The Economic Evaluation of HPV Vaccination as a Prevention of Non-Cervical Cancer Using Modelling Approaches: A Systematic Review

. The cost-effectiveness of human papillomavirus (HPV) vaccine for non-cervical cancer including anogenital cancers and head and neck cancers has been evaluated in many countries. This is important for the decision-makers in health policy as they have a limited budget for an enormous option of health technology. The objective of this study is to systematically review the health economic studies in order to evaluate the cost-effectiveness of HPV vaccination for preventing non-cervical cancer including anogenital cancer and head and neck cancer. Approximately 496 articles were obtained from three databases (ProQuest: 430, Scopus: 40 and Pubmed: 29). The screening and selection of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The final articles were assessed by using the Consolidated Health Economics Evaluation Reporting Standards (CHEERS) checklist. Based on the review of fifteen articles, most articles concluded that HPV vaccination was cost-effective compared with current standard care. One study showed that HPV vaccination may be cost-effective if only the price is lowered. HPV vaccination is considerably a cost-effective solution to prevent non-cervical cancer based on the studies conducted in many countries particularly the ones with high income. Kkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkk


Introduction
Human papillomavirus (HPV) infection is now a well-established cause of cervical cancer, anogenital cancers (anus, vulva, vagina and penis) and head and neck cancers.In the global, it is estimated as 8% of the cancer burden, or approximately 690,000 cancer cases annually [1].Although anogenital cancers are much less frequent compared to cervical cancer, their association with HPV makes them potentially preventable and subject to similar preventative strategies as those for cervical cancer [2].Research has demonstrated that HPV vaccines are safe and effective in reducing HPV-related infections, genital warts, and pre-cancer [3].Some countries have started to use HPV vaccination as a prevention of other HPV-related cancers including anogenital cancer and head and neck cancer.One effective prevention and control strategy is the use of HPV vaccines designed to prevent HPV infection and HPV-related cancers. 1

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Corresponding email: endarti_apt@ugm.ac.idIt is believed that the HPV vaccine plays an important role in preventing cervical cancer in women.However, HPV vaccination is not just an issue for women since men also have risks of getting HPV infection.Moreover, high HPV vaccine coverage in men has significant benefits for women by reducing the risk of cervical cancer [4].In 2019, four programs started as gender-neutral in Dominica, Niue, Saint Kitts and Nevis, and Saint Lucia) and 10 more expanded vaccinations to males in Belgium, Belize, Chile, Denmark, Germany, Guyana, Ireland, Luxembourg, United Kingdom, and Uruguay [5].
HPV Vaccination Program in Indonesia has been introduced (partially in several provinces) since 2016 and is expected to be fully implemented in 2023 covering all regions and targeting girls only for grade 5-6 elementary school.
This information is notably important for the decision-makers in health policy as they have a limited budget for an enormous option of health technology.Therefore, the objective of this study is to systematically review the health economic studies in order to evaluate the cost-effectiveness of HPV vaccination for non-cervical cancer including anogenital cancers and head and neck cancers.

Method
The screening and the selection of the articles were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [6] (Fig. 1).

Data Source and Search Strategy
A systematic search was developed in three main databases (Pubmed, Scopus and ProQuest) that was performed on 28-30 July 2023 using some keywords in order to reach between the comprehensive and specific search results as explained below: Pubmed (filters: free full text, last 10 years, written in English) ("cost-effectiveness"[Title/Abstract] OR "cost utility" [ Scopus (filters: articles, written in English, last 10 years) (cost-effectiveness OR cost-utility OR costbenefit OR "economic evaluation") AND ("human papillomavirus" OR hpv) AND ( vaccine OR vaccination OR immunization ) AND ( non-cervical AND cancer OR "anogenital cancer" OR "head and neck cancer" OR "penile cancer" OR "anal cancer" OR "vulvar cancer" OR "vaginal cancer" OR "oropharyngeal cancer" OR "oral cavity cancer" OR "nasopharyngeal cancer" ) ProQuest (filters: scholarly journal, article, in the last 10 years, English, not SR) (cost-effectiveness OR cost-utility OR cost-benefit OR "economic evaluation") AND ( "human papillomavirus" OR hpv ) AND ( vaccine OR vaccination OR immunization ) AND ( noncervical AND cancer OR "anogenital cancer" OR "head and neck cancer" OR "penile cancer" OR "anal cancer" OR "vulvar cancer" OR "vaginal cancer" OR "oropharyngeal cancer" OR "oral cavity cancer" OR "nasopharyngeal cancer") All references were imported into CSV file and transferred to Microsoft Excel for duplicate removal and screening by title and abstract.

Eligibility Criteria
The inclusion criteria in this systematic review were health economic studies on HPV vaccination for non-cervical cancer including anogenital cancer and head and neck cancers since 2017 and articles were written in English.
The study selection process consisted of two main stages.Initially, titles and abstracts of all references were screened to identify potentially relevant articles.Subsequently, the full texts of these identified articles were retrieved and evaluated further.During this process, any duplicate articles were removed, as well as those that were not relevant to the topic under investigation.The inclusion criteria of this review were full economic evaluations, available in fulltext, published in English, presenting data on Quality-Adjusted Life Years (QALY) and Incremental Cost-Effectiveness Ratio (ICER).Additionally, the articles had to be original research and openly accessed.Several types of articles were excluded from the review, such as review articles, reports, letters, comments and book chapters.Since this systematic review is specific to the economic evaluation of non-cervical cancer, the articles that only discuss cervical cancer and precancerous would be excluded.Furthermore, the economic evaluation that did not use a modeling approach was also excluded.

Study Quality Assessment
The quality assessment of the included studies was conducted by the reviewer using the Consolidated Health Economics Evaluation Reporting Standards (CHEERS) checklist [7].

Data Extraction
The reviewer (NRH) independently extracted information related to health economic analysis from each selected study.The extracted information included the first authors' names and publication years, the country where the study was conducted, the type of health economic study, the study's objective, the research methodology (model) used, the perspective adopted in the analysis, the time horizon considered, details about the HPV vaccination methods (such as vaccine price, age target, and coverage), the discount rate used, clinical outcomes, the calculated ICER, the study's conclusion, and any sensitivity analyses results.

Data Analysis Method
To ensure whether the intervention of each study is cost-effective or not, the Incremental Cost-Effectiveness Ratio (ICER) should be compared with the cost-effectiveness threshold (CET) of each country.All costs, ICER and threshold were converted to US dollar in 2022 value by taking inflation into account [8] [9].

Result
From the search, approximately 496 articles were obtained from three databases (ProQuest: 430, Scopus: 40 and Pubmed: 29).Finally, we found 15 articles that are eligible to be reviewed from Pubmed, Scopus and ProQuest databases.
A cost-utility analysis (CUA), adopting Quality Adjusted Life Years (QALYs) as the main study outcome, was performed by 6 different studies.The other 2 studies performed cost effectiveness analysis (CEA) that used clinical parameters as study outcome, 7 studies combining CEA and CUA simultaneously.
Almost all studies using HPV vaccination as a prevention not only to one specific disease/cancer but to multiple kinds of cancer attributable to HPV, both cervival cancer and non-cervical cancer such as anogenital cancer (penile cancer, anal cancer, vulvar cancer vaginal cancer) and head and neck cancer (oropharyngeal cancer) [10]- [22].Only two studies from China and Australia that specifically assessed cost-effectiveness of HPV vaccination to prevent anal cancer, particularly in men who have sex with men (MSM) [23], [24].
Most of the studies tried to expand the HPV vaccination program to both girls and boys.There are 9 studies compared gender-neutral vaccination versus girl only vaccination [10], [17]- [19], [21], [22], [25] [20] [15], two studies assessed the costeffectiveness HPV vaccination program for specific high risk group e.i.men who have sex with men (MSM) [24] [23].Other two studies proposed the extended HPV vaccination for "mid adults" (females aged 12-26 years and males aged 12-21 years) [12], [13].One study compared the costeffectiveness of routine HPV vaccination, catch up vaccination and no vaccination in girls and women [16].The last study compared routine vaccination with catch up versus without catch up [10].

Study Design
Since the clinical outcomes of HPV vaccination, such as reduction in cancer incidence and mortality are difficult to obtain from clinical trials, a mathematical model is commonly used in the costeffectiveness analysis of HPV vaccination.All studies implemented modeling (Table 2).Many of the studies implemented dynamic transmission models (5 studies).There are studies using mathematical models, dynamic compartmental model, dynamic population-based and Markov model.
The perspective chosen for economic evaluation is a crucial factor that significantly impacts both the data utilized in the analysis and the resulting conclusions drawn from the studies.Different studies have employed various perspectives, such as the health care system (eight studies) and health care payer (five studies).However, in two studies, the perspective of their health economic analysis was not explicitly mentioned.In addition, none of the studies utilized the societal perspective in their evaluations.
To achieve a comprehensive understanding of the cost-effectiveness of HPV vaccination, it is essential to employ a long time horizon since the full impact of the vaccination on cancer incidence and mortality reduction will only become evident after several decades of implementation.The majority of studies have utilized a lifetime horizon, typically spanning 100 years, to capture the longterm effects.However, there are also instances where studies employed shorter time horizons, such as 10 years or 85 years.Interestingly, one study took a different approach by using a specific time frame in years, covering the period between 2017 and 2036.
In health economic studies, especially when using modeling and considering long time horizons, the discount rate becomes an important consideration.Most studies have utilized a discount rate of 3%.However, there are also studies that have employed different discount rates, such as 1.5%, 2%, 4%, and 5%.
Regarding the type of HPV vaccine evaluated, the majority of studies focused on the 9-valent (nonavalent) HPV vaccine.Only one study separately examined the 2-valent (bivalent) and 4valent (quadrivalent) HPV vaccines.Additionally, some studies compared the 4-valent vaccine to the 9-valent vaccine, and others compared the 2-valent vaccine to the 9-valent vaccine.Moreover, there was a study that compared three different HPV vaccines: the bivalent, quadrivalent, and nonavalent versions.
Vaccine coverage varied from 24.9-90% in many countries based on the vaccination program.Vaccine price is also varied in many countries.Most studies targeted HPV vaccination for boys and girls from age 9-14 years old.There are four studies that targeted from age 12 to 45 years especially study that aimed to extend the upper age limit of HPV vaccination.

Study Outcome
For all CUA studies, the health outcome was Quality Adjusted Life Years (QALY), while for CEA studies the outcome can be clinical, e.i. the number of HPVrelated cancer averted, number of death caused by HPV-related cancer averted.The main information provided by health economic studies is the ICER which explains the cost-effectiveness of a new intervention in comparison with a gold standard, previous recommendation or existing intervention (Table 3).
For high income countries like Australia, European Countries (The Netherlands, Belgium, Italy, Spain and Swedia), and Singapore, the cost-effectiveness threshold has been officially set in each country.Surprisingly, based on the study by Chesson in 2018 and 2020 United States which is the most high-income country has not established an official CET [12] [13].However, the other study from US used willingness to pay (WTP) as less than USD169,615 as a costeffectiveness threshold [15].Moreover, other countries that have not established the threshold used 1-3 times Gross Domestic Product (GDP) per capita as recommended by the World Health Organization (WHO) [28].Both France and Hong Kong used onetime GDP as a cost-effectiveness threshold [25] [14].
Whereas, CE Threshold can affect the costeffectiveness of HPV vaccination in a country.Based on the review of fifteen articles, most articles concluded that HPV vaccination was cost-effective compared with current standard care.One study conducted in Spain showed that HPV vaccination may be cost-effective if only the price is lowered [17].A study by Choi stated that HPV vaccination was only cost-effective for males [15].Studies conducted by Chesson, in 2018 to expand HPV vaccination for males from age 21 to age 26 years and in 2020 to include adults aged 27-45 years resulted that HPV vaccination is much less cost-effective than the comparison strategy of routine vaccination for adolescents at age ages 11 to 12 years and catch-up vaccination for women through age 26 years and men through age 21 years [12], [13].

Sensitivity Analysis
The sensitivity analysis method that used in fifteen articles were varied (Table 4).Most studies used oneway/univariate sensitivity analysis to address uncertainty and assess the robustness of the results in the health economic study [14] [17] [15] [19] [16] [25] [10] [22] [18].One study used probabilistic sensitivity analysis only [24].One study combined one-way and multi-way sensitivity analysis [12], two studies used both deterministic and probabilistic sensitivity analysis [13], [20], [21].Interestingly, there was a study used different type of sensitivity analysis named Latin model output [23].LHS is one of popular sampling Hypercube sampling (LHS) with a Monte Carlo Simulation Method to estimate the uncertainties in the method for Monte Carlo Simulation that the researcher can divide the input space into equal intervals and select a single random value for each interval.LHS can enhance the accuracy and efficiency of the simulation by ensuring uniform coverage of the input space and preventing random number clustering [29].Parameters that affect the most to the ICER such as discount rate [16] [17], [25] [18], vaccine price [12], [13], [21], [24], duration of vaccine protection [18] [25], vaccination coverage [7] [19] [10], utility of disease [16] [20], treatment cost.

DISCUSSION
This systematic review was undertaken to address the shortcomings of a previous study conducted by Abidi et al. in 2020 [30].The earlier review primarily focused on economic evaluations of HPV vaccination in the context of cervical cancer prevention.In contrast, the current review aims to fill the gap by specifically examining the cost-effectiveness of HPV vaccination for preventing non-cervical cancers, including anogenital cancers such as anal, penile, vulvar, vaginal, and head and neck cancers like oropharyngeal cancer.
The majority of the studies reviewed were carried out in high-income countries, where specific costeffectiveness thresholds have been established.By comparing the Incremental Cost-Effectiveness Ratio (ICER) with these thresholds, it is possible to determine whether HPV vaccination is considered costeffective for preventing non-cervical cancer.Based on the review, the majority of studies indicated that HPV vaccination is indeed cost-effective.However, in one study from Spain, certain adjustments may be required, such as reducing the vaccine price, to achieve costeffectiveness for HPV vaccination in preventing noncervical cancer.Another study aimed to reach 80% vaccination coverage only cost-effective for males, not for females.And the last two studies recommend that HPV vaccination is only cost-effective for routine vaccination for girls and boys ages 11-12 years and catch-up vaccination for women through age 26 years and men through age 21 years, not more than that.
All the health economic studies included in this review adopted a modelling approach to estimate the long-term costs and outcomes associated with the use of HPV vaccines, focusing on the progression of cancer.The majority of these studies utilized a dynamic model, which offers a more comprehensive depiction of how infectious diseases, like HPV infection, spread throughout a population, considering factors such as herd immunity.Dynamic models require more extensive and complex data, including information like sexual contact matrices and force of infection, which might be more readily available in developed countries.On the other hand, some studies opted for a static model, commonly known as a Markov model.This approach was deemed sufficient for describing the natural history of non-cervical cancer in a population, particularly when vaccination coverage is potentially high.The static model allows for a simpler representation of the disease progression in such cases [31].
Sensitivity analysis has a critical role in health economic studies.The most popular type is oneway/univariate sensitivity analysis.There were some studies that combined two types of sensitivity analysis to assess the robustness of the result of the study.
The systematic review presented here encountered certain limitations.One notable limitation was the lack of available studies from low-middle-income countries.This is concerning as these countries tend to have higher HPV infection incidence and face resource constraints, necessitating cost-effective strategies.To address this gap and develop more effective vaccination approaches, future studies should focus on non-cervical diseases in low-middle-income countries as potential outcomes that can influence the effectiveness of HPV vaccination.By exploring these aspects, researchers can better tailor vaccination strategies to meet the specific needs and challenges of different regions, including those with limited budgets.Deterministic one-way sensitivity analyses Duration of protection, discount rate Cheung et al., [10] Deterministic one-way sensitivity analyses vaccination coverage and discount rate Simons et al., [27] One-way/univariate deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) variation in vaccine price, herd immunity from females and vaccine efficacy Chesson et al., 2020 [13] one-way and multi-way probabilistic sensitivity analysis current and historical vaccination coverage, vaccine price, and the impact of HPV diseases on quality of life Chesson et al., 2018 [12] one-way and probabilistic sensitivity analysis Vaccine price Wolff et al., 2018 [22] Deterministic sensitivity analyses were performed to investigate how varying the input parameters affected the results.
Vaccine coverage (higher than 90%) Mennini et al., 2017 [18] One-way sensitivity and scenario analyses were conducted and the cost-effectiveness results are displayed in Tornado diagrams discount rate, duration of protection Zhang et al., 2017 [23] Latin Hypercube sampling with a Monte Carlo Simulation Method Not stated

CONCLUSION
HPV vaccination is considerably as a cost-effective solution to prevent non-cervical cancer based on the studies conducted in many countries particularly the ones with high income.It is recommended to conduct an economic evaluation to estimate the costeffectiveness HPV vaccination as a prevention of noncervical cancers in low and middle income country like Indonesia.It is suggested to begin the study by expanding the HPV vaccination target to boys or adult women through ages 26 years.

DECLARATION OF COMPETING INTEREST
The author declares that she has no competing interests or personal relationships that could have appeared to influence the work reported in this study.

Table 1 .
Study Characteristics of the health economic studies of HPV Vaccination for Non-cervical cancer CEA: cost-effectiveness analysis, CUA: cost utility analysis, HPV: human papillomavirus, MSM: men who have sex with men, GNV: gender-neutral vaccination, FOV: female-only vaccination, OPC: oropharyngeal cancer, US: United States,CIN: cervical intraepithelial neoplasia, VaIN: vaginal intraepithelial neoplasia

Table 2 .
Methodological Aspects and the Base-case Paramaters of Health Economic Studies of HPV vaccination

Table 3 .
Clinical and economic outcomes of health economic studies of HPC vaccine

Table 4 .
Sensitivity analysis of health economic studies of HPV vaccination