Cervical Cancer Prevalence in sub-Saharan Africa and HPV Vaccination Policy: A Public Health Grand Challenge?

Cervical cancer cases in low-income countries (LICs) are on the rise, whereas the reverse is true for high-income countries (HICs). With sub-Saharan Africa carrying the highest burden of cervical cancer cases and deaths globally, demand for governments in the region to act proactively in addressing the situation is a clarion call. Unfortunately, this is not the case as cervical cancer receives low attention from governments in the sub-Saharan region compared to other disease areas. Cervical cancer research interest and prevention policy has also been found to be low among researchers in sub-Saharan Africa. This paper comments on the sub-Saharan cervical cancer and HPV vaccination policy narrative and clarifies the imperative for action; in particular, given the resulting morbidity and mortality due to cervical cancer is preventable. The paper emphasizes scientists’ call to promote health and the need for governments to consider research and researchers’ opinion when designing policy to eradicate cervical cancer. The prevalence of the disease and the mortality rate in the sub-Saharan region represent a public health grand challenge. Engaging relevant stakeholders to actively collaborate in reducing and eventually eliminating the disease is encouraged.


Introduction
"Women are not dying because of diseases we cannot treat. They are dying because societies have yet to make the decision that their lives are worth saving."

Dr. Mahmoud Fathala Past President, International Federation of Gynaecology and Obstetrics (FIGO)
One life lost is one too much to ignore, but when it comes to cervical cancer, it is reported that "(a) total of 740 women die each day" from the disease globally [1]. Cervical cancer is a leading (4 th ) cause of cancer among females and affects over half a million globally in a year [2][3][4][5]. In sub-Saharan Africa, it is the leading cause of cancer death among women [5,6].
The 2020 assessment by GLOBOCAN indicates that there were 604,000 new cases and 342,000 deaths from cervical cancer globally [5]. It has been estimated that about 372.2 million females under the age of 15 years are at risk of cervical cancer in Africa, of which 119,284 are diagnosed every year, and 81,687 die from the disease (68.5% mortality rate) [7]. The World Health Organization (WHO) has estimated that as resource-poor regions like sub-Saharan Africa struggle in managing the disease, "without an effective intervention, global cervical cancer deaths will increase to 460,000 by 2040" [8].
Continuing evidence shows that regions with low Human Development Index (HDI) score experience disproportionately high levels of cervical cancer incidence and mortality rate [5,9,10]. This supports the high prevalence of cervical cancer cases and mortality in sub-Saharan Africa where the HDI has been historically low with high Human Poverty Indices (HPI). While this is the case, the high prevalence of the disease in low-income countries (LICs) has been attributed to the lack of political will, cultural issues, and poor health systems that cannot identify and treat precancerous lesions promptly [11][12][13].
the introduction of nationwide HPV vaccination programs [14,16,17]. For instance, a woman in the U.S. has a 70% chance of surviving cervical cancer while the survival chances for a woman in sub-Saharan African is 21% [18]. The high prevalence of cervical cancer in LICs delineates a case of global health inequity [19,20]. Gossa and Fetters have referred to this inequity as an ethical problem that expresses an "epidemiological tragedy" needing prioritization from policymakers and international donors [21]. According to the WHO, most people who are actively involved in sexual activity will be infected with HPV at some point in their lives [39]. This presents a societal health risk that requires government policy actions to avert needless suffering and risk of death for women due to HPV-associated cervical cancer.

HPV-Associated Cervical Cancer and Vaccine Intervention
With over 200 different strains of HPV, about 15 strains have been identified as high-risk strains that cause various types of cancers (e.g., cervix, vulva, vagina, anus, penis, and oropharynx) [22,23]. Of these strains, the 16 and 18 strains have been identified as an etiological cause of cervical cancer [24][25][26]. Whereas HPV infections are themselves "asymptomatic and transient" with nearly 70% clearing in the first year of infection and nearly 91% clearing in the second year of infection, high-risk strains (16 and 18) parasitically persist longer than normal [26]. The persistence of HPV infections over several years can lead to "grade 2 or 3 cervical intraepithelial neoplasia (CIN) and cervical cancer" (ibid).
In a meta-analysis of 192 studies that tested over one million women globally for cervical HPV infection, Bruni and colleagues showed that the adjusted HPV prevalence among women with normal cytological findings was estimated to be 11.7% per 100,000 women (95% confidence interval (CI): 11.6-11.7%) [27]. The study shows that sub-Saharan African regions reported the highest adjusted prevalence of 24% at 95% confidence intervals (ibid). Sadly, most of these deaths occur among women who live in poverty [19].
The HPV vaccination regimen is designed on a 3-dose program to be given at 0, 2, and 6-month time-point. Dobson and colleagues in a randomized clinical trial study of HPV vaccine in younger adolescents however showed that a 2-dose schedule for girls was "possible" [36]. While this is the case, a cohort study of 10,204 women in Alberta, Canada concluded that women who received full vaccination (> 2 doses) had a lower adjusted odds ratio (OR) of 0.72 (95% confidence interval [CI] 0.63-0.82) [37]. Those who had 2 dose HPV vaccination had an adjusted OR of 0.50 (95% CI 0.30-0.85) (ibid). The study suggests that the 3-dose regime provided greater protection and lowers the risk of cervical cancer among women. Even though the 3-dose schedule may provide lower risk, a cost-effectiveness assessment conducted by Laprise and colleagues have shown that a 2-dose schedule that provides a protection period of at least 10 years is cost effective [38]. The authors concluded vaccination with a 2-dose schedule that provides "longer than 30 years" is better than a 3-dose schedule (ibid). While some countries maintain the 3-dose schedule, the 2-dose schedule proves to be equally potent and economically cost-effective.

HPV Vaccination Programs in sub-Saharan African Regions
Even though cervical cancer remains a life-threatening disease globally, vaccination against high-risk HPV strains (16 and 18) has prophylactically led to the prevention of the disease. While many HICs have explored and incorporated HPV vaccination in their healthcare programs (e.g., national immunization) besides other traditional interventions such as screening, this is not the case in most resource-poor settings -especially in sub-Saharan Africa where case incidence and mortality rates are high (see Table 1). This is further exacerbated by inadequate vaccine access in LICs where universal access to primary healthcare is often limited or unavailable [40], precluding opportunities for cervical cancer screening as a secondary prevention strategy that occurs in HICs [41]. For example, as of 2019, only nine sub-Saharan African States have been identified to have a Nationwide HPV vaccination program (see Table 1). According to HPV Information Center, three countries have announced the introduction of HPV vaccination program while 18 have a pilot project in place to introduce the vaccination nationwide (see Table 1). 19 countries however have no HPV vaccination program in place (see Table 1).

Challenges to HPV Vaccination in sub-Saharan African Regions
The availability of HPV vaccines in HICs has been successful mostly through responsive government priority setting [42][43][44], which is not the case in resource-poor settings like sub-Saharan Africa ( Table 2). For example, in a comprehensive epidemiological review of cervical cancer disease burden in sub-Saharan Africa, the authors noted that the extent of the cervical cancer problem has been "under-recognized and underprioritized" [45] in comparison to other high mortality diseases such as HIV ⁄ AIDS, tuberculosis and malaria.
Even though some African nations developed initiatives and programs to promote awareness and introduce HPV vaccines to their citizens, program and policy inertia due to various factors that hinder HPV vaccine uptake and coverage has made this a challenge. In a recent study, the authors reported that only 1-2% of women between the age of 10-20 received HPV vaccination in the region [46]. A driving factor to the problem to the low HPV vaccination problem has been attributed to the lack of resources to finance and deploy the vaccines in the region [47]. While the Global Alliance for Vaccine Immunization (GAVI) provides support to some LICs to enable access to HPV vaccines, other countries are unable to do so due to their

Causes
Description Effects

Mitigating Strategies Benefits
Healthcare System Due to healthcare logistical challenges in many sub-Saharan African nations, the quality of healthcare is usually inadequate or below the acceptable standard.
Cervical cancer may not be properly diagnosed or detected.
Cost-effective incremental improvement in healthcare logistics should be adopted to bring all healthcare facilities to an acceptable standard.
Improvement in logistics and training of staff to effectively provide cervical cancer interventions.

Financial Resource Allocation
Health issues such as cervical cancer may compete for the same allocated financial resource for health intervention. Governments may inequitably allocate resources to address diseases that are highly endemic or affect a larger portion of the population. This may push diseases such as cervical cancer that affect a section of the public to the backburner.
Cervical cancer case numbers may increase.
Governments should negotiate effectively with vaccine manufacturers for the best deal possible that they can afford. This must be in addition to the utilization of all available donor supports (e.g. Gavi).
Availability of cervical cancer interventions such as screening and HPV vaccines.

Policy Specificity
Some sub-Saharan African countries do not have a specific policy that addresses cervical cancer.
Cervical cancer receives less visibility within the policy space.
Governments should have a specific policy that details prevention and control strategies.
Governments will have a working document that will obligate them to act following the plans in the policy document.

Priority Setting
Governments may have a high interest in some areas of governance such as the economy, defense, or youth unemployment. Such political realities and context may be influenced by various stakeholders whose interest in cervical cancer prevention may be of low priority. inability to meet certain pre-qualification requirements [48]. This directly expands the inequity that exists in HPV vaccination among countries, especially in the sub-Saharan African region.

Conclusion
While acknowledging the contributions of sub-Saharan African scholars in the cervical cancer prevention and control narrative, there is a subtle passiveness as expressed in the number of articles coming from the region and the leadership role taken in joint publishing [49].
This disengages an active participation space for scholarships that could inform policymakers on interventional strategies. Cervical cancer prevention and control in sub-Saharan Africa also seems to be of low priority in the region due to possibly competing disease areas or other governmental interests than cervical cancer prevention and control. For example, in Ghana, where cervical cancer is the most common cancer among women, it is the least prioritized for intervention by governments [50,51]. According to a report by the International Agency for Research on Cancer (IARC), 8.57 million women from the ages of 15 years and above are at risk of cervical cancer in Ghana [52]. Not surprisingly, cases of cervical cancer continue to rise in Ghana [23,[50][51][52][53]. While this is the case, citizens' knowledge remains low about cervical cancer, HPV, and/or HPV vaccination. A cross-sectional study of 285 adolescents in Ghana shows that about 91.2% of the participants had not heard of HPV and 95.4% had not heard of HPV vaccination, for example [54]. Previous studies reported similar findings in Ghana, indicating low public education on cervical cancer, its prevention, and/ or control [50,55,56]. In a systematic review estimating the knowledge and awareness of the HPV vaccine and acceptability to vaccinate in sub-Saharan Africa, the authors concluded that "there is an urgent need for more education to inform the public about HPV, HPV vaccine, and cervical cancer, particularly to key demographics, (adolescents, parents and healthcare professionals)" [57].
The International Covenant on Economic, Social, and Cultural Rights (ICESCR) highlights health as a fundamental human right to the enjoyment of the highest attainable standard of physical and mental health. Most sub-Saharan African countries are signatories to the ICESCR, through which they commit to protecting citizens' right to health as a fundamental human right. Sub-Saharan governments are thus obligated to take measures to protect the health of their citizens, in this case, women against cervical cancer.
Cervical cancer not only threatens women's health but also contributes to worsening the socio-economic challenges in the sub-Saharan region due to lost human capital. It thus presents a public health grand challenge that is imperative to address by engaging all stakeholders, including scientists, and particularly governments in the sub-Saharan region, working together to reduce and eventually eliminate the disease in alignment with the WHO's global strategy to eliminate cervical cancer by 2030 [58]. Acknowledgment I wish to thank Prof. Mary E. Wiktorowicz and Prof. A.M. Viens for their reviews and suggestions.

Conflicts of Interest
No conflict of interest is declared for this work.

Funding
No funding was received for this work.

Vaccine Hesitancy
The fear that HPV vaccine may not be safe or efficacious. Some people may also refuse vaccination on religious or cultural grounds, while others may refuse vaccination based on inaccurate information.
Low uptake if HPV vaccines are available to the public (e.g., pilot or national program). This may increase HPV-related cervical cancer.
Governments and relevant stakeholders must embark on mass education using social media portals, TVs, radios, and print media.
Nationwide coverage and high uptake of HPV vaccination.

Education
Public information on cervical cancer, HPV, or HPV vaccination in some sub-Saharan African nations is low.
Ignorance of the disease may increase risk and eventually case numbers.
Public education through media outlets, community education outreach, school programs, and religious platforms should be encouraged.
Awareness may reduce the risk and case numbers.