A time series analysis of detection and mortality of hepatitis C in Brazil, 2008–2018

Hepatitis C is a severe global public health problem. It is estimated that around 71 million people worldwide (1% of the population) live with the hepatitis C virus (HCV) and that approximately 400,000 people die annually as a result of complications of the disease, mainly due to cirrhosis and hepatocellular carcinoma [1]. Brazil is a continent-sized country with pronounced socio-spatial inequalities. The most recent serological survey, conducted between 2005 and 2009, revealed an overall prevalence of anti-HCV antibodies of 1.38% in the capital cities of the five Brazilian macro-regions and the Federal District. Seropositivity ranged from 0.68% in the Northeast Region to 2.10% in the North Region [2].

The World Health Organization’s (WHO) proposal is to reduce new hepatotropic virus infections and their associated mortality by 90% and 65%, respectively, by 2030 [3]. The Brazilian Ministry of Health, in accordance with the WHO, has outlined a national strategy to achieve this goal. The general objective of the Plan for the Elimination of Hepatitis C in Brazil is to expand access to prevention, diagnosis, and treatment of hepatitis C, involving the three spheres of government (federal, state, and municipal), to reduce new infections and mortality [4].

In Brazil, as in the rest of the world, access to healthcare is expensive, and regional inequalities lead to differences in diagnosis and access to treatments. It is, therefore, of fundamental importance to conduct epidemiological studies that contribute to characterization of the disease in different regions of the country, in order to contribute to the design of strategies for combating and eliminating hepatitis C throughout Brazil. There are no recent studies in Brazil on the trend behavior of the disease in its different regions. For this reason, the objective of this study is to analyse the time trend of the incidence and mortality of hepatitis C in Brazil during the period from 2008 to 2018, according to sociodemographic and clinical characteristics.

This study has presented important data regarding the detection and mortality rate of hepatitis C in Brazil in recent years, as well as differences in the epidemiological profile of the disease in different regions of the country.

Mandatory notification of hepatitis C was implemented by the Brazilian surveillance system in 1996. Until 2014, individuals with anti-HCV reactive serology in addition to detectable HCV-RNA were considered confirmed cases. However, since 2015, in order to increase the sensitivity of new case detection, the criteria have been modified, and every individual with at least one of the reagent tests (Anti-HCV or HCV-RNA) is now considered a confirmed case. These changes are in line with the goals of the hepatitis C Elimination Plan in Brazil, which aims to estimate the number of hepatitis C cases nationwide based on epidemiological data, and to expand access to treatment and diagnosis [4]. Consequently, starting in 2015, an increase was observed in the detection rate throughout the national territory, with emphasis in the South and Southeast Regions, which remained above the national rate for every year in the time series. Higher detection rates have been reported in these two regions in previous studies [2, 12, 13], and they may be explained by the fact that the regions are populous, and they have greater access to health services [13, 14]. Another factor that may explain the high rates of hepatitis C in the South and Southeast Regions of Brazil is the high rate of people who use injected drugs, given that this factor is strongly associated with positivity for hepatitis C [15, 16].

The HCV-RNA molecular test requires adequate infrastructure and specialized labour; thus, these tests are carried out by state central laboratories located in capital cities. With the more flexible confirmation criteria and the mass distribution of rapid tests to municipal testing centres in recent years [17], there has been greater capacity for detection of new cases in municipalities with less health infrastructure. This has been made evident by the spatial analysis conducted in this study, which indicates an increase in the detection rate along a spatial axis that involves the South, Southeast, Central-West, and North Regions (Fig. 4), in addition to a time pattern of growth in ten Brazilian states. It is important to highlight that the change in the criterion for confirming cases occurred only at the level of epidemiological surveillance. A reactive result to the anti-HCV assay in a sample represents evidence of prior contact with HCV. It is known that approximately 80% of people infected with HCV will become chronic carriers of the infection [18]. For this reason, the Brazilian Ministry of Health has recommended that the results of the anti-HCV assay should be complemented with the use of an assay for direct detection of the viral agent (HCV RNA or HCV-Ag) [19].

In relation to sociodemographic characteristics, a higher incidence of HCV was observed in males. Higher prevalence of HCV in men is related to greater exposure to risk factors, such as the use of inhaled drugs, injected drugs, and sexual activity [20, 21]. In this study, we observed an increasing trend in the detection rate in both sexes; however, there was a decrease in the male-to-female ratio due to a greater increase in the number of cases in women during the period analysed. This trend had already been observed in a previous study carried out in Rio de Janeiro, Brazil, which observed a decrease in the male-to-female ratio, from 1.2 to 0.9, in cases of HCV between the years 2008 and 2012 [21]. The increase in cases among women may reflect behavioural changes over the years, where women may have been more exposed to risk factors for infection. Studies have shown that women who use injected drugs practice behaviours with higher risks of exposure, including higher rates of sharing equipment and syringes [22, 23]. In line with this, a recent meta-analysis of 28 studies showed that women who use injected drugs have a 36% greater risk of HCV infection compared to men [24].

In relation to age, the highest detection rates were observed in individuals over 50 years old, with the age group from 55 to 59 years standing out (35.5 cases per 100,000 in 2018). It is important to observe that there was a significant increasing trend in the detection rate among young adults between 20 and 29 years old, especially between 2013 and 2018. It is also worth highlighting that there was an increasing trend in individuals under 5 years of age and in those over 60 years (APC 18.5 and 15.0, respectively). Previous studies have demonstrated a higher prevalence of HCV in young people and in adults over 45 years old [2, 13, 20, 25]. The main explanation for the increased incidence of HCV in these age groups involves changes in the mechanisms of disease transmission over the years.

Hepatitis C is a silent disease, where most individuals develop the chronic form [18]. Many individuals became infected before 1992, when screening still did not occur in blood banks [26]. The use of glass syringes that were reused for application of drugs was also an important source of contamination before the 90 s [27, 28]. This would explain the increased diagnosis in elderly individuals who were exposed many years ago. In the young population, on the other hand, risk of exposure to HCV is due to the sharing of drug use equipment (syringes, needles, and pipes) and frequent tattooing and piercing without due attention to sterilization or use of disposable equipment [13]. These findings corroborate a trend of change in the source of infection, where we observed a reduced transfusion transmission from 2008 to 2018, and an increase in sexual transmission and by drug use. However, it is important to highlight the fragility of this variable, given that it is difficult to establish the true source of infection. This is reflected in the increase in the proportion of fields marked unknown during the period analysed. In addition, the increase in the detection rate in children under 5 years of age may reflect greater access to prenatal care for pregnant women in recent years. Vertical transmission occurs in up to 5% of newborns whose mothers are infected; this is influenced by the mother’s viral load, by the HIV status, and by the immunogenetic profile of the mother and child [29].

Although the majority of individuals who were infected identified as White, during the period analysed, a decline was observed in the proportion of those who identified as White, in addition to an increase in those who identified as Black, mixed, and Indigenous. This trend of change in the race profile may reflect greater access to hepatitis C diagnosis over the years in the regions in the North of the country, as well as in more vulnerable populations. As demonstrated through spatial analysis, at the beginning of the analysed period, hepatitis C was more concentrated in the South and Southeast Regions of the country, which are the regions with the highest human development indices and those with greater more individuals who identify as White [12, 14]. With increased access to diagnostic tests and more flexible confirmation criteria, the regions in the North of the country, where there are more individuals who identify as mixed race and Indigenous and lower human development indices [14, 30, 31], have led to changes in the disease profile in Brazil. This finding is corroborated by the data on level of education, where an increase was observed in the proportion of individuals who were illiterate and those who had not completed secondary or tertiary education.

About 30% of all people who are HIV-positive have been involved with use of injected drugs, and 85% of these individuals who use drugs are infected with both HIV and HCV [12]. We observed a higher prevalence of HCV-HIV coinfection in the Southeast and South Regions of Brazil, with a decreasing trend in the country. The South had the highest rate, which was greater than the national rate (9.3%). These findings may reflect the high degree of urbanization in the South and Southeast Regions of Brazil, which favours a greater prevalence of people who use injected drugs, which are an important source of hepatitis C and HIV infections [12, 32]. In 2020, Nutini et al. demonstrated a higher prevalence of HCV-HIV coinfection in the South Region of Brazil, where the mean age of coinfected individuals was lower than that of individuals who were monoinfected with HCV [33]. On the other hand, the decreasing trend in HCV-HIV coinfection in the country may reflect increased access to diagnostic tests over the years, as the prevalence of HCV-HIV coinfection could have been overestimated in previous years, due to a greater demand for test orders in individuals who were previously infected with HIV.

During the period from 2008 to 2018, 21,233 deaths were registered due to hepatitis C in Brazil, representing an average mortality of 0.96 per 100,000 inhabitants, with a predominance of males (60.6%). In general, a decreasing trend was observed for mortality nationwide, and it was more significant starting in 2016. Two regions showed a decreasing trend in mortality: the South and the Central-West starting in 2013. This decreasing trend in mortality due to hepatitis C in Brazil may be explained by the introduction of new direct-acting antiviral agents in recent years, which have greater efficacy in treating HCV and have significantly contributed to the goal of eliminating HCV worldwide [20]. These medications were introduced in Brazil in 2013, and, since then, the Brazilian Ministry of Health has updated its clinical protocol and therapeutic guidelines with the inclusion of new medications and expanded access to treatment, which, since 2017, has included all diagnosed cases of chronic hepatitis C in Brazilian territory [34]. It is important to note that the present study only considered those whose underlying cause of death was acute (B 17.1) or chronic (B 18.2) hepatitis C. Therefore, the causes of death recorded as a complication or aggravation associated with HCV, such as liver cirrhosis or liver cancer, may cause an underestimation of the HCV mortality rate found here [35, 36].

On the other hand, as a country, Brazil faces major challenges to reaching the goal of eliminating hepatitis C by 2030, especially in view of challenges posed by the COVID-19 pandemic in 2020, which has affected the control programs for several infectious diseases in Brazil, including HCV [5, 37, 38]. The worldwide impacts of the COVID-19 pandemic have jeopardized all the advances observed in recent years, not only due to the evident impact on the entire health system, but also due to the lack of investigations that evaluate the relationship between the two viruses.

There are some limitations to this study, including the use of secondary data. There is a possibility of underreporting, given that asymptomatic individuals are rarely tested, in addition to the possibility of incorrect records with incomplete data. Regional differences in the quality of surveillance systems directly influence data quality, given that underreporting is greater in more vulnerable areas and in those with less access to health services. In 2010, some states, especially those located in the North and Northeast regions, still had coverage below 90% and proportions of deaths classified as “ill-defined causes” above 10% [39]. Lastly, the notification system does not allow for separate analysis according to the diagnostic method (anti-HCV or HCV-RNA), so we were unable to differentiate between active and past infection in our analyses. This may have influenced, at least in part, the increasing trends observed for some indicators, especially after 2015, when the confirmation criteria was changed in Brazil.

This study provides important data regarding the behaviour of hepatitis C in Brazil over a 10-year period. A change was observed in the epidemiological profile of the disease, caused mainly by changes in diagnostic confirmation criteria and the introduction of new medications that have contributed to reduced mortality in recent years. Also evident are the differences in the disease profile in different regions of Brazil, as a result of regional differences related to the sociodemographic profile and health and social infrastructure conditions.

An active surveillance system is needed, with strategies developed according to the population profile of each region of Brazil, with expanded diagnosis for all risk groups, in addition to the development of prevention strategies through health education, which will make it possible to slow contagion and promote awareness so that the population will seek testing centres. A joint effort between governments, medical societies, and the industry is also needed to guarantee access to treatment for all individuals who are infected. Only then will it be possible to eliminate hepatitis C in Brazil.