HPV‐vaccination and cancer cervical screening in 53 WHO European Countries: An update on prevention programs according to income level

Abstract Human papillomavirus (HPV) is the most common sexually transmitted disease in the world. The aim of our study is to describe the differences in HPV‐vaccination coverage and screening programs in WHO European Countries notably according to income levels. Multiple correspondence analysis was applied to examine the association among the following variables: Gross National Income (GNI) levels (Lower‐Middle Income, LMI; Upper‐Middle Income, UMI; and High Income, HI); type of CC screening program (coverage; opportunistic/organized); vaccination payment policies (free or partial or total charge); mortality rates/100 000 (≤3; >3‐6; >6‐9; >9); incidence rates/100 000 (≤7; >7‐15; >15‐21; >21). Data HPV‐vaccination start (years) (2006‐2008; 2009‐2011; 2012‐2014; >2014; no program); coverage HPV‐vaccination percentage (≤25; 26‐50; 51‐75; >75); data screening start (years) (<1960; 1960‐1980; 1981‐2000; >2000); primary screening test (HPV, cytology), and screening coverage percentage (≤25; >25‐50; >50‐75; >75). A high income is associated with: start of screening before 1960, medium‐high screening coverage, organized screening, start of vaccination in the periods 2009‐2011 and 2012‐2014 and high immunization coverage. On the other hand, lower‐middle income is associated with: late start of vaccination and screening programs with cytology as primary test, high mortality and incidence rates and lower‐medium vaccination coverage. Our results show a useful scenario for crucial support to public health decision‐makers. Public health authorities should monitor the HPV‐vaccinated population in order to determine more precisely the effects on short‐ and long‐term incidence and mortality rates. In fact, the greater the vaccination coverage, the greater will be the efficacy of the program for the prevention of CC and other HPV‐related diseases.


| Sources of WHO European epidemiological data
The main data source, the GLOBOCAN 2012 website of the International Agency for Research on Cancer (IARC), provides access to several databases that allow assessing the impact of CC in 184 Countries or territories. 38 These data were supplemented using the literature, ministerial web site of WHO ER Countries, World Bank Open Data Web site and the World Cancer Registry (X edition). 17

| Multiple correspondence analysis
The results of MCA are shown in Figures 2 and 3. We identified two dimensions that explain 82% of the variance: the first is 49% and the second being 33%.
The first quadrant (top right) identified the following variables: an early initiation of vaccination programs based on HPV screening as primary test; a high-screening coverage and low incidence and mortality rates. In addition, low-vaccination coverage and different payment policies (free, partial or total charge) for vaccination programs are located in this quadrant. High income, screening before 1960, medium-high screening coverage, start of vaccination in the periods 2009-2011 and 2012-2014, and high-immunization coverage are in the fourth quadrant (bottom-right). On the left side, we can see medium-low and medium-high income, low attention to primary and secondary prevention with high rates of occurrence. In the second quadrant (top left), instead, we can observe upper-middle income, total absence of screening and vaccination programs, medium-low incidence and mortality rates. The third quadrant (bottom left) stands out with lower-middle income, late start of vaccination programs and screening with cytology as primary test, medium-high mortality and incidence rates, and medium vaccination coverage ( Figure 2). It is important to highlight that most EU-28 Countries are mainly located between the first and fourth quadrants with high income. On the contrary, the Countries outside of the EU-28 are located between the second and third quadrant with upper-middle income and lower-middle income (Figure 3).

| DISCUSSION
In 2015, 526.000 women developed CC worldwide and caused 239.000 deaths. 39 The pap-test screening programs, allowing an early diagnosis of precancerous lesions and a timely treatment of the same, have allowed to reduce the incidence of cervical cancer. Vaccination prevents precancerous lesions, reduces cancer and related treatments to eliminate precancerous lesions. Vaccination, acting much earlier in the history of disease development, prevents chronic infection resulting in pre-cancerous lesions. Vaccination and screening programs are fundamental because they are potentially cost-effective and allow decreasing incidence and mortality rates of CC. 40 Screening, however, will remain fundamental for prevention of CC despite HPV vaccines. 41 In fact, a factor that determines the differences in the incidence of CC among Countries is the screening coverage of the population. 7 Monitoring HPV-vaccination coverage is important to evaluate the performance of vaccination programs and the potential impact of HPV vaccine on cervical cancer. In fact, cervical cancer screening programs will need to be adjusted to the number of vaccinated people eligible for screening. However, despite the documented effectiveness of HPV vaccine, there is still an incomplete availability to this prevention action in the world population. Bruni et al 42 showed high differences in number of women vaccinated according to gross income level countries; in fact, high-quality primary and secondary cancer prevention is nearly always available in wealthy countries with gross national income (GNI) level. 42 Moreover, higher income allows access to better resources and living standards and can increase the ability to maintain healthy behaviors. 43 Syse and Lyngstand showed that high income is also related to higher survival rate. 44 Our study shows that European Countries with higher income have higher screening and immunization coverage probably due to organized screenings starting before 1960 that determined low incidence and mortality rates, respect to those with lower-middle income. High-income countries have HPV screening test as the primary test and total or free partial charge HPV vaccination.
Eastern European and Asian Countries have lower-middle income and show high incidence and mortality rates. These countries have an opportunistic screening with lower-screening coverage and lower-immunization coverage probably because HPV vaccine was introduced later. Globally, the coverage of vaccination is higher in countries with high income; by 2016, 71% of HI countries, 35% UMI countries, 8% of LMI countries, and 6% of LI countries had introduced the HPV vaccine. 45 Only eight of the 70 countries who reported HPV vaccine introduction by the end of 2016, made the vaccine available to boys in addiction to girls (Australia, Austria, Barbados, Brazil, Canada, Italy, Switzerland, and the United States). 46 According to Brisson et al, 47 greater benefits can be acquired for both female and male by increasing HPV-vaccination coverage among girls. In addition, vaccination of both sexes would be more equitable. 48 In light of this, we would like to point out that: first, the strategy of including males in vaccination campaigns has, without a doubt, the function of reducing the circulation of the virus (herd-effect) and the transmission of infection between the two sexes. It has also the advantage of countering the occurrence of HPV-related diseases affecting male anatomic sites, such as the penis. Second, it is important to stress that both sexes have the same right to benefit from the advantages of anti-HPV vaccination. In fact, according to European regulations, it is a right of every citizen to take advantage of disease prevention programs, where there is an effective means of prevention like the anti-HPV vaccine. Third, a universal anti-HPV vaccination program reduces the prejudices created around a female-only vaccination, helping to reduce sociocultural barriers and thereby increasing acceptability and vaccination coverage.
Public health authorities should monitor the HPV-vaccinated population in order to determine more precisely the effects on short-and long-term incidence and mortality rates.
A useful scenario for crucial support to public health decision-makers is the strength of our paper. On the other hand, a limitation could be that the data that came from low-income countries must be considered with caution, both because they come from local registries (rather than the population-based cancer registries used for the other countries) and because the International Classification Disease, 9th revision, codes are not always accurate.