FormalPara Key Points

The economic burden and hospitalization rates associated with HPV-related diseases were estimated from a regional perspective in Italy.

Between 2008 and 2011 resources allocated and hospitalization rates highlighted a decreasing trend in both the Veneto and the Marche regions.

Over 72 % of hospital admissions were strictly linked to HPV and caused a mean annual burden of €3.89 million in Veneto and €1.60 million in Marche.

1 Introduction

HPV (human papillomavirus) is the virus most often responsible for sexually transmitted infection. To date, more than 100 types of papillomavirus infecting human beings have been identified. Of these, about 40% are associated with a wide range of genital diseases [1]. It has been estimated that about 75% of sexually-active women are infected with any type of HPV virus during their lifetime [2]. Most infections are transient and asymptomatic; however, in some cases, HPV involves a high-oncogenic risk associated with the onset of cancers. When this happens, the infection can progress to pre-cancerous and cancerous lesions. In particular, genotypes 16 and 18 are highly risky virus variances, causing 70% of invasive cervical cancer and dysplasia globally [3, 4]. Overall, the HPV virus is responsible for 88% of anal cancers in both sexes, 70% of vaginal cancers, 43% of vulvar cancers and 50% of penis cancers [5].

Many studies have been conducted in Italy on the prevalence and incidence of HPV infections [6,7,8]. However, these studies often reported heterogeneous data due to the different populations analysed. Therefore, to date there have been no epidemiological studies taking into account a representative sample of the whole Italian population. A systematic revision of the literature attempted to systematize the available epidemiological and economic information in the specific national context, estimating an annual direct cost associated with the main HPV-related diseases higher than €528.6 million (range €480.1–€686.2 million) [4]. A study conducted in Veneto examining the hospitalization rates of the different HPV-related diseases in a cohort of 5 million citizens showed that the burden of HPV-related diseases on hospital resources is a major public health problem [3].

The objective of this study was to estimate the overall and average economic impact per patient in two Italian regions, Veneto and Marche, between 2008 and 2011. For this purpose, hospitalizations associated with HPV-related diseases were analysed based on the administrative data of the two examined regions.

2 Methods

This was an observational retrospective study based on data extracted from the health information systems of the Veneto and Marche regions. Hospital discharge records (HDRs) referring to the period 2008–2011 were analysed in order to identify hospitalization rates and the costs associated with HPV-related diseases. Information related to the hospital discharges of all accredited public and private hospitals in Veneto and Marche, both for ordinary and day-care regimes, were taken into account.

Total costs related to hospitalizations were calculated using the diagnosis-related groups (DRGs) of hospitalized patients at the time of their discharge based on their age, gender and the consumption of resources during their hospital stay. According to the DRG-based reimbursement system, every hospitalized patient was assigned to a group of diagnostically homogeneous cases so that patients with the same DRG were assigned the same reimbursement charges. Specifically, we included hospitalizations related to resident patients in the Veneto or Marche region, aged ≥ 18 years and presenting with one of the following International Classification of Diseases, 9th revision–Clinical Modification (ICD-9-CM) codes as primary or secondary diagnosis: Genital warts: ‘Condyloma acuminatum’ (078.11); ‘Anal cancers’ (154.2–154.8); Oropharyngeal cancers: ‘Oropharyngeal cancer’ (146.0–146.9) and ‘Head, face and neck cancers’ (171.0); Genital cancers: ‘Penis cancer’ (187.1–187.9) and ‘Cervical cancer’ (180.0–180.9).

HPV-related hospitalization rates for the overall population were calculated comparing the number of hospitalized patients, broken down by type and age, to the corresponding resident population at the beginning of the discharge year [9].

In addition, a further estimation of the hospitalization rates and costs strictly linked to the presence of the HPV virus was calculated by applying diagnosis-specific weights obtained from the literature (Table 1). Specifically, it was assumed that 100% of the hospitalizations due to ‘Condyloma acuminatum’ (Genital warts) [10, 11] and ‘Cervical cancers’ were strictly associated with HPV [1, 12] compared to 50% of hospitalizations due to ‘Penis cancer’ [5], 77% to ‘Anal cancer’ [5], and 26% to ‘Oropharyngeal cancer’ [13]. The diagnosis-specific weights were applied to the hospitalizations per single diagnosis and this allowed our analysis to obtain a more specific estimation of the economic burden strictly related to HPV virus.

Table 1 Weights used for HPV strictly related disease calculation
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The data analysis was generated using SAS software, Version 9.2 of the SAS System for Windows, Copyright © 2002–2008 SAS Institute Inc. (SAS Institute, 2008). Personal data were replaced with a random series of codes, in order to anonymise the database in compliance with the Italian privacy laws.

3 Results

A total of 10,586 hospitalizations were recorded between 2008 and 2011 in the Veneto and Marche regions, 8044 (76%) and 2542 (24%), respectively. Overall, 45.7% were for male patients, while 54.3 % were for females. In Table 2, hospitalizations are reported by age, sex and diagnosis for each region separately.

Table 2 HPV-related hospitalizations in Veneto and Marche (2008–2011)
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Between 1 January 2008 and 31 December 2011, 7034 patients were hospitalized with potential HPV-related diseases: 5299 in Veneto (75.3%) and 1735 in Marche (24.7%). Each year about 1325 patients were hospitalized in Veneto and 434 in Marche. The most frequent diseases were genital warts in Veneto (2275 patients) and genital cancer in Marche (728 patients).

On average, from 2008 to 2011, 1.68 hospitalizations per patient were estimated in Marche and 1.47 in Veneto. The majority of hospitalizations in Marche were due to genital cancer (1.69 mean hospitalizations per patient), while in Veneto they were due to oropharyngeal cancer, with a mean of 1.96 hospitalizations per patient.

3.1 Hospitalization Rates

Hospitalization rates on the overall population were obtained reporting the number of hospitalized patients on the resident population in each region. The average hospitalization rate per year over the period 2008–2011 was 49.4 per 100,000 individuals in Veneto, and 48.4 per 100,000 individuals in Marche. Overall, a decreasing trend was estimated: in Veneto there were 57.2 hospitalizations per 100,000 individuals in 2008, versus 39.7 in 2011 and a similar trend was reported in Marche that passed from a rate of 52.5 hospitalizations in 2008 to 44.9 per 100,000 individuals in 2011 (Table 3).

Table 3 Hospitalization rates per 100,000 individuals (Marche, Veneto)
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3.2 Costs

Between 2008 and 2011, each treated patient resulted in an average annual expense, in terms of hospitalizations related to cancer, of €6063 in Veneto and €6237 in Marche. With regard to genital warts, the mean cost per patient in Veneto was €2107 and in Marche €1672. In Table 4 we report the cost per patient by disease and year of analysis.

Table 4 Hospitalization costs per patient, year (Veneto and Marche 2008–2011)
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In Table 5 costs are illustrated by gender, for which an independent-samples t test was conducted to compare the mean values. A significant difference in the scores was obtained for genital cancer in both the Veneto (p = 0.009) and the Marche regions (p = 0.004). In particular, in Veneto, genital warts evidenced an average cost per patient equal to €4855 per male compared to €6870 per female. In Marche the same costs were equal to €4459 per male and €6202 per female.

Table 5 Hospitalization costs per patient, gender (Veneto and Marche)
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In conclusion, the total estimate of the annual economic impact on the regional health services was calculated. As a result, hospitalizations accounted, on average, for €5.78 million (SD 0.8) in Veneto and €2.24 million in Marche (SD 0.17), as reported in Table 6.

Table 6 Total annual expenses due to HPV-related diseases, Veneto and Marche populations (2008–2011)
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In the Veneto region, the disease with the highest economic burden in terms of hospitalizations was oropharyngeal cancer: €2.08 million, corresponding to 36% of the total mean annual cost. In the Marche region the highest expense resulted from genital cancers, 47% of the total cost with an expense of over €1.06 million a year (Fig. 1), versus €1.61 million in Veneto, about 28% of the total average expenses. Furthermore, in Marche the cost of oropharyngeal cancer was estimated at €632 thousand, about 28% of the regional burden of HPV-related diseases. Anal cancer had a limited impact in Veneto, €882 thousand, corresponding to 15% of the costs incurred by the regional health service. Finally, genital warts accounted for 8% of the expenses in Marche and 21% in Veneto.

Fig. 1
figure 1

Percentage of expenses by disease of the mean total (Veneto and Marche 2008–2011)

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Overall, between 2008 and 2011 resources allocated to hospitalizations highlighted a decreasing trend in both regions (Fig. 2). On average the study estimated a reduction of 22% between the first and the last year of analysis (−28.67% in Veneto and −16.06% in Marche). The decrease was higher in Veneto, especially between 2010 and 2011.

Fig. 2
figure 2

Total mean cost (Veneto and Marche 2008–2011)

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3.3 Costs Strictly Related to the HPV Virus

On average, 72% of hospitalizations were strictly related to the presence of HPV virus. As a consequence, the average economic impact of HPV strictly-related diseases per year was equal to €3.89 million in Veneto and €1.60 million in Marche (annual mean values). The disease causing higher costs in terms of hospitalizations both in Veneto and in Marche was genital cancer: €1.47 million in Veneto (37.8% of total costs) and €982,899 in Marche (61.0%). Moreover, genital warts in Veneto resulted in an expense of €1.19 million, 30.8% of the total cost, while anal cancer in Marche cost €290,843, 18.0% of the mean total per year. In Table 7 the average costs per year are reported by gender and ranges, taking into account weights from the literature.

Table 7 Total mean cost per gender and disease (Veneto and Marche)
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Considering the weightings, hospitalization rates on the resident population that were strictly related to HPV amounted to 34.88 per 100,000 individuals in Veneto and 37.74 in Marche. Both in Veneto and in Marche these rates were higher for women, 43.01 and 52.31 per 100,000 individuals respectively, compared to 26.22 of males in Veneto and 21.98 in Marche.

4 Discussion

This study represents a first attempt to quantify the hospitalization rates of HPV-related diseases [3], as well as a measure of the economic burden of these hospitalizations from the Italian National Health Service perspective. At the time of the analysis, the population over 18 years old accounted for over €5.3 million, €4 million in Veneto and €1.3 in Marche, which was almost 9% of the total Italian population [9]. Hence, the strength of the study lies in the size of the population analysed, especially if we consider that the data are representative of all hospitals in the Veneto and Marche territories. Thus, this work represents progression from the previous study conducted only in Veneto [3].

Overall, the hospitalization rates of the two regions were comparable: 49.44 hospitalizations in Veneto and 48.41 in Marche per 100,000 individuals. In agreement with the incidence rates reported in literature [4, 15], the highest hospitalization rate in Veneto was due to genital warts (16.22 per 100,000 individuals), while in Marche genital cancers caused 23.42 hospitalized patients per 100,000 individuals. Overall, in both regions, the hospitalization rates showed a decreasing trend between 2008 and 2011 that were in agreement with the annual report on hospital discharge performances by the Italian Ministry of Health [16], and we expect this to continue in the years to come. Moreover, as a result of the new vaccination strategy adopted in Italy (both boys and girls aged 12 years) [17] and the introduction of the nine-valent HPV vaccination, health gains due to primary prevention are expected to allow for further decreases [18].

In both regions, the decrease was steady during the period of analysis, although higher in Veneto: −43.88% from 2008 to 2011, compared to −16.56% in Marche. The only disease with an opposite trend was anal cancer, which showed a slight increase of the hospitalization rates in the Marche region (6.92 in 2011 compared to 6.43 in 2008 per 100,000 individuals). In Veneto, the same disease showed a greater decrease, going from 9.37 in 2008 to 4.95 hospitalizations per 100,000 individuals in the last year considered. In 2008 there was a higher number of secondary diagnoses compared to other years. This was due to hospitalizations related to the administration of chemotherapy that from 2007 began to be replaced by day-hospital chemotherapy treatments (Resolution of the regional Committee no. 734 of 20 March 2007: Chemotherapy and radiotherapy health services, Official Bulletin of the Veneto Region 2007. 37:106–109). The 2008 data were also due to an increase in the number of cases, as already highlighted in the previous study on Veneto [3]. In both regions the mean cost by disease was higher for malignant tumours (anus cancer, genital and oropharyngeal cancers) compared to genital warts. However, non-cancerous diseases like genital warts caused a considerable economic burden, especially in Veneto, where it was cost more than €1.19 million, 21% of the mean annual total, compared to the corresponding burden in the Marche region (about €171 thousand, equal to 8%). A relevant contribution of the present study is also the estimation of costs strictly related to the HPV virus. Although the estimation was based on the literature [1, 5, 10,11,12,13] and not on administrative data, it was possible to estimate that over 72% of the admissions related to hospitalizations were strictly linked to HPV. These hospitalizations caused a mean annual burden of about €3.89 million in Veneto and €1.60 million in Marche. Therefore, 67% of the estimated costs for the diseases being analysed can be strictly associated with the HPV virus in Veneto, while they account for 71% in Marche.

The present analysis may have some limitations. First of all, the regional hospital discharge forms may have codification problems; therefore some information may be missing and/or be wrongly reported. In this case, our analysis may have missed this information (due to the inclusion criteria), with the risk of underestimating the economic and epidemiological burden of the considered HPV-related diseases. Additionally, not all diseases led to hospitalization and this may be a further source of underestimation. Therefore, the hospitalizations are underestimates of the generic prevalence referring to the population, and it may be assumed that the missing information does not significantly invalidate the results. Furthermore, due to a lack of available data, direct costs attributable to GPs and additional treatments were not included, nor were costs related to Recurrent Respiratory Papillomatosis (RRP) disease that, although rare, could be relevant to the overall estimation of the hospitalization costs of HPV-induced malignancies. Lastly, it may be deemed that the reference time span (2008–2011) is too short, especially if compared to the previous study based only on Veneto [3], or the national burden estimates based on the literature. Being limited to two regions, the analysis may not be very significant. However, these regions accounted for almost 9% of the total number of patients in Italy and, for management and epidemiological characteristics, Marche and Veneto are two of the best-performing regions in terms of health service management. They may represent good examples to study the economic impact of HPV-related diseases in Italy.

5 Conclusions

This study represents a useful tool to quantify the economic burden of HPV-related diseases in terms of hospitalizations. The expenses observed in the two regions represent a significant cost and management driver, also in view of the decisions in terms of HPV prevention policies nationally.