The health economics evaluation of HPV vaccine with different immunization strategies in Zhejiang Province based on the PRIME tool

The health economics evaluation of HPV vaccine with different immunization strategies in Zhejiang Province based on the PRIME tool | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The health economics evaluation of HPV vaccine with different immunization strategies in Zhejiang Province based on the PRIME tool Yan Liu, Qixin Xie, Wenwen Gu, Jian Du, Zhaojun Lu, Jing Wang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3895745/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: To evaluate the health economics of human papillomavirus (HPV) vaccination for school-age female children in Zhejiang Province under different immunization regimens. Methods: The PRIME tool recommended by the World Health Organization (WHO) was used to evaluate the health economics of HPV vaccination by modifying and replacing local data with custom parameters, and the results of sensitivity analysis and economics were combined to select the optimal immunization strategy. Results: Assuming a free HPV vaccination program among all school-age female children (13 years old) in Zhejiang Province from 2022, the net annual costs to be invested in the scenario of using domestic bivalent and imported bivalent, imported quadrivalent, and ninevalent HPV vaccines to carry out immunization in the province with a full vaccination coverage of 80% of the target vaccination population and a discount rate of 3% are 153 million, 433 million, 597 million, and 967 million, respectively. For each disability-adjusted life year (DALY) saved due to cervical cancer, the incremental costs (CER) were 34,700, 97,800, 135,000, and 170,300 Yuan for different HPV vaccines, respectively, compared with no intervention program. The incremental cost effectiveness ratios (ICER)/annual GDP per capita ratio is 0.31, 0.87, 1.19, and 1.51 for different HPV vaccines. The recommended solution is to apply domestic bivalent vaccine, discount 80% of vaccine procurement cost, and achieve 90% coverage of full vaccination. Conclusion: The immunization strategy for children of school-age females using the domestically produced bivalent HPV vaccine in Zhejiang Province has a highly favorable performance in terms of health economics. cervical cancer PRIME human papillomavirus (HPV) vaccine health economics Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Cervical cancer is one of the most common malignant tumors of the female reproductive system and is the second most common tumor in women globally, following breast cancer. The number of cases is increasing and tending to become younger, seriously threatening the health of women in China. The latest data shows that there were 604,000 new cases and 342,000 deaths from cervical cancer worldwide in 2020, and it is estimated that there will be 798,000 new cases and 481,000 deaths by 2040, representing increases of 32.0% and 40.8% respectively compared to 2020[1]. In 2020, there were 110,000 new cases and 59,000 deaths from cervical cancer in China, an increase of about 3.5% and 23.0% compared to 2018, respectively, making it clear that the prevention and control of cervical cancer is urgent, especially in China, which has a high incidence and mortality rate[2]. At the same time, cervical cancer is also the only cancer with a clear cause and can be prevented by vaccination against the human papillomavirus (HPV)[3]. HPV vaccines have high immunogenic properties, and antibody positivity for vaccine types reaches or approaches 100% after full vaccination, with the highest immune response in girls aged 9-15 years[4]. Currently, it has been clearly established that HPV infection is the highest risk factor for cervical cancer, and continuous HPV infection is a necessary condition for the development of cervical cancer[5]. Vaccination of young women with HPV vaccine is the most effective means of preventing cervical cancer[6]. Since 2016, China has successively marketed two-dose, four-dose, and nine-dose HPV vaccines, but due to high vaccine prices and difficulties in appointment, HPV vaccination rates are low[7]. The 2030 Global Strategy to Accelerate the Elimination of Cervical Cancer states that the HPV vaccination rate of school-age girls should reach 90%, so we need to assess the health economics of HPV vaccination. Recently, some municipalities have gradually introduced free vaccination programs for girls in lower secondary school in China. Survey had found that cervical cancer caused by 16/18 type HPV in China was as high as 84%, higher than the international level[8]. Based on existing evidence, the World Health Organization (WHO) suggests that the efficacy and effectiveness of two-dose, four-dose, and nine-dose HPV vaccines in preventing cervical cancer caused by 16/18 type HPV is equivalent in terms of immunogenic properties, and all three HPV vaccines can prevent the occurrence of most cervical cancer[9]. Public health decision-makers should make scientifically based decisions based on cost-effectiveness, and more than 90 countries around the world have already included HPV vaccines in their national immunization plans. Presently, several types of HPV vaccines are now available in multiple countries[10]. Some studies had also found that the bivalent HPV vaccine provided protection against other types of HPV viruses[11]. After the widespread promotion of HPV vaccine in multiple countries, the rate of high-risk HPV infections and cervical cell abnormalities among young women has significantly decreased. Therefore, getting vaccinated against HPV is an important means of reducing effectively the incidence of cervical cancer and reducing the burden of disease caused by this illness. At the same time, the World Health Organization (WHO) recommends that public health service decision-makers make scientifically informed decisions based on a targeted health economics evaluation of HPV vaccines, taking into account cost-effectiveness when incorporating the vaccine into immunization plans[12]. This study utilized the "papilloma virus rapid interface for modeling and economics (PRIME)" recommended by the WHO website for the health economics research of HPV vaccines. The study was conducted to evaluate the health economics of four HPV vaccines (Xiamen Wantai, GlaxoSmithKline, Merck Sharp & Dohme) for use in the immunization program for the age-eligible population in Zhejiang Province, to provide a theoretical basis for the government to make reasonable and effective public health decisions, and provides data support for the subsequent implementation of free HPV vaccination for eligible girls. Data and methods 1.1 PRIME overview PRIME is a static proportional outcomes model. The purpose of PRIME's design is to provide a quick and simple economic evaluation tool for non-professional users. By simulating demographic data, the incidence and mortality rates of cervical cancer related to HPV by age group, and then by inputting related data, the corresponding results are obtained for health economics evaluation. Compared with dynamic transmission models, this model does not consider the indirect effects (such as herd immunity) generated by vaccination and the impact of changes in sexual behavior, and compared with static progression models, the process of natural history of the population from HPV infection to disease occurrence is not simulated, nor does it take into account the impact of cervical cancer screening on incidence rate. The PRIME tool mainly relies on EXCEL operation and is divided into four modules, which 1. Country selection (Country) module, used to select the country to be analyzed. The corresponding data of each country have been integrated into the data table to become local parameters. PRIME stores data of 179 countries worldwide, and by selecting the corresponding country, local data of that country can be called for health economics evaluation. 2. Customization (Customization) module, which allows the modification of the 15 local default parameters of the indicators called by the country selection, and the modification values will replace the default values for automatic calculation and reflection in the result output window. 3. Age-related parameters (Age Data) module, mainly including default values and customization values, researchers can input corresponding values based on actual situations, and updated values will replace default values for automatic calculation and reflection in the result output window. 4. Result output (Output) module, the output indicators in the result output module are the key indicators for evaluating the cost-benefit of vaccines. 1.2 interpretation of PRIME output results The PRIME outputs mainly carry out the health economic evaluation of the HPV vaccine from three aspects: cost-benefit, cost-effectiveness, and cost-utility. Benefit indicators are generally measured in currency, including medical expenses saved and labor value losses avoided in the future due to vaccination; utility is generally measured in disability-adjusted life years (DALY) or quality-adjusted life years (QALY); and effect indicators are typically measured in health outcomes or clinical treatment indicators, such as reduced incidence and mortality of cervical cancer after vaccination. (1) Cost-benefit: the direct cost and discounted cost of different intervention programs compared to no intervention, the incremental cost and incremental DALY; (2) Cost-utility: the cost-effectiveness ratio (CER), which is the ratio of the cost of saving a unit of DALY, and the incremental cost-effectiveness ratio (ICER) compared to existing standard strategies are obtained. When compared to no intervention, CER can be used instead of ICER for calculation; (3) Cost- effectiveness: reduction in the incidence or incidence rate and mortality or mortality rate of cervical cancer before and after vaccination, the cost required for each effect generated, etc. 1.3 custom parameters The "Country Selection Module" in the PRIME tool is selected as China, and the corresponding default parameters will be automatically filled in the PRIME tool. In order to make this health economic evaluation more in line with the situation in Zhejiang Province, the default parameters such as birth cohort population, vaccination target population, vaccine cost, treatment expenditure and per capita gross domestic product (GDP) are modified in the "Custom Parameters" section. The number of female birth cohort population and the number of female target age population for vaccination are calculated based on the permanent population of women in Zhejiang Province in 2021 (214,695) and the 13-year-old female population (314,598). The per capita GDP is calculated based on the "Zhejiang Statistical Yearbook (2021)" (113,032 Yuan). The cost of the vaccine is calculated based on the 4 types of HPV vaccines published by the Zhejiang Second Class Vaccine Government Procurement Cloud Platform in 2021, and the vaccination schedule for the 13-year-old age group; the cost of the domestically produced two-dose HPV vaccine (Xiamen Wantai) is 329/dose × 2, the imported two-dose HPV vaccine (GlaxoSmithKline) is 580/dose × 3, the imported four-dose HPV vaccine (Merck Sharp & Dohme Gardasil) is 798/dose × 3, and the imported nine-dose HPV vaccine (Merck Sharp & Dohme Gardasil) is 1298/dose × 3. The cost of vaccine transportation and management is calculated based on the management, transportation and vaccination service fee for second-class vaccines published by Zhejiang Province's Bureau of Prices in 2021, which is 25 yuan per dose. Regarding "the average cost of cervical cancer treatment," we customarily modify based on a direct economic burden research data from China. By weighted average calculation of the treatment costs of cervical cancer in hospitals of various grades and stages, the direct treatment cost of each cervical cancer patient is 51,136 yuan[13]. The cost in the PRIME model is converted into US dollars, and the output result is converted into yuan based on a conversion rate of 1 US dollar to 6.7 yuan. Additionally, according to relevant research data, high-risk HPV infections mainly include 13 gene types such as HPV16/18/33/52/58, and the protection rate of cervical cancer with HPV16/18 type bivalent/quadrivalent vaccine is 70%, while the protection rate with HPV16/18/33/52/58 type ninevalent vaccine is 90%[14, 15]. 1.4 Evaluation path and output results Based on the results of the PRIME run, the economic evaluation of 4 HPV vaccines was conducted from three aspects: cost-benefit analysis (CBA), cost-effectiveness analysis (CEA), and cost-utility analysis (CUA). Sensitivity analysis was also performed on the uncertain factors of the four HPV vaccination strategies, and the decrease in the incidence of cervical cancer under different vaccination strategies was explored. The optimal vaccination strategy was selected and provided a theoretical basis for the subsequent implementation of free HPV vaccination in Zhejiang Province. Cost-benefit analysis uses monetary representation of effects to verify the usefulness of health services by reducing the cost of disease diagnosis and treatment through the implementation of health services. Cost-effectiveness analysis refers to simulating a certain intervention program and observing the number of cases or deaths that can be reduced or even avoided, or calculating the monetary cost required to reduce one case or death. Cost-utility analysis is performed by simulating the cost of an intervention program in monetary terms and the benefits in terms of a health utility indicators, which is the commonly evaluated as the cost-effectiveness ratio (CER), the cost of saving one disability-adjusted life year (DALY). When comparing an intervention program with a non-intervention program, CER is equivalent to the incremental cost-effectiveness ratio (ICER). WHO provides recommendations on the economics of health economics evaluations: if ICER/per capita GDP per year is less than 1, the program is highly economically feasible. According to the principle of monetary time value, the value of money changes as time changes. To reduce the impact of the change in monetary value, this study uses the same discount rate for the input and output of costs. Results 2.1 Health economics results of adopting different HPV vaccination strategies Assuming that the target population for HPV vaccine in Zhejiang Province is 13-year-old eligible female children and the full-course coverage rate is 80%, custom modifications were made to the birth cohort population, the target population for vaccination, the cost of HPV vaccine, the treatment expenditure for cervical cancer, and the per capita GDP of Zhejiang Province. PRIME tools were used to calculate the health economics results of different HPV vaccine vaccination strategies (Table 1). 2.1.1 Cost-benefit analysis The effectiveness of bivalent and quadrivalent HPV vaccines in preventing cervical cancer caused by HPV16/18 is comparable[16], so the number of cases of cervical cancer prevented by administering bivalent or quadrivalent HPV vaccines is the same. Based on the results obtained from the PRIME tool, we found that when 13-year-old eligible female children are vaccinated with HPV vaccines and the full-course coverage rate is 80% per year, the domestic bivalent, imported bivalent, and imported quadrivalent HPV vaccines can prevent 1273 cases of cervical cancer in the target population, and the imported ninevalent HPV vaccine can prevent 1637 cases of cervical cancer. When the discount rate is 3%, the bivalent, quadrivalent, and ninevalent HPV vaccines can reduce the treatment costs of cervical cancer by 0.24 and 0.30 billion yuan, respectively. At the same time, the net cost of using domestic bivalent, imported bivalent, imported quadrivalent, and imported ninevalent HPV vaccine vaccination strategies is 1.53, 4.33, 5.97, and 9.67 billion yuan, respectively, per year. 2.1.2 Cost-effectiveness analysis "Compared to not being vaccinated, vaccinating 13-year-old girls with the HPV vaccine and achieving a coverage rate of 80% can significantly reduce the incidence of cervical cancer in the target population across all age groups. With a discount rate of 3%, the cost of reducing one case of cervical cancer using domestically produced bivalent, imported bivalent, imported quadrivalent, and imported ninevalent HPV vaccines is 333,100, 939,700, 1,297,600, and 1,636,600 yuan, respectively. On the other hand, with a discount rate of 3%, the cost of reducing one death from cervical cancer using domestically produced bivalent, imported bivalent, imported quadrivelnt, and imported ninevalent HPV vaccines is 786,500, 2,218,500, 3,063,500, and 3,863,900 yuan, respectively." 2.1.3 Cost-utility analysis The output of PRIME model results showed that when the discount rate was 3%, and the full coverage rate of 13-year-old eligible female children was 80%, compared to the un-implemented HPV vaccine vaccination strategy, vaccinating with bivalent or quadrivalent HPV vaccines can save the lives of 4,130 person-years of target vaccination population due to deaths caused by cervical cancer. Vaccinating with ninevalent HPV vaccines can save the lives of 5,310 person-years. At the same time, vaccinating with bivalent or quadrivalent HPV vaccines can reduce non-DALY by 293 person-years caused by cervical cancer, and vaccinating with ninevalent HPV vaccines can reduce non-DALY by 377 person-years. The CER of the immunization programs of domestically produced bivalent, imported bivalent, imported quadrivalent, and imported ninevalent HPV vaccines are 34,700, 97,800, 135,000, and 170,300 yuan, respectively. Compared with the per capita GDP of Zhejiang Province at the same time, the ratios of ICER/per capita GDP for the immunization programs of domestically produced bivalent, imported bivalent, imported quadrivalent, and imported ninevalent HPV vaccines are 0.31, 0.87, 1.19, and 1.51, respectively. The immunization program using domestically produced bivalent HPV vaccines can make the incremental cost of saving one DALY caused by cervical cancer only 0.31 of the per capita gross domestic product, which is lower than one healthy person's annual labor production value. The immunization program using imported bivalent HPV vaccines can make the incremental cost of saving one DALY caused by cervical cancer 0.87 of the per capita gross domestic product, which is also lower than one healthy person's annual labor production value. 2.2 Sensitivity analysis Considering the longer cycle of HPV vaccine administration, for different immunization regimens, this study assumes that the discount rate, vaccine cost, treatment cost, target vaccination age group, and overall vaccine coverage rate are adjusted for single factors, and performs single factor sensitivity analysis when the discount rate (1%-5%), vaccine cost (original vaccine cost ± 20%), treatment cost (original treatment cost ± 20%), target vaccination age group (12-14 years old), and overall vaccine coverage rate (70%-90%) fluctuate up and down, with other factors remaining unchanged. When administering the domestic bivalent HPV vaccine, the ICER/per capita GDP ratio is relatively stable when a single factor is adjusted and the vaccine cost fluctuates the most, followed by the treatment cost, with the target vaccination age group and overall vaccine coverage rate having a smaller impact (Figure 1). When administering the imported bivalent HPV vaccine, when the discount rate is 5%, the ICER/per capita GDP ratio is 1.69 > 1, and the discount rate has a significant impact on the ICER/per capita GDP ratio (Figure 2). Additionally, when administering imported quadrivalent and ninevalent HPV vaccines, the ICER/per capita GDP ratio is > 1 when the discount rate, vaccine cost, treatment cost, and target vaccination age group change, and there is a clear impact (Figure 3 and 4). The ICER/per capita GDP ratio increases with the increase of the discount rate and vaccine cost and decreases with the increase of the treatment cost and target vaccination age group, with no impact on the overall vaccine coverage rate. 2.3 Recommended solution The results of the economic evaluation and sensitivity analysis of the four HPV vaccine immunization schemes output by the PRIME tool show that the recommended HPV vaccine immunization scheme in Zhejiang Province is to use domestic bivalent HPV vaccine, set 13-year-old eligible female children as the target vaccination group, with a vaccination coverage rate of 90%, and the net cost required is 134 million yuan. The ICER/per capita GDP ratio is 0.23, which is the optimal choice and has high economic viability (Table 2). Implementing the HPV vaccine according to the optimal choice, using domestic bivalent HPV vaccine, from 2023, continuously vaccinate 13-year-old eligible female children in Zhejiang Province every year. As the coverage rate of the target group continues to increase, the incidence rate of cervical cancer in the target group continues to decrease. Compared with unvaccinated HPV vaccine, regardless of 70%, 80%, or 90% coverage rate, the incidence rate of cervical cancer in the target population is significantly lower than that of the non-vaccinated population. When the coverage rate of the target population is 80%, the incidence rate of cervical cancer in the target population is below 3/100,000 in all age groups. When the coverage rate of the target population is 90%, the incidence rate of cervical cancer in the target population throughout their lifetime is below 2/100,000 in all age groups (Figure 5). Discussion Our study found a highly favorable performance in terms of health economics (cost-effectiveness, cost effectiveness, and cost utility) for the immunization strategy of school-age female children applying the domestically produced bivalent HPV vaccine in Zhejiang Province, and sensitivity analysis showed that the vaccine cost price was the main influencing factor in applying the domestically produced bivalent HPV vaccine, therefore, in the recommended scheme, the domestically produced bivalent HPV vaccine was adopted and the vaccine cost was selected price of 80% and 90% coverage of the whole vaccine. At the same time, the higher the vaccination coverage rate the greater the decrease in the all-age cervical cancer incidence rate in the target population, which is beneficial to the prevention and treatment of cervical cancer. In terms of cost-effectiveness, the application of the domestic bivalent HPV vaccine requires a net cost of $153 million per year, which can prevent 1273 cases of cervical cancer occurrence and 804 cervical cancer deaths for the target population, with good cost-effectiveness compared to quadrivalent and nine-valent. At present, bivalent HPV vaccines for the prevention of cervical cancer due to HPV infection have shown some cost-effectiveness worldwide, and more than 100 countries have included HPV vaccines in their national immunization programs[17]. Zou[18] found that domestic bivalent HPV vaccines for girls aged 9-14 years in China could effectively reduce the incidence of cervical cancer, with significant cost-effectiveness. A foreign study showed that a study on the cost-effectiveness of HPV vaccination in 9-year-old girls in Iran found that three doses of HPV vaccination were not cost-effective from a social perspective and that two doses of HPV vaccination or a reduction in the price of the vaccine may be cost-effective[19]. It is suggested that the cost-effectiveness obtained from vaccination is influenced by various factors such as the cost of vaccine supply, vaccine dose, and price, which need to be considered together. In terms of cost utility, we found that vaccination with bivalent HPV vaccine saved DALYS of 4130 person-years due to cervical cancer deaths in the target population of vaccination; the ratio of ICER/GDP per capita with the immunization regimen of domestic bivalent HPV vaccine was 0.31. According to the World Health Organization (WHO) recommendation when ICER is compared with GDP per capita, the threshold value is less than 1, which has high economics, being in the period of 1-3, both are equally economical[20, 21]. Xu[22] found an optimal economic ICER/GDP value of 0.35 when a domestic bivalent HPV vaccine immunization regimen was used among 13-year-old female children of school age in Guangdong Province; consistent with the results of a health economics evaluation study by Luo Pan et al. for bivalent HPV vaccination in Wuhan[23]. In addition to applying the static model assessment, Song[24] evaluated the economic benefits of implementing 19 interventions such as bivalent HPV vaccination and regular screening based on a dynamic model and concluded that vaccination with domestic HPV vaccine had; good economic benefits. Our study found that vaccination with bivalent, quadrivalent, and nine-valent HPV vaccines are cost-effective. A foreign study found that the cost-effectiveness of vaccinating 10,000 12-year-old girls in Estonia with 2 doses of bivalent, quadrivalent, or nine-valent HPV vaccine was assessed and compared by constructing a Markov model, and found that vaccination with different vaccination strategies was cost-effective[25]. However, one study also predicted the cost-effectiveness of bivalent, quadrivalent, and nine-valent HPV vaccination for 12-year-old girls in Italy and found that the cost-effectiveness of HPV vaccination became more significant as the number of vaccination doses increased[26]. The possible reasons for this are related to the different allocation of health resources in different regions, vaccination policies, and changes in vaccine prices. ~ The PRIME tool is a health economics assessment tool recommended by the World Health Organization (WHO) for HPV vaccines, which has the advantages of being efficient, fast and specific. Since the population in China varies greatly and the economic development of different regions varies, the PRIME tool can be used to conduct a localized health economics assessment of HPV vaccine, which can provide a specialized theoretical basis for the subsequent introduction of HPV vaccine immunization planning policies in different regions. However, the PRIME tool also has limitations in that it does not consider the impact of screening as well as viral transmission on the incidence and mortality of cervical cancer[27]. Also, the application of the tool is based on the premise that the vaccine's ability to provide complete protection against cervical cancer caused by the corresponding type can be sustained throughout life without considering indirect effects, provided that the method and scale of screening for cervical cancer do not change significantly during the model's prediction time. To verify the feasibility of the PRIME tool, one study conducted a health economics evaluation using the PRIME tool for 179 countries, while comparing it with other complex models with similar findings and consistent ICER values for both, indicating that the PRIME tool can meet the HPV vaccine health economics evaluation. Based on the results of the above study, we found that different HPV vaccination regimens have certain cost effects in Zhejiang Province for female children of age 13 years with 80% full coverage and 3% discount rate. Combining the results of health economics evaluation and sensitivity analysis, the recommended HPV vaccine regimen for Zhejiang Province is a domestic bivalent HPV vaccination regimen with 80% of the current vaccine price and 90% of the full vaccine coverage. This study provides some basis for the subsequent inclusion of HPV vaccine in immunization planning and the development of cervical cancer prevention and control strategies by health service decision makers in Zhejiang Province. Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Data Availability Data derived from public domain resources These data were derived from the following resources available in the public domain: 1、the permanent population of women in Zhejiang Province in 2021； 2、Zhejiang Statistical Yearbook (2021)； 3、the Zhejiang Second Class Vaccine Government Procurement Cloud Platform in 2021； 4、Zhejiang Province's Bureau of Prices in 2021； 5、Tao,S.Y, et al., Study on direct economic burden and influencing factors in patients with cervical cancer and precancerous lesions %J Chinese Journal of Preventive Medicine. 2018. 52(12): p. 1281-1286. 6、Signorelli, C., et al., Human papillomavirus 9-valent vaccine for cancer prevention: a systematic review of the available evidence. Epidemiol Infect, 2017. 145(10): p. 1962-1982. 7、15. Serrano, B., et al., Human papillomavirus genotype attribution for HPVs 6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions. Eur J Cancer, 2015. 51(13): p. 1732-41. Competing interests The authors declare that they have no competing interests. Funding Not applicable Authors' contributions Yan Liu and Qixin Xie were responsible for designing the experiments, data analysis, and writing the paper. Junfang Chen was in charge of reviewing the fermentation experiments, data analysis, and providing support in the writing process. All authors read and approved the final manuscript. Acknowledgements Not applicable References Bray, F., et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018. 68(6): p. 394-424. Liu Z.C, et al., Interpretation on the report of Global Cancer Statistics 2020 %J Journal of Multidisciplinary Cancer. 2021. 7(02): p. 1-14. 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Võrno, T., et al., Cost-effectiveness of HPV vaccination in the context of high cervical cancer incidence and low screening coverage. Vaccine, 2017. 35(46): p. 6329-6335. Mennini, F.S., et al., Cost-effectiveness analysis of the nine-valent HPV vaccine in Italy. Cost Eff Resour Alloc, 2017. 15: p. 11. Bi, Z.F, et al., Introduction of papillomavirus rapid interface for modelling and economics (PRIME) and an example of China′s data analysis %J Chinese Journal of Preventive Medicine %J Chinese Journal of Preventive Medicine. 2019. 53(7): p. 744-751. Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables1and2.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qixin","middleName":"","lastName":"Xie","suffix":""},{"id":294677810,"identity":"1b8bbee9-55de-4270-bac8-b41e0ce197d2","order_by":2,"name":"Wenwen Gu","email":"","orcid":"","institution":"Hangzhou Center for Disease Control and Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wenwen","middleName":"","lastName":"Gu","suffix":""},{"id":294677811,"identity":"c30328f5-2947-4b22-bdde-565e34dd42da","order_by":3,"name":"Jian Du","email":"","orcid":"","institution":"Hangzhou Center for Disease Control and Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"Du","suffix":""},{"id":294677812,"identity":"25e642ad-7fc4-4679-a833-ab0871a83c60","order_by":4,"name":"Zhaojun Lu","email":"","orcid":"","institution":"Hangzhou Center for Disease Control and Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhaojun","middleName":"","lastName":"Lu","suffix":""},{"id":294677813,"identity":"a107426d-bc1e-494a-b8ba-f6afc3c15a66","order_by":5,"name":"Jing Wang","email":"","orcid":"","institution":"Hangzhou Center for Disease Control and Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Wang","suffix":""},{"id":294677814,"identity":"842ef631-99aa-4310-99c2-4767c76caa09","order_by":6,"name":"Yuyang Xu","email":"","orcid":"","institution":"Hangzhou Center for Disease Control and Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuyang","middleName":"","lastName":"Xu","suffix":""},{"id":294677815,"identity":"4c6b6162-52fd-4d69-a29a-3194c52f0f9b","order_by":7,"name":"Yingying Yang","email":"","orcid":"","institution":"Hangzhou Center for Disease Control and Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yingying","middleName":"","lastName":"Yang","suffix":""},{"id":294677816,"identity":"f47d1df5-526e-496e-9ddf-e225d1018ee9","order_by":8,"name":"Junfang Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYBACAwaGZAYGHjk5Nvb2AyRpMTbm4zmTQLQWZiBlnDhPwsGAOC3m/AceG/yQMUhvk2BIYPhRsY2wFsuGA8mJPTwGuW3SjQcYe87cJsJhBxuSDzPw/MltkzmQwMzYRoyWwwwgLQbpbBIJBkRqOcaQnAzUkkCCljMMyYZAvxi2AQP5IHF+OX8mWeJnj4G8fHv7wQc/KojQAozGBAbGHgjzADHqgYAdqPAHkWpHwSgYBaNgZAIAcDc5K3+/E40AAAAASUVORK5CYII=","orcid":"","institution":"Hangzhou Center for Disease Control and Prevention","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Junfang","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-01-25 02:44:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3895745/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3895745/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55517397,"identity":"f7926ddd-7cd7-49e4-9e9e-04d8a4bc7232","added_by":"auto","created_at":"2024-04-29 13:24:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":176830,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3895745/v1/e56527f88ecd334805e09897.png"},{"id":55517395,"identity":"27ebd73a-10d1-4d6a-a581-4810bc33b237","added_by":"auto","created_at":"2024-04-29 13:24:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":185101,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure 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04:32:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1054767,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3895745/v1/df82eb8c-4fb5-4086-b5cd-9b48956f5dbb.pdf"},{"id":55518273,"identity":"e4306aef-00cd-443a-9d10-a5a94401ad3a","added_by":"auto","created_at":"2024-04-29 13:32:41","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":516848,"visible":true,"origin":"","legend":"","description":"","filename":"Tables1and2.docx","url":"https://assets-eu.researchsquare.com/files/rs-3895745/v1/2c7bcbf63ab2c4bbe53dfe39.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The health economics evaluation of HPV vaccine with different immunization strategies in Zhejiang Province based on the PRIME tool","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCervical cancer is one of the most common malignant tumors of the female reproductive system and is the second most common tumor in women globally, following breast cancer. The number of cases is increasing and tending to become younger, seriously threatening the health of women in China. The latest data shows that there were 604,000 new cases and 342,000 deaths from cervical cancer worldwide in 2020, and it is estimated that there will be 798,000 new cases and 481,000 deaths by 2040, representing increases of 32.0% and 40.8% respectively compared to 2020[1]. In 2020, there were 110,000 new cases and 59,000 deaths from cervical cancer in China, an increase of about 3.5% and 23.0% compared to 2018, respectively, making it clear that the prevention and control of cervical cancer is urgent, especially in China, which has a high incidence and mortality rate[2]. At the same time, cervical cancer is also the only cancer with a clear cause and can be prevented by vaccination against the human papillomavirus (HPV)[3]. HPV vaccines have high immunogenic properties, and antibody positivity for vaccine types reaches or approaches 100% after full vaccination, with the highest immune response in girls aged 9-15 years[4]. Currently, it has been clearly established that HPV infection is the highest risk factor for cervical cancer, and continuous HPV infection is a necessary condition for the development of cervical cancer[5]. Vaccination of young women with HPV vaccine is the most effective means of preventing cervical cancer[6].\u003c/p\u003e\n\u003cp\u003eSince 2016, China has successively marketed two-dose, four-dose, and nine-dose HPV vaccines, but due to high vaccine prices and difficulties in appointment, HPV vaccination rates are low[7]. The 2030 Global Strategy to Accelerate the Elimination of Cervical Cancer states that the HPV vaccination rate of school-age girls should reach 90%, so we need to assess the health economics of HPV vaccination. Recently, some municipalities have gradually introduced free vaccination programs for girls in lower secondary school in China. Survey had found that cervical cancer caused by 16/18 type HPV in China was as high as 84%, higher than the international level[8]. Based on existing evidence, the World Health Organization (WHO) suggests that the efficacy and effectiveness of two-dose, four-dose, and nine-dose HPV vaccines in preventing cervical cancer caused by 16/18 type HPV is equivalent in terms of immunogenic properties, and all three HPV vaccines can prevent the occurrence of most cervical cancer[9]. Public health decision-makers should make scientifically based decisions based on cost-effectiveness, and more than 90 countries around the world have already included HPV vaccines in their national immunization plans.\u003c/p\u003e\n\u003cp\u003ePresently, several types of HPV vaccines are now available in multiple countries[10]. Some studies had also found that the bivalent HPV vaccine provided protection against other types of HPV viruses[11]. After the widespread promotion of HPV vaccine in multiple countries, the rate of high-risk HPV infections and cervical cell abnormalities among young women has significantly decreased. Therefore, getting vaccinated against HPV is an important means of reducing effectively the incidence of cervical cancer and reducing the burden of disease caused by this illness. At the same time, the World Health Organization (WHO) recommends that public health service decision-makers make scientifically informed decisions based on a targeted health economics evaluation of HPV vaccines, taking into account cost-effectiveness when incorporating the vaccine into immunization plans[12]. This study utilized the \u0026quot;papilloma virus rapid interface for modeling and economics (PRIME)\u0026quot; recommended by the WHO website for the health economics research of HPV vaccines. The study was conducted to evaluate the health economics of four HPV vaccines (Xiamen Wantai, GlaxoSmithKline, Merck Sharp \u0026amp; Dohme) for use in the immunization program for the age-eligible population in Zhejiang Province, to provide a theoretical basis for the government to make reasonable and effective public health decisions, and provides data support for the subsequent implementation of free HPV vaccination for eligible girls.\u003c/p\u003e"},{"header":"Data and methods","content":"\u003cp\u003e\u003cstrong\u003e1.1 PRIME overview\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePRIME is a static proportional outcomes model. The purpose of PRIME\u0026apos;s design is to provide a quick and simple economic evaluation tool for non-professional users. By simulating demographic data, the incidence and mortality rates of cervical cancer related to HPV by age group, and then by inputting related data, the corresponding results are obtained for health economics evaluation. Compared with dynamic transmission models, this model does not consider the indirect effects (such as herd immunity) generated by vaccination and the impact of changes in sexual behavior, and compared with static progression models, the process of natural history of the population from HPV infection to disease occurrence is not simulated, nor does it take into account the impact of cervical cancer screening on incidence rate.\u003c/p\u003e\n\u003cp\u003eThe PRIME tool mainly relies on EXCEL operation and is divided into four modules, which 1. Country selection (Country) module, used to select the country to be analyzed. The corresponding data of each country have been integrated into the data table to become local parameters. PRIME stores data of 179 countries worldwide, and by selecting the corresponding country, local data of that country can be called for health economics evaluation. 2. Customization (Customization) module, which allows the modification of the 15 local default parameters of the indicators called by the country selection, and the modification values will replace the default values for automatic calculation and reflection in the result output window. 3. Age-related parameters (Age Data) module, mainly including default values and customization values, researchers can input corresponding values based on actual situations, and updated values will replace default values for automatic calculation and reflection in the result output window. 4. Result output (Output) module, the output indicators in the result output module are the key indicators for evaluating the cost-benefit of vaccines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.2 interpretation of PRIME output results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe PRIME outputs mainly carry out the health economic evaluation of the HPV vaccine from three aspects: cost-benefit, cost-effectiveness, and cost-utility. Benefit indicators are generally measured in currency, including medical expenses saved and labor value losses avoided in the future due to vaccination; utility is generally measured in disability-adjusted life years (DALY) or quality-adjusted life years (QALY); and effect indicators are typically measured in health outcomes or clinical treatment indicators, such as reduced incidence and mortality of cervical cancer after vaccination. (1) Cost-benefit: the direct cost and discounted cost of different intervention programs compared to no intervention, the incremental cost and incremental DALY; (2) Cost-utility: the cost-effectiveness ratio (CER), which is the ratio of the cost of saving a unit of DALY, and the incremental cost-effectiveness ratio (ICER) compared to existing standard strategies are obtained. When compared to no intervention, CER can be used instead of ICER for calculation; (3) Cost- effectiveness: reduction in the incidence or incidence rate and mortality or mortality rate of cervical cancer before and after vaccination, the cost required for each effect generated, etc.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.3 custom parameters\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe \u0026quot;Country Selection Module\u0026quot; in the PRIME tool is selected as China, and the corresponding default parameters will be automatically filled in the PRIME tool. In order to make this health economic evaluation more in line with the situation in Zhejiang Province, the default parameters such as birth cohort population, vaccination target population, vaccine cost, treatment expenditure and per capita gross domestic product (GDP) are modified in the \u0026quot;Custom Parameters\u0026quot; section.\u003c/p\u003e\n\u003cp\u003eThe number of female birth cohort population and the number of female target age population for vaccination are calculated based on the permanent population of women in Zhejiang Province in 2021 (214,695) and the 13-year-old female population (314,598). The per capita GDP is calculated based on the \u0026quot;Zhejiang Statistical Yearbook (2021)\u0026quot; (113,032 Yuan). The cost of the vaccine is calculated based on the 4 types of HPV vaccines published by the Zhejiang Second Class Vaccine Government Procurement Cloud Platform in 2021, and the vaccination schedule for the 13-year-old age group; the cost of the domestically produced two-dose HPV vaccine (Xiamen Wantai) is 329/dose \u0026times; 2, the imported two-dose HPV vaccine (GlaxoSmithKline) is 580/dose \u0026times; 3, the imported four-dose HPV vaccine (Merck Sharp \u0026amp; Dohme Gardasil) is 798/dose \u0026times; 3, and the imported nine-dose HPV vaccine (Merck Sharp \u0026amp; Dohme Gardasil) is 1298/dose \u0026times; 3. The cost of vaccine transportation and management is calculated based on the management, transportation and vaccination service fee for second-class vaccines published by Zhejiang Province\u0026apos;s Bureau of Prices in 2021, which is 25 yuan per dose.\u003c/p\u003e\n\u003cp\u003eRegarding \u0026quot;the average cost of cervical cancer treatment,\u0026quot; we customarily modify based on a direct economic burden research data from China. By weighted average calculation of the treatment costs of cervical cancer in hospitals of various grades and stages, the direct treatment cost of each cervical cancer patient is 51,136 yuan[13]. The cost in the PRIME model is converted into US dollars, and the output result is converted into yuan based on a conversion rate of 1 US dollar to 6.7 yuan. Additionally, according to relevant research data, high-risk HPV infections mainly include 13 gene types such as HPV16/18/33/52/58, and the protection rate of cervical cancer with HPV16/18 type bivalent/quadrivalent vaccine is 70%, while the protection rate with HPV16/18/33/52/58 type ninevalent vaccine is 90%[14, 15].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.4 Evaluation path and output results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the results of the PRIME run, the economic evaluation of 4 HPV vaccines was conducted from three aspects: cost-benefit analysis (CBA), cost-effectiveness analysis (CEA), and cost-utility analysis (CUA). Sensitivity analysis was also performed on the uncertain factors of the four HPV vaccination strategies, and the decrease in the incidence of cervical cancer under different vaccination strategies was explored. The optimal vaccination strategy was selected and provided a theoretical basis for the subsequent implementation of free HPV vaccination in Zhejiang Province.\u003c/p\u003e\n\u003cp\u003eCost-benefit analysis uses monetary representation of effects to verify the usefulness of health services by reducing the cost of disease diagnosis and treatment through the implementation of health services. Cost-effectiveness analysis refers to simulating a certain intervention program and observing the number of cases or deaths that can be reduced or even avoided, or calculating the monetary cost required to reduce one case or death. Cost-utility analysis is performed by simulating the cost of an intervention program in monetary terms and the benefits in terms of a health utility indicators, which is the commonly evaluated as the cost-effectiveness ratio (CER), the cost of saving one disability-adjusted life year (DALY). When comparing an intervention program with a non-intervention program, CER is equivalent to the incremental cost-effectiveness ratio (ICER). WHO provides recommendations on the economics of health economics evaluations: if ICER/per capita GDP per year is less than 1, the program is highly economically feasible.\u003c/p\u003e\n\u003cp\u003eAccording to the principle of monetary time value, the value of money changes as time changes. To reduce the impact of the change in monetary value, this study uses the same discount rate for the input and output of costs.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e2.1 Health economics results of adopting different HPV vaccination strategies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAssuming that the target population for HPV vaccine in Zhejiang Province is 13-year-old eligible female children and the full-course coverage rate is 80%, custom modifications were made to the birth cohort population, the target population for vaccination, the cost of HPV vaccine, the treatment expenditure for cervical cancer, and the per capita GDP of Zhejiang Province. PRIME tools were used to calculate the health economics results of different HPV vaccine vaccination strategies (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.1.1 Cost-benefit analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe effectiveness of bivalent and quadrivalent HPV vaccines in preventing cervical cancer caused by HPV16/18 is comparable[16], so the number of cases of cervical cancer prevented by administering bivalent or quadrivalent HPV vaccines is the same. Based on the results obtained from the PRIME tool, we found that when 13-year-old eligible female children are vaccinated with HPV vaccines and the full-course coverage rate is 80% per year, the domestic bivalent, imported bivalent, and imported quadrivalent HPV vaccines can prevent 1273 cases of cervical cancer in the target population, and the imported ninevalent HPV vaccine can prevent 1637 cases of cervical cancer. When the discount rate is 3%, the bivalent, quadrivalent, and ninevalent HPV vaccines can reduce the treatment costs of cervical cancer by 0.24 and 0.30 billion yuan, respectively. At the same time, the net cost of using domestic bivalent, imported bivalent, imported quadrivalent, and imported ninevalent HPV vaccine vaccination strategies is 1.53, 4.33, 5.97, and 9.67 billion yuan, respectively, per year.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.1.2 Cost-effectiveness analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026quot;Compared to not being vaccinated, vaccinating 13-year-old girls with the HPV vaccine and achieving a coverage rate of 80% can significantly reduce the incidence of cervical cancer in the target population across all age groups. With a discount rate of 3%, the cost of reducing one case of cervical cancer using domestically produced bivalent, imported bivalent, imported quadrivalent, and imported ninevalent HPV vaccines is 333,100, 939,700, 1,297,600, and 1,636,600 yuan, respectively. On the other hand, with a discount rate of 3%, the cost of reducing one death from cervical cancer using domestically produced bivalent, imported bivalent, imported quadrivelnt, and imported ninevalent HPV vaccines is 786,500, 2,218,500, 3,063,500, and 3,863,900 yuan, respectively.\u0026quot;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.1.3 Cost-utility analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe output of PRIME model results showed that when the discount rate was 3%, and the full coverage rate of 13-year-old eligible female children was 80%, compared to the un-implemented HPV vaccine vaccination strategy, vaccinating with bivalent or quadrivalent HPV vaccines can save the lives of 4,130 person-years of target vaccination population due to deaths caused by cervical cancer. Vaccinating with ninevalent HPV vaccines can save the lives of 5,310 person-years. At the same time, vaccinating with bivalent or quadrivalent HPV vaccines can reduce non-DALY by 293 person-years caused by cervical cancer, and vaccinating with ninevalent HPV vaccines can reduce non-DALY by 377 person-years. The CER of the immunization programs of domestically produced bivalent, imported bivalent, imported quadrivalent, and imported ninevalent HPV vaccines are 34,700, 97,800, 135,000, and 170,300 yuan, respectively. Compared with the per capita GDP of Zhejiang Province at the same time, the ratios of ICER/per capita GDP for the immunization programs of domestically produced bivalent, imported bivalent, imported quadrivalent, and imported ninevalent HPV vaccines are 0.31, 0.87, 1.19, and 1.51, respectively. The immunization program using domestically produced bivalent HPV vaccines can make the incremental cost of saving one DALY caused by cervical cancer only 0.31 of the per capita gross domestic product, which is lower than one healthy person\u0026apos;s annual labor production value. The immunization program using imported bivalent HPV vaccines can make the incremental cost of saving one DALY caused by cervical cancer 0.87 of the per capita gross domestic product, which is also lower than one healthy person\u0026apos;s annual labor production value.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Sensitivity analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsidering the longer cycle of HPV vaccine administration, for different immunization regimens, this study assumes that the discount rate, vaccine cost, treatment cost, target vaccination age group, and overall vaccine coverage rate are adjusted for single factors, and performs single factor sensitivity analysis when the discount rate (1%-5%), vaccine cost (original vaccine cost \u0026plusmn; 20%), treatment cost (original treatment cost \u0026plusmn; 20%), target vaccination age group (12-14 years old), and overall vaccine coverage rate (70%-90%) fluctuate up and down, with other factors remaining unchanged.\u003c/p\u003e\n\u003cp\u003eWhen administering the domestic bivalent HPV vaccine, the ICER/per capita GDP ratio is relatively stable when a single factor is adjusted and the vaccine cost fluctuates the most, followed by the treatment cost, with the target vaccination age group and overall vaccine coverage rate having a smaller impact (Figure 1). When administering the imported bivalent HPV vaccine, when the discount rate is 5%, the ICER/per capita GDP ratio is 1.69 \u0026gt; 1, and the discount rate has a significant impact on the ICER/per capita GDP ratio (Figure 2). Additionally, when administering imported quadrivalent and ninevalent HPV vaccines, the ICER/per capita GDP ratio is \u0026gt; 1 when the discount rate, vaccine cost, treatment cost, and target vaccination age group change, and there is a clear impact (Figure 3 and 4). The ICER/per capita GDP ratio increases with the increase of the discount rate and vaccine cost and decreases with the increase of the treatment cost and target vaccination age group, with no impact on the overall vaccine coverage rate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Recommended solution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of the economic evaluation and sensitivity analysis of the four HPV vaccine immunization schemes output by the PRIME tool show that the recommended HPV vaccine immunization scheme in Zhejiang Province is to use domestic bivalent HPV vaccine, set 13-year-old eligible female children as the target vaccination group, with a vaccination coverage rate of 90%, and the net cost required is 134 million yuan. The ICER/per capita GDP ratio is 0.23, which is the optimal choice and has high economic viability (Table 2).\u003c/p\u003e\n\u003cp\u003eImplementing the HPV vaccine according to the optimal choice, using domestic bivalent HPV vaccine, from 2023, continuously vaccinate 13-year-old eligible female children in Zhejiang Province every year. As the coverage rate of the target group continues to increase, the incidence rate of cervical cancer in the target group continues to decrease. Compared with unvaccinated HPV vaccine, regardless of 70%, 80%, or 90% coverage rate, the incidence rate of cervical cancer in the target population is significantly lower than that of the non-vaccinated population. When the coverage rate of the target population is 80%, the incidence rate of cervical cancer in the target population is below 3/100,000 in all age groups. When the coverage rate of the target population is 90%, the incidence rate of cervical cancer in the target population throughout their lifetime is below 2/100,000 in all age groups (Figure 5).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study found a highly favorable performance in terms of health economics (cost-effectiveness, cost effectiveness, and cost utility) for the immunization strategy of school-age female children applying the domestically produced bivalent HPV vaccine in Zhejiang Province, and sensitivity analysis showed that the vaccine cost price was the main influencing factor in applying the domestically produced bivalent HPV vaccine, therefore, in the recommended scheme, the domestically produced bivalent HPV vaccine was adopted and the vaccine cost was selected price of 80% and 90% coverage of the whole vaccine. At the same time, the higher the vaccination coverage rate the greater the decrease in the all-age cervical cancer incidence rate in the target population, which is beneficial to the prevention and treatment of cervical cancer.\u003c/p\u003e\n\u003cp\u003eIn terms of cost-effectiveness, the application of the domestic bivalent HPV vaccine requires a net cost of $153 million per year, which can prevent 1273 cases of cervical cancer occurrence and 804 cervical cancer deaths for the target population, with good cost-effectiveness compared to quadrivalent and nine-valent. At present, bivalent HPV vaccines for the prevention of cervical cancer due to HPV infection have shown some cost-effectiveness worldwide, and more than 100 countries have included HPV vaccines in their national immunization programs[17]. Zou[18] found that domestic bivalent HPV vaccines for girls aged 9-14 years in China could effectively reduce the incidence of cervical cancer, with significant cost-effectiveness. A foreign study showed that a study on the cost-effectiveness of HPV vaccination in 9-year-old girls in Iran found that three doses of HPV vaccination were not cost-effective from a social perspective and that two doses of HPV vaccination or a reduction in the price of the vaccine may be cost-effective[19]. It is suggested that the cost-effectiveness obtained from vaccination is influenced by various factors such as the cost of vaccine supply, vaccine dose, and price, which need to be considered together.\u003c/p\u003e\n\u003cp\u003eIn terms of cost utility, we found that vaccination with bivalent HPV vaccine saved DALYS of 4130 person-years due to cervical cancer deaths in the target population of vaccination; the ratio of ICER/GDP per capita with the immunization regimen of domestic bivalent HPV vaccine was 0.31. According to the World Health Organization (WHO) recommendation when ICER is compared with GDP per capita, the threshold value is less than 1, which has high economics, being in the period of 1-3, both are equally economical[20, 21]. Xu[22]\u0026nbsp;found an optimal economic ICER/GDP value of 0.35 when a domestic bivalent HPV vaccine immunization regimen was used among 13-year-old female children of school age in Guangdong Province; consistent with the results of a health economics evaluation study by Luo Pan et al. for bivalent HPV vaccination in Wuhan[23]. In addition to applying the static model assessment, Song[24]\u0026nbsp;evaluated the economic benefits of implementing 19 interventions such as bivalent HPV vaccination and regular screening based on a dynamic model and concluded that vaccination with domestic HPV vaccine had; good economic benefits.\u003c/p\u003e\n\u003cp\u003eOur study found that vaccination with bivalent, quadrivalent, and nine-valent HPV vaccines are cost-effective. A foreign study found that the cost-effectiveness of vaccinating 10,000 12-year-old girls in Estonia with 2 doses of bivalent, quadrivalent, or nine-valent HPV vaccine was assessed and compared by constructing a Markov model, and found that vaccination with different vaccination strategies was cost-effective[25]. However, one study also predicted the cost-effectiveness of bivalent, quadrivalent, and nine-valent HPV vaccination for 12-year-old girls in Italy and found that the cost-effectiveness of HPV vaccination became more significant as the number of vaccination doses increased[26]. The possible reasons for this are related to the different allocation of health resources in different regions, vaccination policies, and changes in vaccine prices. ~\u003c/p\u003e\n\u003cp\u003eThe PRIME tool is a health economics assessment tool recommended by the World Health Organization (WHO) for HPV vaccines, which has the advantages of being efficient, fast and specific. Since the population in China varies greatly and the economic development of different regions varies, the PRIME tool can be used to conduct a localized health economics assessment of HPV vaccine, which can provide a specialized theoretical basis for the subsequent introduction of HPV vaccine immunization planning policies in different regions. However, the PRIME tool also has limitations in that it does not consider the impact of screening as well as viral transmission on the incidence and mortality of cervical cancer[27]. Also, the application of the tool is based on the premise that the vaccine\u0026apos;s ability to provide complete protection against cervical cancer caused by the corresponding type can be sustained throughout life without considering indirect effects, provided that the method and scale of screening for cervical cancer do not change significantly during the model\u0026apos;s prediction time. To verify the feasibility of the PRIME tool, one study conducted a health economics evaluation using the PRIME tool for 179 countries, while comparing it with other complex models with similar findings and consistent ICER values for both, indicating that the PRIME tool can meet the HPV vaccine health economics evaluation.\u003c/p\u003e\n\u003cp\u003eBased on the results of the above study, we found that different HPV vaccination regimens have certain cost effects in Zhejiang Province for female children of age 13 years with 80% full coverage and 3% discount rate. Combining the results of health economics evaluation and sensitivity analysis, the recommended HPV vaccine regimen for Zhejiang Province is a domestic bivalent HPV vaccination regimen with 80% of the current vaccine price and 90% of the full vaccine coverage. This study provides some basis for the subsequent inclusion of HPV vaccine in immunization planning and the development of cervical cancer prevention and control strategies by health service decision makers in Zhejiang Province.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eData Availability\u003c/p\u003e\n\u003cp\u003eData derived from public domain resources\u003c/p\u003e\n\u003cp\u003eThese data were derived from the following resources available in the public domain:\u003c/p\u003e\n\u003cp\u003e1、the permanent population of women in Zhejiang Province in 2021；\u003c/p\u003e\n\u003cp\u003e2、Zhejiang Statistical Yearbook (2021)；\u003c/p\u003e\n\u003cp\u003e3、the Zhejiang Second Class Vaccine Government Procurement Cloud Platform in 2021；\u003c/p\u003e\n\u003cp\u003e4、Zhejiang Province\u0026apos;s Bureau of Prices in 2021；\u003c/p\u003e\n\u003cp\u003e5、Tao,S.Y, et al., Study on direct economic burden and influencing factors in patients with cervical cancer and precancerous lesions %J Chinese Journal of Preventive Medicine. 2018. 52(12): p. 1281-1286.\u003c/p\u003e\n\u003cp\u003e6、Signorelli, C., et al., Human papillomavirus 9-valent vaccine for cancer prevention: a systematic review of the available evidence. Epidemiol Infect, 2017. 145(10): p. 1962-1982.\u003c/p\u003e\n\u003cp\u003e7、15. Serrano, B., et al., Human papillomavirus genotype attribution for HPVs 6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions. Eur J Cancer, 2015. 51(13): p. 1732-41.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eYan Liu and Qixin Xie were responsible for designing the experiments, data analysis, and writing the paper. Junfang Chen was in charge of reviewing the fermentation experiments, data analysis, and providing support in the writing process. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray, F., et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018. 68(6): p. 394-424.\u003c/li\u003e\n\u003cli\u003eLiu Z.C, et al., Interpretation on the report of Global Cancer Statistics 2020 %J Journal of Multidisciplinary Cancer. 2021. 7(02): p. 1-14.\u003c/li\u003e\n\u003cli\u003eWalboomers, J.M., et al., Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol, 1999. 189(1): p. 12-9.\u003c/li\u003e\n\u003cli\u003eForman, D., et al., Global burden of human papillomavirus and related diseases. Vaccine, 2012. 30 Suppl 5: p. F12-23.\u003c/li\u003e\n\u003cli\u003eSerrano, B., et al., Epidemiology and burden of HPV-related disease. Best Pract Res Clin Obstet Gynaecol, 2018. 47: p. 14-26.\u003c/li\u003e\n\u003cli\u003eChen, Y., et al., Human papillomavirus infection and cervical intraepithelial neoplasia progression are associated with increased vaginal microbiome diversity in a Chinese cohort. BMC Infect Dis, 2020. 20(1): p. 629.\u003c/li\u003e\n\u003cli\u003eZhang, X., et al., HPV vaccine acceptability and willingness-related factors among Chinese adolescents: a nation-wide study. Hum Vaccin Immunother, 2021. 17(4): p. 1025-1032.\u003c/li\u003e\n\u003cli\u003eSerrano, B., et al., Potential impact of a 9-valent HPV vaccine in HPV-related cervical disease in 4 emerging countries (Brazil, Mexico, India and China). Cancer Epidemiol, 2014. 38(6): p. 748-56.\u003c/li\u003e\n\u003cli\u003eHerrero, R., P. Gonz\u0026aacute;lez, and L.E. Markowitz, Present status of human papillomavirus vaccine development and implementation. Lancet Oncol, 2015. 16(5): p. e206-16.\u003c/li\u003e\n\u003cli\u003eWang H.Q, et al., Expert consensus on immunoprophylaxis of human papillomavirus-related diseases (abridged) %J Vaccine and Immunization Branch. 2019. 25(06): p. 718-735.\u003c/li\u003e\n\u003cli\u003eBogaards, J.A., et al., Bivalent Human Papillomavirus (HPV) Vaccine Effectiveness Correlates With Phylogenetic Distance From HPV Vaccine Types 16 and 18. J Infect Dis, 2019. 220(7): p. 1141-1146.\u003c/li\u003e\n\u003cli\u003eSingh, D., et al., Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative. Lancet Glob Health, 2023. 11(2): p. e197-e206.\u003c/li\u003e\n\u003cli\u003eTao,S.Y, et al., Study on direct economic burden and influencing factors in patients with cervical cancer and precancerous lesions %J Chinese Journal of Preventive Medicine. 2018. 52(12): p. 1281-1286.\u003c/li\u003e\n\u003cli\u003eSignorelli, C., et al., Human papillomavirus 9-valent vaccine for cancer prevention: a systematic review of the available evidence. Epidemiol Infect, 2017. 145(10): p. 1962-1982.\u003c/li\u003e\n\u003cli\u003eSerrano, B., et al., Human papillomavirus genotype attribution for HPVs 6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions. Eur J Cancer, 2015. 51(13): p. 1732-41.\u003c/li\u003e\n\u003cli\u003eZhao, X.L, et al. Interpretation of the 2022 WHO HPV vaccine position paper %J Chinese Preventive Medicine. p. 1-7.\u003c/li\u003e\n\u003cli\u003eVaccine and Immunology Branch of Chinese Preventive Medicine Association, Expert consensus on immunoprophylaxis of human papillomavirus-related diseases (abridged) %J Chinese Journal of Preventive Medicine. 2019. 53(12): p. 1218-1235.\u003c/li\u003e\n\u003cli\u003eZou, Z., et al., Domestic HPV vaccine price and economic returns for cervical cancer prevention in China: a cost-effectiveness analysis. Lancet Glob Health, 2020. 8(10): p. e1335-e1344.\u003c/li\u003e\n\u003cli\u003eYaghoubi, M., et al., Cost-Effectiveness Analysis of the Introduction of HPV Vaccination of 9-Year-Old-Girls in Iran. Value Health Reg Issues, 2018. 15: p. 112-119.\u003c/li\u003e\n\u003cli\u003eLi, K., et al., The distribution and prevalence of human papillomavirus in women in mainland China. Cancer, 2019. 125(7): p. 1030-1037.\u003c/li\u003e\n\u003cli\u003eKombe Kombe, A.J., et al., Epidemiology and Burden of Human Papillomavirus and Related Diseases, Molecular Pathogenesis, and Vaccine Evaluation. Front Public Health, 2020. 8: p. 552028.\u003c/li\u003e\n\u003cli\u003eXu, X.J. et al., Health Economics Evaluation of Different HPV Vaccination Strategies in Guangdong Province %J China Cancer. 2022. 31(02): p. 139-145.\u003c/li\u003e\n\u003cli\u003eLuo, P., et al., Rapid Evaluation of Health Economics of Bivalent HPV Vaccination in Wuhan Based on PRIME Tool %J China Pharmacist. 2020. 23(06): p. 1115-1118.\u003c/li\u003e\n\u003cli\u003eSong, X.B., et al., Health economic evaluation of human papillomavirus vaccines in the developing countries:systematic reviews %J Chinese Journal of Preventive Medicine. 2016(1): p. 85-90.\u003c/li\u003e\n\u003cli\u003eV\u0026otilde;rno, T., et al., Cost-effectiveness of HPV vaccination in the context of high cervical cancer incidence and low screening coverage. Vaccine, 2017. 35(46): p. 6329-6335.\u003c/li\u003e\n\u003cli\u003eMennini, F.S., et al., Cost-effectiveness analysis of the nine-valent HPV vaccine in Italy. Cost Eff Resour Alloc, 2017. 15: p. 11.\u003c/li\u003e\n\u003cli\u003eBi, Z.F, et al., Introduction of papillomavirus rapid interface for modelling and economics (PRIME) and an example of China\u0026prime;s data analysis %J Chinese Journal of Preventive Medicine %J Chinese Journal of Preventive Medicine. 2019. 53(7): p. 744-751.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e "}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"cervical cancer, PRIME, human papillomavirus (HPV) vaccine, health economics","lastPublishedDoi":"10.21203/rs.3.rs-3895745/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3895745/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eTo evaluate the health economics of human papillomavirus (HPV) vaccination for school-age female children in Zhejiang Province under different immunization regimens.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe PRIME tool recommended by the World Health Organization (WHO) was used to evaluate the health economics of HPV vaccination by modifying and replacing local data with custom parameters, and the results of sensitivity analysis and economics were combined to select the optimal immunization strategy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAssuming a free HPV vaccination program among all school-age female children (13 years old) in Zhejiang Province from 2022, the net annual costs to be invested in the scenario of using domestic bivalent and imported bivalent, imported quadrivalent, and ninevalent HPV vaccines to carry out immunization in the province with a full vaccination coverage of 80% of the target vaccination population and a discount rate of 3% are 153 million, 433 million, 597 million, and 967 million, respectively. For each disability-adjusted life year (DALY) saved due to cervical cancer, the incremental costs (CER) were 34,700, 97,800, 135,000, and 170,300 Yuan for different HPV vaccines, respectively, compared with no intervention program. The incremental cost effectiveness ratios (ICER)/annual GDP per capita ratio is 0.31, 0.87, 1.19, and 1.51 for different HPV vaccines. The recommended solution is to apply domestic bivalent vaccine, discount 80% of vaccine procurement cost, and achieve 90% coverage of full vaccination.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe immunization strategy for children of school-age females using the domestically produced bivalent HPV vaccine in Zhejiang Province has a highly favorable performance in terms of health economics.\u003c/p\u003e","manuscriptTitle":"The health economics evaluation of HPV vaccine with different immunization strategies in Zhejiang Province based on the PRIME tool","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-29 13:24:36","doi":"10.21203/rs.3.rs-3895745/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a161b1f0-7892-4e36-9d34-f05a94081cc3","owner":[],"postedDate":"April 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-18T04:24:05+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-29 13:24:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3895745","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3895745","identity":"rs-3895745","version":["v1"]},"buildId":"omnImTCwR2MFx8CMYfrG7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}