Received: 28 June 2019 Revised: 8 May 2020 Accepted: 11 October 2020 DOI: 10.1111/ajco.13513 ORIGINAL ARTICLE A systematic review of the barriers to implementing human papillomavirus vaccination programs in low- and middle-income countries in the Asia-Pacific Abbygail Therese Ver1 Kevin Miko Buac1 Kin Israel Notarte1 John Nazareno III1 Jacqueline Veronica Velasco1 J. Alfred Lozañes2 Dominic Antonio2 Warren Bacorro1,3 1 Faculty of Medicine and Surgery, University of Santo Tomas, Manila, Philippines 2 College of Medicine, University of the East – Ramon-Magsaysay Memorial Medical Center, Quezon City, Philippines 3 Department of Radiation Oncology, Benavides Cancer Institute, University of Santo Tomas Hospital, Manila, Philippines Correspondence Warren Bacorro, MD, Faculty of Medicine and Surgery, University of Santo Tomas, Manila 1008, Philippines. Email: wrbacorro@ust.edu.ph Abstract Aim: The increasing burden of human papillomavirus (HPV)-related diseases in lowand middle-income countries (LMICs) could be alleviated by effective HPV vaccination programs. In this systematic review, we examined barriers to introduction, implementation, and/or sustainability of HPV vaccination programs in LMICs in the Asia-Pacific region (AP-LMICs). Methods: A systematic search of literature from the past 10 years (2010-2019) was performed through PubMed, Cochrane CENTRAL, and Google Scholar. Studies were included if they reported barriers to HPV vaccination in AP-LMICs. All study designs were included except commentaries and editorials. The journal articles were assessed using the Joanna Briggs Institute critical appraisal checklists. Results: A total of 46 eligible articles were included. An increase in publications was noted from 2010 to 2019. Barriers were diverse and were classified into four levels–– government, healthcare providers (HCPs), society, and individual. The top specific barriers that were identified across AP-LMICs are lack of funding and political support at the government level, lack of awareness among HCP and lack of vaccination programs at the level of health providers, and the perceived cost/benefit ratio for the individual level. Conclusion: Barriers to successful implementation of HPV vaccination programs differ among Asia-Pacific LMICs. Policymakers will need to evaluate the relative importance of these barriers in their target areas and population in order to draft an effective dissemination and implementation strategy. KEYWORDS Asia-Pacific, cervical cancer, dissemination and implementation science, human papillomavirus, LMICs, vaccination Asia-Pac J Clin Oncol. 2021;1–16. wileyonlinelibrary.com/journal/ajco © 2021 John Wiley & Sons Australia, Ltd 1 VER ET AL . 2 1 INTRODUCTION Search results from all databases were checked for replicates and Human papillomavirus (HPV) is a sexually transmitted infection that then initially screened for inclusion using the titles and abstracts. For can be passed through mouth, skin, or genital contact. Despite its further screening, the following operational definitions were used. prevalence, HPV infection is usually cleared by the body. Persistent LMICs included low––(Gross National Income, GNI, per capita of $995 infection by high-risk HPV strains could lead to malignancy, such as or less) and lower-middle income (GNI $996-$3985) economies as Vaccination against high-risk defined by the World Bank.13 The Asia Pacific region referred to East HPV strains, which have been available since 2006, has been shown Asia, South Asia, Southeast Asia, and Oceania. A barrier was consid- to decrease the prevalence of HPV-related malignancies.4–7 How- ered to be any factor that prevents the implementation of a national ever, HPV-related diseases continue to impact low- and middle-income HPV vaccination program, including physical, psychological, financial, countries (LMICs), where 85% of the morbidity and mortality caused geographical, cultural, language, and resource barriers.14 Specifically, oropharyngeal and cervical cancers.1–3 Further, the increase in HPV-driven physical barriers include objects that prevent an individual from get- malignancies, such as oropharyngeal, as well as oral, laryngeal, penile, ting to the health care facility. Psychological barriers are thoughts anal, and vulvar cancers, indicates that this is a health issue for all or understanding of the individual on the service, which includes the genders.9 general doctrines and misconceptions of the subject at hand. Finan- by cervical cancer takes place.8 Effective prevention and management of HPV-related diseases, cial barriers are the cost to access the service. Geographical barri- including routine screening, public health policy, follow-up treatment, ers are noted when individuals live some distance away from where WHO rec- the service is available. Cultural and language barriers include, but ommends including HPV immunization in national immunization pro- are not limited to, cases where information about healthcare access is grams especially in countries where cervical cancer is a public health available only in English. Finally, resource barriers are present when problem.11 However, if the current HPV vaccination program fails to the appropriate service is unavailable. The reference list of each eli- expand, it is estimated that in the next 50 years approximately 45 mil- gible article was manually checked for further potentially relevant lion women would be diagnosed with cervical cancer, with two-thirds of studies. public education, and awareness, are lacking in LMICs.10 To prevent this and ensure the success of Full text of each article was retrieved and assessed for final eligibility HPV vaccination programs in LMICs, it is, therefore, important to iden- independently by any two reviewers (AV, KN, JV, KB, JN, JL, and DA). tify and address the barriers to HPV vaccine accessibility, most espe- Any disagreement was resolved by consensus of all authors (AV, KN, cially the AP-LMICs. JV, KB, JN, JL, DA, and WB). cases occurring in LMICs.12 The authors sought to systematically review barriers to the institution and effective implementation of HPV vaccination programs in AP- 2.2 LMICs. Data extraction Any two independent reviewers (AV, KN, JV, KB, JN, JL, and DA) were 2 METHODOLOGICAL APPROACH assigned to extract data for each article. A third reviewer (AV, KN, JV, KB, JN, JL, and DA) checked the extracted data for completeness and 2.1 Search strategy and eligibility criteria accuracy. Disagreements were resolved by consensus of all the authors (AV, KN, JV, KB, JN, JL, DA, and WB). A comprehensive search was carried out in PubMed, Cochrane CEN- The journal and year of publication and the LMICs covered by each TRAL, and Google Scholar for articles published from January 1, 2010 article were noted. A checklist consisting of barrier categories and to March 31, 2019. Various combinations of the following key terms levels was used and refined as additional categories or subcategories were used: human papillomavirus, vaccine, immunization, low-income emerged on further review. Addition of categories or subcategories countries, middle-income countries, barriers, problems, availability, was based on a consensus of all authors. Information was extracted implementation, access, acceptance, sociocultural, political, logistic, from each paper on (1) barrier, (2) barrier category (physical, psycho- financial, cervical cancer, and Asia Pacific. Key term combinations used logical, financial, geographical, cultural, language, and resource), and (3) are listed in the Supplementary Material. levels (government, healthcare provider [HCP], and society or individ- The following types of studies published in the English language were included for screening: descriptive studies, observational analytic studies, experimental analytic studies, mixed methodology studies, ual). Any intervention to barriers discussed, whether actually implemented or proposed, in any of the articles was likewise extracted. reviews, and analyses on HPV vaccination and its barriers. The following were excluded: commentaries, editorials, ongoing research, unpublished studies, and other working papers. Other systematic reviews and 2.3 Critical appraisal and risk of bias meta-analyses were also checked to review for relevant studies. Articles predating 2010 were excluded to limit review to current literature The Joanna Briggs Institute Critical Appraisal checklists for analyt- generalizable to the present situation. ical cross-sectional studies, systematic reviews, prevalence studies, VER ET AL . 3 FIGURE 1 Screening and appraisal of journal articles for use in the review study and qualitative research were used to assess the risk of bias in 25 2010-2014 Each article was individually appraised by two researchers. For each item in the appropriate appraisal checklist, a judgment was made whether a high, low, or unclear risk for bias was present. The rationale for the judgment was noted. Disagreements were resolved by consensus of all authors. To simplify and synthesize, the risk of bias assessment was tabulated, grouping the articles into any of the following categories: (1) systematic reviews, (2) cohort studies, (3) cross-sectional studies, and (4) Number of published article individual articles at the study and outcome levels.15 Summary measures 20 15 10 5 0 qualitative research. 2.4 2015-2019 Government Health provider Society Individual F I G U R E 2 Identified barriers that delimit the successful implementation of HPV vaccinations in Asia-Pacific from 2010 to 2019 The articles were classified according to the year of publication (20102014 and 2015-2019) in order to examine the trend over time. The 3.2 Study characteristics identified barriers were classified into the categories mentioned above and into four levels at which they are considered to operate. A critical A total of 14 systematic reviews, 6 cohort, 15 analytic cross-sectional, synthesis of the prevalent barriers, barrier categories, and levels and 11 qualitative studies were included. Of these, 22 were published in the LMICs and over time was done. This synthesis was analyzed in 2010-2014, and 24 in 2015-2019. For both periods, the most tack- against the socioeconomic profile and relevant World Indices of the led barrier among the published articles in the past 10 years was at LMICs. the HCP level (Figure 2). From 2010 to 2014, the second most tack- The data that support the findings of this study are available from the corresponding author upon reasonable request. led barrier was at the individual level, particularly on the awareness of people regarding the HPV vaccination program. From 2015 to 2019, the second widely tackled barrier was at the government level, particularly lack of political support. Society-level barriers were least tackled 3 RESULTS throughout the years. A total of 15 AP-LMICs were identified from the systematic review 3.1 Study selection (Figure 3). India was the most widely studied country, followed by Vietnam and Bhutan. The least studied countries (addressed in only one The search strategy identified a total of 4676 journal articles. After article) were Mongolia and Papua New Guinea, which have among the removal of duplicates, initial screening, eligibility assessment, and crit- highest cervical cancer rates, as well as Micronesia, Pacific Island coun- ical appraisal, 46 unique articles were considered eligible (Figure 1). tries, and Sri Lanka. VER ET AL . 4 Bangladesh Bhutan Cambodia India Indonesia Kiribati Laos Micronesia Mongolia Nepal Pacific Island Countries Papua New Guinea Philippines Sri Lanka Vietnam 0 FIGURE 3 2 4 6 8 10 12 Number of CitaƟons 14 16 18 Number of citations regarding HPV vaccination among LMICs in Asia Pacific from 2010 to 2019 Table 1 summarizes the barriers identified at each level and for three were associated with high risk, due to selection; and two, unclear each LMIC. At the government level, lack of funding (19 article cita- risk, due to selection, measurement, confounding, and/or attrition bias tions), resources allocation (18), and political support for HPV screen- (Table S4). Of the qualitative studies (n = 11), eight were associated ing and prevention (7) were the prevailing themes. Further, govern- with unclear risk, due to participant and/or researcher/sponsor bias ment projects and national programs were examined in terms of exe- (Table S5). cution and effect. At the HCP level, barriers were reported as lack of awareness of HPV and HPV vaccination among HCPs (26), unavailability and/or poor accessibility of healthcare establishments(16) and prac- 4 DISCUSSION titioners (4), and lack of recommendations of physicians with regard to HPV prevention (7). HCPs were evaluated based on how they address We reviewed documented barriers in LMICs against the current pre- their patients’ concerns regarding HPV, and their views on HPV pre- vailing socioeconomic milieu to gain insights, which could inform vention, specifically through vaccination. At the society level, differ- approaches to designing and improving HPV vaccination programs. In ent aspects that influence the prevailing perception and attitude of particular, we examined World Bank indices pertaining to economy, the people toward vaccines and approach to HPV prevention were education, healthcare, competing public health issues, infrastructure, explored, including the level of literacy (11), health literacy (11), culture poverty, and gender equality (Table 2, data derived from World Bank, (11), religion (5), and English literacy (2). At the individual level, barri- 2019; WHO, 2018).16,17 These factors impact national healthcare pol- ers were reported as personal perception (24), in terms of its safety, icy and capability as well as influence individual health-seeking behav- efficacy, and cost, and of HPV vaccination and vaccinations in general; ior and acceptance of HPV vaccination. individual health-seeking behavior based on the awareness of personal health and diseases (20), knowledge of HPV as a disease (7), and individual approach to accessing quality medical care (4). 4.1 Regional profile The top specific barriers that were identified across AP-LMICs are funding (14 countries) and political support (13) at the government Poverty headcount ratios are highest in Micronesia (41.2%), Papua level, lack of awareness and vaccination programs (14) at the level of New Guinea (39.9%), and Mongolia (28.8%), and lowest in Sri Lanka health providers, and the perceived cost/benefit ratio (12) for the indi- (4.1%), Vietnam (6.7%), Bhutan (8.2%), and Indonesia (9.8%). Adult lit- vidual level. eracy rate is generally high (80-98%), but low in Papua New Guinea (62%), Bhutan (67%), Nepal (68%), Bangladesh (74%), and India (74%). Bangladesh has the highest population density (1240/km2 ), which is 3.3 Risk of bias assessment more than double that of India (455), in second, and more than triple that of Philippines (358), Sri Lanka (346), and Vietnam (308). The rest Of the systematic reviews (n = 14), one was associated with high risk have lower population densities (2-196), being lowest in Mongolia (2), for bias, due to quality of and bias from the primary studies; and seven, Papua New Guinea (19), Bhutan (20), and Laos (31). Except for Mongo- unclear risk, due to same (Table S2). Of the cohort studies (n = 6), lia (68%) and Indonesia (55%), urban population represents less than one was associated with high risk, due to nonidentification of con- 50% of the total (13-47%). Except for Vietnam (1769), Mongolia (1690), founding factors; and four, unclear risk, due to selection, confounding, and Indonesia (1283), the number of secure internet servers per 1 mil- and/or attrition bias (Table S3). Of the cross-sectional studies (n = 15), lion people is low (50-412). VER ET AL . TA B L E 1 Identified barriers to HPV vaccine implementation from 2010 to 2019 Bangladesh Bhutan Cambodia India Indonesia Kiribati Laos MicronesiaaMongoliaa Nepal Pacific Island Countriesa Funding 2 5 3 5 2 2 1 1 4 – 1 Political support 2 8 6 9 1 3 2 1 1 5 – 1 2 – 6 Fund allocation 1 3 3 1 1 – – – – 3 – – – – 3 Awareness and vaccination programs 1 5 4 14 1 2 3 – 1 5 1 1 1 1 10 Availability and accessibility of facilities 3 5 4 4 3 2 2 – – 5 – – 1 1 4 Availability and accessibility of physicians – 2 1 1 2 – – – – 1 – – 1 – – Recommendations from physicians – – – 4 2 – – – – 1 – – – – 2 Level of health literacy – 3 3 7 1 2 1 – – 3 – – 1 – 5 Level of education 2 3 3 7 1 1 2 – – 4 – – 1 1 2 Culture 1 2 3 5 2 – – – – 4 – – – – 2 Religion – – – 2 1 – – – – – – – – – 1 Barriers Papua New Guineaa Philippines Sri Lankaa Vietnam 2 8 GOVERNMENT LEVEL 2 1 HEALTHCARE PROVIDER SOCIETY (Continues) 5 6 TA B L E 1 (Continued) Barriers Bangladesh Bhutan Cambodia India Indonesia Kiribati Laos MicronesiaaMongoliaa Nepal Pacific Island Countriesa Level of English literacy – 1 1 – – – – – – 1 – – – – – Level of awareness – 4 5 7 1 2 1 – – 6 1 – 2 – 4 Perceived efficacy and safety – 3 4 7 3 1 – – – 5 1 – 2 – 5 Perceived cost/benefit ratio 1 3 4 5 2 2 1 – 1 4 – 1 4 – 4 Perceived risk of getting HPV 1 – 1 6 1 – – – – 2 1 – 2 – 2 Personal acceptance of vaccine – 1 2 5 1 1 – – – 3 1 – 1 – 3 Perceived gravity of HPV disease 1 – – 3 1 – – – – 2 – – 1 – 1 Capability for OOP spending – – – 1 – – – – – 1 – – 1 – 1 Papua New Guineaa Philippines Sri Lankaa Vietnam INDIVIDUAL a Data derived from only a single source article. VER ET AL . VER ET AL . TA B L E 2 Socioeconomic profiles, development and healthcare indices, and incidence of HPV-related cancers in LMICs in the Asia-Pacific Papua Pacific New Island Countries Guinea Bangladesh Bhutan Cambodia India Indonesia Kiribati Laos Micronesia Mongolia Nepal Population (in thousands) 161 356. 04 754.39 16 249.80 1 352 617.33 267 663.43 115.85 7 061.51 112.64 3 170.21 28 087.87 2 457.37 Religion Muslim Buddhist Buddhist Muslim – Buddhist Christian Buddhist Hindu Philippines Sri Lanka Vietnam 8 606.32 106 651.92 21 670 98 540.40 Christian Christian Buddhist Folk religion GENERAL INFORMATION Government type Hindu Federal ParliaParliamentary Constitutional Parliamentary menrepubmonarconstitary lic chy tutional repubmonarlic chy Federal SemiFederal Presidential ParliaPresidential Presidential Communist republic in repubmenrepubrepubstate free lic tary lic lic associarepubtion lic with US – – Communist Parliamentary Presidential Presidential state Democrepubrepubracy lic lic under a constitutional monarchy; a Commonwealth realm ECONOMY GDP per capita (USD) 1 698.3 3 243.3 1 510.3 2 010 3 980.3 1 625.3 2 542.5 3 568.3 4 121.7 1 033.9 4 224.5 2 730.3 3 102.7 4 102.5 2 566.6 8.2 17.7 21.9 9.8 21.8 23.4 41.2 28.4 25.2 – 39.9 21.6 4.1 6.7 POVERTY Poverty 24.3 headcount ratio at national poverty line (% of population) (Continues) 7 8 TA B L E 2 (Continued) Bangladesh Bhutan Cambodia India Indonesia Kiribati Laos Micronesia Mongolia Nepal Papua Pacific New Island Countries Guinea Philippines Sri Lanka Vietnam EDUCATION Literacy rate, 77 adult male (% of males ages 15 and above) 75 87 82 97 – 90 – 98 79 93 65 98 93 96 71 57 75 66 94 – 79 – 99 60 89 58 98 91 94 Literacy rate, 74 adult total (% of people ages 15 and above) 67 81 74 96 – 85 – 98 68 91 62 98 92 95 Literacy rate, adult female (% of females ages 15 and above) URBANIZATION Population density (people per km2 of land area) 1,240 20 92 455 148 143 31 161 2 196 38 19 358 346 308 Urban population (% of total population) 37 41 23 34 55 54 35 23 68 20 39 13 47 18 36 – 1 000 000 9 486 170 2 903 430 – 1 500 – – 350 000 – – 745 350 120 000 4 500 INFRASTRUCTURE Investment in transport with private participation (USD) 179 500 (Continues) VER ET AL . VER ET AL . TA B L E 2 (Continued) Bangladesh Bhutan Cambodia India Indonesia Kiribati Laos Micronesia Mongolia Nepal Papua Pacific New Island Countries Guinea Investment in water and sanitation with private participation (USD) 327 000 – – 583 300 314 620 – – – – – – 71 000 18 960 – 88 900 Mobile cellular subscription (per 100 people) 100 93 119 87 119 51 52 21 133 139 86 48 126 143 147 Secure internet servers (per 1 million people) 116 178 81 188 1 283 43 20 186 1 690 182 168 50 93 412 1 769 Population growth (annual %) 1.1 1.2 1.5 1.0 1.1 1.5 1.5 1.1 1.8 1.7 1.5 2.0 1.4 1.0 1.0 Immunization, DPT (% of children ages 12-23 months) 98 97 92 89 79 95 68 75 99 91 84 61 65 99 75 Immunization, measles (% of children ages 12-23 months) 97 97 84 90 75 84 69 73 99 91 83 61 67 99 97 Philippines Sri Lanka Vietnam HEALTHCARE WOMEN’S HEALTH (Continues) 9 10 TA B L E 2 (Continued) Bangladesh Bhutan Cambodia India Indonesia Kiribati Laos Micronesia Mongolia Nepal Papua Pacific New Island Countries Guinea Women making their own informed decisions regarding sexual relations, contraceptive use, and reproductive health care (% of women age 15-49) – – 76 – – – – – – 48 – – 81 – – Contraceptive prevalence, any methods (% of women ages 15-49) 62 66 56 54 61 22 54 55 55 53 39 32 54 62 76 Teenage mothers 31 (% of women ages 15-19 who have had children or are currently pregnant) – 12 8 10 – 17 – – 17 – – 9 5 3 Prevalence of HIV, 0.1 total (% of population ages 15-49) 0.3 0.5 – 0.4 – 0.3 – 0.1 0.1 – 0.8 0.1 0.1 0.3 Philippines Sri Lanka Vietnam OTHER PUBLIC HEALTH ISSUES (Continues) VER ET AL . VER ET AL . TA B L E 2 (Continued) Bangladesh Bhutan Cambodia India Indonesia Kiribati Laos Micronesia Mongolia Nepal Papua Pacific New Island Countries Guinea Philippines Sri Lanka Vietnam Incidence of tuberculosis (per 100 000 people) 221 149 302 199 316 349 162 108 428 151 – 432 554 64 182 Prevalence of undernourishment (% of population) 15 – 16 15 8 3 17 – 13 9 6 – 13 9 9 183 160 145 177 92 185 88 45 186 70 145 121 36 43 173 Maternal mortality ration (modeled estimate, per 100 000 live births) INCIDENCE OF HPV-RELATED CANCERS Cervical Uteri Crude rates per 100 000 9.8 12.5 11.9 14.9 24.5 – 9.2 19.3 23.4 19.3 – 24.8 13.6 10.4 8.6 Oropharyngeal Crude rates per 100 000 2.2 0.49 0.61 1.3 0.49 – 0.45 0.56 0.45 0.83 – 1.2 0.40 1.6 0.52 Source: World Bank, 2019; WHO, 2018.16,17 11 VER ET AL . 12 Child immunization rates are high (83-99%), but are low in Papua 4.3 Political support New Guinea (61%), Philippines (65-67%), Laos (68-69%), Micronesia (73-75%), Indonesia (75-79%), and Vietnam (75-97%). Contraceptive Even with adequate financial resources, lack of political support could use is below 80%, and is lowest in Kiribati (22%) and Papua New Guinea remain a key barrier to prioritization and resource allocation for (32%). Competing public health issues differ. Teenage motherhood is HPV vaccination programs, such as in the Philippines. In comparison, higher in Bangladesh (31%), Laos (17%), and Nepal (17%) than the rest Bhutan, with a comparable GDP per capita as the Philippines, has (3-12%). HIV prevalence is lower than worldwide prevalence (0.8%), been able to achieve high implementation and high coverage rates but TB incidence (/100 000) remains high. It is highest in the Philippines through strong political support.22,23 Political support is necessary to (554), Papua New Guinea (432), and Mongolia (428), and lowest in Sri encourage prioritization of HPV, to initiate collaboration among stake- Lanka (64), Micronesia (108), Bhutan (149), and Nepal (151). Preva- holders and to establish financial and delivery systems for national lence of undernourishment is lower than worldwide prevalence (13%) coverage.24 Political support could be gained with strong base of but is higher in Laos (17%), Cambodia (16%), Bangladesh (15%), and evidence and recognition of the public health problem, which could India (15%). Maternal mortality ratio is very low (< 100) or low (100- be derived from national cancer registries. Literature supporting the 299) across all the LMICs. It is highest in Nepal (186), Laos (185), and importance and cost effectiveness of cervical cancer prevention pro- Bhutan (183), and lowest in Sri Lanka (36), Vietnam (43), and Mongolia grams and HPV vaccination is becoming more robust through the (45). years.25,26 Cervical cancer incidence (/100 00) in LMICs is generally more than A strong evidence base could also help win high-level nongovern- 10 (10.4-24.8), with the highest rates seen in Papua New Guinea (24.8), mental advocacy, which in turn could mobilize resources toward imple- Indonesia (24.5), and Mongolia (23.4). Lower rates are reported in Viet- mentation and sustainment of a national HPV vaccination program. nam (8.6), Laos (9.2), and Bangladesh (9.8). Where national financial resources could not sustain such a program, it becomes clear that external aid and support from the private and nongovernmental sectors become paramount. 4.2 Funding Despite being all classified as LMICs, countries had a wide range in 4.4 Healthcare situation GDP. Countries that have a higher GDP have less identified barriers to HPV vaccination overall. This is more noticeable at the government Each country has a unique healthcare situation and faces several level. The majority of countries noted all three barriers in the govern- competing health priorities. Countries with other health issues, such ment level; however, the countries which had the highest GDPs had as low immunization rates and high tuberculosis cases, may translate less barriers. For example, Sri Lanka and Bangladesh have similar cer- to barriers in HPV vaccination, such as fund allocation, and availability vical cancer rates but Sri Lanka has one of the highest GDP and has sat- and accessibility of health facilities and providers. On the other hand, isfactory data in World Bank indices––fewer citizens living below the the effectiveness of its existing healthcare system will impact the addi- poverty line, lesser competing public health issues, high immunization tional requirements––financial, personnel, technical, or otherwise––of rates, and higher internet and mobile network coverage. On the other establishing a national HPV vaccination program. Further, satisfactory hand, Bangladesh has one of the lowest GDP, has greater proportion of immunization rates may reflect favorable societal acceptance and citizens living below the poverty line, and has more competing public effectiveness of immunization programs that are already in place.27 health issues. Currently, HPV immunization programs target only 12% of the pop- HPV vaccination programs require large financial resources to exe- ulation worldwide, and in Southeast Asia, only Thailand, Malaysia, and cute. The Global Alliance for Vaccines and Immunization (Gavi) has Laos have implemented the HPV vaccination nationally.28,29 This has recognized the importance of providing financial assistance. They sup- been attributed to the inefficiency of healthcare structures, such as a ply HPV vaccinations at a lower cost to eligible countries. This ideally lack of public health policy, underdeveloped clinical facilities, and lack lowers financial barriers and allows LMICs to introduce HPV vaccina- of personnel, especially where HCP deficiency in reproductive health tion into their national programs.18 However, sustainable funding is as clinics is to be further exacerbated by additional requirements for the important. Countries which are no longer eligible for Gavi support must HPV vaccination program.27,30,31 Barriers and resource requirements eventually rely on their own financial capabilities, and this can cause are further augmented by terrain and accessibility.23 policymakers to become hesitant in pursuing a national HPV vaccination program.19 Further, countries also have competing public health issues and 4.5 HCP perspectives HPV vaccination may be relegated to lower priority.20 This proves a challenge to improving HPV vaccination coverage rates, as the In implementing vaccination programs, an important factor for its absence of government support is considered a barrier to HPV success is collaboration among local leaders, basic health unit staff, vaccination.21 school staff, and other stakeholders. Involvement of community health VER ET AL . 13 workers and local leaders increases vaccination acceptance and uptake attainment, in particular, are more aware of cervical cancer, prevention, within the community.19,32 and screening, and are more willing to undergo HPV vaccination.37,39,40 HCP attitudes regarding the HPV vaccine can influence its uptake. Physicians who regard the vaccine as optional and thus fail to strongly endorse it was seen as a significant factor for parents not to accept 4.7 Health literacy the vaccine.33 Traditional/religious healers’ influence can have a negative or positive effect on vaccination. Focus on curative, rather than While education could provide literacy and critical thinking, with- preventive medicine, was also seen as a factor that negatively affected out awareness and insight about HPV vaccination, higher educational vaccinations.27 attainment would not translate to increased usage. In China, there is no Communication between HCPs and the public was also seen to influ- significant relationship established between higher educational attain- ence the acceptance of HPV vaccination. A lack of communication ment and undergoing screening.41 Disparities in awareness were also between HCPs and young women or parents about HPV vaccination observed between urban and rural communities, as demonstrated in a was seen as a factor in low uptake of HPV vaccine.33 Limited knowledge study among Indian women.41 These disparities are explained not only about HPV and cervical cancer has been described in the healthcare by differences in educational attainment, secondary to the availability workforce.34 of educational facilities and resources, but also by differences in access In Turkey, half of the pediatricians noted cervical cancer as the only consequence of HPV infection and were unaware that the to information. use of condoms does not prevent HPV transmission.35 In India, only Technology, such as Internet access, are portals for individuals half of the medical students knew the correct vaccine schedule and to be informed regarding health concerns. The World Bank indices that HPV vaccine requires three doses.36 The problem in this miscon- show that Mongolia, Sri Lanka, and Vietnam have more citizens with ception is reflected in vaccine complacency, and the perceived signifi- secured access to the Internet. These same countries boast of lower cance of a certain vaccine. Physicians should communicate with their amounts of cases of teenage pregnancy and maternal mortality rate. patients about HPV vaccination as it is a positive predictor in vaccina- Access to the Internet can help women contact support groups and tion acceptance.37 become aware about issues in reproductive health. On the other hand, the Internet could likewise be a source of misinformation. Technology, thus, represents an opportunity and a threat to bridging gaps in 4.6 Literacy and educational attainment information. People who belong to lower economic status mostly get informa- Despite generally high literacy rates, education level and health lit- tion from the media, friends, and family.37 They are especially prone eracy remain barriers in most countries. This highlights the need to receiving wrong information and to developing misconceptions if for inclusion of an effective health education campaign as a compo- unable to think critically and to verify against reliable sources. While nent of HPV vaccination programs. Health departments must pro- rural areas may suffer from lack of information, urban areas suffer from vide accurate and accessible information regarding HPV vaccination rampant misconceptions.42 and dispel rumors and fears.19 This ultimately will decrease soci- Information is best provided by health professionals or trained edu- etal and individual barriers and encourage HPV vaccination uptake cators. Doctors and nurses could play an important role in being edu- among the population. Vietnam and Sri Lanka have one of the high- cators to their patients.38 They need to be given training in communi- est literacy rates and more satisfactory World Bank healthcare indices, cation skills to allow them to properly inform their patients regarding including low cases of teenage motherhood, lower maternal mor- HPV and HPV vaccines. Health education can include explaining the tality rate, and greater access to contraceptive use among females. causes of HPV and vaccinations to patients during consultations and As importantly, these indices could reflect better health literacy, home visits. better understanding of health risks, and greater acceptance for vaccination. In a study conducted in Indonesia, parents who are not well aware of HPV and HPV vaccination have children who have not taken HPV Where adult literacy rate is low such as in Papua New Guinea, vaccination.43 Cultural norms may hinder awareness, especially where Bhutan, and Nepal, health education strategies must overcome liter- the discussion of sexual behavior is considered taboo and thus sex- acy and language barriers and be made accessible to the general pub- ual education is limited. Schools could become avenues for educat- lic. Language used must be appropriate to the target in order to ensure ing on sexual health, and school teachers could be trained to promote that barriers such as level of English literacy remain low. HPV and HPV vaccine awareness.19,44 Incorporating health literacy in Education, which is an important sociocultural element of the social the educational curriculum or providing educational activities about determinants of health, is an important factor and barrier in HPV health and diseases could greatly help increase awareness regarding The degree of educational HPV and HPV-related disease prevention.45 Workshops, pamphlets, attainment influences the beliefs and attitudes of individuals toward and demonstrations are effective means of health education, and can HPV and HPV vaccines. In many LMICs, there are lapses in behav- improve not only the attitudes of students, but also of their parents, iors and attitudes of people observed. Women with higher educational regarding HPV and HPV vaccines.45,46 and HPV vaccine awareness and usage.38 VER ET AL . 14 Outside formal education, community education, such as dissemina- safety of the HPV vaccine.34,37 In the Philippines, the dengue vaccine tion of educational materials that include vaccine efficacy and safety scare has resulted in significant drop in vaccine confidence.50 Empha- information, could be effective.27,42 sis on safety and efficacy of the vaccine could increase the enrollment to vaccination programs.42,44,46 4.8 Religion 4.10 Vaccine affordability Religion may affect public opinion regarding vaccination, directly or indirectly. A religion may directly impose restrictions among its Beyond acceptance, a major reason for limited vaccine uptake is its members, or its teachings may indirectly influence individual per- cost, as well as a perceived low risk of acquiring HPV and HPV-related spective and decision making. Christianity, especially Catholicism, disease, and thus a high cost-benefit ratio. Education regarding the has been known for its opposition against extra-marital sex and prevalence of HPV infection and its risks, and comparison of cost of contraception; however, its stand on HPV vaccination and its impact vaccination when compared to cancer treatment could help dispel such on the decision making and acceptance among its members are less doubts.37,51 studied.47 Among Indonesians, it was found that religious affiliation, Women generally understand their risks and need for the whether Muslim, Hindu, or Christian, had no influence on attitudes vaccine better compared to men, and there is a greater aware- toward HPV vaccination among Indonesian parents.43 In Thailand, ness among women who are married or in a relationship com- it was observed that the Buddhist population had higher acceptance pared to those who are not.52 Nevertheless, in unfavorable of the HPV vaccine, attributed to the belief of “karma” in dealing economies, individual spending prioritizes survival and money with things they cannot control, such as the risk of cancer, with the spent on preventive measures could be luxury than need. The vaccine there to resolve this belief.48 On the other hand, religion may vaccine competes with daily expenditure for food, shelter, and become a barrier for those whose belief instructs that vaccination is education.53 “unnatural.”38,48 In LMICs, HPV vaccine is less likely to be promoted as gender- In our review, religion was not a prevalent barrier, being cited neutral since it would be less cost-effective than when promoting it as such only in three countries––India (predominantly Hindu), only in women.54 This is problematic not only because this would Indonesia (predominantly Muslim), and Vietnam (Folk religion). not address male carriers and HPV-related diseases among men, but On the other hand, religion was not cited as a barrier for Nepal also because there remains a disparity in salaries between males and (also predominantly Hindu) or Bangladesh (predominantly Mus- females. Based on World Bank indices, Laos, Nepal, and Papua New lim). In none of the Buddhist or Christian countries was religion Guinea have less than 15% female employment rate. Laos and Nepal reported a barrier. Bhutan, a predominantly Buddhist country, was have among the highest number of teenage pregnancies, while Papua one of the first LMICs to implement a national HPV vaccination New Guinea has the highest rate of cervical cancers among the AP- program.22 LMICs. Further studies should clarify the influence of religion on society HPV vaccination acceptance and decision making in the AP-LMICs. 4.11 4.9 Vaccine acceptance Summary and recommendations Vaccine coverage in AP-LMICs remains to be low and is limited to those participating in the vaccination program. As of 2014, only While some studies have found that women who have a higher knowl- 1% and 0.1%, respectively, of the female population ages 10-20 edge of cervical cancer and its risk factors are more willing to access have been vaccinated.51 This is due to poor implementation by both the vaccine, others found high parental HPV vaccine acceptance the government and healthcare professionals, perception of the despite limited knowledge.43,49 Indeed, vaccine confidence or accep- community, and vaccine costs. The underlying factors are diverse tance arises not only from trust in the effectiveness and safety of vac- and interrelated. Programs must be tailored to fit the challenges cines, but also from faith in the motivation of policymakers who imple- and cultural priorities of each country. Leadership, advocacy, and ment the program.33 intersectoral partnership are essential to sufficiently address the Public health officials should demonstrate integrity, transparency, issue of HPV vaccine implementation.46 Ultimately, financial bar- and effectiveness. In most countries, HPV vaccination was only inte- riers from both the providers’ and the recipients’ sides need to be grated into their policies after affirming their safety. Despite continued overcome. The fact that LMICs bear 56% of the global burden of efforts by WHO and the Centers for Disease Control and Prevention to cervical cancer means that simply lowering the cost of vaccination reassure the public, reports on the side effects, especially from devel- without prior screening for cervical cancer contributes greatly unnec- oped countries, continue to foster doubts among the people.33 In sev- essary costs and diminishes the cost-effectiveness of the vaccine as a eral studies in Asia, over half of respondents reported doubts regarding whole.30 VER ET AL . 5 15 CONCLUSION Several barriers to HPV vaccination in LMICs operate at four levels– –government, HCP, society, and individual. Organizations and policymakers who aim to initiate, reinforce, or sustain HPV vaccination programs must be able to take into account these themes and strive to incorporate them in their strategy. Through systematic review, the lack of political and HCP support were found to be the most prevalent barriers. This is evident in the lack of funding allocation by the government and the lack of health facilities, health personnel, and capability to implement vaccination-related services. This finding highlights the need for increased investment in each country’s healthcare sector in order to achieve greater HPV vaccination coverage rates. As LMICs have limited resources, findings of this study serve as a guide for policymakers to identify which areas they should focus on in order to implement efficient HPV vaccination programs. CONFLICT OF INTEREST The authors do not have any disclosure. AUTHORS’ CONTRIBUTIONS AV, KN, JV, KB, JN, JL, DA, and WB contributed in the study conceptualization and design. AV, KN, JV, KB, JN, JL, and DA collected data. AV, KN, JV, KB, JN, JL, DA, and WB analyzed the data. AV, KN, JV, KB, JN, JL, DA, and WB wrote and revised the manuscript. 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A systematic review of the barriers to implementing human papillomavirus vaccination programs in low- and middle-income countries in the Asia-Pacific. Asia-Pac J Clin Oncol. 2021;1-16. https://doi.org/10.1111/ajco.13513