The economic burden of HPVrelated diseases: Croatia
Key highlights
• Human Papillomavirus (HPV) infection remains one of the most prevalent sexually transmitted infections worldwide, affecting millions of individuals annually.
• In Croatia, the average age of first sexual contact is 17 for both males and females. Given that 83.79% of the population is aged 17 or older, a substantial portion is at risk of HPV infection and related diseases.
• Cervical cancer (CC) is the most common HPV-related cancer in Croatia and the third most frequent cancer among women aged 15 to 44.
• Approximately 421 HPV-attributable cancer cases and 226 deaths occur annually in Croatia, with CC accounting for two-thirds of the case incidences.
• Genital warts (GW) are most common in women under 40.
• The average cost of cervical intraepithelial neoplasia (CIN) treatment depends on the stage: CIN1 costs EUR 105.36, CIN2 costs EUR 286.63, and CIN3 costs EUR 475.74.
• The total cost of CIN management in the first year following diagnosis is EUR 1,588,520, with CIN1 accounting for EUR 422,504, CIN2 for EUR 293,507, and CIN3 for EUR 872,509.
• CC is the most expensive HPV-related cancer when estimated based on the most recent incidence data (2020), with an annual incidence cost of EUR 3,012,646 and a mortality cost of EUR 1,265,192.
• The combined annual incidence and mortality costs of all other HPV-attributable cancers are EUR 400,651 and EUR 674,120, respectively.
• The most financially cumbersome is the oropharyngeal mortality among men, followed by the female vulvar cancer mortality. Regarding the HPV-attributable incidence costs, vulvar cancer is the costliest, followed by female anal cancer.
• The indirect costs of productivity loss due to HPV-related diseases in Croatia amount to EUR 5,312,203 annually.
• On average, CC patients take 124.8 sick leave days per year.
• The total annual cost of HPV-associated premalignant lesions and cancer treatment is estimated at EUR 10,314,020.
• Croatia introduced gender-neutral 9vHPV vaccination in 2016. Despite considerable improvements in the vaccination coverage over the past years, only 52.78% of 14year-old girls and 36.05% of boys are vaccinated well below the WHO target of 90% uptake.
• The catch-up vaccination cohort of 18–25-year-olds has a very low (<1%) vaccination coverage rate.
• Gender-neutral HPV vaccination has been shown to be highly cost-effective.
• Should the HPV vaccination campaign succeed, the projected annual savings per year would amount to EUR 3,050,883– EUR 6,570,031.
• Despite ongoing efforts since 2012, CC screening remains opportunistic. New initiatives are being developed in various counties to improve and standardize the national CC screening program.
• Challenges persist in tackling HPV-related cancers and diseases in Croatia, including low screening and vaccination coverage, as well as disparities in healthcare access due to income and education level. The full impact of HPV vaccination and CC screening on reducing costs and incidences in Croatia will become clear once the measures are fully implemented.
3.2.1
3.2.1.1
3.2.1.2
Abbreviations
Abbreviation Definition
2vHPV
4vHPV
9vHPV
ASCCP
CC
CIN
ECO
FIGO
GDP
GNV
GW
HPV
HRK
HSIL
HZZO
IARC
ICC
ICER
INT
LY
PVFLP
VCR
WHO
YLL
YPLL
2-valent Human Papillomavirus Vaccine
4-valent Human Papillomavirus Vaccine
9-valent Human Papillomavirus Vaccine
American Society for Colposcopy and Cervical Pathology
Cervical Cancer
Cervical Intraepithelial Neoplasia
European Cancer Organization
International Federation of Gynaecology and Obstetrics
Gross Domestic Product
Gender-Neutral Vaccination
Genital Warts
Human Papilloma Virus
Croatian kuna (HRvatska Kuna)
High-grade Squamous Intraepithelial Lesion
Croatian Health Insurance Fund
International Agency for Research on Cancer
Invasive Cervical Cancer
Incremental Cost-Effectiveness Ratio
International dollar
Life-Year
Present Value of Future Lost Productivity
Vaccination Coverage Rate
World Health Organization
Years of Life Lost
Years of Productive Life Lost
1. Introduction
Human Papillomavirus (HPV) infection remains one of the most prevalent sexually transmitted infections worldwide, affecting millions of individuals annually. In Croatia, as in many other countries, HPV poses a significant public health challenge due to its association with various cancers, including cervical, vulvar, vaginal, anal, penile, and oropharyngeal cancers, as well as other conditions such as genital warts (GW) [7-9] These diseases not only impact individual health but also impose substantial socioeconomic burdens on healthcare systems and society at large.
Understanding the socioeconomic impact of HPV-related diseases is crucial for several reasons. Firstly, the direct medical costs associated with treating HPV-induced cancers are substantial, encompassing diagnosis, treatment, and long-term care. Moreover, indirect costs, such as productivity losses due to morbidity and premature mortality, further exacerbate the economic burden. The economic impact of HPV-related diseases underscores the importance of effective prevention strategies, including vaccination and screening programs, in mitigating both health and financial consequences.
Investigating the socioeconomic aspects of preventive measures against the virus is imperative for accurately allocating resources to mitigate the health burden caused by HPV-related diseases. Vaccination against high-risk HPV types has demonstrated significant effectiveness in reducing infections and, subsequently, preventing cancers. Early detection through screening programs allows for timely intervention, potentially preventing the progression of precancerous lesions to invasive cancer. By assessing the cost-effectiveness of these interventions, policymakers and healthcare providers can make informed decisions about resource allocation and public health policies.
In Croatia, as elsewhere, the socioeconomic impact of HPV-related diseases and the effectiveness of preventive measures warrant comprehensive analysis. This report aims to explore these facets, providing insights into the current landscape, identifying gaps in knowledge, and recommending strategies to enhance public health outcomes and economic efficiency in managing HPV infections and associated diseases.
2. Methodology
To this aim, we performed a targeted literature review in PubMed to identify indexed literature as well as grey literature sources to find additional and complementary sources of information. For the PubMed search, articles were screened and identified using key terms such as “economic,” “costs,” “cost-effectiveness,” and “cost of illness,” along with HPV-related terms. Studies focusing on the economic impact of HPVrelated diseases and studies reporting the economic effects of preventive measures were included in our review, both in English and Croatian language. Furthermore, a targeted Google search was conducted to identify any additional relevant information. Only credible sources, such as governmental websites (e.g., Hrvatski zavod za javno zdravstvo) and standardized information aggregators (Index Mundi, World Bank Group, Worldometer), were considered. The identified articles and documents were then reviewed to extract relevant data on the costs associated with HPV-related diseases, including direct medical costs, indirect costs, and broader economic impacts. The original article values were reported for the sake of traceability, followed by values inflated to 2025 euros (EUR) in brackets. This methodology ensures a comprehensive overview of the economic burden, incorporating both peer-reviewed studies and authoritative grey literature sources.
3. The Croatian Landscape
Figure 1 Map of Croatia and its key statistics.
Statistics for Croatia Population (2025) [1]
3.9 million
Nominal GDP per capita (2023) [2]
USD 21,865.5
Currency
Prior to 1 January 2023: Croatian kuna (HRK)
Since 1 January 2023: Euro (EUR/€)
HPV prevention programs [3, 4]
Vaccination: (2016); (2016)
Cervical cancer screening: opportunistic, a pilot in Virovitica-Podravina County (2023)
Vaccine coverage (2023) [5] [6]
Aged 14: 52,78% ; 36,05%
3.1 HPV transmission and HPV-related diseases in Croatia
Since sexual intercourse is the primary route of transmission, all sexually active individuals are at risk of genital HPV infection. In Croatia, the median age at first sexual intercourse was 17 years for both males and females in 2010 [7] Given that 83,79% of the population is aged 17 and older, a substantial portion of the Croatian population is at risk of HPV infection and, consequently, HPV-related diseases (calculated based on the data from [10]).
Cervical cancer (CC) is the most prevalent HPV-related cancer in Croatia and the third most common female cancer in women aged 15 to 44 years in the country [7] It has a crude (non-age-standardized) incidence rate of approximately 13.3 cases per 100,000 women per year, leading to about 276 new CC cases being diagnosed annually (estimations for 2020 [11]). Based on these values, the female population size was estimated to be 2,075,188, while the total population size for both sexes is 3,953,958 in 2020 [1]. Moreover, CC ranks as the 14th leading cause of cancer-related deaths among
females in Croatia, with a crude mortality rate of 7.06 deaths per 100,000 women per year, leading to about 150 death cases annually (estimations for 2020) [7].
Other HPV-related cancers include cancers of the oral cavity, vulva, vagina, anus, penis, larynx, and oropharynx, some of which have stronger link to HPV infection than others [8, 9, 12].It is important to emphasize that, unlike CC, where nearly all cases are caused by HPV, the virus is responsible for various proportions of other cancers, for instance: 88.0% of anal, 78.0% of vaginal and 50% of penile cancer. Only a small fraction of oral cavity (2.2%) and laryngeal (2.4%) cancers are attributable to HPV, indicating that other risk factors, such as alcohol consumption or smoking, might be the driving forces in their development [12]. Considering this, the second most common HPV-attributable malignancy in women after CC is anal cancer (with an estimated HPV-attributable incidence rate of 28/2,075,188*100,000=1.35 per 100,000 women in 2020), closely followed by vulvar cancer (1.20 per 100,000 women in 2020). Among men, the HPVdriven incidence of penile cancer was calculated to be 26/ 1,878,770*100,000=1.38 cases in 2020, followed by oropharyngeal cancer (0.96 per 100,000 men). Oropharyngeal cancer has the highest HPV-driven mortality rate for both sexes, with a crude mortality rate of 0.85 per 100,000 individuals. . A summary of the annual number of cases and deaths for CC and other HPV-related cancers, the percentage of cancers attributed to HPV, and the total number of HPV-attributable cases is presented in Table 1.
Table 1 The estimated annual number of new cancer cases and deaths per cancer type, HPV attribution, and the total number of HPV-attributable cancer cases in Croatia in 2020
Cancer type Annual number of cases (2020) [11]
number of deaths (2020) [7]
attribution (2012) [12]
number of HPVattributable cases [11] Total number of HPVattributable deaths [7]
Abbreviations: HPV, Human Papilloma Virus;
The total number of HPV-attributable cases and deaths was estimated by multiplying the annual number of cancer cases reported in 2020 in Croatia by the percentage of these
cancers attributed to HPV. As a result, 421 HPV-attributable cancer cases and 226 deaths were estimated to occur annually in Croatia.
HPV-related diseases other than cancer include cervical intraepithelial neoplasia (CIN), which is a precursor to CC. CIN refers to precancerous lesions or abnormal growth of cells observed in the cervix [7]. It is diagnosed by analysing cervical tissue obtained through a biopsy or surgical excision, often during routine screening to prevent progression to invasive cancer [7]. The condition is classified into three grades: CIN1, CIN2, or CIN3, based on the degree of malignant cell growth and thickness of the abnormal epithelium layer [7]. Specific data on the prevalence of CIN1, CIN2, and CIN3 in Croatia are limited. For 2012, Uhernik et al. reported 4,010, 1,024, and 1,834 newly diagnosed cases of CIN1, 2, and 3, respectively [13]. Additionally, data from the International Agency for Research on Cancer (IARC) demonstrated the burden of HPV infection by showing the prevalence of high-risk HPV types 16 and 18 (HPV-16 and HPV18) among women with CIN. These high-risk strains had a prevalence of 13.5% among patients with low-grade cervical lesions (i.e., CIN1) and 20.6% among those diagnosed with high-grade cervical lesions (i.e., CIN2 and CIN3) [7]. Another report found high-risk HPV-16 in 57.9% of high-grade cervical lesions [14].
Another non-cancerous disease associated with HPV is GW, usually caused by the lowoncogenic HPV-6 and 11 strains [15] Importantly, individuals diagnosed with GW often concurrently harbour multiple HPV strains, including high-risk oncogenic variants, which may warrant close clinical attention [15]. Finding data on the incidence of GW in different countries can be challenging due to several factors, such as underreporting and lack of screening. In one study, the GW incidence was assessed in 100 men, and the high-risk HPV-16, 18, 31 and 33 were found in 21.21% of the cases [16]. In a more recent study, 221 sexually active women with GW were examined for the presence of high-grade squamous intraepithelial lesion (HSIL; corresponds to CIN2 and CIN3) or genital cancer [15] The research found that one 152 women (68.8%) with colposcopic abnormality and 111 women (50.2%) with abnormal cervical smear had GW a number significantly higher than in the control group [15]. Therefore, the presence of GW indicates a higher risk of developing genital cancers [15] The age distribution showed that 185 women (83.7%) were younger than 39. The incidence of GW for different age groups reported in the study can be found in Table 2
Table 2 Age-specific incidence of genital warts in Croatian women, 2011 [15]
40-49 24 (10.9%) >50
(4.5%) Unknown
(0.9%)
Although changes in HPV vaccination rates and reporting practices may influence GW incidence in the long term, the impact of vaccination on current GW trends remains uncertain. The vaccination coverage rate (VCR) among 15-year-old girls has risen significantly, from 3% in 2016 to 55% in 2023, with the sharpest increase seen in the last three years [17]. However, since the coverage was low for most of the past decade, it is likely premature to expect a strong effect on GW incidence by 2025. The GW incidence should be re-evaluated when cohorts with high HPV VCR reach the ages of highest GW incidence. If Croatia attains the 90% vaccination coverage target by 2030, a significant reduction in GW and HPV-associated (pre-)cancerous lesion incidence is expected over the subsequent decade. The available reports on GW incidence are outdated (from 2002 [16] or 2011 [15]), highlighting the need for more recent data to accurately evaluate current trends for this condition.
3.2 Socioeconomic burden of HPV-related diseases in Croatia
HPV-related diseases are not only associated with increased mortality but also impose significant costs on individuals and society. The socioeconomic burden of these diseases was estimated using available data that we obtained from the literature. This involved extracting reported healthcare costs incurred by both the healthcare system and patients for each HPV-related disease. Whenever possible, we also extracted societal costs, which include, for instance, productivity losses due to absenteeism or mortality, informal care costs, and productivity losses associated with caregiving.
3.2.1 Healthcare costs
3.2.1.1
Cervical cancer and cervical intraepithelial neoplasia (CIN)
Data on the economic burden of HPV-related diseases in Croatia is limited. In one study, the cost per incident case of CC was reported to be USD 8,800 in 2017 (EUR 10,915 adjusted for 2025 inflation), while the cost per death was USD 6,800 (EUR 8,435) [8]. All conversion coefficients and exchange rates used to inflate the values to 2025 euros are presented in Appendix 1. Considering the annual number of CC cases (n=276) in 2020, the total annual costs of all CC cases are calculated at USD 2,428,800 in 2017 (EUR 3,012,646 in 2025) [8, 11]. Likewise, the total annual cost of CC deaths (n=150) is estimated at USD 1,020,000 in 2017 (EUR 1,265,192 in 2025) [7, 8].
Another source provided estimations for the costs of CC treatment [18]. The age and disease stage of 346 invasive cervical cancer (ICC) patients diagnosed in 2008 were obtained from the Croatian National Cancer Registry and linked with the Croatian Health Insurance Fund Claims Database. ICC patients utilized the following healthcare services: hospitalizations, outpatient healthcare, prescribed medicines, prescribed goods and appliances, and personal sick leave. As the last category falls under indirect costs, it is presented in a separate section of this report (3.2.2). As for the direct costs, hospitalizations dominate the healthcare services utilization, although the study shows that these significantly decrease over time from 90% in the first year upon diagnosis to 4% in the fifth year. A similar trend was noticed for the other healthcare service categories, with the first year accounting for 71% of the expenses, 11% spent in the second year, 9% in the third year, 5% in the fourth year and 4% in the fifth year. Over the 5-year period, the total ICC treatment cost was estimated to be EUR 2,028,304 in 2012 (EUR 2,697,645 adjusted for 2025 inflation), of which hospitalizations accounted for 78%, outpatient care for 18%, prescribed medicines for 3%, and prescribed medical goods and appliances for 1% [18]. Year one was the costliest, with direct treatment costs for all patients amounting to EUR 1,429,764 (EUR 1,901,586 adjusted for inflation). The breakdown of healthcare costs per ICC patient in year one is detailed in Table 3. The average direct cost of ICC patient treatment over 5 years was estimated at EUR 4,729 (EUR 6,289 adjusted for inflation).
Table 3. Healthcare costs per ICC patient diagnosed in 2008 in year one
Total costs in the first year after CIN diagnosis were also reported by Uhernik et al. This is detailed in Table 4, with the 2025 inflation adjustment to reflect current price equivalents [18]. Importantly, total costs in the first year after CIN3 diagnosis were the highest, with estimated costs of EUR 656,022 (EUR 872,509 in 2025), followed by EUR 317,672 for CIN1 in that year (EUR 422,504 in 2025) and EUR 220,682 for CIN2 (EUR 293,507 in 2025), with all estimates originally reported in 2012 values and including sick leave (indirect) costs per CIN stage, which could not be separated from the direct costs based on the available data [13]. When assessing the healthcare service used in the first year upon diagnosis, most CIN patients (84%) were treated in an outpatient setting, unlike CC patients, who are more commonly hospitalized. While changes in screening and HPV vaccination could potentially impact CIN incidence and severity, it remains uncertain how much early detection efforts have improved in Croatia over the past years. Recent data indicate that the five-year overall survival rate for CC remains at 61%, and it is the only cancer type for which the 5-year survival has not improved compared to patients diagnosed in 2011–2015 [19]. This indicates that early detection rates may still be low. Given this, the extent to which shifts in CIN incidence and treatment costs have occurred since 2012 remains unclear. Still, the findings highlight the significant economic burden that different stages of CIN place on healthcare systems, especially when the cancer is diagnosed at the late, most severe stage (CIN3).
Abbreviations: HPV: Human Papilloma Virus, CIN: Cervical Intraepithelial Neoplasia
The direct costs for GW for Croatia could, unfortunately, not be obtained from the literature This gap not only hinders accurate financial assessments but also impacts the broader public health strategy. When direct costs such as those related to diagnosis, treatment (e.g., cryotherapy, laser removal, or topical treatments), and follow-up care are not fully accounted for, the overall burden of genital warts is underestimated.
Table 4 Estimation of total costs in the first year after CIN diagnosis in the year 2012, per grade
3.2.1.2 Other HPV-related cancers and diseases
Although the link between HPV and other cancers is not as definitive as the 100% association between HPV and CC, these HPV-related diseases also contribute significantly to the overall healthcare and associated costs. Costs per incidence and death case for various HPV-related cancers other than CC are presented in Table 5 and Table 6, respectively, with prices inflated to 2025 euros. To calculate a rough estimation of the total incidence and death costs, based on the most recent data, the annual number of (death) cases was multiplied by the cost per incidence/death case and HPV attribution per cancer type.
Anal F:32; M: 20 F:USD 2,100 (EUR 2,605); M:USD 2,600 (EUR 3,225)
Oropharyngeal F:11; M: 60 F:USD 2,600 (EUR 3,225); M:USD 2,200 (EUR 2,729)
Penile 52 USD 1,700 (EUR 2,109)
USD 59,136 (EUR 73,357) M:USD 45,760 (EUR 56,760)
8,809 (EUR 10,926); M:USD 40,656 (EUR 50,432)
44,200 (EUR 54,834)
Total - - - USD 323,001 (EUR 400,651) F, females; M, males
Total HPV-attributable incidence costs were calculated as #of cases x cost per case x HPV attribution
Table 5 Estimation of total incidence costs for various HPV-related cancers
Table 6. Estimation of total death costs for various HPV-related cancers
Cancer type Annual number of cases in 2020 [7]
Cost per death case in 2017 USD (inflated to 2025 EUR) [8]
Vulvar 50 USD 7,100 (EUR 8,807)
Vaginal 10 USD 7,200 (EUR 8,931)
Anal F: 8; M: 4 F:USD 8,200 (EUR 10,171); M:USD 8,400 (EUR 10,419)
Oropharyngeal F: 12; M:88 F:USD 8,500 (EUR 10,543); M:USD 8,300 (EUR 10,295)
Penile 13 USD 8,500 (EUR 10,543)
Total HPV-attributable death costs in 2017 USD (inflated to 2025 EUR) (calculated)
(EUR 109,647)
(EUR 69,662)
F: USD 57,728 (EUR 71,604) M: USD 29,568 (EUR 36,675)
F: USD 31,416(EUR 38,967) M: USD 224,963 (EUR 279,036)
(EUR 68,530)
Total - - - USD 543,480 (EUR 674,120) F, females; M, males
Total HPV-attributable death costs were calculated as #of cases x cost per case x HPV attribution
Based on our calculations, the total annual incidence costs for various HPVattributable cancers are approximately USD 323,001 (EUR 400,651). The total HPVattributable annual death costs are USD 543,480 (EUR 674,120). The most financially cumbersome is the oropharyngeal mortality among men, followed by the female vulvar cancer mortality. Among mortality costs, oropharyngeal cancer in men is the most expensive, followed by vulvar cancer. Regarding the HPV-attributable incidence costs, vulvar cancer is the costliest, followed by female anal cancer. Interestingly, both CC and all other non-CC HPV-related cancers had the lowest costs per incident case and cost per death (adjusted for purchasing power parity) out of 11 countries examined by Qendri et al. [8].
3.2.2 Indirect costs
A report from 2024 assessed the indirect costs associated with the following types of HPV-related cancers, including oral cavity, oropharyngeal, cervical, vulvar, vaginal, anal, penile, nasopharyngeal, hypopharyngeal, pharyngeal, and laryngeal cancers before the COVID-19 pandemic [9]. These costs, arising primarily due to productivity losses, can be substantial They arise from absenteeism related to cancer treatment, premature death, and the caregiving responsibilities shouldered by family members or others
Additionally, there are emotional and psychological impacts on patients and their families, which may lead to further mental health care costs.
In Croatia, there were 177 deaths in 2019 due to HPV-related cancers (crude mortality rate of 0.0044%), with 2,780 years of life lost (YLL) and 702 years of productive life lost (YPLL) [9]. YLL represents the total years of life lost due to premature mortality, while YPLL accounts for the years lost before retirement age. Data from 2019 were used to avoid confounding from the impact of the COVID-19 pandemic. Of the 177 deceased, 141 (~80%) were female, highlighting the significant impact of CC on mortality. The overall present value of future lost productivity (PVFLP) amounted to EUR 4,284,035 (EUR 5,312,203 adjusted for inflation), with an average PVFLP per death of EUR 24,219 (EUR 30,032 adjusted for inflation). Approximately 66% of these deaths were attributed to CC, followed by 9% from anal cancer and 7% from oropharyngeal cancer. A detailed breakdown of deaths, YLL, YPLL, PVFLP, and PVFLP per death, broken down by sex and cancer type, is available in Figure 2.
Figure 2. Total number of deaths, YLL, YPLL, PVFLP and PVFLP/death in Croatia by sex and cancer type in 2019 (Supplement 13 in [9]). The life expectancy in Croatia was 75 years for males and 82 for females, with the retirement age being 65.0 years and 62.8 years, respectively.
The study by Uhernik et al. reported a portion of the indirect costs for CC, specifically those related to personal sick leave separately [18] Similar to other healthcare services, the highest proportion of CC patients (17%) utilized personal sick leave in the first year upon diagnosis. That year, sick leave costs were estimated at EUR 1,971 (EUR 2,622, adjusted for 2025 inflation) per person and EUR 108,449 (EUR 144,237 in 2025) in total for 55 CC patients who took leave Over 5 years, the costs totalled €148,767 (€197,861 in 2025). On average, CC patients took 124.8 sick leave days per year, but its overall financial burden is estimated as moderate.
Economic burden HPV-related diseases (CRO)
The indirect costs for GW were not found in the literature. It is known that the presence of GW causes annoyance rather than significantly impacting premature mortality or reducing productive years of life. However, psychosocial effects, such as anxiety, distress, and reduced quality of life, may still contribute to an economic burden that is not easily quantifiable in traditional cost analyses. Moreover, the lack of indirect costs for GW likely underestimates the total burden of HPV in Croatia. Without comprehensive data, it is challenging to fully capture the economic impact of HPV-related diseases, including the treatment of genital warts, which can lead to significant healthcare costs.
The estimations and the findings of Uhernik et al. and Sabale et al. emphasize the substantial economic burden of HPV-related pre-cancerous lesions and cancers in Croatia, particularly due to personal sick leave, premature mortality, and lost productivity [9, 18]. Given this, targeted interventions such as HPV vaccination, early screening, and improved treatment accessibility are essential to reducing mortality, preserving productive life years, and alleviating the economic impact of HPV-related cancers.
3.2.3 Total costs
A Croatian report from 2011 assessed the total yearly costs associated with HPV screening, CIN and CC treatment [20]. The following costs were retrieved from the Health Insurance Fund (HZZO) price list: Pap smear, colposcopy, genotyping of HPV, biopsy, and conization. The model assumed 5% of abnormal Pap smear findings yearly of a total of 470,000 Pap smears. Of those, 50% were assumed HPV-positive, of which 50% would have abnormal colposcopy findings and a further 50% would require further treatment. The costs are displayed in Table 7 in 2010 HRK (inflated to 2025 euros in brackets).
Based on these costs, the expenses foropportunistic screening and precancerous lesion treatment were calculated, whereas the expenses associated with early- and late-stage CC treatment, sick leave, comorbidity and disability were projected from other countries with an adjustment for Croatian GDP per capita in 2011. They amounted to HRK 75,000 (EUR 14,095) per case for early-stage (Stage I and IIA, according to the International Federation of Gynaecology and Obstetrics [FIGO] classification) and 150,000 HRK (EUR 28,189) per case for late-stage (IIB-IVB) CC treatment. The total annual costs of screening amount to HRK 20,412,100 (EUR 3,836,037); the pre-invasive lesion treatment, HRK 19,862,000 (EUR 3,727,583); CC treatment, HRK 45,000,000 (EUR 8,456,830), summing up to approximately HRK 85,247,100 (EUR 16,020,449). Without screening, the yearly costs amount to HRK 64,835,000 (EUR 12,184,412).
Table 7. Costs involved in HPV screening and the treatment of CIN and CC
Procedure
Biopsy
Conization
Early-stage cervical cancer treatment (I-IIA)
Late-stage cervical cancer treatment (IIBIVB)
lesion treatment
lesion treatment
(EUR 132)
(EUR 610)
Total - - -
(EUR
85,247,100 (EUR 16,020,449).
Since the article [20] dates back to 2011, we initially hypothesized that the total costs were lower today due to the impact of (opportunistic) CC screening and HPV vaccination in reducing disease incidence. However, our calculation showed only marginally lower total HPV-associated costs, as presented in Table 8. They were found as a sum of the direct and indirect costs of CIN treatment for the year 2012 (EUR 1,588,520) [18], specifically CC incidence costs estimated from the report by Qendri et al. [8] (EUR 3,012,646), other HPV-attributable cancer incidence costs in the year 2020 (EUR 400,651) [8], and indirect productivity and early mortality-associated costs of all HPV-associated cancers (EUR 5,312,203) [9]. All of these total EUR 10,314,020 annually, roughly 17% lower than EUR 12,184,412 reported by Ćorušić et al. [20], though differences in data sources should be taken into account. The implementation of a systematic CC screening program and an increase in the HPV VCR is expected to further lower the costs associated with the treatment of (pre-)cancerous lesions caused by HPV. However, the full economic impact will become clearer once screening programs are fully established, and VCR goals are met.
Table 8. Overall calculated direct and indirect costs of CIN and CC treatment, inflated to 2025 values
3.3 Economic and societal benefits of HPV-related preventive measures
To fight the occurrence of HPV-related diseases and reduce the socioeconomic burden associated with the virus, several preventive measures have been initiated in Croatia, including HPV vaccination However, a fully operational national CC screening program is not yet in place, and efforts are needed to establish a structured program that ensures systematic screening. This aligns with the global World Health Organization (WHO) and the European Cancer Organization (ECO) “90–70–90” goals for 2030, which state that 90% of girls should be fully vaccinated against HPV by the age of 15; 70% of women should be screened for CC by the age of 35 and again by the age of 45; and 90% of diagnosed pre-cancerous lesions and invasive cancers should be treated [4] The realistic aim is to bring the CC incidence to less than 4 per 100,000 women [4] Furthermore, Croatia also has its own country-specific CC-related goals for 2030: reducing the incidence and mortality rate of CC by 50%, improving the response rate for screening invitations to a minimum of 60%, and reducing the CC mortality by 25% [4] To achieve these objectives, a national screening program must be effectively implemented. This section delineates the current state of the country’s preventive programs, including coverage rates, followed by the estimation of financial gains that could be achieved through successful HPV programs, highlighting that meeting the HPVrelated targets set by the WHO, ECO, and Croatia can lead to long-term economic benefits.
3.3.1 Vaccination
Vaccination is the primary, highly effective method for preventing CC and other HPVrelated diseases, as well as reducing the financial burdens they impose. Local HPV vaccination efforts started in 2007 and 2008, with the quadrivalent (4vHPV, Gardasil 4) and bivalent (2vHPV, Cervarix) vaccines for girls and women aged 9–26 [6]. Nationwide, in 2016, the nonavalent vaccine Gardasil 9 (9vHPV) became freely available but not
mandatory for gender-neutral vaccination (GNV) of 14–15-year-olds and was included in the National Immunisation Program [21]. The vaccination coverage remained below 10% one year after the initiation of the program in 2017, which was attributed to low health literacy among parents and educators [22]. This is further confirmed by a survey conducted in 2020, which revealed that 50% of parents were unaware that the HPV virus can cause various types of cancers and as many as a third did not know that free HPV vaccination was available for eighth-graders [4]. Other cited concerns were vaccine safety and efficacy, misconceptions connecting vaccination with risky sexual behaviour and general distrust in the national healthcare system [23]. Religious beliefs influence HPV vaccination rates in Croatia, with higher levels of religiosity being associated with increased vaccine hesitancy. Some religious communities view the HPV vaccine as promoting sexual activity, leading to hesitancy among parents who believe it may encourage behaviour contrary to their religious teachings [24].
In line with the GNV expansion in Croatia, the study by Qendri et al. (2020) suggests that GNV is economically attractive, underscoring the potential public health benefits in countries with varying vaccination uptakes, like Croatia [8]. The results demonstrated that, with the uptake of the 9vHPV vaccine among girls below 20% in 2020, vaccinating 100,000 girls in Croatia was projected to prevent approximately 318 cancer cases per cohort of 200,000 preadolescents (comprising 100,000 girls and 100,000 boys). The vaccination impact was the lowest among the 11 countries examined (Austria, Belgium, Croatia, Estonia, Italy, Latvia, the Netherlands, Poland, Slovenia, Spain, and Sweden), possibly owing to the low vaccine uptake value. Importantly, extending the vaccination to the boys at the same coverage level could prevent an additional 168 cancer cases, highlighting the potential benefits of GNV. The incremental cost-effectiveness ratio (ICER) for implementing GNV in Croatia is estimated at 9,390 international dollars (INT, which takes into account the purchasing power parity in different countries) in 2017 per life-year (LY) gained ICER is a measure of cost-effectiveness; it determines the extra money needed to gain an additional year of healthy life. WHO defines a highly costeffective intervention as having an ICER of ≤1xGDP per capita (INT 25,264 in 2017 for Croatia), and a cost-effective intervention as having an ICER of ≤ 3xGDP per capita (INT 75,792 in 2017). In practice, the cost-effectiveness ICER threshold in many countries equals 0.5–1.5xGDP per capita [25]. Croatia, despite having mandatory costeffectiveness analysis, does not have a cost-effectiveness threshold defined, which means that the decision-making process relies not only on the ICER threshold but on a more comprehensive assessment of various factors [26] Altogether, considering the presented ICER thresholds and vaccination uptake, GNV was considered to be highly cost-effective in Croatia (INT 9,390<INT 25,264) However, when the vaccine uptake was projected to increase to 80%, the GNV was no longer cost-effective
Since 2023, HPV vaccination has been actively recommended and offered on a voluntary basis to all children aged 10/11–14/15 [6]. However, that year, the vaccination rates for 14–14-year-old females and males were still underwhelming, estimated at 52,78% and 36.05%, respectively [5]. Moreover, free catch-up vaccination has been available since 2019 for men and women up to 25 years old, subject to vaccine availability and provided upon request [6]. The catch-up cohort coverage is low, with extremely limited data, making it difficult to estimate the percentage. One study found self-reported coverage rates among young adults (18–25 years old) to be 25.0% for females and 11.7% for males [6], significantly below the proposed WHO and EU targets. The real VCR for this age group is likely much lower than the self-reported percentages: based on the HPV vaccine doses administered in 2022, it is estimated to be less than 1% [27]. The prevalence of the highly oncogenic HPV-31 type was found to be reduced in the post-vaccination cohort; however, the prevalence of the most oncogenic HPV-16/18 remained stable in 20202023, which underscored the necessity to improve the vaccination coverage in an attempt to eradicate HPV-related cancers [21].
Ćorušić et al. demonstrated that a 100% vaccination coverage against HPV-16/18 would result in various cost reductions (Table 9).
Table 9 Estimation of cost reductions following a 100% vaccination coverage [20]:
8,573,000 in 2010 (EUR 959,005–EUR 1,611,120 in 2025)
Diagnostic and therapeutic procedures for preinvasive cervical lesions
Morbidity and mortality from cervical cancer
–70% HRK 9,931,000–HRK 13,903,000 in 2010 (EUR 1,866,328 – EUR 2,612,785 in 2025)
HRK 27,000,000–HRK 33,750,000 in 2010 (EUR 5,074,098–EUR 6,342,622 in 2025)
A total savings of HRK 42,034,000–HRK 56,226,000 in 2010 (equivalent to EUR 7,899,431–EUR 10,566,527 in 2025) was projected. Considering the total financial HPV burden from the article by Ćorušić et al. (EUR 16,020,449), vaccination could reduce the total cost by up to 63.7%. However, since our calculated total HPV related costs only amount to EUR 10,314,020, the expected net cost reduction would not exceed EUR 6,570,031.
Another estimate from grey literature suggests that if the vaccination campaign is successful, HRK 23,000,000 per year (EUR 3,050,883) could be saved, and 88% of premature deaths caused by CC could be prevented through HPV vaccination [28].
3.3.2
Cervical cancer screening
Despite extensive efforts to lower the CC incidence, it remains a significant healthcare challenge in Croatia In 2022, the country ranked 11th in CC incidence and 12th in CC mortality among EU member states [29] Given that CC has a long pre-clinical phase (10–20 years), it is highly preventable through regular screening and early treatment. The screening methods include visual inspection with acetic acid, cervical cytology (Pap smear), or HPV DNA testing Several views exist on the CC screening pipeline. The most basic one suggests that a high-sensitivity test be performed first (such as an HPV DNA test), followed by a high-specificity analysis only for those tested positive to determine the disease management. In case of a negative primary screening result, the recommended screening interval is at least 5 years [30]. Opposite to that, the American Society for Colposcopy and Cervical Pathology (ASCCP) 2012 consensus guidelines recommend different screening modes dependent on the woman’s age, with cytology being the baseline method. For 21–29-year-olds, cytology is suggested every 3 years. For women aged 30–65, a combination of cytology and HPV testing is preferred every 5 years, with cytology every 3 years being the next best option. Finally, for women over 65 years, no screening is recommended if no CIN2+ has been observed in the last 20 years. For HPV16/18-positive 30–65-year-olds, immediate colposcopy should be scheduled, and in case other high-risk HPV types are detected, additional testing is scheduled over 12 months [30]. The ATHENA screening trial showed that a high-risk HPV test alone from age 25 is as efficient as cytology-based strategies, and it permits the extension of the testing interval, requiring fewer tests in a lifetime [30]. While international recommendations provide useful guidance, Croatia’s national CC screening guidelines are currently being updated. Once published, these new guidelines will shape future screening practices and cost-effectiveness assessments.
Croatia has a long history of CC screening. The first Croatian opportunistic screening efforts were initiated as far back as 1953 in Zagreb, and since then, a network of laboratories has been set up to cover the screening needs of the Croatian female population. Additionally, Croatia has been training cytotechnicians specialized in gynaecological cytology since 1967. The country has all the necessary infrastructure and manpower (gynaecologists, standard operating procedures for CC treatment, and laboratories) to potentially succeed in fighting CC [31]. Despite this, screening coverage remains suboptimal, largely due to interruptions in national screening programs, socioeconomic disparities, and stigma surrounding HPV.
The National Cervical Cancer Screening programme was launched in Croatia in 2012, targeting women aged 25–64 for a cytology assessment every three years [22]. By 2016,
the program transitioned to a population-based model; however, it was suspended the same year. After its reorganisation in 2018, the program faced further disruptions only two years later [4, 22]. As a result of these developments, cervical screening in Croatia has remained opportunistic since 2012, despite continuous efforts to implement a successful nationwide framework. The program was eventually reinstated in 2023, starting with a 12-month-long pilot phase launched in the Virovitica-Podravina county, signalling Croatia’s commitment to efficient CC prevention [4, 22]. The main goal for the country remains to shift from the current opportunistic screening model towards a more effective system that also allows for an early identification and efficient prevention of CC [4].
Nevertheless, the most recent statistics report high screening coverage, with a 2019 survey reporting that 90% of women asserted having been screened for CC in the last five years [3]. In the same year, 60% of women in Croatia had a Pap smear test in the past three years, a decrease from 64% reported in 2014 [22]. Notably, screening rates vary by income (77% vs 44% in the highest and lowest income quintiles, respectively) and education (80% vs 33% for women with tertiary vs lower education levels, respectively) [22]. Therefore, substantial efforts should be focused on tackling the low-income and low-education groups to attain the proposed screening goals by 2030.
To strengthen CC prevention, Croatia participates in several EU-wide and national CC screening programs. For instance, it partakes in the “Action Now” Plan offered by the ECO, which brings together civil society organizations and professional groups to improve CC screening practices [4]. Another cross-country initiative, “Before Time,” was recently launched in Croatia, Bosnia and Herzegovina, and Montenegro to promote education on HPV, HPV vaccination, and CC screening. As part of this project, a pilot self-sampling program is planned in Zadar County [29] Currently, self-sampling is not yet widely available in Croatia. However, given the social stigma associated with HPV in Croatia, self-sampling has the potential to improve overall CC screening coverage by providing a more private and convenient alternative. Even in the Netherlands, where HPV-related stigma is relatively low, self-sampling has become the preferred method of sample collection since its introduction in 2017 [32]. This method has a comparable sensitivity for CIN2+ detection and only a slightly lower specificity compared to cliniciancollected samples. If the Croatian pilot program proves successful, self-sampling could be considered for broader implementation, as was the case in the Netherlands. While it did not significantly increase the already high screening participation rate in the Netherlands, its success highlights the potential of self-sampling to enhance acceptability and ease of access in screening programs [32]
To further increase participation in CC screening programs, several key strategies can be implemented. These include active promotion by general practitioners, comprehensive training of healthcare personnel, implementing quality standards at all screening locations to bring back faith in the national healthcare system, and public health education campaigns aimed at dispelling the stigma surrounding HPV. Improving testing accessibility is also crucial. This can be achieved by offering home-based self-testing kits, deploying mobile screening units to reach underserved populations, and integrating HPV screening with other routine healthcare visits to maximize convenience. Additionally, adopting an opt-out model where women of eligible age are automatically enrolled unless they choose otherwise can further increase participation [4].
In conclusion, HPV vaccination and CC screening in Croatia have evolved significantly over the past years. To maximize the impact of vaccination against HPV and CC screening, efforts should now focus on increasing HPV vaccination coverage among adolescents, expanding awareness campaigns, and enhancing participation in CC screening programs. This report highlights the importance of culturally sensitive public health strategies that engage religious communities, provide clear information about the benefits and safety of the HPV vaccine, and respect religious values while promoting health. Given the substantial economic and health burden of HPV-related cancers, sustained investment in prevention strategies is essential to reducing mortality, improving quality of life, and alleviating healthcare costs in Croatia.
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5. Appendix
Appendix 1 Coefficients used for currency conversions and inflation to 2025 euro.
The conversion coefficient of 2025 USD to 2025 EUR was 1.04 (valid as of 07 February 2025) [35]