Knowledge, Acceptance, and Willingness to Pay for Human Papillomavirus (HPV) Vaccine: A Systematic Review

. Cervical cancer is the fourth most common type of cancer incidence in women. It has been recognized that Human Papillomavirus (HPV) is causative agent in the pathogenesis of cervical cancer. In 2022, 117 countries have included HPV vaccine in their national immunization program. Understanding participants’ decision regarding their children and themselves being vaccinated is important to ensure high coverage of the vaccine. This study aimed to conduct a systematic review of knowledge, acceptance, and willingness to pay for HPV vaccine. The required information was collected by searching with relevant keywords during October-December 2022 for articles published from 2013 – 2022 in PubMed, Scopus, ScienceDirect, and SpringerLink. The data were analyzed in Excel and reported descriptively. Finally, 22 studies were included to review. Most of the participants were female (96.44%) and the majority had health workers background (50.09%). The knowledge of mostly results was poor (40.9%). The acceptance of HPV vaccine was high, the range vary from 39–98.8%, especially for the vaccine with higher degree, longer duration of protection, lower out-of-pocket, and lower risk of side effects. Overall, the respondents’ attitude was positive toward vaccination. The most frequent method used for measuring WTP was CVM (54.54%). The average WTP range from 0.1– 17.51% to GDP per capita (9.9–745.25 USD). The cost was the primary reason that impact to the willingness to pay and acceptance. Results showed that the acceptance rate of HPV vaccination and WTP were relatively high when the vaccine was offered for free or reasonable price, even though their knowledge was poor. It is recommended to reduce the cost of vaccination program and to increase knowledge, awareness, and attitude of people.


Introduction
Cervical cancer is the fourth most common cancer among women globally, with an estimated new cases and deaths were more than 600,000 and 300,000 in 2020 respectively.Furthermore, 90% of them occured in lowand middle-income countries [1].Human Papillomavirus (HPV), especially variants 16 and 18, has been identified as the causative agent in the pathogenesis of cervical cancer [2].In 2006, the United States granted a license for the first HPV vaccine [3].As of March 2022, 117 countries (corresponding to approximately one-third of the global target population) have introduced HPV vaccine into their  Corresponding author: endarti_apt@ugm.ac.id national routine immunization schedules, with 10 new introductions planned by the end of 2022 [4].
Clinical trials and post-marketing surveillance have shown that HPV vaccines are safe and effective in preventing infections with HPV infections, high grade precancerous lesions and invasive cancer [5].SAGE advised the following updates to HPV dosage schedules: 1-2 dose schedules for the major target population of girls aged 9 to 14, 1-2 dose schedules for young women aged 15-20, and 2 doses separated by 6 months for women over the age of 21 [6].Since the HPV vaccine should be administered to young adolescents, understanding parents' decision-making processes regarding their children being vaccinated is important to ensure high coverage of the vaccine [7].Beside the vaccine prices, there were some other obstacles.Barriers include low risk perception, parents' beliefs that their daughters do not require vaccinations because they are not sexually active, worries about safety and efficacy, ignorance of the necessity for vaccination, and a lack of information [8].
To help address this gap, this study aimed to conduct a systematic review of knowledge, acceptance, and willingness to pay for HPV vaccine.The analysis was conducted to synthesize evidence of participants' information needs, views and preferences regarding HPV vaccination.The availability of such information is critical for decision-making and planning to implement the most suitable interventions to develop HPV vaccination as one of the most effective cancer prevention programs.

Methods
Methods are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist [9].

Data Source and Search Strategy
A search strategy was developed in PubMed, Scopus, ScienceDirect, and SpringerLink.The timeframe selected for searching the articles is the ones which have published during 2013 -2022.The strategy included an extensive list of keywords and related subject headings to broaden the search by finding articles related to HPV vaccine.The following key words were used in search strategy using operator Boolean construction: "Willingness to Pay" AND "HPV vaccine" AND "knowledge, acceptance, attitude", and all articles were retrieved from 23rd October to 17th December 2022.

Eligibility Criteria
Studies were included if they were reporting: knowledge, acceptance, attitude, Willingness to Pay and factors associated of participants concerning HPV vaccine.Studies were excluded if they were reviews, abstracts, editorials, conference reports, and not using English language.Furthermore, other economic evaluations such as cost benefit analysis, cost effective analysis, and cost utility analisis were also excluded.

Study Quality Assessment
The quality of included studies was evaluated by reviewer using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [10].The checklist options include "Yes", "No", "Unclear", and 'Not Applicable".It is also to identify bias in each study.

Data Extraction
Two forms of data extraction were designed.The 1st form was for extracting general characteristics of the included studies, while the 2nd was for extracting the studies' results.Key data for general characteristics extracted included author, year, country, aim of study, setting, study design, duration of observation, number of respondents, instrument, and method for measuring WTP.Key data to extract the study results included demographics, % of positive WTP, WTP, % of GDP per capita, knowledge, attitude and acceptance, factors influenced in WTP, reason for not WTP, and other results.

Data Analysis Method
Extracted data were analysed in Excel.The countries' currency value reported in included studies was presented in original currency and USD [11].In some studies, the value was reported as a percentage of the participants (e.g: 45.5% participants were willing to pay for the HPV vaccine).To calculate the percentage of WTP from GDP per capita, the amounts of WTP counted by currency in USD were converted to 2022 USD using free online website US Inflasion Calculator then were divided by GDP per capita (counting the highest amount if there were some WTP measurements) in the year of study (2022) [12].The World Bank data were used as a basis for calculating GDP per capita and country segmentation based on economic status [13].

Details of Included Studies
Out of 487 articles found from databases and other sources, 43 were excluded due to duplication between databases.In the title and abstract screening phase, 117 were also excluded.A total of 97 studies were excluded from full-text review.Additionally, 2 studies were found by hand searching.Finally, 22 articles were included in this study, as presented in Figure 1.All of the studies included in the final set were published in the last ten years (2013 -2022).The characteristics and results of the reviewed articles were presented in Table 1 and 2.
Regarding their aims, the articles fell into 4 categories.The majority (19) focused on willingness to pay; 14 on knowledge, awareness and acceptance; 8 on attitude; and 3 on factors associated with WTP.
All included studies were cross-sectional and used questionnaires as the instrument to data collecting method.Twelve of them used a self-administered questionnaire, 5 used structured questionnaire, 4 with online survey, and 4 prefer to face-to-face interview.

Knowledge, Attitude and Acceptance of HPV and HPV Vaccine
Mostly studies assessed knowledge of HPV or knowledge of its vaccination.Of the 22 studies included, awareness and/or knowledge were assessed with various method of  The attitude toward HPV vaccine were positive.Most of them would accept the vaccine for their children or themselves.Acceptance rates in the studies range 39 -98.8%.Significant factors associated with acceptance are location of high school, study year, paternal educational level, annual household income, monthly disposable income, perceived self-confidence in taking the HPV vaccine in the near future, having no barriers to taking time off to take the HPV vaccination, and regular exposure to HPV vaccination information in the mass media.Despite positive attitude and high acceptance, the awareness and knowledge about cervical cancer and HPV vaccine were poor [15], [17], [20], [22], [24], [26], [27], [29], [31], moderate [30], [32], [33], [35], to high [16], [21], [25], [28].Lack of knowledge were caused by rare information and difficulty to access [20].
Misconceptions and suspicions related to cervical cancer and the HPV vaccine were also common.Some participants were afraid of the safety and possible side effects due to the vaccine [18], [22], [30].A small number of studies examined the religious beliefs regarding the HPV vaccine [18].Religious norms also influenced how parents saw the need for the vaccine.Some parents believed they had raised their children properly and they would not engage in premarital sex, and therefore a vaccine to prevent sexually transmitted infection was not needed at that stage of their lives [7].Surprisingly, a study mentioned that 70.7 % of its respondents have thought that vaccination will encourage the young population to become sexually active [33].

Willingness to Pay for HPV Vaccine
Out of the 22 articles reviewed in the study, 12 studies used Contingent Valuation Method (CVM) to elicit WTP, 4 studies used Discrete Choice Experiment (DCE), and 6 studies used market price.In general, cost of the vaccine was viewed as an important factor.Most participants thought that the HPV vaccine was expensive (10 studies).and cost was important factor when deciding whether or not to give the vaccine to their children.Many parents reported a high intention to vaccinate their children if the vaccine was going to be provided for free.Even if it was not free, many stated they were willing to pay for the vaccine so long as the price was reasonable [23].
The WTP were also counted for the proportion based on GDP per capita.The result showed that the percentage of WTP (converted to USD rate in 2022) compared to 2022 GDP per capita range from 0.91-1.34%(9.9-14.49USD) in low-income economics, 0.1-17.34%(55-417.5 USD) in lower-middle income economics, 0.32-17.51%(41.91-745.25 USD) in upper-middle income economics, and 1.83-1.87%(241-247 USD) in high income economics.Based on economic status of the countries, the highest proportion was in Thailand (UMICs) [29].Some studies cited reasons for unwillingness to pay related to unwillingness to accept.In 10 out of 22, the cost was the main reason.Other reasons were afraid of safety and side effects of the vaccine [18], [22], [30], religious belief [18], felt unnecessary to be vaccinated [21], [22], [25], being male [21], unsuitable age [21], and presumption that vaccinating young will encourage sexual activity [33].

Discussion
Most of the reviewed studies were conducted in Asian, especially South East Asian countries, others were in Africa and South America.These setting areas were aligned with the Globocan Data Report 2020 that mentioned cervical cancer caused by HPV as the most commonly diagnosed cancer and the leading cause of cancer death in those regions [1].Epidemiological studies of cancers, especially cervical cancer, have shown that this type of cancer is one of the most common cancers in these regions.In addition, cervical cancer-related deaths in South East Asia are among the highest in the world [36].For the past few decades, mortality and incidence rates of cervical cancer actually have decreased in the majority of the world's regions.The decreases are attributed to elements that are either associated with rising socioeconomic averages or a declining risk of persistent infection with high-risk HPV as a result of advances in genital cleanliness, decreased parity, and a declining prevalence of sexually transmitted diseases.Despite the observations of rising risk among younger generations of women in some countries which may in part reflect changing sexual behavior and increased transmission of HPV that is insufficiently compensated by screening approach, cervical cancer screening programs have accelerated declines in many countries in Europe, Oceania, and Northern America.Although incidence rates are still high, rates have also fallen in the 2000s throughout the Caribbean and in Central and South America (such as Argentina, Chile, Costa Rica, Brazil, and Colombia).Furthermore, premature cervical cancer mortality has increased dramatically in recent generations in regions lacking efficient screening, such as Eastern Europe and Asia [1].
One of the studies focused on vaccination for boys.An interesting finding is that no participant mentioned their sons' prior HPV immunization.This is understandable as many countries still targeting girls aged 9-14 as priorities.WHO recommends that where possible and practical, vaccination of secondary targets, such as boys and older females, is advised, after the primary target girls were highly achieved [37].Some of high-income countries that have achieved high coverage of girls vaccinated start planning to move from a girls-only HPV vaccination strategy to universal or gender-neutral strategy [38].This may affect the availability and adequacy of the HPV vaccine worldwide.
According to some studies, people considered HPV vaccination was only for female, and male did not need it [21].The same circumstances regarding knowledge level of people about HPV vaccine and related disease also happened in other countries.In Indonesia, a study conducted a structurededucational intervention to parents because of their low level of knowledge about HPV infection and the vaccines.Only 48.8% of parents and 49.2% of parents, respectively, had heard of the vaccine and HPV infection before receiving the intervention [39].Meanwhile in Vietnam, only 18.9% of the parents achieved good level of knowledge about HPV and HPV vaccine [17].Along with the knowledge level findings, it is recommended to policy makers to create innovative approaches to raise the people knowledge level widely.However, our findings showed that the HPV vaccine acceptance was relatively high.Significant factors associated with acceptance are location of high school, study year, paternal educational level, annual household income, monthly disposable income, perceived self-confidence in taking the HPV vaccine in the near future, having no barriers to taking time off to take the HPV vaccination, and regular exposure to HPV vaccination information in the mass media, similar with the previous systematic review in 2018 [40].
The result also showed a relatively high WTP if vaccine was offered free or at reasonable price.These results were in line with previous systematic review of ASEAN countries [7].This may also due to high prevalence of this type of cancer and its association with high-risk sexual behavior, also the growth of educational level and higher household income.As WHO recommends the HPV vaccine be included in countries vaccination program since had been introduced in 2006, about one third of global population in 117 countries has been introduced HPV vaccination as national immunization program today, making it become one of the most common types of cervical cancer prevention.This action was taken early based on many previous studies stated that HPV vaccination was very cost effective, measured with every disability-adjusted life-year averted costing less than the gross domestic product per head in 87% or 156 of 179 countries [41].
As the WTP was high before learning the vaccine price then dropped after knowing the high price offered, it is important to pay more attention to the policies and strategies provided by many organizations including WHO and Government in each country as policymakers, in order to gain better control and to increase cost-effectiveness of prevention methods.Reducing the cost, simplifying the access of the vaccination program, maintaining the vaccine availability and its supported cold chain facilities, followed by developing user-friendly and all over information system will be beneficial.HPV vaccination should be part of a multifaceted public health strategy entailing screening, condoms, and education of all stakeholders to reduce the significant burden of sexual transmitted diseases [42].
On the other hand, the results study also showed that people's knowledge and awareness of HPV infection and HPV vaccination were poor.In this regard, developing effective interventions to increase those things that related to acceptance and WTP is critical.
This systematic review provided summaries of the concerns in all included studies.However, this review had several limitations.The author could not conduct a metaanalysis due to the type of data reporting.In this study, only published articles in English version that were reviewed due to author's language literation.In addition, although it is easier to identify published articles with the use of online databases in this study, evidence selection biases from missed studies continue to be a problem when systematically reviewed.Moreover, unpublished studies that have related topic but cannot be included here potentially will be publication bias.These conditions can lead to reporting bias toward its findings.Therefore, findings from this review should be interpreted cautiously.

Conclusion
Results showed that the acceptance rate of HPV vaccination and WTP were relatively high among individuals when the vaccine was offered for free or reasonable price, even though their knowledge was poor.According to the results of this study, it is recommended for the government to reduce the cost of vaccination program and to increase knowledge, awareness, and attitude of people through better healthcare interventions and suitable approaches.

Table 1 .
Characteristics of the 22 studies .Eight studies assessed awareness with an initial question 'Have you heard/are you aware of HPV?" and rows of other "Yes or No" questions related.Other 6 studies assessed awareness and/or knowledge of HPV and HPV vaccination by answering "True or False" questions.
**some studies used >1 combination methods in eliciting WTP Abbr: WTP = Willingness to Pay, DCE = Discrete Choice Experiment.measurements