Artigos

1. Background
Human Papillomavirus (HPV) is the most common cause of sexually transmitted infections in the world, and its transmission occurs through direct contact with the infected person's skin, membrane, or body fluids1 and is related to lesions in the cervix or genital area, being recognized as the main cause of cervical cancer in addition to other types of cancer2. There are more than 200 different types of this virus. However, the most frequent types that cause 70% of cancer cases are types 16 and 182,3.
There are three types of vaccines: bivalent (protects against HPV types 16 and 18), quadrivalent (HPV 6, 11, 16, and 18), and nonvalent (HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58)4. All three types of vaccines are proven to be effective in preventing HPV and reducing the risk of cervical cancer, especially when immunization takes place before the beginning of sexual life (WHO, 2020). Despite this knowledge, worldwide anti-vaccination movements are increasingly frequent and persuasive, often impacting parents’ and caregivers’ opinions and influencing vaccination decision-making5.
In addition to vaccine hesitancy, other contextual factors such as low family income and parental education, as well as living in rural areas, are related to lower levels of awareness and vaccination coverage against HPV among adolescent girls6,7. Furthermore, geographic region and area of residence are relevant aspects to be considered when it comes to vaccination, especially for large countries, where areas within the same country might have different contexts, policies, and health conditions, resulting in heterogeneity in HPV vaccine availability and vaccination coverage8–10.
Globally, HPV vaccination rates are suboptimal. Only around 35% of women are vaccinated in high-income regions, with even lower coverage in poorer areas, where less than 3% of women are vaccinated against HPV, meaning that among all women vaccinated, only 1% were from low-income or lower-middle-income countries11. Nevertheless, research evaluating the prevalence of non-vaccination against HPV is concentrated in high-income countries12.
The aim of this study is to assess socioeconomic inequalities in the prevalence of non-vaccination against HPV among Brazilian adolescent girls, based on the area of residence, maternal education, and wealth index, in addition to the spatial distribution of these inequalities according to Brazilian federation units.
2. Methods
2.1 Study design and sample
This cross-sectional study used data from the 2019 edition of the Brazilian National Survey of School Health (PeNSE). This nationally representative school-based survey included adolescents from the 7th grade of elementary school to the 3rd grade of high school attending public or private schools located in both urban and rural areas during the 2019 school year. The study was conducted by the Brazilian Institute of Geography and Statistics (IBGE) in collaboration with the Brazilian Ministry of Health.
The sample was sized to estimate the parameters for each of the 26 state capitals and the Federal District. The sampling strategy comprised three stages: in the first, the municipalities and/or groups of municipalities were selected (primary sampling unit); in the second stage, the schools were selected (secondary sampling unit); in the third stage, the classes were selected (tertiary sampling unit). Students comprised the sample in each stratum. All participants of the selected classes present on the day of data collection were invited to participate. Data were collected through a self-administered questionnaire via smartphone under the supervision of trained researchers. More details regarding the methodology can be found elsewhere (Brasil. Ministério da Saúde, 2019).
The Free Informed Term of Consent was presented to the students. This study is based on a public domain database, and the original project was approved by the Brazilian National Research Ethics Committee (CONEP: n. 3.249.268, from 08.04.2019.).
2.2 Outcome
Our outcome was the percentage of non-vaccination against HPV among girls. The following question was used to assess the outcome: “Have you been vaccinated against the HPV virus?” (no; yes).
2.3 Stratifiers and other covariates
To investigate inequalities in non-vaccination, we included the following stratifiers: area of residence (urban/rural), maternal education (none, incomplete elementary, complete elementary, high school, superior level), and wealth index. The wealth index was built based on principal component analysis of the ownership of domestic assets (landline, cellphone, computer, internet, car, and motorcycle) and household characteristics (number of bathrooms and the presence of a maid).
Due to the high cultural and social variability in Brazil, we opted to explore intersectionality, investigating inequalities according to the federation units of the country. (Acre - AC; Alagoas - AL; Amapá - AP; Amazonas - AM; Bahia - BA; Ceará - CE; Distrito Federal - DF; Espírito Santo - ES; Goiás - GO; Maranhão - MA; Mato Grosso - MT; Mato Grosso do Sul - MS; Minas Gerais - MG; Pará - PA; Paraíba - PB; Paraná - PR; Pernambuco - PE; Piauí - PI; Roraima - RR; Rondônia - RO; Rio de Janeiro - RJ; Rio Grande do Norte - RN; Rio Grande do Sul - RS; Santa Catarina - SC; São Paulo - SP; Sergipe - SE; Tocantins – TO).
Additionally, GDP and IDH for each federation unit were used in order to verify the relationship between contextual variables and inequalities. GDP was obtained in the IBGE site and IDH in the ‘Atlas Brasil,’ a partnership between the ‘Programa das Nações Unidas para o Desenvolvimento (PNUD)’ and the ‘Instituto de Pesquisa Econômica Aplicada (IPEA).’
2.4 Statistics
We presented a sample description with frequencies and 95% confidence intervals for the included sample and for the unvaccinated girls. The prevalence of non-vaccination according to Brazilian states was presented in a map. To explore inequalities, we presented the proportion of unvaccinated girls according to stratifiers for each Brazilian state in equiplots (www.equidade.org/equiplot), providing a visu-al representation of the prevalence in each category of the stratifier. For ordinal stratifiers (wealth quintiles and maternal education), we presented the Slope Index of Inequality (SII). The SII is a complex measure of absolute inequalities for ordered dimensions. The index varies from -100 to 100, with zero representing the absence of inequalities. Negative values represent a higher proportion of unvaccinated girls among the poorest/less educated, while positive values indicate a higher proportion of non-vaccination among the wealthiest/more educated. We included supplementary tables with values of estimates and respective confidence intervals as the equiplots and SII are presented in graphs.
To understand the inequality differences between states of Brazil, an ecological analysis was performed verifying the correlation between SII for wealth and maternal education with GDP and IDH. To visualize the relationship between inequalities and contextual variables, scatter plots were presented. To improve the data visualization, GDP was presented on a logarithmic scale.
All analyses accounted for the complex sampling structure. For this procedure, we used the survey (survey) command in the statistical package. The analyses were performed in Stata 16.1.
3. Results
The sample comprised 80,788 girls with ages between ?13 and ?18 years. Around 26.0% did not receive any dose of the HPV vaccine. The prevalence of unvaccinated girls was higher among the youngest (31.8% (95%CI: 29.2%; 34.5%)) compared to older girls (about 25.0%). Non-vaccination prevalence was higher among girls having mothers with no education (33.3% (95%CI: 30.1%; 36.7%)), compared to other maternal educational categories (from 22.5% to 26.4%) (Table 1).
Figure 1 shows the prevalence of unvaccinated girls according to Brazilian states. The prevalence ranged from 17.3% to 34.2%. The three states with higher prevalence were RN, MS, and MT (34.2%, 31.9%, and 31.8%, respectively). While in ES, DF, and MG, lower prevalence was observed (17.3%, 21.1%, and 21.3%, respectively).
Figure 2 and Supplementary Tables 2, 3, and 4 present the prevalence of unvaccinated girls according to Brazilian states and socioeconomic stratifiers. Regarding the area of residence, the results varied widely according to state. Statistically significant differences were found in five states. In four of them (RO, BA, MT), unvaccinated girls were more frequent in urban areas (MA, SC, MS, DF), while in one of them (RR), this was more common in the rural area. Concerning maternal education, lower levels presented a higher prevalence of non-vaccination in almost all states. Regarding wealth, the pattern varied across states. In MS, the wealthiest group presented the highest proportion of unvaccinated girls. In MT and MG, the poorest group presented a higher proportion of unvaccinated girls (Figure 2 and Supplementary Table X).
Results for SII complemented the findings once it considered the size of groups and the intermediate groups. For four states (RR, MA, MG, and SC), the SII shows a higher non-vaccination proportion among the poorest (between 10 and 20 percentage points of difference). For maternal education, in 11 states (AC, AP, RR, AL, BA, CE, MA, PI, RN, SE, and SP), the proportion of girls unvaccinated was higher among those with mothers less educated (at least 10 percentage points of difference).
Figure 4 presents the relationship of SII for wealth and maternal education with contextual variables. For both wealth and maternal education, the lower the vulnerability of poor girls and adolescents of less educated women, the higher the GDP and HDI. All correlations were moderate, although only the correlation of SII for maternal education and IDH was significant (r=0.570; p=0.002).
4. Discussion
The prevalence of non-vaccination in our sample was 26.4%. However, this percentage varied widely across the states of Brazil, ranging from 17.3% in ES to 34.2% in RN. Regarding inequalities, we did not find any marked difference at the national level. On the other hand, looking at the states of the country, in general, we found a higher prevalence of non-vaccination against HPV in rural areas. Specifically regarding wealth and education, some states presented a higher proportion of unvaccinated girls among the poorest (AC, AP, GO, MA) and with less educated mothers (AC, AM, AP, GO, MG, MT). In contrast, other states presented a higher proportion among the wealthiest (BA, MS) and those with more educated mothers (ES, MS, PB).
Our results showed that non-vaccination prevalence was higher among adolescents who did not know about the HPV vaccine. Adolescent knowledge about HPV and HPV vaccination is frequently associated with vaccine uptake13. A study performed in Spain with girls aged 15 years showed that those who scored higher knowledge about the HPV vaccine presented a higher prevalence of vaccination14. In the US, a study performed with adolescents aged 13 – 17 years showed that among the top reported reasons for not vaccinating was no knowledge about the vaccine15. Another relevant factor for adolescents’ immunization adherence is parental knowledge/concerns about vaccination. In France, a study observed that most adolescents described a passive role in HPV vaccination decision-making, following their parents ‘lead16. Parents’ concerns reported in the literature are regarding the safety of the immunobiological and possible adverse reactions, doubts about its effectiveness, and fear that the vaccine could encourage sexual initiation. In addition, the wide dissemination of erroneous or false information regarding vaccines potentially amplifies resistance to the vaccine17.
Given that Brazil is a country with continental dimensions, in which national strategies could present differences in implementation by the states or municipalities, the wide variability found in the prevalence of non-vaccination across states was not a surprising finding. A previous study also found heterogeneity within the Brazilian states in terms of vaccination coverage, which could be due to state-level public policies impacting the availability of vaccines8. Furthermore, despite the availability of a universal health system, Brazil still faces growing socioeconomic and health inequalities and requires efficient political action, focusing on health-related research and technology and improvement in public awareness 18, which could, ultimately, lead to better vaccination coverage.
Some Brazilian states presented a higher proportion of non-vaccinated adolescents among the wealthiest groups (BA, MS) and with more educated mothers (ES, MS, PB), which is an unexpected pattern. The lack of awareness about the vaccine and the virus, the lack of confidence in the efficacy of the immunizing, as well as the hesitancy of parents in vaccinating their adolescent girls due to cultural or religious beliefs, could have contributed to those findings5,19. Furthermore, despite the HPV vaccine being freely available in the public health sector since 201420, the vaccination campaigns were often carried out in public schools or health centers3, which might not comprehend girls with higher income or highly educated families in some locations. However, further research on the motives for non-vaccination against HPV among high-income and highly educated settings is needed to better understand this phenomenon, especially in the above-referred states of Brazil.
Our last finding explores the relationship between wealth and educational inequalities (measured by SII), HDI, and GDP – two contextual variables from Brazilian states. The correlations were positive and moderate, varying from 0.3 to 0.6. In other words, Brazilian states with higher GDP or HDIM presented higher disparities regarding zero-dose immunization. If we look for SII values, we will identify that for those states in worthy contextual situations (lower HDI and GDP), groups with lower education and the poorest presented a prevalence of zero-dose HPV between 15 and 25 percentage points higher than the groups with higher education and the wealthiest. The inverse health inequality hypothesis could help to understand this pattern. This hypothesis tells us that new health interventions tend to be adhered to by privileged groups first, and with time, vulnerable groups, initially left behind, increased their coverage21. In the Brazilian case, HPV vaccination among adolescents is a recent strategy, so one explanation for lower coverage of immunization among the poorest states could be the time of implementation of the vaccine.
We need to highlight some limitations of this work. First, the complete vaccination schedule for HPV in Brazil includes two doses, but PeNSE did not collect this information. However, we believe this issue was minimized due to the analysis of non-vaccination as the outcome. Second, our data is based on adolescent self-reports that may not be as precise as vaccination cards or mother reports generating an overestimation of zero-dose HPV prevalence. Finally, as we are presenting results by state, some groups might present a small sample size, which could lead to lower statistical power (Supplementary Table 1).
This work also presents some strengths. The main one is the representative sample of girls from 13 to 14 years old in Brazil, an upper-middle-income country with a universal public health system, where the HPV vaccine is a relatively new procedure. Also, our study explores inequalities at a disaggregated level, exploring inequalities beyond national estimates, which could hide the real situation of HPV vaccination in Brazil. Lastly, the use of a complex inequality measure, such as the SII, adds robustness to our findings.
To the best of our knowledge, this is the first study to assess socioeconomic inequalities in relation to non-vaccination against HPV infection in Brazilian adolescents. The present analyses could help understand the social determinants of vaccination coverage related to geographic location and state-level public policies, such as access to information about the vaccine, vaccination campaigns, and the health services that make them available. Thus, our findings reinforce the need to monitor the proportion of vaccination against HPV not only at the national level but at a disaggregated level so that educational actions and public health policies can be developed, focusing on expanding vaccination coverage according to the specificities of each location, prioritizing subgroups of the population that are most in need of such interventions.

CONFLICT OF INTERESTST STATEMENT
The authors declare no conflict of interest.

5. References
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14. Navarro-Illana P, Diez-Domingo J, Navarro-Illana E, Tuells J, Alemán S, Puig-Barberá J. “Knowledge and attitudes of Spanish adolescent girls towards human papillomavirus infection: where to intervene to improve vaccination coverage.” BMC Public Heal 2014 141. 2014;14(1):1-8. doi:10.1186/1471-2458-14-490
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20. MINISTÉRIO DA SAÚDE SECRETARIA DE VIGILÂNCIA EM SAÚDE DEPARTAMENTO DE VIGILÂNCIA DAS DOENÇAS TRANSMISSÍVEIS COORDENAÇÃO-GERAL DO PROGRAMA NACIONAL DE IMUNIZAÇÕES.
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