Introduction

Cervical cancer is the fourth most common cancer among women worldwide (1). The prevalence of cervical cancer in the Sub-Saharan region is 11.4% and the consequent fatality rates are considerable (2). The human papillomavirus (HPV) is one of the most significant risk factors for cervical cancer. HPV can be transmitted through sexual contact, including vaginal or oral sex with an infected person (3). HPV has more than 100 strains, of which HPV16 and HPV18 account for about 70% of invasive cervical cancers (4,5). The HPV vaccine can prevent cervical cancer effectively. The World Health Organization (WHO) recommends routine HPV vaccination for girls aged 9-14 years (prior to sexual activity) through national immunization programs, “catch-up vaccinations” for unvaccinated adults older than 15 years with high-risk behavior, and for HIV-positive women (6). A minimum six-month interval must be ensured between the first and the second dose. The WHO currently does not recommend the HPV vaccination for boys (7). Since 2007 the HPV vaccine has been approved in the United States and the European Union (8). National HPV vaccination programs have been implemented in at least 107 countries worldwide (9). HPV vaccination is a part of the routine immunization program in many high-income countries (8).

The HPV vaccination rate for women in the USA and Australia is about 37.6% and 32%, respectively (10), but is lower in Asian countries (3). Implementation of an HPV vaccination program is probably the most effective way of reducing the burden of cervical cancer (11), especially when screening tests are not available, limited, or of poor quality (12). According to the WHO, no study has reported major adverse effects of the HPV vaccine (13).

However, the HPV vaccine is not affordable in those countries that need it the most. In fact, cervical cancer mirrors health inequity more than any other female cancer (8,14); approximately 90% of deaths due to cervical cancer occur in low-income countries (1).

The  Eastern Mediterranean Region (EMR) of the WHO extends from Iran to Djibouti, covers 22 countries (Table 1) and a population of 680 million (15). Although some nations, including those of the Persian Gulf have common roots, the EMR countries differ significantly in terms of their geopolitical status, cultural backgrounds, income levels, and health expenditure rates. Moreover, some countries, such as Afghanistan, Yemen and Syria are experiencing prolonged social instabilities and conflict. A considerable part of the population of EMR countries has been displaced in recent years due to internal wars.

Despite the huge burden of cervical cancer, especially in low- and middle-income countries (16), only two nations in the EMR have implemented HPV vaccination in their national vaccination program (NVP) (17). The present study aimed to assess the barriers experienced in incorporating HPV vaccination in the NVP of EMR countries.

Material and Methods

Published articles which addressed HPV vaccination were searched for a narrative review.

Determining the research question

The review was based on the following research question: What are the main barriers to HPV vaccination in EMR countries?

Identifying relevant studies

We performed a systematic search in a range of electronic databases, including Medline, Scopus, Embase, and Web of Science (initial search in June 2021; last update in December 2021).

The following keywords were used: “HPV”, “vaccine” “vaccine strategy”, “barrier”, obstacle”, and “EMR countries”. The names of the 22 member states of the EMR were searched separately. The classification of EMR countries is summarized in Table 1.

Inclusion and exclusion criteria

All types of studies dealing with HPV vaccination in EMR countries, published exclusively in the English language, were included. Reports that were not in line with the purpose of the study or did not provide their full text were excluded.

Selection of studies

We reviewed all types of articles published about EMR countries. The search was not subject to any limitations in terms of time or methodology. Reference lists of all identified studies were screened manually. Vaccination-related guidelines published by the ministry of health in each EMR country and the WHO-EMRO were searched. The review process consisted of two screening steps: a) reviewing the title and summary of the articles, and b) reviewing the full texts.

Collating, summarizing, and reporting the results

We reviewed studies that included data concerning programs, strategies, barriers, and implementation of an HPV vaccination program in EMR countries. As we aimed to identify existing gaps and guide future research, we dispensed with quality assessment or an extensive data synthesis of the published reports.

Results

Search results

We reviewed investigations from 2012 to 2021 based on various methodologies. Of 85 publications found in the various databases, 10 were duplicate articles. After reviewing the titles and abstracts of the remaining reports, 45 were excluded. Finally, 31 studies from 15 EMR countries [Arab states (n=23), African countries (n=3), and non-Arab countries (n=5)] were included in a narrative review. The characteristics of the studies are summarized in Table 2.

Cervical cancer and HPV prevalence

We lack precise statistics regarding the incidence and prevalence of cervical cancer for any EMR member state. Currently, in Afghanistan in each year about 862 women are identified with cervical cancer and 570 die from the disease (18). Cervical cancer ranks second after breast cancer in some countries, such as Yemen, Djibouti, Somalia and Afghanistan (19). An increase in life expectancy has been registered in all EMR countries. The risk of cancer is increasing with age. Both population growth and population aging have led to more numerous cases of cancer. Changes in lifestyle are regarded as one of the most important risk factors for cervical cancer. The HPV infection has increased markedly in recent times due to unsafe sexual activity (20). The overall prevalence of HPV in Egypt was estimated at 10-23% (21,22). Bansal et al. (23) estimated an HPV prevalence of 5.8% among women in Qatar with a normal cytology, and 18.4% in women with an abnormal cervical cytology. In Kuwait, the prevalence of HPV was reported to be about 2.5% and higher than 50% in women with a normal and abnormal cytology, respectively (24,25).

HPV vaccination status in EMR countries

According to the report of the WHO, at the annual workshop of the EMRO held in Lebanon in 2019 it was noted that only Libya and the United Arab Emirates) UAE (had integrated HPV vaccination in their national vaccination programs, while a third country (Morocco) plans to do so (26,27). In some countries, such as Iran, the private sector is responsible for providing vaccines. Therefore, the HPV vaccine is neither affordable nor available to all persons (28).

Barriers to HPV vaccination in EMR countries

Knowledge and awareness

Lack of knowledge is a fundamental obstacle to HPV vaccination. Adequate knowledge about the role of HPV as a risk factor for cervical cancer is crucial. In a study comprising 746 female students in Pakistan, Gul et al. (29) reported that nearly 85% had no information about the HPV vaccine and, surprisingly, more than 95% would like to receive it. Knowledge of the HPV vaccination was moderate or poor in Bahrain, Morocco, Oman, and Lebanon, expressed as a distrust of the vaccine (30,31,32,33,34).

Due to the absence or paucity of public education, the majority of the residents in the EMR countries are unaware of the availability of the HPV vaccine. Recommendations for HPV vaccination by physicians and the workforce in the health sector are very important, as these will influence parents’ acceptance of the vaccine for their daughters (35). However, health care providers themselves do not have sufficient knowledge about the vaccine. Studies performed in Saudi Arabia and Iraq showed that physicians and medical students are poorly informed about the subject (36,37,38,39).

About 54% of student nurses in Sudan were aware of the HPV vaccine (40). The studies revealed that the main sources of information for medical and nursing students were mass media, including TV and web pages, as well as self-learning (36).

Published studies reveal that there is concern about the long- and short-term side effects of the HPV vaccine (30). Women are afraid of its potential side effects (20). In a study in Syria, Al Saad et al. (41,42) reported that mothers were unwilling to vaccinate their daughters against HPV due to concerns about the adverse effects and safety of the vaccine.

Economic barriers regarding the cost-effectiveness of HPV vaccination program

Given the population structure (large and growing young population) in EMR countries, the large number of persons eligible for vaccination, and the number of required doses (3 doses), the provision of a sufficient budget for public vaccination is a challenging issue for many countries in the region (34). The HPV vaccine is almost as expensive as other vaccines (35). The cost of each dose ranges from 13 to 100 US$ (43), making vaccination programs unaffordable for many low-income countries. The cost of one dose of HPV vaccine (Gardasil 4) is about 13 US$, as the cost is not covered completely or even partially by insurance companies (44). Therefore, the majority of eligible persons in Iran do not receive the vaccine (28). However, in a secondary analysis of the Iranian Ministry of Health data, Mohammadpour et al. (28) concluded that the use of Gardasil has increased very markedly in the last five years. Shaikh et al. (45) reported that the cost of vaccination is a barrier in Pakistan: the surveyed persons said they refrained from HPV vaccination because it was not affordable.

A correlation was observed between income levels and HPV vaccination (45). The Global Alliance for Vaccines and Immunization (GAVI) could negotiate with industry to provide a low-cost vaccine, or co-finance its provision. In 2011 Merck announced that a single dose of the HPV vaccine will be distributed on behalf of GAVI for 5 US$ (43). Similar programs could be devised to provide affordable HPV vaccines. It should be noted that the HPV vaccine is affordable for countries with a gross domestic product just below 1,000 US$ when each dose is supplied for 1-2 US$ (8). Some EMR nations, including Saudi Arabia, Oman and Qatar are not low-income countries, but their governments doubt the cost-effectiveness of HPV vaccination on a nationwide basis  (28). It appears that the opinion of the government about the missing cost benefit of Gardasil is the main factor underlying the integration of the HPV vaccine in the NVP of each country (46). Health economy experts assessed the cost benefit, cost effectiveness, and affordability of the vaccine in Oman. They also evaluated the burden of HPV and stated that the integration of the HPV vaccine in the NVP of Oman is not cost effective (47).

The paucity of data about the burden of cervical cancer, its annual incidence, as well as the direct and indirect costs of treatment impairs the development of an up-to-date guideline and decisions about the HPV vaccine in EMR countries. The cost-effectiveness of mass vaccination against HPV depends on the incidence of cervical cancer and the cost of vaccine (48). To make an appropriate decision, experts would need to obtain valid data about the direct and indirect costs of treating precancerous lesions and invasive carcinoma. Vaccination is obviously a cost-effective measure in countries with a high incidence of cervical cancer (48).

Social insecurity in conflict zones

Timely delivery of the HPV vaccine in conflict zones is very challenging. It requires a reliable infrastructure, such as an uninterrupted cold chain. Schools are one of the appropriate places for the HPV vaccine. However, a very large number of girls in poor and conflict-ridden societies do not attend school or drop out after primary school (49). Of the 22 member states of the EMR, six suffer from internal wars and insecurity.

Cultural norms/religion

EMR countries have a relatively young population. Given social taboos, the age of sexual debut in this region is not clear. However, it is estimated that the usual age is 19-23 years (50). There is evidence of changing sexuality and gender relations in EMR countries. The age of marriage and the prevalence of premarital sexual activity are increasing (51). The HPV vaccine is known to prevent sexually transmitted diseases and this raises cultural as well as religious concerns in society. Given that all EMR member states are predominantly Muslim, a considerable proportion of the population in some countries are conservative in regard to sexual activity. Islam does determine the sexual behavior of individuals in EMR countries; sexual activity should occur within the context of marriage. In the same vein, religious activists may oppose the HPV vaccine because they believe it encourages premarital sexual activity (52). Cultural circumstances cause mothers to believe that their daughters are not at risk for HPV and do not need the vaccine (41). According to religious authorities, given that young people have no premarital sexual contact, they do not need the HPV vaccine (49). In a study comprising 600 women in the UAE, Ortashi et al. (53) noted that 17% of women believed the HPV vaccine may not be culturally acceptable.

Discussion

Cervical cancer is regarded as one of the leading causes of cancer deaths among women in EMR countries (19). This review summarizes the HPV vaccination program in the EMR. Barriers to vaccination were mainly lack of knowledge and awareness, doubts about the cost-effectiveness of the HPV vaccination program, social insecurity in conflict zones, and cultural norms or religious beliefs. Lack of knowledge about the HPV vaccine was one of common barriers in EMR countries. Lack of knowledge creates a vacuum and encourages the spread of misinformation on social networks (54). Educational initiatives aimed at women may be most successful if designed to increase awareness of their susceptibility to HPV infection and transmission. School-based meetings would serve as a useful sensitization strategy to enhance the quantity and quality of knowledge about cervical cancer and the HPV vaccine. Vaccine safety is one of the prime concerns of parents and young persons. We need culturally sensitive training programs addressing parents and emphasizing the absence of side effects of the vaccine (55). Inclusion of the HPV vaccination in the curricula of undergraduate-level medicine and paramedics is also essential. A change in policies regarding the HPV vaccine is essential because we anticipate an increase in the burden of cervical cancer over the coming years (56).

Our analysis showed that the cost and cost-effectiveness of the vaccine are further barriers to its acceptance in the target population. Previous studies reported the highest vaccination coverage rates for HPV in countries where vaccines are funded by the national budget (57). Providing HPV vaccine free of charge or at a low cost will be essential in low-income countries. In view of the fact that GAVI covers the provision and delivery of the HPV vaccine for low- and lower-middle income countries, upper- and middle-income countries are confronted with serious challenges in purchasing the vaccine (58).

Male guardianship is an issue in EMR countries. As the male-dominated culture requires the spouse’s consent to a woman’s vaccination, men’s education should be included in the agenda of the health system. Women’s access to the vaccination would depend on men being sufficiently informed about it (59). Advocacy programs will be needed for introducing the HPV vaccine. Addressing the burden of cervical cancer is a critical issue and requires a suitable cancer registry system (60).

Strong partnership and collaboration with all stakeholders will be needed to implement the HPV vaccination program (61). All of the involved parties should be aware of their clear roles from the point of distribution to implementation. In some countries, we need to identify specific needs, such as technical or financial support, a suitable plan of action, and appropriate monitoring.

Some factors, such as the level of income, knowledge, and the employment of mothers facilitate the acceptance of the HPV vaccine. Recommendations about the vaccine by health care authorities and its approval by decision-makers in each country would encourage mothers to accept the vaccine (41).

Conclusion

There is an urgent need for greater social awareness about the necessity of HPV vaccination. Addressing HPV vaccination in undergraduate medicine and the paramedic curriculum is an essential step towards improving HPV vaccination coverage in these countries. The burden of cervical cancer should be publicized on the basis of robust data proving the effectiveness and significance of HPV vaccination and justifying its cost-effectiveness. Policy-makers should be sensitized to the economic benefits of the vaccination. Ensuring the support of GAVI in eligible countries will be a crucial step in achieving high vaccination coverage. Non-GAVI countries should be encouraged to allocate national resources to HPV vaccination in an optimal way (62).

Peer-review:Externally peer-reviewed.

Author Contributions: Concept: S.H., F.L., Data Collection or Processing: S.H., L.A., I.A.; Writing: S.H., L.A., I.A.

Conflict of Interest: No conflict of interest is declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.