ABSTRACT
The study aimed to examine the economic and epidemiological burden of human papillomavirus (HPV) on both men and women in the Czech Republic. It extended beyond the typically studied cervical cancer to encompass a rising incidence of non-cervical HPV-related cancers. The utilization of administrative healthcare claims data enabled the identification of HPV-related diseases using ICD-10 codes. For each identified disease, the proportion corresponding to disease cases directly attributable to HPV was analyzed in terms of the associated healthcare costs. Furthermore, the years of life lost (YLL) and indirect costs associated with premature mortality were calculated using gender-specific life expectancies and average salaries, employing the human capital approach. The findings indicate that there were over 100,000 incident cases of HPV-related diseases between 2018 and 2020, with the majority of these occurring in females (84.2%), and the average age of the patient was 40.6 y. The total medical costs incurred by HPV-related diseases exceeded 1 billion CZK (€41.1 million) over the study period (2018–2020), with an estimated 27,436 y lost due to premature mortality. The indirect costs, attributable exclusively to productivity losses from premature mortality, amounted to over 3.29 billion CZK (€127.7 million). These results highlight the substantial financial and health burdens HPV imposes on the Czech healthcare system, underscoring the necessity for informed policy-making and cost-effective HPV interventions, including enhanced vaccination and preventive programs.
KEYWORDS: Human papillomavirus, HPV-related diseases, burden of disease, claims data
Introduction
Human papillomavirus (HPV) is a group of more than 200 related viruses, some of which have been associated with the onset of diverse medical conditions. HPV is prevalent worldwide and linked to a broad spectrum of clinical conditions, ranging from benign lesions to invasive cancers. Although many HPV infections are asymptomatic and transient, persistent infections caused by high-risk genotypes, most notably HPV-16 and HPV-18, but also types such as HPV-31, −33, −45, −52, and −58 are known to cause a range of precancerous lesions and cancers.1,2 Low-risk HPV types, such as HPV-6 and HPV-11, are primarily associated with benign conditions like genital warts and recurrent respiratory papillomatosis. However, emerging evidence suggests that even low-risk types may contribute to carcinogenesis under certain conditions.3
HPV is most widely known for its role in the development of pre-malignant cervical lesions and cervical cancer, which remains one of the leading causes of cancer morbidity and mortality among women, particularly in low- and middle-income countries.2 However, the oncogenic potential of HPV is not limited to cervical cancer. There is an increasing body of evidence linking high-risk HPV genotypes with a wide range of cancers in both men and women, including cervical, anal, vulvar, vaginal, and penile cancers, as well as several head and neck cancers – most notably oropharyngeal cancers, but also cancers of the tonsil, base of the tongue, and hypopharynx.4 Of these, oropharyngeal cancer, which affects the base of the tongue and tonsils, is of particular concern given the rising incidence observed in numerous countries, particularly among men. Indeed, some studies indicate that oropharyngeal cancer, which is caused by HPV, may soon become the most prevalent HPV-related cancer in certain regions, exceeding the incidence of cervical cancer.5–8
The impact of HPV-related illnesses extends beyond the realm of cancer. For example, low-risk HPV types are responsible for a considerable number of cases of genital warts, a highly prevalent condition that, although non-life-threatening, can cause psychological distress and necessitates medical intervention. Moreover, although genital warts are typically regarded as benign, numerous studies have documented an elevated risk of developing more severe conditions, including cervical intraepithelial neoplasia grade 2 or higher, penile intraepithelial neoplasia, and anogenital cancers, in individuals with a history of genital warts.9 Recurrent respiratory papillomatosis, a rare condition mainly caused by HPV types 6 and 11, can also place a burden on healthcare systems due to the necessity of repeated surgical treatments to remove papillomas from the respiratory tract.10
The economic burden of HPV-associated diseases is considerable and encompasses both direct and indirect costs. In addition to the human toll, the financial impact of HPV-associated diseases places a significant strain on healthcare systems and economies, particularly in countries with limited resources.11–13 To date, two studies have been conducted in the Czech Republic that evaluate the economic burden of diseases associated with HPV infection.14,15 In both cases, the studies were modeling studies. To the best of our knowledge, no previous studies have employed real-world data to quantify the economic burden of all HPV-related diseases in the Czech Republic. The objective of this analysis was to address this gap in knowledge and enhance understanding of the economic burden associated with HPV-related disease in the Czech Republic. The availability of up-to-date, country-specific burden of disease data can significantly enhance the capacity of governments to make informed decisions that support the improvement of public awareness, health policies, health care budgets, or immunization or screening programs. The feasibility of strengthening these areas is greatly enhanced when comprehensive data are readily accessible.
Materials and methods
Study design
This was a retrospective, incidence-based study utilizing real-world data on the economic and epidemiological burden of HPV-related diseases in the Czech Republic between 2017 and 2021. The incident cases of the analyzed cancers and precancerous conditions from 2018 to 2020 were examined. Due to the inherent complexity of distinguishing in administrative data whether the treatment was initial or a continuation from the previous year, the year 2017 was used to identify patients who initiated treatment for a given diagnosis in 2018–2020. This was done on the basis that no care related to the diagnosis was recorded in the preceding year or years. The incident cases for 2021 were not processed, as only partial costs would have been analyzed for these cases. In contrast, cases from 2017 to 2021 were analyzed for episodic diagnoses, where treatment is short-term. The study employed administrative data, sourced from six (out of seven) health insurance companies, which collectively represent approximately 44% of the total insured population in the Czech Republic (approximately 4,642,000 individuals across all age groups). To extrapolate data for the entire population, the proportion of patients from the six analyzed insurers and the remaining one (split by sex) was employed. This was used to extrapolate data for each year to the entire population. In the case of men, the proportion of patients covered by the six aforementioned insurance companies was 43.1% in 2017, 43.1% in 2018, 43.3% in 2019, 43.6% in 2020 and 42.1% in 2021. In the case of women, the data indicate that six health insurance companies covered 45.1% of patients in 2017, 45.1% in 2018, 45.3% in 2019, 45.5% in 2020 and 44.8% in 2021. The study extracted anonymized administrative claims data for individuals diagnosed with conditions potentially associated with HPV, identified using predefined ICD-10 disease codes (Appendix 1). Because administrative data do not distinguish between HPV-positive and HPV-negative cases, individual-level HPV causality could not be established. Therefore, HPV attribution was performed at the population level by applying published HPV-attributable fractions (HPV-AFs) derived from the literature (Appendix 2).
For each diagnostic category, the total number of incident cases was multiplied by the corresponding HPV-AF specific to the disease site and population in order to estimate the proportion of cases statistically attributable to HPV. Due to the lack of comprehensive data for vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN) grade 1, PAFs were not used in these cases. For anal intraepithelial neoplasia (AIN), ICD-10 classification does not differentiate between grades 1 and 2; therefore, the value assigned to AIN grade 2 was also applied to grade 1. For oral intraepithelial neoplasia (OIN), a single value of 2.2% was applied in all cases due to similar limitations in data availability; this value was derived from published estimates of HPV prevalence in oral mucosal lesions.16
To evaluate the robustness of estimates of direct medical costs and the uncertainty associated with the applied population attributable fractions (PAFs), a deterministic sensitivity analysis was conducted in which PAF values were varied by ±20%. In cases where the upper bound of this range exceeded 100%, the PAF was capped at a maximum value of 100%.
Based on this approach, data on diagnosed diseases (including incidence, number of cases, and deaths) and associated costs were identified for subsequent analysis. An overview of data sources, inclusion criteria, and case identification is provided in Appendix 9 in the Supplementary Materials.
Costs
The analysis was conducted from a societal perspective, incorporating both direct medical costs reimbursed by the public healthcare system and indirect costs associated with productivity losses due to premature mortality.
The Czech health insurance system provides comprehensive coverage of healthcare services, including inpatient hospital care, outpatient specialist services, diagnostic imaging, and reimbursed pharmacotherapy, including high-cost oncology treatments. As a result, the analyzed claims data capture the full spectrum of direct medical costs associated with HPV-related disease management within the public healthcare system. Out-of-pocket expenditures in this context are negligible and therefore do not materially affect the estimated cost burden.
The direct medical costs incurred for incident cases pertaining to HPV-related conditions were identified within the database and categorized as outpatient, inpatient, medical device, and medication costs. Direct medical costs were derived from health insurance claims and reflect reimbursed healthcare expenditures. Outpatient costs include reimbursed specialist visits, diagnostic procedures, and ambulatory interventions provided in outpatient settings, while inpatient costs represent aggregated reimbursements for hospital admissions, including procedures, diagnostics, and inpatient care associated with the hospital stay. The claims database does not provide item-level cost breakdowns; therefore, all costs are reported as aggregated reimbursements by care setting and cost category.
The indirect costs and the number of years of life lost (YLL) associated with premature mortality were estimated using a population-level approach. Disease-specific deaths were identified in the administrative claims data based on cancer diagnoses associated with the terminal episode of care. Because individual-level attribution of death to HPV is not possible using claims data, HPV-attributable fractions derived from the literature were applied to diagnosis-specific mortality to estimate the proportion of premature deaths statistically attributable to HPV. YLL were calculated by summing the expected remaining life years for each individual, defined as the difference between the age at death and the remaining life expectancy for a given age and sex. Country- and gender-specific life expectancy values were obtained from the Czech Statistical Office (Appendix 3). Indirect costs were estimated using the human capital approach by summing the difference between the age at death and the statutory retirement age (gender-specific) (Appendix 4), multiplied by the median annual salary in the Czech Republic (Appendix 5). Median salary data were obtained from the Czech Statistical Office. Estimates reflect HPV-attributable premature mortality at the population level rather than individual-level causal attribution.
As the administrative data lacked the capacity to differentiate between prevalent and incident cases of HPV disease, the annual cost of HPV-related disease was therefore a composite figure comprising the first-year medical cost and the continuous year cost. The following formula was employed to calculate the total cost per patient per year for cancers: total cost per patient per year = (365.25 ×total cost in follow-up period) / follow-up period. This approach accounts for variable follow-up durations across patients but assumes uniform cost distribution over time. For conditions characterized by intensive initial treatment followed by lower-cost surveillance, annualized estimates may underestimate initial-phase costs and overestimate maintenance-phase costs.
A similar methodology was employed in the calculation of the cost per patient year for precancerous conditions. In lieu of the observed period, the value of the disease period was employed in the calculation.
A different methodology was employed to calculate the costs associated with anogenital warts and recurrent respiratory papillomatosis, given that these are episodic diseases. In order to ascertain the costs associated with each episode, the number of episodes occurring within the study period was identified. The total cost in the follow-up period was then divided by the number of episodes to determine the cost per episode.
For diagnoses where HPV-attributable fractions were applied, both direct medical costs and indirect costs were allocated proportionally at the population level. In the absence of individual-level information on HPV status and cost stratification, this approach assumes that the average cost intensity within each diagnostic category is distributed proportionally to the estimated HPV-attributable share. Differences in treatment intensity, disease course, or productivity losses between HPV-positive and HPV-negative cases at the individual level could not be assessed using administrative claims data.
For international comparability, cost estimates reported in the main manuscript were additionally converted from Czech koruna (CZK) to euros (€). Currency conversion was performed using average annual exchange rates for the respective calendar years, based on official historical exchange rate statistics: 1 CZK = 0.039 EUR (2018), 1 CZK = 0.03896 EUR (2019), and 1 CZK = 0.0378 EUR (2020). Supplementary materials report cost data in CZK only.
Statistical analysis
The data were managed and analyzed using the R statistical software package. The results were aggregated and stratified according to ICD-10 codes and gender (where applicable). Where appropriate, the data were described using summary statistics, including the mean and standard deviation. Inferential statistical analyses were not conducted in the present study; instead, the focus was on descriptive statistics to characterize the study population.
Results
Epidemiology
Over the course of the study period (2018–2020), 112,543 incident cases of HPV-related diseases were identified. The majority of cases were female (84.2%). The mean age was approximately 40 y, with males exhibiting a slightly younger age profile than females (39.0 and 39.9 y, respectively).
The mean age remained relatively consistent throughout the study period, with minimal fluctuations observed in individual years. Table 1 presents a summary of the number of patients analyzed in each year, with a breakdown by gender, accompanied by data on the age of the patients. The most frequent diagnoses in men were A63.0 (anogenital warts), K62.8 (anal IN I and II), J38.2 (nodules of vocal cords), C32 (Malignant neoplasm of larynx) and C09 (Malignant neoplasm of tonsil), which collectively represented 67.4% of all male incident cases. The most frequently occurring diagnoses in women were N87.0 (CIN I), N87.1 (CIN II), A63.0 (anogenital warts), D06 (CIN III) and J38.2 (nodules of the vocal cords). Collectively, these five diagnoses accounted for 45.6% of all incident cases in women.
Table 1.
Total (observed) number of incident cases analyzed in each year, with a breakdown by sex and age characteristics.
| Parameter | Total | 2018 | 2019 | 2020 |
|---|---|---|---|---|
| Gender | ||||
| Male (%) | 17,759 (15.8) | 6,870 (14.7) | 5,884 (16.4) | 5,005 (16.6) |
| Female (%) | 94,784 (84.2) | 39,725 (85.3) | 29,942 (83.6) | 25,118 (83.4) |
| Age | ||||
| Mean (sd) | 40.6 (14.8) | 40.6 (14.7) | 40.5 (14.9) | 40.8 (15.0) |
| Male: mean (sd) | 42.0 (16.3) | 40.5 (16.3) | 42.3 (17.4) | 43.8 (18.1) |
| Female: mean (sd) | 40.3 (14.3) | 40.6 (14.4) | 40.1 (14.2) | 40.1 (14.2) |
All incidence estimates reported in this study represent population-level HPV-attributable estimates derived using published HPV-attributable fractions rather than confirmed HPV status at the individual patient level.
Direct medical costs
Table 2 provides an overview of the costs incurred for the treatment of incident cases in each year, with a breakdown by gender. The total costs incurred during the study period amounted to more than CZK 1 billion. Outpatient costs constituted the largest item, accounting for 62.2% of the total, while hospitalization costs accounted for 33.5%. The expenditure on medical devices and medicinal products consumed outside medical facilities and on prescription, respectively, was relatively minimal. The total direct medical costs were approximately 2.4 times higher in women than in men (756.7 mil. CZK vs. 306.6 mil. CZK).
Table 2.
HPV-attributable direct medical costs by year and sex (CZK and €).
| Parameter | Total | 2018 | 2019 | 2020 |
|---|---|---|---|---|
| Costs | ||||
| Total costs [CZK] | 1,063,283,919 (€ 41,054,276) |
350,978,244 (€ 13,688,151) |
380,146,630 (€ 14,810,513) |
332,159,046 (€ 12,555,612) |
| Outpatient costs [CZK] | 660,972,297 (€ 24,774,725) (62.2%) |
227,594,500 (€ 8,876,186) |
241,909,725 (€ 9,424,803) |
191,468,072 (€ 7,237,493) |
| Inpatient costs [CZK] | 356,893,575 (€ 13,760,770) (33.5%) |
106,775,381 (€ 4,164,240) |
122,467,980 (€ 4,771,353) |
127,650,214 (€ 4,825,178) |
| Medical device costs [CZK] | 9,217,541 (€ 350,404) (0.9%) |
3,362,464 (€ 131,136) |
3,709,792 (€ 144,533) |
2,145,285 (€ 81,092) |
| Medicinal product costs [CZK] | 36,200,510 (€ 1,398,263) (3.4%) |
13,245,900 (€ 516,590) |
12,059,136 (€ 469,824) |
10,895,474 (€ 411,849) |
| Male | ||||
| Total costs [CZK] | 306,624,568 (€ 11,828,494) |
88,761,184 (€ 3,461,686) |
113,423,798 (€ 4,418,991) |
104,439,586 (€ 3,947,816) |
| Outpatient costs [CZK] | 183,047,785 (€ 7,063,953) |
54,443,130 (€ 2,123,282) |
68,461,238 (€ 2,667,250) |
60,143,417 (€ 2,273,421) |
| Inpatient costs [CZK] | 104,396,056 (€ 4,024,316) |
28,655,680 (€ 1,117,572) |
37,722,987 (€ 1,469,688) |
38,017,389 (€ 1,437,057) |
| Medical device costs [CZK] | 4,160,881 (€ 160,900) |
1,005,536 (€ 39,216) |
2,078,977 (€ 80,997) |
1,076,369 (€ 40,687) |
| Medicinal product costs [CZK] | 15,019,850 (€ 579,325) |
4,656,841 (€ 181,617) |
5,160,598 (€ 201,057) |
5,202,412 (€ 196,651) |
| Female | ||||
| Total costs [CZK] | 756,659,351 (€ 29,225,782) |
262,217,059 (€ 10,226,465) |
266,722,832 (€ 10,391,522) |
227,719,460 (€ 8,607,796) |
| Outpatient costs [CZK] | 477,924,512 (€ 18,474,528) |
173,151,370 (€ 6,752,903) |
173,448,487 (€ 6,757,533) |
131,324,655 (€ 4,964,072) |
| Inpatient costs [CZK] | 252,497,519 (€ 9,736,454) |
78,119,701 (€ 3,046,668) |
84,744,993 (€ 3,301,665) |
89,632,825 (€ 3,388,121) |
| Medical device costs [CZK] | 5,056,660 (€ 195,862) |
2,356,929 (€ 91,920) |
1,630,815 (€ 63,537) |
1,068,916 (€ 40,405) |
| Medicinal product costs [CZK] | 21,180,659 (€ 818,938) |
8,589,059 (€ 334,973) |
6,898,538 (€ 268,767) |
5,693,062 (€ 215,198) |
Costs in euros were calculated using average annual CZK – EUR exchange rates (2018: 0.039; 2019: 0.03896; 2020: 0.0378). Total € values represent the sum of year-specific converted amounts.
A year-on-year analysis of the costs revealed that the total expenditure in 2018 was CZK 350,978,244. This figure increased to CZK 380,146,630 in 2019, representing a growth of approximately 7.5% compared to the previous year. However, in 2020, a notable decline was observed in total costs, which decreased to CZK 332,159,046, representing a reduction of approximately 12.4% from the previous year. A similar pattern was observed in the case of outpatient costs, which in 2018 amounted to CZK 227,594,500, rising to CZK 241,909,725 in 2019, representing a 5.4% increase. However, outpatient costs exhibited the same notable decline in 2020, reaching CZK 191,468,072, representing a 20.5% reduction compared to the previous year. hospitalization costs exhibited a different trend. In 2018, the cost of hospitalization was CZK 106,775,381, rising to CZK 122,467,980 in 2019, representing a 14.1% increase. By 2020, these costs continued to rise, reaching CZK 127,650,214, representing a further 4.2% increase compared to 2019 (Table 2).
The results presented in Appendix 6 summarize the findings of a sensitivity analysis in which population attributable fractions (PAFs) were varied by ±20% to assess the uncertainty surrounding cost estimates. Total healthcare costs associated with the condition of interest were estimated to range between CZK 851.2 million and CZK 1,138.3 million over the study period 2018–2020. Annual costs showed moderate variability, with the lowest expenditures observed in 2020. Across all years, outpatient care constituted the largest cost component, accounting for approximately 62% of total costs, followed by inpatient care (approximately 33%). Costs related to medical devices and medicinal products represented a relatively small proportion of total expenditures. Sex-stratified analyses revealed that females accounted for the majority of total costs, with estimates ranging from CZK 605.3–783.5 million, compared with CZK 245.9–354.8 million in males.
The seven most costly diagnoses (out of all 32 analyzed diagnoses) were responsible for 75% of the total direct costs associated with the treatment of HPV-related diseases (Figure 1). In Appendix 7 and 8, the number of cases, the total cost and the cost per patient or cost per episode for each diagnosis evaluated is shown with a breakdown for the years evaluated.
Figure 1.
HPV-attributable direct medical costs (CZK) for the seven highest-cost diagnoses, study period 2018–2020. Values represent HPV-attributable estimates derived by applying published HPV-attributable fractions to total observed costs.
Indirect costs
Patients with HPV-attributable cancers incurred a loss of nearly CZK 3 billion in earnings between 2018 and 2020, while also experiencing a loss of 27,436 y of life. For males, the greatest indirect costs were associated with diagnoses of C21 (Malignant neoplasm of anus and anal canal). A diagnosis of C32 (Malignant neoplasm of larynx) was associated with the highest rate of premature mortality in males, with a cumulative total of 2,066 lost years of life over the analyzed period. In the female population, the highest indirect costs and the highest rate of premature mortality were associated with the C53 (Malignant neoplasm of cervix uteri) diagnosis, amounting to over CZK 1 billion and resulting in 9,387 lost years of life, respectively (Table 3).
Table 3.
HPV-attributable indirect costs and years of life lost (YLL) by diagnosis.
| Diagnosis | Lost salary [CZK] (median salary) |
YLL [years] |
||||
|---|---|---|---|---|---|---|
| Men | Women | Men | Women | |||
|
All cancers |
1,154,209,870 (€ 44,782,343) |
1,766,481,146 (€ 68,536,447) |
11,992 |
|
15,444 |
|
| C01 | MN of base of tongue | 105,952,965 (€ 4,111,775) |
33,321,694 (€ 1,292,878) |
1,001 | 375 | |
| C02 | MN of other and unspecified parts of tongue | 164,744,712 (€ 6,392,090) |
59,546,171 (€ 2,309,397) |
1,277 | 729 | |
| C03 | MN of gum | 25,780,339 (€ 1,000,276) |
6,015,645 (€ 233,407) |
259 | 178 | |
| C04 | MN of floor of mouth | 81,482,511 (€ 3,161,521) |
28,078,647 (€ 1,089,451) |
821 | 297 | |
| C05 | MN of palate | 16,079,757 (€ 623,894) |
25,553,755 (€ 991,490) |
289 | 171 | |
| C06 | MN of other and unspecified parts of mouth | 62,905,506 (€ 2,440,825) |
18,735,452 (€ 726,937) |
462 | 200 | |
| C09 | MN of tonsil | 126,436,723 (€ 4,905,743) |
23,538,371 (€ 913,295) |
1,436 | 277 | |
| C10 | MN of oropharynx | 94,138,624 (€ 3,651,775) |
15,887,975 (€ 616,454) |
996 | 285 | |
| C13 | MN of hypopharynx | 101,304,965 (€ 3,929,032) |
14,634,297 (€ 567,812) |
1,191 | 166 | |
| C21 | MN of anus and anal canal | 169,957,095 (€ 6,594,395) |
128,894,541 (€ 5,001,098) |
1,654 | 1,626 | |
| C32 | MN of larynx | 132,186,821 (€ 5,131,651) |
8,567,255 (€ 332,811) |
2,066 | 236 | |
| C51 | MN of vulva | – | 51,458,005 (€ 1,996,571) |
– | 853 | |
| C52 | MN of vagina | – | 43,471,299 (€ 1,687,887) |
– | 664 | |
| C53 | MN of cervix uteri | – | 1,308,778,039 (€ 50,783,587) |
– | 9,387 | |
| C60 | MN of penis | 73,239,852 (€ 2,841,706) |
– | 540 | – | |
Indirect costs in euros (€) were calculated using a weighted average CZK – EUR exchange rate for 2018–2020 (1 CZK = 0.0388 EUR). Values represent total productivity losses over the entire study period.
Discussion
This study presents a comprehensive assessment of the economic burden of HPV-related diseases in the Czech Republic using administrative data. By adopting a societal perspective, the analysis extends beyond direct healthcare expenditures to capture the broader economic impact of HPV-related diseases, including productivity losses due to premature mortality, thereby providing a more complete picture of the overall burden on society. Our findings highlight the significant direct and indirect costs associated with HPV-related diseases, emphasizing the need for more robust prevention and treatment strategies, particularly in view of the substantial burden these diseases place on healthcare systems and society.
During the study period (2018–2020), over 100,000 incident cases of HPV-related diseases were identified, with a significant proportion of these cases occurring in women (84.2%). This gender disparity is consistent with global trends, as women are disproportionately affected by HPV-related diseases, particularly cervical intraepithelial neoplasia (CIN) and cervical cancer.4 It is noteworthy that the mean age at diagnosis exhibited minimal variation between sexes, with a relatively low mean age observed in both women (40.3 y) and men (42.0 y). The observed younger mean age may be influenced by a number of factors. The earlier detection of precancerous lesions, frequently as a result of screening programs, contributes to a younger age profile in comparison to invasive cancers. Moreover, the inclusion of benign conditions such as genital warts and respiratory papillomatosis, which are more prevalent in younger individuals, likely contributes to a lower overall average age. While these conditions are generally considered nonmalignant, recurrent respiratory papillomatosis has been associated with rare cases of malignant transformation, particularly in patients with long-standing disease or multiple recurrences. These findings are consistent with the well-established understanding that HPV infections tend to peak in younger adults shortly after sexual debut, followed by a decline in prevalence with increasing age as individuals clear the virus.17,18
The most prevalent diagnoses among men and women align with the extensive range of HPV-related diseases, encompassing both benign conditions such as genital warts and more serious conditions such as cancer. It is noteworthy that anogenital warts (A63.0) and cervical intraepithelial neoplasia (N87.0, N87.1, D06) constituted the most frequent diagnoses, thereby underscoring the considerable healthcare resources that are required for the management of these conditions.
The incidence of head and neck cancers increased by 16% in men and 8.6% in women between 2018 and 2019. This growth continued in 2020, with a further 4.4% increase in incidence in the male population and 2% in the female population. Although the claims data do not include virological confirmation of HPV status, these trends are consistent with international evidence suggesting that the rising incidence of head and neck cancers – particularly oropharyngeal cancers – is increasingly driven by HPV infection.
The results concerning the direct medical costs of HPV-associated diseases from 2018 to 2020 demonstrate notable trends and differences across the years, as well as significant disparities between genders. Over the course of the study period, the total costs exceeded one billion CZK, with the largest share attributed to outpatient care (62.2%), followed by hospitalization costs (33.5%). A year-on-year analysis of the costs reveals a growth of approximately 7.5% in total expenditure from 2018 to 2019. However, in 2020, a notable decline was observed, with total costs decreasing by approximately 12.4% from the previous year. A comparable trend was evident in the outpatient costs, which exhibited an increase of 5.4% from 2018 to 2019. In 2020, there was a notable decline in outpatient costs, with a reduction of 20.5% compared to the previous year. It seems probable that this reduction is attributable to the considerable disruption to healthcare systems across the globe resulting from the impact of the global pandemic of Covid-19. This substantial reduction is consistent with the broader trend observed during the pandemic, whereby access to outpatient services was constrained due to the implementation of lockdowns, the introduction of healthcare restrictions, and a reluctance amongst patients to seek non-urgent care. This pattern is consistent with those reported for other health conditions across Europe during 2020, where population-level analyses documented substantial reductions in outpatient consultations, cancer screening programme participation, and new diagnosis rates, reflecting both healthcare system restrictions and patient reluctance to seek care.19,20 The observed divergence between trends in incidence and total costs reflects changes in the composition of HPV-related diagnoses over time rather than a simple one-to-one relationship between case numbers and expenditure. While the overall incidence of HPV-related conditions declined during the study period, several high-cost malignant diagnoses, particularly head and neck cancers and cervical cancer, increased in incidence and prevalence. In contrast, low-cost benign conditions such as genital warts showed a sustained decline. This compositional shift toward more resource-intensive diagnoses helps explain why total costs did not decrease proportionally with incidence. The COVID-19 pandemic likely contributed to reduced utilization of outpatient services and delayed diagnosis of less severe conditions; however, the continued growth of hospitalization costs and the increasing burden of high-cost cancers indicate that compositional effects played a major role in shaping expenditure trends. While benign conditions such as genital warts contribute substantially to overall incidence, the economic burden is predominantly driven by malignant HPV-related diseases, which are less frequent but substantially more resource-intensive. As anticipated, the findings revealed a notable disparity in direct costs between the two genders. The total direct medical costs were significantly higher for women than for men, with the former group incurring costs amounting to CZK 756.7 million and the latter to CZK 306.6 million. This discrepancy is likely attributable to the higher incidence of HPV-related conditions among women, mainly cervical cancer and its precursors, which necessitate regular screening, diagnosis, and treatment. Moreover, the elevated expense associated with the management of cervical cancer, encompassing screening programmes such as Pap smears and HPV DNA testing, also contributes to the overall healthcare burden. The decline in costs for women was particularly noteworthy in 2020. In contrast, the reduction in costs for men was less pronounced, and hospitalization costs in the male population remained relatively stable. This probably reflects the continued necessity for the treatment of serious HPV-associated conditions, such as head and neck cancers, which frequently necessitate more rigorous treatment modalities.
In the sensitivity analysis, we explored the impact of varying population attributable fractions (PAFs) by ±20% on estimates of direct medical costs. The observed cost patterns remained consistent across all cost categories, with outpatient care representing the primary driver of total expenditure in both sexes. Inpatient costs accounted for a comparatively larger share of total costs among males, a finding that persisted across the full range of tested PAF values. Importantly, cost estimates remained stable within the predefined uncertainty bounds over the study period, suggesting that the overall economic burden is relatively robust to plausible variation in HPV attribution assumptions. It should be noted, however, that the proportional cost allocation assumes equal cost intensity between HPV-positive and HPV-negative cases, which may not hold for all diagnoses. For oropharyngeal cancers specifically, HPV-positive tumors are associated with better prognosis and potentially lower treatment costs than HPV-negative cases, suggesting that HPV-attributable costs for these diagnoses may be somewhat overestimated.
In addition to direct medical costs, the indirect costs associated with premature mortality (productivity losses due to death before retirement age) were considerable, amounting to approximately CZK 3 billion. Men and women experienced a notable decline in earnings and productivity as a consequence of HPV-related cancers, with a total of 27,436 y of life lost (YLL). In the female population, cervical cancer (C53) had the greatest impact, with a total of over CZK 1 billion in lost wages and 9,387 y of life lost, even though cervical cancer is one of the most preventable cancers through vaccination and regular screening.
With respect to vaccination-related considerations, this study did not include adverse events associated with HPV, as its primary aim was to estimate the economic and epidemiological burden of HPV-related diseases rather than to evaluate vaccination safety. Adverse events following HPV vaccination are generally rare and predominantly mild, and their economic impact is expected to be negligible compared with the burden of HPV-related diseases. In addition, vaccine adverse events cannot be reliably identified or attributed using administrative claims data without detailed vaccination records; therefore, their exclusion is unlikely to materially affect the overall burden estimates.
The efficacy of targeted vaccination programs in reducing overall HPV transmission has been demonstrated in a multitude of studies, with the potential for the elimination of various HPV-associated diseases.21,22 In the Czech Republic, a gender-neutral HPV vaccination program has been implemented, resulting in one of the highest vaccination rates in the CEE region. As reported by the National Health Information System, 69.2% of 13-year-old girls and 42.5% of 13-year-old boys have received the vaccination in 2021.23 Nevertheless, there is still a gap in vaccination coverage among older adolescents and adults who did not receive the vaccine at the recommended age. The mean age at diagnosis in our study (40.6 y overall) indicates that the majority of patients belong to birth cohorts that were too old to have received the HPV vaccine through the national program introduced in 2012 for 13-year-old girls (extended to boys from 2018). The economic burden documented in this study therefore largely reflects pre-vaccination era epidemiology and is expected to diminish in younger vaccinated cohorts as they age. This finding reinforces the importance of catch-up vaccination programs and continued monitoring of HPV-related disease burden across age strata. It is anticipated that the unvaccinated cohort will exert a considerable influence on the economic burden that HPV-related conditions will impose on the healthcare system in the near future. The implementation of comprehensive HPV vaccination programs, including catch-up vaccination, when combined with effective screening and treatment strategies, has the potential to significantly reduce the burden of HPV-related illnesses in the Czech society.
Our findings are consistent with those of previous studies conducted in other European countries, which have demonstrated that the economic burden of HPV-related cancers is substantial and represents a significant global burden.12,24,25 However, by incorporating all HPV-related conditions, including genital warts and respiratory papillomatosis, which are frequently excluded from economic evaluations, we present a more comprehensive picture of the economic burden posed by HPV, not only in terms of cancer but also in the ongoing management of benign but costly diseases.
A limitation of this study is the reliance on HPV-attributable fractions derived from international literature, which may not fully reflect the epidemiological patterns of HPV-associated conditions in the Czech Republic. These fractions are based on data from diverse populations and healthcare systems that may differ with respect to HPV prevalence, screening practices, vaccination coverage, and population-specific risk factors. As a result, the true HPV-attributable burden in the Czech Republic may deviate from the estimates presented in this analysis.
In addition, this study relies on ICD-10 diagnostic codes derived from administrative claims data, which do not differentiate between HPV-positive and HPV-negative cases and may encompass heterogeneous clinical entities with diverse etiologies. This limitation is particularly relevant for benign lesions and head and neck diagnoses, where HPV attribution cannot be determined at the individual patient level. Consequently, HPV-attributable fractions were applied to estimate the burden at the population level rather than to establish case-level causality.
Although the analyzed data cover approximately 44% of the insured population and include multiple statutory health insurance funds, national estimates rely on extrapolation. While sex-specific extrapolation by calendar year was applied, residual differences in population structure or healthcare utilization across insurers cannot be fully excluded and may introduce some uncertainty into national burden estimates. Future analyses should also consider reporting diagnosis-specific age-standardized incidence rates using Czech Statistical Office population data to facilitate more rigorous epidemiological comparisons.
An additional limitation relates to the proportional allocation of both direct and indirect costs based on HPV-attributable fractions. HPV-positive and HPV-negative cases within the same diagnostic category may differ with respect to stage at diagnosis, treatment pathways, therapeutic response, recurrence patterns, and productivity losses. However, administrative claims data do not allow costs or outcomes to be stratified by HPV status. Consequently, cost estimates reflect population-level allocations rather than individual-level differences, which may affect the precision of diagnosis-specific estimates but does not undermine the overall assessment of HPV-attributable burden at the population level.
Furthermore, certain diagnostic categories included in the analysis, such as D10 (benign neoplasm of mouth and pharynx), D14 (benign neoplasm of the respiratory system), and J38.2 (nodules of vocal cords), lack specificity with respect to HPV-related pathology. These codes were included as proxies due to the absence of dedicated ICD-10 codes for conditions such as recurrent respiratory papillomatosis (RRP). As a result, individual-level attribution to HPV cannot be established for these diagnoses, and their use may contribute to residual misclassification. This limitation is particularly relevant in the context of RRP, where the use of D14 and related laryngeal codes as proxies for adult-onset disease is suboptimal and may lead to underestimation of the true incidence and economic burden of this condition. Similarly, the limited anatomical granularity of ICD-10 coding for head and neck cancers restricts precise identification of HPV-related subsites, which may further contribute to uncertainty in HPV attribution.
Several additional limitations should be noted. The one-year look-back period (2017) may not fully exclude prevalent or recurrent cases for conditions with long natural histories (e.g., CIN, VIN, RRP), potentially overestimating incidence and associated costs; for episodic diagnoses, recurrence identification is similarly limited. Direct non-medical costs (patient transportation, informal care, out-of-pocket expenditures) were not captured, likely underestimating the true societal burden, particularly for patients with malignant diagnoses requiring specialist center care. Finally, indirect costs reflect productivity losses from premature mortality only; morbidity-related absenteeism and reduced work capacity among surviving patients were not included, further underestimating the productivity burden.
Despite these limitations, the applied methodology is consistent with established burden-of-disease approaches and provides the first comprehensive real-world estimate of the economic and epidemiological burden of HPV-related conditions in the Czech Republic.
Conclusion
In conclusion, the economic burden of HPV-related diseases on the healthcare system and society in the Czech Republic is substantial, with significant direct and indirect costs. The burden of healthcare costs falls disproportionately on women due to the financial implications of cervical cancer and its precursors. Conversely, men are increasingly bearing the financial costs associated with HPV-related head and neck cancers. It is therefore clear that comprehensive vaccination and screening programs remain critical to the reduction of the incidence and economic burden of these diseases. The aforementioned findings thus underscore the continued importance of investment in public health initiatives aimed at the prevention of HPV-related morbidity and mortality.
Supplementary Material
Acknowledgments
Conception/design: A.T., V.K., J.A., J.Z., K.M., G.D., J.G.M; Investigation: V.K., K.M., G.D., J.G.M; Data analysis: V.K.; Project administration: A.T., J.G.M., I.Š.; Data interpretation: V.K., I.Š.; Manuscript writing: I.Š.; Manuscript review: V.K., A.T., M.R., J.A. Final approval of manuscript: All authors.
Biography
Ivana Šarkanová, Msc., Ph.D. is a scientific researcher at the Department of Biomedical Technology, Faculty of Biomedical Engineering, Czech Technical University in Prague, and Director of CEEOR company. She is a long-standing member of the CzechHTA research team. She holds a doctoral degree in biochemistry from the Faculty of Natural Sciences, Comenius University in Bratislava, combining a strong life-science foundation with applied research in health technology assessment (HTA), health economics, and outcomes research. Her work focuses on cost-effectiveness modelling, quality-of-life assessment, patient-reported outcomes, and real-world evidence studies, with a particular emphasis on rare diseases. She teaches HTA and health economic evaluation at CTU. She has extensive leadership experience managing multidisciplinary teams and coordinating complex health outcomes research projects across the Central and Eastern European region. She is the author of several publications in prestigious scientific journals and international conference proceedings.
Funding Statement
This work was financially supported by MSD Czech Republic.
Disclosure statement
J.A. and J.Z. are employees of MSD Czech Republic.
Data availability statement
Data is provided within the manuscript or supplementary information files.
Abbreviations
- AF
Attributable Fraction
- AIN
Anal Intraepithelial Neoplasia
- CIN
Cervical Intraepithelial Neoplasia
- COVID-19
Coronavirus Disease 2019
- CZK
Czech Koruna
- HPV
Human Papillomavirus
- HPV-AF
Human Papillomavirus–Attributable Fraction
- ICD-10
International Classification of Diseases, 10th Revision
- IN
Intraepithelial Neoplasia
- MN
Malignant Neoplasm
- OIN
Oral Intraepithelial Neoplasia
- RRP
Recurrent Respiratory Papillomatosis
- SD
Standard Deviation
- VIN
Vulvar Intraepithelial Neoplasia
- VaIN
Vaginal Intraepithelial Neoplasia
- YLL
Years of Life Lost
Supplemental material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2026.2696062
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Supplementary Materials
Data Availability Statement
Data is provided within the manuscript or supplementary information files.