the Belgian Knowledge Centre for Healthcare (KCE)Citation3. According to this report, screening activities in Belgium for the year 2005 represented a cost of €65 million. This cost includes consultations (with a gynaecologist in 90% of cases) and tests performed (including specimen handling and result analysis): ‘Pap’ smear tests (1.3 million), biopsies (19,507) and colposcopies (402,218).
The present study aimed to estimate the economic burden of HPV-related diseases in Belgium, focusing on CC, cervical dysplasia and GWs, both from the healthcare payers and the societal perspective.
*Figure obtained by extrapolation of the UK genital wart incidence to the population of the 27 states of the European Union (Eurostat 2007).
†Gardasil® is a registered trademark of Merck & Co., Inc.
Methods
Study sources
Two main sources were used to collect the data required for this study retrospectively.
The Intercontinental Marketing Services (IMS) Hospital Disease Database was used to provide information on resource use and costs associated with patients hospitalised for the treatment of CC and GWs, and a panel of experts was set up to collect data regarding outpatient medical care for cervical dysplasia and GWs.
The hospital database contained data from the Minimum Basic Data Set (MBDS, also known as MKG/RCM: ‘Minimale Klinische Gegevens’/‘Résumé Clinique Minimal’) to which Belgian hospitals have contributed for each admitted patient since 1991. In the publicly funded Belgian healthcare system, MBDS reporting is a legal obligation for fulfilment of the reimbursement criteria established by the Belgian social security administration (the National Institute of Sickness and Disability Insurance (INAMI/RIZIV)) and to ensure adequate hospital funding by the federal public health authorities. Each patient carries a unique identification code throughout a given calendar year, which allows anonymous longitudinal case analysis over a well-defined and time-limited follow-up period, as patients cannot be traced beyond a 1-year period.
In this analysis, the 2004 full-year data (the most recent data available at the time of analysis) were used. In the database, case-mix data from 38 hospitals, representing approximately 11,908 beds (corresponding to 21.38% of the total number of hospital beds excluding psychiatric hospitals, 1-day admissions included, in Belgium in 2004) and 1,035,000 hospitalisations, were collected. The panel is representative with regards to type and size of hospital captured (‘General <250 beds’ 24.7% captured, ‘General 250–500 beds’ 36.6%, ‘General >500 beds’ 33.3% and ‘University hospitals’ 22% captured) and geographic distribution (65% Northern Belgium, 35% Southern Belgium). The MBDS includes in-hospital and day clinic admissions and contains the following inpatient data for each individual: demographic information; all conditions diagnosed and all inpatient procedures performed (both reported using 9th Revision of the International Classification of Diseases, Clinical Modification (ICD-9-CM) codesCitation21; and the All-Patients Refined–Diagnosis-Related Group)Citation22. Mortality indices and the severity of the condition prompting hospitalisation are also recorded, together with the length of stay, drug use, diagnostic tests and procedures performed.
Simultaneously, a total of nine clinical experts (six from the Flemish Region and three from the Brussels and Walloon Regions) participated in a survey to collect information on the physicians’ day-to-day management of HPV-related diseases (CIN and GWs). The expert survey was performed using a written questionnaire. Based on his/her clinical knowledge and expertise, each member of the expert panel was asked to provide their best estimate for the year 2006 for various figures requested related to treatment pathways following screening results, procedures and interventions.
Study analysis
CC management
Data on CC treatment were collected through the IMS Hospital Disease Database. CC patients were primarily selected on the basis of the ICD-9-CM code 180.xx (‘malignant neoplasm of cervix uteri’) as the primary diagnosis. Further classification into International Federation of Gynecology and Obstetrics (FIGO) stages was performed on the basis of additional ICD-9-CM co-diagnoses, indicating spread and metastases (stage I patients only had the 180.xx ICD-9-CM code, whereas stages II–IV had additional diagnostic codes to identify spread). lists the codes that were used to classify the patients. It was impossible to distinguish between stages II and III using the ICD-9-CM codes alone, so these two stages were pooled for the purpose of the analysis. For all selected patients, the total pharmaceutical resource use and cost, together with procedures and surgery performed, length of stay (hotel cost) and other required variables such as in-hospital mortality, were extracted from the database.
Table 1. ICD-9-CM codes for FIGO stage classification of cervical cancer patients.
CIN management
The clinical expert survey investigated the proportion of patients treated according to their degree of dysplasia, treatment procedures performed during a 1-year follow-up period, the proportion of patients who took time off work during their treatment and the mean number of workdays lost by CIN grade (CIN 1, 2 and 3). It also provided the distribution of procedures performed at hospital or ambulatory level.
GW management
Another part of the expert investigation was dedicated to analysis of the treatment pathway (number of visits, tests performed, treatment procedures etc.) for external GWs and for each line of treatment (first- to third-line). In addition, the proportion of hospitalised patients, not provided by the expert survey, was estimated from the IMS Hospital Disease Database, identifying GW patients with ICD-9-CM code 078.11 ‘condyloma acuminatum’ as the primary diagnosis. Combining both types of information, a global treatment pathway, including hospital and ambulatory treatments, was assessed.
Cost evaluation
For all the analyses, two perspectives were considered, the public healthcare payer perspective (HCPP), including direct medical costs (i.e. hospital, procedures and physician visit costs) reimbursed by the healthcare payer, and the societal perspective (SP), including all direct medical patient costs and productivity-related costs. Costs were calculated for the year 2006.
CC management cost
For patients with CC, a total annual hospital cost was calculated by summing all costs incurred for all hospital admissions within the calendar year. The hospital costs considered here were only calculated from the HCPP (the INAMI/RIZIV in Belgium) since real patient co-payment can only be calculated directly from the hospital invoice. Costs (mean and 95% confidence interval (CI)) are specified for the total population, per FIGO stage and for fatal disease. Calculation of the 95% CIs was based on the student's T distribution in order to accommodate for the sometimes low sample sizes (N<30). For fatal disease, all patients dying within the year of observation were considered, and their hospitalisation costs for the last 3 months before death were defined as the cost of fatal disease (i.e. the hospital costs for the last 3 months alive).
Ambulatory costs were not considered, but productivity loss has been estimated using the methodology published by the French National Cancer InstituteCitation23. Productivity loss was calculated on the basis of the national average monthly wage including social benefits (2004 data from the Belgian National Statistics Institute)Citation24. Figures were updated to 2006 and a cost per workday (assuming 20 days per month) was calculated (€132.69)Citation24 and used to value lost workdays. Considering a mean number of workdays lost of 120 days per CC case (based on French published dataCitation23 as no Belgian data were available) and based on the Belgian activity rate in womenCitation25, the total number of workdays lost was estimated. Based on the unit cost by workday lost, total productivity-related costs were calculated.
CIN and GW management costs
Average ambulatory costs associated with the treatment pathway for CIN and GWs were calculated by multiplying the mean resource use estimates (provided by the expert survey) with the unit cost for the corresponding item of resource use. Unit costs (extracted from the INAMI/RIZIV websiteCitation26 and presented in ) are based on a health service nomenclature, which lists the services paid for by the healthcare system.
Table 2. Unit costs (in Euros (€)).
For CIN patients, the expert survey also provided data on the proportion of medical care given at hospital level. The hospital cost of conisation (ICD-9-CM procedure code 67.2 ‘conisation of cervix’) and hysterectomy (procedure codes 68.3–68.9 for partial or total abdominal, laparoscopic or vaginal hysterectomies) was investigated with the IMS Hospital Disease Database (). Then, for the hospital-based procedures for which no IMS hospital data were available (laser, cryotherapy and cervix amputation), a 1-day hospitalisation cost (€305.98) and a patient hospitalisation fee (€40.33) was added to the procedure cost, the latter only for the SP (). Productivity loss was calculated based on work days lost for CIN management reported in the expert survey.
With regard to GW patients, a mean cost of hospitalisation was calculated based on the hospital cost extracted from the IMS database. Therefore, the total cost of GW management encompassed both the ambulatory treatment cost and the hospitalisation fees. Productivity loss was not reported for GW patients.
Economic burden of disease
The annual economic burden was estimated by multiplying the total annual number of CC, CIN and GW patients with the respective mean cost of management. The number of CC and GW patients was retrieved from Belgian published sourcesCitation4,Citation27,Citation28. As no data are available on the epidemiology of CIN in Belgium, a literature review of available European sources was performed to assess the number of CIN patients diagnosed annually in Belgium.
A sensitivity analysis was performed on CC costs using two other Belgian sourcesCitation29 to assess the annual number of CC cases and by applying a 10% variation around the number of workdays lost.
Results
Cervical cancer management and associated costs
From the 2004 Hospital Disease Database, it was possible to extract a total of 175 CC patients, comprising 112, 22 and 41 FIGO stages I, II+III and IV patients, respectively. ‘Cost of fatal disease’ was calculated on the 37 patients (7, 6 and 24 patients in FIGO stages I, II+III and IV, respectively) who died in hospital during the course of the year. Overall, the average annual hospital cost of a CC patient was estimated to be €9,716 (95% CI €8,062–11,369), whereas the split per FIGO stage demonstrated that higher FIGO stages were associated with higher annual costs (€6,777, 95% CI €5,335–8,218; €8,495, 95% CI €5,467–11,524; and €18,400, 95% CI €13,480–23,320 for FIGO stages I, II+III and IV, respectively). Of the total cost, the hotel cost proved to be the largest part (49% of total cost), followed by procedures cost (32% of total). Pharmaceutical product cost was the lowest contributor to the total cost (18% of total). The mean ‘cost of fatal disease’ was relatively high (€16,960, 95% CI €12,942–20,978). It was lowest for FIGO stage I patients (€8,879, 95% CI €2,309–15,450) and highest in FIGO stage II+III (€23,430, 95% CI €6,677–40,184) and stage IV (€17,699, €12,934–22,465).
Considering the 667 annual new CC casesCitation4,Citation27 and the mean hospital cost of CC treatment, the annual population cost of CC treatment in Belgium has been estimated to be €6.5 million (95% CI €5.4 million–7.6 million) from the HCPP. Moreover, considering that 91% of active womenCitation23 diagnosed with CC would stop working for an average of 120 daysCitation23, the number of workdays lost has been estimated for each age class, resulting in a total productivity-related cost of €3.25 million ().
Table 3. Estimate of annual productivity-related costs of CC in the Belgian population.
When taking into account a lower (595)Citation29 and higher estimate (818, extrapolated from the IMS Hospital Disease Database) for number of CC cases and applying a ± 10% variation on the number of workdays lost, the annual cost of CC management was estimated to be between €5.8 million and €7.9 million from the HCPP and between €8.4 million and €12.3 million from the SP.
Cervical intraepithelial neoplasia management and associated costs
According to the expert survey, 19% of CIN 1 patients were given treatment, compared with an expected higher proportion of treated CIN 2 and CIN 3 patients (77% and 93%, respectively). Full results are presented in .
Table 4. Treatment pathway for CIN.
For CIN 1 patients, the two main procedures were conisation and laser therapy, each applied in approximately one-half of the treated patients. For CIN 2 and 3 patients, the most frequently prescribed treatment was conisation (80.3 and 93.7% of treated patients, respectively), mostly in an ambulatory care setting. Taking into account the proportion of hospital-based interventions and multiplying resource use with the mean cost per procedure () led to estimated costs per CIN stage as shown in .
Table 5. Mean annual cost of CIN treatment by categories.
The mean number of workdays lost was 1, 1.9 and 2.4 days for CIN 1, CIN 2 and CIN 3 patients, respectively. The mean cost of productivity loss was included into the overall mean annual treatment cost for each CIN stage (for SP only). The most costly treatment was associated with CIN 3 (SP €609.4), followed by CIN 2 (SP €481.5) and CIN 1 (SP €267.2) ().
Three different sources were used to assess the number of CIN patients in Belgium. Considering the 19,507 biopsies performed in BelgiumCitation3, a maximum of 19,507 CIN cases could be diagnosed annually in Belgium. An Italian publicationCitation31 mentioned that 53.8% of biopsies led to a CIN diagnosis. Applied to Belgium, this would lead to approximately 10,495 CIN patients. Using the CIN distribution in biopsies reported in a recent French studyCitation19, it was considered that 39% of CIN were CIN 1 and 61% were CIN 2/3, leading, respectively, to 4,093 CIN 1 and 6,402 CIN 2/3 patients annually in Belgium.
Considering the percentage of treated patients from the expert panel (19% of CIN 1 and 85% of CIN 2/3) and the mean cost estimates for CIN patients, the estimated total cost of CIN management in Belgium has been estimated at €173,353 (HCPP) and €212,591 (SP) for CIN 1 and €1.80 million (HCPP) and €2.95 million (SP) for CIN 2/3.
Genital wart management and associated costs
On average, GWs were far more likely to be subject to first-line treatment (approximately 94%) than second- (25%) and third-line treatment (12.5%), as detailed in . Patients with GWs were more likely to consult gynaecologists than General Practitioners or dermatologists. The Pap smear was the most frequent first-line examination, whereas biopsy was the preferred second- and third-line test. Pharmacological treatment was the most common first-line treatment, whereas cryotherapy and laser therapy were the preferred second- and third-line treatments, respectively.
Table 6. Medical resource use for genital warts (mean frequencies).
The mean ambulatory cost was estimated at €236.3 from a HCPP and €295.4 from a SP (detailed in ).
Table 7. Mean ambulatory cost (in Euros (€)) of genital wart treatment.
The overall incidence rate of GWs is estimated at 76 per 100,000 person-years for the Belgian population as a whole (both male and female)Citation28, corresponding to a total number of 7,989 GW cases (3,909 males and 4,079 females) annually in Belgium.
Hospitalisations for GWs were reported in the IMS Hospital Disease Database in 77 male patients and 95 female patients. A mean cost per hospitalised GW patient was estimated at €1,083 for men and €996 for women. Since the database covered 21.38% of the total (11,908 beds captured out of 55,693 total hospital beds in Belgium), an extrapolation factor has been applied to obtain estimates for Belgium. Based on the 172 hospitalisations reported for GWs, an estimated number of 804 patients (360 males and 444 females) are hospitalised each year in Belgium due to GWs. The hospitalisation rate is therefore 9.2% for male GW patients and 10.9% for female GW patients.
A total mean cost of GW management was then estimated at €371.7 (SP) for female patients and €367.9 (SP) for male patients ().
Considering the 7,989 GW cases in Belgium, the total treatment cost of GWs represented €2.53 million (HCPP) and €2.95 million (SP).
Overall, the annual economic burden of CC, cervical dysplasia and GW management in Belgium was therefore estimated at €10.98 million and €15.85 million from the HCPP and SP, respectively ().
Table 8. Economic burden associated with management of CC,CIN and GWs in Belgium.
Conclusion and discussion
This study allowed an estimate of the annual cost of management of HPV-related diseases (i.e. CC, CIN and GW diseases) in addition to the €65 million spent for CC screening in BelgiumCitation3. Considering the 667Citation4 new patients diagnosed annually in Belgium, the total annual cost of CC was estimated at €9.7 million (SP). The estimated 10,495 CIN 1, 2 and 3 patients diagnosed each year led to an annual cost of €3.17 million (SP). Finally, the estimated annual number of GWs diagnosed was 7,989, leading to an annual cost of €2.95 million (SP).
Considering the scarce literature data currently available, this study provides significant insight into HPV-related diseases in Belgium. First, it provides relevant information on CC treatment and management of cervical dysplasia and GW patients. Second, a cost of disease management was calculated both from the HCPP and SP.
However, there are three limitations that need to be acknowledged regarding the present study.
The first limitation concerns the expert survey. The expert sample may not be representative of the country's overall physician population. The panel consisted of well-known practitioners in the HPV field in Belgium, therefore their practices may be different from those of other healthcare centres, leading to a bias. Moreover, the experts were not obliged to check their patient registries; they were only asked to formulate their responses on the basis of their clinical practices and experience. This factor could have introduced some bias (i.e. overestimate or underestimate) in their responses.
The second limitation is linked to hospitalisation associated with CIN and GW treatments. For certain procedures performed for CIN treatment (laser, cryotherapy and cervix amputation), only 1 day of hospitalisation was considered. This figure may be conservative and could lead to an underestimation of the real costs associated with hospital-based procedures. Furthermore, experts were not asked about hospitalisation and the length of stay for GW patients. To assess the hospital-based GW treatment costs, an estimation was made based on the number of hospitalised patients from the IMS database.
The third limitation concerns the estimation of productivity loss for patients with CC. A mean number of 120 workdays lost was considered for active women who stop working because of CC. This estimate was retrieved from a French published source and based on an international literature review. Although Belgian data would more accurately reflect the situation in Belgium, this information has yet to be published.
This study highlights the fact that the burden of HPV-related diseases, including CIN and GW management and CC treatment (€10.98 million from a HCPP for 10.5 million inhabitantsCitation32) in Belgium seems relatively low compared with other European countries. Indeed, in France HPV-related disease costs reached an amount of approximately €82.5 million (for approximately 60 million inhabitants) excluding treatment costs of male patients with GWsCitation18–20. In the UK, this cost was estimated at £79 million (for approximately 60 million inhabitants)Citation17. This difference may be explained by the potential underestimates of this study. First, in the base case only incident CC patients were considered for assessment of the annual CC burden although mean CC hospital costs were estimated among prevalent and incident cases, which are probably lower than treatment costs of incident cases only. Indeed, Wolstensholme and WhynesCitation33 reported that 80% of the costs were incurred during the first year following CC diagnosis. A sensitivity analysis was performed using the number of prevalent CC cases extrapolated from the hospital database, which led to an annual cost of CC treatment of €11.9 million annually (SP). With regards to CIN costs, a recent study published by the KCECitation34 in Belgium reported a mean cost per CIN 2+ patient of €368.50 (HCPP), thus higher than the author's estimates (€282.40 when considering the proportion of CIN 2/3 treated).
Finally, other HPV-related diseases, such as vulval and vaginal cancers, were not considered in this study. Further analyses would be required to gain a complete picture of the burden of HPV-related diseases in Belgium.
These results are also of interest in light of results from recent clinical trials in young women with a quadrivalent HPV vaccine (HPV types 6, 11, 16 and 18), which showed up to 100% efficacy in preventing disease due to the targeted HPV-types in non-infected femalesCitation35,Citation36. Modelling studies have assessed the potential clinical benefits of the implementation of a quadrivalent HPV 6/11/16/18 vaccine alongside screening practices. In France, compared with screening only, vaccinating 80% of a cohort of 14-year-old girls with the quadrivalent HPV vaccine would reduce the lifetime risk by 65% for CC, 47% for CIN 2/3, 21% for CIN 1 and 66% for GWsCitation37. In the US, compared with current practice, vaccinating 70% of girls before the age of 12 years would reduce the incidence of GWs by 83% and CC by 78% due to HPV 6/11/16/18Citation38. In Belgium, a recently published study reported that vaccination of 84% of 12-year-old girls with a HPV vaccine targeting HPV types 16/18 only could achieve a reduction of 49.3% of CC casesCitation34. One can therefore expect a significant decrease in the burden associated with the management of CC, cervical dysplasia and GWs in Belgium with the implementation of a HPV vaccination programme alongside the current CC screening programme.
Acknowledgements
Declaration of interest: This research was supported by an unrestricted research grant from Sanofi Pasteur MSD.
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