Mortalidade por carcinoma hepatocelular associado às hepatites virais B e C no estado de São Paulo, Brasil

Rev Bras Epidemiol rbepid Revista Brasileira de Epidemiologia Rev. bras. epidemiol. 1415-790X 1980-5497 Associação Brasileira de Saúde Coletiva RESUMO: Objetivos: Este estudo tem como objetivo descrever e analisar a distribuição temporal e espacial dos óbitos por carcinoma hepatocelular associados às hepatites virais B e C no estado de São Paulo. Métodos: Estudo ecológico dos óbitos por carcinoma hepatocelular associados a hepatites virais B e hepatites virais C no estado de São Paulo, de 2009 a 2017, com dados do Sistema de Informação sobre Mortalidade. A tendência temporal foi analisada por regressão linear, com método de Prais-Winsten. Os óbitos foram descritos segundo as características sociodemográficas, por meio de frequências absolutas e relativas, e foram espacialmente distribuídos segundo departamento regional de saúde. Resultados: Dos óbitos por carcinoma hepatocelular, 26,3% foram associados a hepatites virais B ou hepatites virais C. Observou-se maior proporção de óbitos por carcinoma hepatocelular associado a hepatites virais C (22,2%) quando comparada àquela associada a hepatites virais B (3,9%). A taxa de mortalidade por carcinoma hepatocelular associado a hepatites virais B apresentou tendência de queda, no entanto a taxa de mortalidade por carcinoma hepatocelular associado a hepatites virais C apresentou tendência estacionária. Predominaram óbitos de pacientes do sexo masculino, de cor branca, de 50–59 anos e com oito a 11 anos de estudo. A análise espacial revelou distribuição heterogênea dos óbitos no estado de São Paulo. Conclusão: A tendência de queda nas taxas de mortalidade por carcinoma hepatocelular associado a hepatites virais B revela um importante avanço no controle do agravo. Entretanto, a taxa de mortalidade por carcinoma hepatocelular associado a hepatites virais C vem-se mantendo estável ao longo do período estudado. A distribuição espacial dos óbitos pode contribuir para levantar hipóteses com vistas ao conhecimento mais aprofundado desses agravos nas regiões. INTRODUCTION Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, the third leading cause of death of neoplastic etiology, and one of the most lethal types of cancer in the world1. It is a malignant tumor that usually appears in cirrhotic patients and is most commonly associated with hepatitis B, hepatitis C, and chronic alcoholism2. More recently, obesity has been recognized as an important risk factor for different types of cancer, including liver cancer3. Globally, viral hepatitis accounted for approximately 1.34 million deaths in 2015. According to World Health Organization (WHO) data (2017), among deaths from viral hepatitis in 2015, 96% occurred due to complications of chronic infection, and the majority was caused by hepatitis B virus (HBV) (66%) and hepatitis C virus (HCV) (30%). Among the complications of chronic infection, 720,000 deaths from liver cirrhosis and 470,000 deaths from HCC can be highlighted4. The possible underreporting of deaths due do HCC associated with viral hepatitis in Brazil and around the world is highlighted. The results of a cohort study carried out on patients with chronic HCV infection in the United States in the period 2006–2010 showed that less than one-fifth of the deaths of HCV-infected people are reported on the death certificate, which indicates a significant underestimation of the number of deaths due to HCV. Among the deaths from liver cancer, HCV was mentioned in 31% of deaths5. According to the study by Tauil et al. who analyzed mortality from HBV in Brazil, from 2000 to 2009, the highest proportion of deaths due to HCC with hepatitis B as an associated cause occurred in 2001 with 6.4% (37/582)6. In contrast, an investigation in 19 medical centers in 8 states in Brazil identified that 39% of the cases of HCC had hepatitis B7. Therefore, it is very likely that there is underreporting of deaths from this disease in the country6. In view of the considerations presented, this study aimed to describe deaths due to HCC associated with HBV and HCV and to analyze the spatial and temporal distribution of these deaths in the state of São Paulo, from 2009 to 2017. METHODS This is an ecological study, with spatial and temporal analysis of deaths due to HCC associated with HBV and HCV in the state of São Paulo, from 2009 to 2017. The study area corresponds to the state of São Paulo, which counts with 645 municipalities, spread over a territorial area of 248,219,63 km², with a total of 43,359,005 inhabitants in 20168. Data on deaths of residents in the state of São Paulo were obtained from the Mortality Information System (SIM), and data on the population living in the state of São Paulo and in the municipalities were the annual population estimates of the State System Data Analysis Foundation (SEADE)9. The files of death certificates for the state of São Paulo for each year of the study were downloaded from the DATASUS website (https://datasus.saude.gov.br/transferencia-de-arquivos/). The files downloaded in DBC format were converted to DBF format, using the TABWIN software, and then analyzed using Excel software. First, deaths with underlying causes of HCC, line (d) of the death certificate, code C22.0 of the ICD-10, were selected. Second, deaths due to HCC that appeared in the other lines of the certificate (consequential and contributing causes) and that were not included in the underlying cause were included. In the next stage, deaths due to HCC that presented HBV and HCV codes (B18.0 – chronic HBV with Delta agent; B18.1 – chronic HBV without Delta agent; B18.2 – chronic HCV) in all lines corresponding to the causes of death were selected. Therefore, deaths due to HCC associated with viral hepatitis were considered, all deaths that had HCC in any line of causes of death and that simultaneously presented HBV or HCV mentioned in the declaration. Generalized linear regression models were constructed using the Prais–Winsten method in the software Stata version 15, considering the significance level of 5%. The time series of age-standardized mortality rates were represented in line graph format, constructed in Microsoft Office Excel 2013. To quantitatively estimate the time trends of mortality rates in the analyzed period, the formula of annual percentage change (APC) was used. The mortality coefficients were age-standardized by the direct method, using as reference the population of the 2010 census of the state of São Paulo. A descriptive analysis of the sociodemographic characteristics of deaths was carried out according to the following variables: sex, age group, color, and schooling. Descriptive variables were analyzed by absolute and relative frequencies and by Pearson’s chi-square test or Fisher’s exact test, considering the significance level of 5%. Maps were built with the spatial distribution of mortality rates, using SIG QGIS software version 3.4. The spatial unit of choice was the Regional Health Department (DRS), responsible for the management of Health Care of the State Department of Health at the regional level. The deaths were geocoded and described according to the DRS of residence, considering the following 3-year period: 2009–2011, 2012–2014, and 2015–2017. Secondary public domain databases were used, without the use of any nominal data that could allow the identification of the subjects. Therefore, the ethical aspects of the research with human beings in force in resolution no. 466 of December 12, 2012, of the National Health Council were respected. RESULTS From 2009 to 2017, 2,499,738 deaths were found in the state of São Paulo. Among these, 5,870 had HCC as the cause of death, with 5,217 (88.9%) presenting HCC as the underlying cause of death and 653 (11.1%) mentioning HCC in the other lines of the death certificate (consequential causes and contributors of death). Among the deaths due to HCC, 1,545 had HBV or HCV as an associated cause of death, that is, 26.3% (1,545/5,870) of deaths due to HCC were attributed to HBV or HCV. There were 1,306 (22.2%) deaths due to HCC associated only with HCV and 226 (3.9%) associated only with HBV, meaning there was a higher proportion of deaths due to HCC attributed to HCV when compared to HBV. Only 13 (0.2%) deaths due to HCC were associated with both viruses (HBV and HCV). Standardized mortality rates due to HCC associated with HBV showed a significant reduction in the analyzed period, from 0.07 per 100,000 inhabitants-year in 2009 to 0.03 per 100,000 inhabitants-year in 2017, with an annual decrease of 10.4% (95%CI -17.0 to -3.2) (Figure 1 and Table 1). It was also observed that these rates were higher in males (Figure 1). Figure 1. Time series of age-standardized mortality rates due to HCC associated with hepatitis B and C viruses, in the state of São Paulo, 2009–2017. Source: Mortality Information System, São Paulo, 2019. *Per 100,000 inhabitants / year. Age-standardized mortality rate – using as reference the population of the 2010 census of the state of São Paulo. Standardized mortality rates due to HCC associated with HCV showed a stationary trend in the analyzed period, from 0.35 per 100,000 inhabitants-year in 2009 to 0.25 per 100,000 inhabitants-year in 2017 (APC=-4.0; 95%CI -8.6 to 0.7) (Figure 1 and Table 1). It was also observed that these rates were higher in males (Figure 1). Table 1. Annual Percentage Change of age-standardized mortality rates due to hepatocellular carcinoma, associated with viral hepatitis, in the state of São Paulo, 2009–2017. APC LL 95%CI LS 95%CI TRENDS Hepatitis B -10.4 -17.0 -3.2 Descending Hepatitis C -4.0 -8.6 0.7 Stationary Hepatitis B (male) -10.2 -18.1 -1.6 Descending Hepatitis C (male) -3.8 -8.1 7.5 Stationary Hepatitis B (female) -8.3 -19.7 4.5 Stationary Hepatitis C (female) -2.6 -8.1 3.1 Stationary LL 95%CI: Lower limit of 95% confidence interval. LS 95%CI: Superior limit of 95% confidence interval. Age-standardized mortality rate – using as reference the population of the 2010 census of the state of São Paulo. Source: Mortality Information System, São Paulo, 2019. Source: Mortality Information System, São Paulo, 2019. *Per 100,000 inhabitants / year. Age-standardized mortality rate – using as reference the population of the 2010 census of the state of São Paulo. Most deaths due to HCC associated with viral hepatitis were male (75.5%), with a higher proportion in cases associated with hepatitis B (87.2%), white (73.9%), in the age group of 50–59 years (35%). The same profile was observed when they were analyzed separately for each type of hepatitis (Table 2). Table 2. Sociodemographic characteristics of deaths due to hepatocellular carcinoma associated with hepatitis B and C viruses, in the state of São Paulo, 2009–2017. Variable Total* Hepatitis B** Hepatitis C** Hepatitis B and C (n=1,545) (n=226) (n=1,306) (n=13) n % n % n % n % Sex Female 379 24.5 29 12.8 348 26.6 2 15.4 Male 1,166 75.5 197 87.2 958 73.4 11 84.6 Age group 20–29 4 0.3 3 1.3 1 0.1 0 0.0 30–39 17 1.1 7 3.1 10 0.8 0 0.0 40–49 153 9.9 40 17.7 113 8.7 0 0.0 50–59 541 35.0 78 34.5 458 35.1 5 38.5 60–69 481 31.1 52 23.0 424 32.5 5 38.5 ≥70 349 22.6 46 20.4 300 23.0 3 23.1 Color White 1,141 73,9 148 65.5 986 75.5 7 53.8 Black 89 5.8 21 9.3 66 5.1 2 15.4 Brown 223 14.4 38 16.8 181 13.9 4 30.8 Yellow 35 2.3 12 5.3 23 1.8 0 0.0 Indigenous 0 0.0 0 0.0 0 0.0 0 0.0 Blank or ignored 57 3.7 7 3.1 50 3.8 0 0.0 Schooling None 82 5.3 21 9.3 60 4.6 1 7.7 1–3 291 18.8 38 16.8 251 19.2 2 15.4 4–7 296 19.2 48 21.2 247 18.9 1 7.7 8–11 342 22.1 36 15.9 301 23.0 5 38.5 ≥12 242 15.7 35 15.5 207 15.8 0 0.0 Blank or ignored 292 18.9 48 21.2 240 18.4 4 30.8 *Difference in the distribution by sex, age group and schooling of total deaths due to hepatocellular carcinoma associated with hepatitis B or C viruses in relation to the total number of general deaths (p<0.001). **Difference in distribution by sex, age group and color of deaths due to hepatocellular carcinoma associated with hepatitis B in relation to deaths due to hepatocellular carcinoma associated with hepatitis C (p<0.001). Source: Mortality Information System, São Paulo, 2019. There was a predominance of deaths in white (73.9%), with a similar proportion when analyzed separately for each type of hepatitis. When analyzing the level of education, a higher proportion of deaths was identified in the category of 8–11 years of study (22.1%), but the cases associated with hepatitis B were predominantly present in individuals with 4–7 years of study (21.2%). It is noteworthy that 18.9% of the analyzed deaths had the education variable left blank or ignored (Table 2). It is noteworthy that the deaths due to HCC associated with viral hepatitis were different in relation to overall deaths regarding sex, age group, and schooling (p<0.001). When analyzing the difference in deaths due to HCC associated with hepatitis B and those associated with hepatitis C, it was found that in women the proportion of deaths due to HCC associated with hepatitis C is higher (26.6%) than in deaths due to HCC associated with hepatitis B (12.8%) (p<0.001). Another important factor observed was the age difference between deaths, noting that the proportion of deaths in the age groups of 30–39 years and 40–49 years is only 0.8% and 8.7%, respectively, when refers to deaths due to HCC associated with hepatitis C. In relation to hepatitis B, there is a greater proportion of deaths, 3.1 and 17.7%, respectively, for the same age groups (p<0.001), indicating that individuals affected by HCC associated with hepatitis B die earlier (Table 2). Regarding the color variable, there was a higher proportion of deaths among whites both in deaths due to HCC associated with hepatitis B and in those associated with hepatitis C, with 65.5 and 75.5%, respectively. It was found that in people with yellow skin, the proportion of deaths due to HCC associated with hepatitis B is higher (5.3%) than in deaths due to HCC associated with hepatitis C (1.8%) (p<0.001) (Table 2). When performing the spatial distribution, the crude mortality rates due to HCC associated with HBV showed a decline over the study periods. In the first period, the highest rate was observed in the Regional Health Department (DRS) of Ribeirão Preto with 0.20 deaths per 100,000 inhabitants/year, followed by the DRS of Greater São Paulo, Botucatu, and São José do Rio Preto, with 0.12, 0.11, and 0.11 deaths per 100,000 inhabitants/year, respectively. In the second triennium, the DRS of Baixada Santista and São José do Rio Preto stood out with 0.14 and 0.13 deaths per 100,000 inhabitants/year, respectively, while in the third study period, the DRS of Barretos stood out, with 0.16 deaths per 100,000 inhabitants/year (Figure 2). Figure 2. Spatial distribution of crude mortality rates due to hepatocellular carcinoma associated with hepatitis B and C viruses, according to the Regional Health Department of residence, in the state of São Paulo, 2009–2017 (per 100,000 inhabitants / year). Source: Mortality Information System, São Paulo, 2019. In relation to crude mortality rates due to HCC associated with HCV, in the first period, the highest rate was observed in the DRS of Ribeirão Preto with 0.60 deaths per 100,000 inhabitants/year, followed by the DRS of Greater São Paulo and São José do Rio Preto stood out, both with 0.48 deaths per 100,000 inhabitants/year and then the DRS of Baixada Santista with 0.34 deaths per 100,000 inhabitants/year. In the second triennium, the highest rates were found in the DRS of Baixada Santista (0.62 deaths per 100,000 inhabitants/year), Greater São Paulo (0.51 deaths per 100,000 inhabitants/year), São José from Rio Preto (0.44 deaths per 100,000 inhabitants/year), and Ribeirão Preto (0.36 deaths per 100,000 inhabitants/year). In the third study period, the DRS of Ribeirão Preto, Baixada Santista, and Greater São Paulo stood out with 0.52, 0.51, and 0.38 deaths per 100,000 inhabitants/year, respectively (Figure 2). DISCUSSION A higher proportion of deaths due to HCC associated with HCV was observed (22.2%) when compared to HBV (3.9%). The mortality rate due to HCC associated with hepatitis B showed a downward trend. However, the mortality rate due to HCC associated with hepatitis C showed a steady trend in the analysis period. The spatial distribution revealed a heterogeneous pattern of mortality rates due to HCC associated with viral hepatitis in the state of São Paulo. The study by Fassio et al. on the etiology of HCC in Argentina concluded that the main etiological factors found in 551 studied HCC cases were alcohol (33%), HCV (32.8%), and HBV (10%)10. These results coincide with those obtained in this study, which found a higher proportion of deaths due to HCC associated with HCV and a lower proportion associated with HBV. Similar to the results of this study, Sato et al. showed a downward trend in mortality from hepatitis B in the period from 2002 to 201611, as well as data from the state of São Paulo showing a rate reduction in hepatitis B detection from 9.41 cases per 100,000 inhabitants in 2009 to 7.56 cases per 100,000 inhabitants in 201412. It is suggested that the decrease in mortality rates due to hepatitis B in our country can be attributed in part to vaccination, with a decrease in prevalence; the measures recommended by preventive actions against HIV infection, initiated in the 1980s, as observed in other countries, may have influenced the reduction of these rates13,14,15,16. These findings highlight that the prevention of primary liver cancer through the HBV vaccine has been showing successful results. The hepatitis B vaccine is highly effective and practically free of complications. As hepatitis B is a major cause of liver cancer in the world, vaccination prevents not only hepatitis but also cancer17. In this same sense, it is likely that the reduction in mortality due to HCC associated with hepatitis B, observed in this study, is due to the high vaccination coverage. Regarding HCC mortality associated with hepatitis C, a steady trend in mortality rates was identified in the analyzed period. In contrast, the study by Akinyemiju et al. shows that between 1990 and 2015, there was an increase in the incidence and mortality of liver cancer worldwide due to HCV18. Mortality rates due to HCC associated with hepatitis B were higher in males. This observation can be explained by male sexual behavior, with men being more exposed to the virus19. The same behavior was observed in mortality rates due to HCC associated with hepatitis C in the study period, with higher rates in males. Similarly, there are findings that men have more attitudes that leave them more exposed to the virus, such as the use of injectable or inhalable drugs, drinking alcohol, and the practice of sexual intercourse without the use of condoms20. There was a predominance of deaths due to HCC associated with HCV in the age group of 50–59 years (35.1%). This fact may be associated with several factors, such as late diagnosis, long latency period of viruses, and the absence of signs and symptoms (which denote the silent character of this type of hepatitis)21. Regarding the level of education, this study pointed out that the majority of deaths due to HCC associated with hepatitis B had from 4 to 7 years of study and the majority of deaths due to HCC associated with hepatitis C had from 8 to 11 years of study. The study by Gonçalves et al., carried out in the state of Pará, from 2010 to 2014, pointed out that most of the notified cases of hepatitis B and C (35%) had low education (elementary school), indicating the relationship between these individuals and the conditions of socioeconomic vulnerability of populations, which can favor the transmission of the disease22. However, two factors can be considered: the sociodemographic differences between the states of Pará and São Paulo and the low filling in of this field, a fact that may have caused a bias in this analysis, as found by Cruz et al. in their study carried out in the state of São Paulo23. In this study, when analyzing the color variable, it was observed that 65.5% of deaths due to HCC associated with hepatitis B were white. With regard to HCC deaths associated with hepatitis C, 75.5% were white. These results coincide with the study by Sato et al., carried out in the city of São Paulo, in which there was a predominance of deaths from hepatitis B and hepatitis C in white individuals12 and diverge from the study by Oliveira et al., in which the majority of notified cases of hepatitis C in a hospital in Goiás (75.1%) were brown24. The DRS that presented the highest mortality rates due to HCC associated with hepatitis B or C over the 9 years of this study may be related to several factors, such as genetic, demographic, socioeconomic, cultural, and historical factors in the population studied. Other issues can be raised in relation to past failures in prenatal control; the quality of the transfused blood, causing a greater occurrence of injuries; change of residence for treatment in larger municipalities, with more structured health services; and other social and behavioral factors, such as the diversity of partners and the early onset of sexual activity. It is considered that the urbanization of these areas can also influence mortality rates25,26. Chronic viral hepatitis has a great impact on patients infected with HIV/AIDS27. According to information from the São Paulo State Secretariat of Health (2018), the Epidemiological Surveillance Group (ESG) of Santos, Barretos, São José do Rio Preto, Ribeirão Preto, and Capital had AIDS mortality rates above the state average (4.9 deaths per 100,000 inhabitants) in the year 201728. Thus, the DRS with higher rates of mortality due to HCC associated with viral hepatitis may be related to possible cases of coinfection in these regions. The Metropolitan Region of Santos stands out in the AIDS epidemic, being one of the cities with the highest incidence rate in the state of São Paulo. This panorama would be related to the fact that the city, through its port, is included in the cocaine trafficking route to Europe and North America29,30,31. These factors may be related to the prominence that the DRS of Baixada Santista presented over the 3-year period of this study. A study carried out in a hospital in the city of Ribeirão Preto-SP showed a prevalence of HIV/HBV of 20.4%32. These results may be related to the highlight that the DRS of Ribeirão Preto presented in this study. Souto et al. evaluated the contribution of different parenteral routes of exposure to hepatitis C, including samples from nine cross-sectional studies, with a total of 3,910 individuals, and confirmed the use of injectable drugs as the main risk factor for HCV33. The study by Passos et al., carried out in the Ribeirão Preto region, with 208 former athletes, showed that the high prevalence of hepatitis C among former athletes was associated with the previous use of injectable stimulants34. This fact may explain the highlight that Ribeirão Preto DRS presented in this study, indicating that the use of injectable drugs in the past decades in this region may have contributed to the results found. In this study, the DRS that presented the highest rates of HCC associated with hepatitis C may reflect social and behavioral problems, such as the large number of injecting drug users in these regions in the past decades. A limitation of this study is the use of secondary data. It is necessary to consider that the time elapsed between the moment of infection by hepatitis B or C and the development of HCC usually takes decades, in other words, the interpretation of these data must be cautious, since it may reflect the diagnosis and treatment in regions with large medical centers, which does not mean that this was where the infection was acquired. The reduction in the mortality rate due to HCC associated with hepatitis B shows an important advance in the control of the disease due to the immunization actions with the hepatitis B vaccine. However, the mortality rate due to HCC associated with hepatitis C has been stable over the study period, indicating the need for actions and measures to reduce these rates. In this sense, the increase in the detection of cases of hepatitis C, through the expansion of the offer of rapid tests or the serology for the population most vulnerable to the risk of infection, as well as for people aged 40 years and above and who may have been infected in the past decades, is an important strategy for diagnosis. In addition, the treatment of affected individuals will contribute to the prevention and control of the disease, with the consequent reduction in cases and deaths due to HCC associated with hepatitis C. The spatial distribution of deaths may contribute to the managers and professionals of the DRS, in the sense of raising hypotheses for more in-depth knowledge of their regions, based on these results. ACKNOWLEDGMENTS The authors thank University of São Paulo, School of Public Health and State Department of Health, Epidemiological Surveillance Center ‘Professor Alexandre Vranjac’ that provided technical support for the development and implementation of this study. REFERENCES 1 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (6): 394-424. https://doi.org/10.3322/caac.21492. Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018 68 6 394 424 https://doi.org/10.3322/caac.21492. 2 2. Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis 2005; 25 (2): 143-54. https://doi.org/10.1055/s-2005-871194 Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis 2005 25 2 143 54 https://doi.org/10.1055/s-2005-871194 3 3. Haslam DW, James WP. Obesity. Lancet 2005; 366 (9492): 1197-209. https://doi.org/10.1016/S0140-6736(05)67483-1 Haslam DW James WP. Obesity. Lancet 2005 366 9492 1197 209 https://doi.org/10.1016/S0140-6736(05)67483-1 5 5. Mahajan R, Xing J, Liu SJ, Ly KN, Moorman AC, Rupp L, et al. Mortality among persons in care with hepatitis C virus infection: the Chronic Hepatitis Cohort Study (CHeCS), 2006-2010. Clin Infect Dis 2014; 58 (8): 1055-61. https://doi.org/10.1093/cid/ciu077 Mahajan R Xing J Liu SJ Ly KN Moorman AC Rupp L Mortality among persons in care with hepatitis C virus infection: the Chronic Hepatitis Cohort Study (CHeCS), 2006-2010. Clin Infect Dis 2014 58 8 1055 61 https://doi.org/10.1093/cid/ciu077 6 6. Tauil MC, Amorim TR, Pereira GF, Araújo WN. Mortalidade por hepatite viral B no Brasil, 2000-2009. Cad Saude Publica 2012; 28 (3): 472-8. https://doi.org/10.1590/s0102-311x2012000300007 Tauil MC Amorim TR Pereira GF Araújo WN. Mortalidade por hepatite viral B no Brasil, 2000-2009. Cad Saude Publica 2012 28 3 472 8 https://doi.org/10.1590/s0102-311x2012000300007 7 7. Gonçalves CS, Pereira FE, Gayotto LC. Hepatocellular carcinoma in Brazil: report of a national survey (Florianópolis, SC, 1995). Rev Inst Med Trop Sao Paulo 1997; 39 (3): 165-70. https://doi.org/10.1590/s0036-46651997000300008 Gonçalves CS Pereira FE Gayotto LC. Hepatocellular carcinoma in Brazil: report of a national survey (Florianópolis, SC, 1995). Rev Inst Med Trop Sao Paulo 1997 39 3 165 70 https://doi.org/10.1590/s0036-46651997000300008 8 8. Fundação SEADE. Informações dos Municípios Paulistas [Internet]. São Paulo; 2018 [cited on Sept. 14, 2018]. Available at: http://www.imp.seade.gov.br/frontend/#/ Fundação SEADE. Informações dos Municípios Paulistas [Internet]. São Paulo; 2018 [cited on Sept. 14, 2018]. Available at: http://www.imp.seade.gov.br/frontend/#/ 9 9. Fundação SEADE. Sistema Seade de Projeções Populacionais [internet]. 2018 [cited on Sept. 14, 2018]. Available at: http://produtos.seade.gov.br/produtos/projpop/index.php Fundação SEADE. Sistema Seade de Projeções Populacionais [internet]. 2018 [cited on Sept. 14, 2018]. Available at: http://produtos.seade.gov.br/produtos/projpop/index.php 10 10. Fassio E, Míguez C, Soria S, Palazzo F, Gadano A, Adrover R, et al. Etiology of hepatocellular carcinoma in Argentina: results of a multicenter retrospective study. Acta Gastroenterol Latinoam 2009; 39 (1): 47-52. PMID: 19408739 Fassio E Míguez C Soria S Palazzo F Gadano A Adrover R Etiology of hepatocellular carcinoma in Argentina: results of a multicenter retrospective study. Acta Gastroenterol Latinoam 2009 39 1 47 52 19408739 11 11. Sato APS, Koizumi IK, Farias NSO, Silva CRCD, Cardoso MRA, Figueiredo GM. Mortality trend due to Hepatitis B and C in the city of São Paulo, 2002-2016. Rev Saude Publica 2020; 54: 124. https://doi.org/10.11606/s1518-8787.2020054002231 Sato APS Koizumi IK Farias NSO Silva CRCD Cardoso MRA Figueiredo GM. Mortality trend due to Hepatitis B and C in the city of São Paulo, 2002-2016. Rev Saude Publica 2020 54 124 https://doi.org/10.11606/s1518-8787.2020054002231 12 12. Coelho DM, Farias N, Camis MCRS. Viral Hepatitis Program in the state of São Paulo, 2000-2015. BEPA 2015; 12 (141): 25-34. Coelho DM Farias N Camis MCRS. Viral Hepatitis Program in the state of São Paulo, 2000-2015. BEPA 2015 12 141 25 34 13 13. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol 2006; 44 (Suppl 1): S6-9. https://doi.org/10.1016/j.jhep.2005.11.004 Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol 2006 44 Suppl 1 S6 9 https://doi.org/10.1016/j.jhep.2005.11.004 14 14. Pereira LM, Martelli CM, Merchán-Hamann E, Montarroyos UR, Braga MC, Lima ML, et al. Population-based multicentric survey of hepatitis B infection and risk factor differences among three regions in Brazil. Am J Trop Med Hyg 2009; 81 (2): 240-7. PMID: 19635877 Pereira LM Martelli CM Merchán-Hamann E Montarroyos UR Braga MC Lima ML Population-based multicentric survey of hepatitis B infection and risk factor differences among three regions in Brazil. Am J Trop Med Hyg 2009 81 2 240 7 19635877 15 15. Ximenes RAA, Figueiredo GM, Cardoso MRA, Stein AT, Moreira RC, Coral G, et al. Population-Based multicentric survey of hepatitis B Infection and Risk Factors in the North, South, and Southeast Regions of Brazil, 10-20 Years After the Beginning of Vaccination. Am J Trop Med Hyg 2015; 93 (6): 1341-8. https://doi.org/10.4269/ajtmh.15-0216 Ximenes RAA Figueiredo GM Cardoso MRA Stein AT Moreira RC Coral G Population-Based multicentric survey of hepatitis B Infection and Risk Factors in the North, South, and Southeast Regions of Brazil, 10-20 Years After the Beginning of Vaccination. Am J Trop Med Hyg 2015 93 6 1341 8 https://doi.org/10.4269/ajtmh.15-0216 16 16. Griensven GJ, Vroome EM, Goudsmit J, Coutinho RA. Changes in sexual behaviour and the fall in incidence of HIV infection among homosexual men. BMJ 1989; 298 (6668): 218-21. https://doi.org/10.1136/bmj.298.6668.218 Griensven GJ Vroome EM Goudsmit J Coutinho RA. Changes in sexual behaviour and the fall in incidence of HIV infection among homosexual men. BMJ 1989 298 6668 218 21 https://doi.org/10.1136/bmj.298.6668.218 17 17. Jorge SG. Hepatitis B [Internet]. Hepcentro. 2003 [cited on Oct 28, 2007]. Available at: http://www.hepcentro.com.br/hepatite_b.htm Jorge SG. Hepatitis B [Internet]. Hepcentro. 2003 [cited on Oct 28, 2007]. Available at: http://www.hepcentro.com.br/hepatite_b.htm 18 18. Global Burden of Disease Liver Cancer Collaboration, Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, et al. The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015. JAMA Oncol 2017; 3 (12): 1683-91. https://doi.org/10.1001/jamaoncol.2017.3055 Global Burden of Disease Liver Cancer Collaboration Akinyemiju T Abera S Ahmed M Alam N Alemayohu MA The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015. JAMA Oncol 2017 3 12 1683 91 https://doi.org/10.1001/jamaoncol.2017.3055 19 19. Aquino JA, Pegado KA, Barros LP, Machado LF. Soroprevalência de infecções por vírus da hepatite B e vírus da hepatite C em indivíduos do Estado do Pará. Rev Soc Bras Med Trop 2008; 41 (4): 334-7. https://doi.org/10.1590/s0037-86822008000400003 Aquino JA Pegado KA Barros LP Machado LF. Soroprevalência de infecções por vírus da hepatite B e vírus da hepatite C em indivíduos do Estado do Pará. Rev Soc Bras Med Trop 2008 41 4 334 7 https://doi.org/10.1590/s0037-86822008000400003 20 20. Gomes DT, Tocantins FR, Souza FBA. Profile of hepatitis C patients and the population’s vulnerability: potentialities for nursing. Rev Pesqui Cuid Fundam (Online) 2010; 2: 512-5. https://doi.org/10.9789/2175-5361.2010.v0i0.%25p Gomes DT Tocantins FR Souza FBA. Profile of hepatitis C patients and the population’s vulnerability: potentialities for nursing. Rev Pesqui Cuid Fundam (Online) 2010 2 512 5 https://doi.org/10.9789/2175-5361.2010.v0i0.%25p 21 21. Margreiter S, Ferreira JM, Vieira ILV, Koneski JM, Souza LH, Assunção ALN, et al. Prevalence study of viral hepatitis B and C in the city of Palhoça – SC. Rev Saúde Pub Santa Cat 2015; 8 (2): 21-32. Margreiter S Ferreiray JM Vieira ILV Koneski JM Souza LH Assunção ALN Prevalence study of viral hepatitis B and C in the city of Palhoça – SC. Rev Saúde Pub Santa Cat 2015 8 2 21 32 22 22. Gonçalves NV, Miranda CSC, Guedes JA, Silva LCT, Barros EM, Tavares CGM, et al. Hepatitis B and C in the areas of three Regional Health Centers of Pará State, Brazil: a spatial, epidemiological and socioeconomic analysis. Cad Saude Colet 2019; 27 (1): 1-10. https://doi.org/10.1590/1414-462X201900010394 Gonçalves NV Miranda CSC Guedes JA Silva LCT Barros EM Tavares CGM Hepatitis B and C in the areas of three Regional Health Centers of Pará State, Brazil: a spatial, epidemiological and socioeconomic analysis. Cad Saude Colet 2019 27 1 1 10 https://doi.org/10.1590/1414-462X201900010394 23 23. Comparação do perfil epidemiológico das hepatites B e C em um serviço público de São Paulo. Arq Gastroenterol 2009; 46 (3): 225-9. https://doi.org/10.1590/s0004-28032009000300016 Comparação do perfil epidemiológico das hepatites B e C em um serviço público de São Paulo. Arq Gastroenterol 2009 46 3 225 9 https://doi.org/10.1590/s0004-28032009000300016 24 24. Oliveira TJB, Reis LAP, Barreto LSLO, Gomes JG, Manrique EJC. Perfil epidemiológico dos casos de hepatite C em um hospital de referência em doenças infectocontagiosas no estado de Goiás, Brasil. Rev Pan-Amaz Health 2018; 9 (1): 51-7. http://doi.org/10.5123/s2176-62232018000100007 Oliveira TJB Reis LAP Barreto LSLO Gomes JG Manrique EJC. Perfil epidemiológico dos casos de hepatite C em um hospital de referência em doenças infectocontagiosas no estado de Goiás, Brasil. Rev Pan-Amaz Health 2018 9 1 51 7 http://doi.org/10.5123/s2176-62232018000100007 25 25. Oliveira CS, Silva AV, Santos KN, Fecury AA, Almeida MK, Fernandes AP, et al. Hepatitis B and C virus infection among Brazilian Amazon riparians. Rev Soc Bras Med Trop 2011; 44 (5): 546-50. https://doi.org/10.1590/S0037-86822011000500003 Oliveira CS Silva AV Santos KN Fecury AA Almeida MK Fernandes AP Hepatitis B and C virus infection among Brazilian Amazon riparians. Rev Soc Bras Med Trop 2011 44 5 546 50 https://doi.org/10.1590/S0037-86822011000500003 26 26. Katsuragawa TH, Cunha RPA, Salcedo JMV, Souza DCA, Oliveira KRV, Gil LHS et al. High seroprevalence of hepatitis B and C markers in the upper Madeira River region, Porto Velho, Rondonia, Brazil. Rev Pan-Amaz Saude 2010; 1 (2): 91-6. http://doi.org/10.5123/S2176-62232010000200011 Katsuragawa TH Cunha RPA Salcedo JMV Souza DCA Oliveira KRV Gil LHS High seroprevalence of hepatitis B and C markers in the upper Madeira River region, Porto Velho, Rondonia, Brazil. Rev Pan-Amaz Saude 2010 1 2 91 6 http://doi.org/10.5123/S2176-62232010000200011 27 27. Silva ACLG, Tozatti F, Welter AC, Miranda CDC. Incidência e mortalidade por hepatite B, de 2001 a 2009: uma comparação entre o Brasil, Santa Catarina e Florianópolis. Cad Saude Colet 2013; 21 (1): 34-9. Silva ACLG Tozatti F Welter AC Miranda CDC. Incidência e mortalidade por hepatite B, de 2001 a 2009: uma comparação entre o Brasil, Santa Catarina e Florianópolis. Cad Saude Colet 2013 21 1 34 9 28 28. SES-SP – Secretaria de Estado da Saúde de São Paulo. Coordenadoria de Controle de Doenças. Centro de Referência e Treinamento em DST/Aids. Programa Estadual de DST/Aids de São Paulo. Boletim Epidemiológico de HIV-AIDS-IST 2018; 35 (1): 1-261. SES-SP – Secretaria de Estado da Saúde de São Paulo. Coordenadoria de Controle de Doenças. Centro de Referência e Treinamento em DST/Aids. Programa Estadual de DST/Aids de São Paulo. Boletim Epidemiológico de HIV-AIDS-IST 2018 35 1 1 261 29 29. Haiek RC, Martin D, Rocha FCM, FS, Silveira DX. Uso de drogas injetáveis entre mulheres na Região Metropolitana de Santos, São Paulo, Brasil. Physis 2016; 26 (3): 917-37. https://doi.org/10.1590/S0103-73312016000300011 Haiek RC Martin D Rocha FCM, FS Silveira DX. Uso de drogas injetáveis entre mulheres na Região Metropolitana de Santos, São Paulo, Brasil. Physis 2016 26 3 917 37 https://doi.org/10.1590/S0103-73312016000300011 30 30. Larcerda R, Stall R, Gravato N, Tellini R, Hudes ES, Hearst N. HIV infection and risk behaviors among male port workers in Santos, Brazil. Am J Public Health 1996; 86 (8): 1158-60. https://doi.org/10.2105/ajph.86.8_pt_1.1158 Larcerda R Stall R Gravato N Tellini R Hudes ES Hearst N. HIV infection and risk behaviors among male port workers in Santos, Brazil. Am J Public Health 1996 86 8 1158 60 https://doi.org/10.2105/ajph.86.8_pt_1.1158 31 31. Mesquita F. Aids: na rota da cocaína – um conto santista. São Paulo: Anita Garibaldi; 1992. 69 p. Mesquita F. Aids: na rota da cocaína – um conto santista. São Paulo: Anita Garibaldi 1992 69 p. 32 32. Souza MG, Passos AD, Machado AA, Figueiredo JF, Esmeraldino LE. Co-infecção HIV e vírus da hepatite B: prevalência e fatores de risco. Rev Soc Bras Med Trop 2004; 37 (5): 391-5. https://doi.org/10.1590/s0037-86822004000500004 Souza MG Passos AD Machado AA Figueiredo JF Esmeraldino LE. Co-infecção HIV e vírus da hepatite B: prevalência e fatores de risco. Rev Soc Bras Med Trop 2004 37 5 391 5 https://doi.org/10.1590/s0037-86822004000500004 33 33. Souto FJ, Fontes CJ, Pignati LT, Pagliarini ME, Menezes VM, Martinelli AL, Figueiredo JF, Donadi EA, Passos AD. Risk factors for hepatitis C virus infection in Inland Brazil: an analysis of pooled epidemiological sectional studies. J Med Virol 2012; 84 (5): 756-62. https://doi.org/10.1002/jmv.23256 Souto FJ Fontes CJ Pignati LT Pagliarini ME Menezes VM Martinelli AL Figueiredo JF Donadi EA Passos AD. Risk factors for hepatitis C virus infection in Inland Brazil: an analysis of pooled epidemiological sectional studies. J Med Virol 2012 84 5 756 62 https://doi.org/10.1002/jmv.23256 34 34. Passos AD, Figueiredo JF, Martinelli Ade L, Villanova M, Nascimento MM, Secaf M. Hepatitis C among former athletes: association with the use of injectable stimulants in the past. Mem Inst Oswaldo Cruz 2008; 103 (8): 809-12. https://doi.org/10.1590/s0074-02762008000800011 Passos AD Figueiredo JF Martinelli Ade L Villanova M Nascimento MM Secaf M. Hepatitis C among former athletes: association with the use of injectable stimulants in the past. Mem Inst Oswaldo Cruz 2008 103 8 809 12 https://doi.org/10.1590/s0074-02762008000800011 Financial support: none