Distribution of hepatitis B infection in Brazil : the epidemiological situation at the beginning of the 21 st century

Brazil was formerly considered a country with intermediate hepatitis B endemicity, with large heterogeneity between Brazilian regions and areas of high prevalence, especially in the Amazon basin. Systematic vaccination of children was initiated in 1998. Between 2004 and 2009, a large population-based study reported decreased prevalence in all regions of Brazil. This review analyzed the current hepatitis B epidemiological situation in Brazil through a systematic search of the scientific literature in MEDLINE, LILACS, and CAPES thesis database, as well as disease notifications to the Information System for Notifiable Diseases. The search strategy identified 87 articles and 13 theses, resulting in 100 total publications. The most recent results indicate reduced hepatitis B prevalence nationwide, classifying Brazil as having low endemicity. Most studies showed HBV carrier prevalence less than 1%. However, there are still isolated regions with increased prevalence, particularly the Amazon, as well as specific groups, such as homeless people in large cities and isolated Afro-descendant communities in the center of the country. This review alsao detected successful vaccination coverage reported in a few studies around the country. The prevalence of anti-HBs alone ranged from 50% to 90%. However, isolated and distant localities still have low coverage rates. This review reinforces the downward trend of hepatitis B prevalence in Brazil and the need to intensify vaccination strategies for young people and adults in specific regions with persisting higher HBV infection prevalence.


INTRODUCTION
Hepatitis B is a viral infectious disease responsible for significant worldwide human morbidity and mortality.This disease burden is due mainly to complications of chronic infections, such as liver cirrhosis and hepatocellular carcinoma (1) (2) .The hepatitis B virus (HBV) is transmitted person-to-person through contact with blood, exudates, and other body fluids such as semen and vaginal secretions.Although iatrogenic dissemination was a common route of transmission throughout the second half of the 20 th century due to blood product transfusion and sharing or reuse of syringes and needles, natural routes of transmission are mainly responsible for the high disease prevalence, including sexual, vertical (perinatal, from mother to newborn), and horizontal transmission from environmental exposure in the home, prisons, and other confinement institutions.

PREVALENCE AND GLOBAL DISTRIBUTION OF HBV
The World Health Organization (WHO) classifies hepatitis B endemicity according to the prevalence of the serological marker of viremia, the hepatitis B surface antigen (HBsAg) (3) .The WHO currently categorizes endemicity as low, intermediate low, intermediate high, or high (Table 1).
The disease distribution is quite heterogeneous, with higher prevalence in densely populated Asiatic locations and regions lacking economic and hygienic resources.The most affected region with high endemicity is Southeast Asia.Sub-Saharan Africa, Oceania, and the Amazon basin are other hyperendemic areas.This last region is traditionally considered hyperendemic despite being sparsely inhabited.Indeed, high prevalence rates also have been reported in other populations in remote and poorly inhabited locations, such as among the native Inuits of the Arctic Circle (4) .Industrialized countries (North America, Australia, Western Europe, and Scandinavia) have lower endemicity rates.As countries become industrialized, there is a progressive reduction of hepatitis B endemicity concomitant with increasing access to better housing conditions, hygiene, and infrastructure, as reported in Taiwan (5) .
Vaccination is another crucial factor for disease control, with effective and safe HBV vaccines first developed in the 1970s.Although initially very expensive, genetic engineering increased production and reduced costs, allowing their use in wide-ranging Thus, in the past decade, the Ministry of Health has sponsored an ambitious project to estimate the prevalence of viral hepatitis in Brazil.The survey, based on a robust multistage random sampling methodology, evaluated almost 20,000 residents from more than 9,000 households in the 27 Brazilian capitals between 2004 and 2009 (19) .The results indicated a lower than expected prevalence of hepatitis B in all regions (20) .Exposure to HBV [measured by levels of antibodies against the core antigen (anti-HBc)] varied in participants 10 to 19 years of age, from 0.6% in the southeast to 1.6% in the South.Among individuals 20 to 69 years of age, the prevalence ranged from 7.9% in the Southeast to 14.7% in the North.The prevalence rates of virus carriers (HBsAg-positive) among those 10 to 19 years of age did not exceed 0.2% in any region.For those between 20 and 69 years of age, the HBsAg prevalence ranged from 0.4% in the Southeast and the Federal District to 0.9% in the Northern region (Table 2).These numbers moved Brazil to a low-prevalence hepatitis B endemicity classification (3) .

CURRENT HEPATITIS B EPIDEMIOLOGICAL DATA IN BRAZIL
This decline was expected, considering the significant socioeconomic improvements for a large portion of the Brazilian population and effective vaccination coverage, especially among children, from the end of the 20 th century.However, the findings of the National Survey remain controversial.The main criticism, acknowledged by the authors, was that limiting the sample to large urban centers (state and federal capitals) could have underestimated the true hepatitis B prevalence in localities with worse health and economic conditions (21) .
By excluding the more remote and poorer regions, the study did not sample localities with the highest historical prevalence of hepatitis B in Brazil.For example, the Purus and Juruá River basins in Amazonas historically had the highest rates (22) .In the State of Espírito Santo, Cachoeiro de Itapemirim municipality was hyperendemic (23) , such as some municipalities in Northwestern Mato Grosso near the border with States of Rondônia and Amazonas (17) (24) .The same situation was reported in Cascavel and Francisco Beltrão municipalities of the State of Paraná, and in other countryside of the States of Santa Catarina and Minas Gerais (18) (25) .These regions are far from the capital, where improvements in living and hygiene conditions are usually implemented more slowly.
By the beginning of the 21 st century, Brazil had become a cosmopolitan and urbanized country, with 84% of the population living outside rural areas [Censo 2010, Instituto Brasileiro de Geografia e Estatística (IBGE)].Considering that less than one-fifth of the population lives in rural areas, it remains unclear whether the results of the National Survey reflect the overall hepatitis B prevalence.
In short, although the results of the National Survey of the Ministry of Health are promising, it is important to continue analyzing data from new Brazilian studies to better understand the current epidemiological environment of hepatitis B, a disease with considerable burdens (2) (12) .New data will help assess the impact of vaccination strategies used so far and therapeutic guidelines adopted in recent years, suggesting complementary measures for control of this endemic disease.The CAPES/MEC database was queried to find unpublished data.The search strategy used as descriptors hepatitis B and epidemiology or prevalence and incidence or survey in the field title or abstract.We had the helpful assistance of the call center staff, available through the electronic address (mec.cube.callsp.inf.br/auto-atendimento).The SINAM/MS database was used to collect data on hepatitis B incidence (http://dtr2004.saude.gov.br/sinanweb/).

RESULTS
The MEDLINE search (http://www.ncbi.nlm.nih.gov/pubmed) performed on April 4, 2015, resulted in 304 citations.After reviewing the titles and abstracts, studies referring to aspects other than the prevalence or incidence of hepatitis B were discarded, as well as those that focused on subpopulations with increased risk for HBV infection, such as patients with human immunodeficiency virus (HIV), patients in renal replacement therapy, poly-transfused patients, patients with chronic liver disease or scleral jaundice, or patients with sexually transmitted diseases.Articles on prevalence in prison inmates, sex workers, or injectable drug users were discarded because these subpopulations were also considered to have increased risk.Non-injectable drug users, however, were retained in this review.Studies that focused on describing the genotypic distribution of HBV among chronic carriers and research on occult infections were also discarded.After this evaluation, 76 articles remained.Two publications had no data on infection prevalence.One focused only on seroprevalence of vaccine coverage (26) , while the other was part of the results of the National Epidemiological Survey in Brazilian State Capitals (20) .Thus, 74 articles was retrieved.
A LILACS/BIREME (http://lilacs.bvsalud.org)search on the same day identified 144 studies.First, references that dealt with hepatitis other than hepatitis B were removed from consideration.Results from subpopulations were also discarded, following the same criteria used for the MEDLINE search.After removing articles already identified in the MEDLINE search, 13 additional articles were identified.Thus, from these two databases, 87 publications were retrieved.
The CAPES database query identified 136 masters or doctoral theses.Most dealt with other aspects of HBV infection, ranging from molecular biology to vaccine considerations.Thirty-four reported prevalence in cross-sectional studies.Among these, 12 had already been identified in the MEDLINE and LILACS searches.Of the remaining 22, two studies were based in other countries, and seven included only risk groups.Finally, 13 dissertations were identified with unique data, resulting in 100 studies.
The results of these studies are presented below, in four groups.Table 3 presents the results of studies from the beginning of the current millennium, among which many references were related to research and surveys carried out in the 1990s.The most recent population studies or those in specific groups (without increased risk) are shown in Table 4. Table 5 and Table 6 contain data specific to pregnant women and blood donors, respectively.The results in pregnant women are presented separately owing to the fact that these studies have become very common in recent years in Brazil and because they represent in particular the risk of vertical transmission.Blood donors were also separated as a group, with notably reduced prevalence due to increasingly insightful recruitment by blood banks to select individuals with minimal risk.

Results from the turn of the century
The data in Table 3 show prevalence across the country, with the highest rates concentrated in the Amazon region, including Mato Grosso (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) (43) (44)   .In all, there were 21 reports, nine (42.8%) with intermediate to high prevalence (>2%).Of these nine, two had prevalence rates above 9%, namely indigenous people in Lábrea, Amazonas, and isolated African descendants in the State of Mato Grosso do Sul (30) (36) .The high prevalence was concentrated, as expected, in the northern region.However, two studies identified high endemicity outside the Amazon basin, in the semi-arid region of the State of Bahia and in African descendants from the Cerrado of the State of Mato Grosso do Sul (34) (36) .Five studies reported prevalence below 1%, and the other six assessed anti-HBc positivity rather than HBsAg.The prevalence of this marker in these studies ranged from 1.2% to 58.4% (27) (29) (44) .**These publications report on the same historical series.

Recent prevalence data
Analysis of data from more recent studies (Table 4) suggests lower prevalence rates nationwide (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56)   (90) .These studies represent more than 90,000 individuals.Among 48 reports, only seven (14.6%) found intermediate to high prevalence.In 28 (58.3%)studies, the prevalence of HBsAg-positive individuals was below 1%.However, there is no guarantee that individuals were not sampled in more than one such study.Three Amazonian communities had prevalence higher than 4%, namely Lábrea (6.2%), a rural population in Rondônia (4.8%), and indigenous peoples in Southeastern Pará (5.4%) (46) (47) (50)   .However, in general, the prevalence rates in most recent studies were systematically lower than those in previous studies.Only two studies showed intermediate-low endemicity outside the Amazon Region (3.3% among homeless in São Paulo, a population considered to be at increased risk, and isolated populations of African descendants in the State of Mato Grosso do Sul) (61) (66) .It should also be emphasized that, contrary to studies performed in the 1990s, the prevalence in more recent studies was less than 7%.

Vaccine coverage
Among studies included in this review, some also analyzed vaccine coverage by measuring the seroprevalence of antibodies against HBsAg (anti-HBs) (26) (52) (58) (72) (78) (79) (82) (83) (85) .These reports were predominantly conducted in adolescents and young adults.As it is common for people to lose documents certifying vaccination in Brazil, authors often use positivity for anti-HBs positivity alongside negativity for HBsAg and anti-HBc as evidence of vaccine coverage.Most of these reports found a prevalence of anti-HBs alone between 55% and 60%, considering the cutoff of 10UI/L as the lower level of anti-HB positivity.When anti-HB titers lower than 10UI/L were considered, prevalence reaches approximately 90% (Table 7).However, two studies (Amazon and northeast) suggested low vaccine coverage (52) (60) .

Incidence data
Several studies presented incidence data, including three studies conducted in Santa Catarina.Kupeck (2001) estimated the risk of HBsAg transmission by studying historical blood donor series in the State of Santa Catarina in the 1990s (109) and concluded that despite reduced risk, the incidence density would be three infections per 1,000 person-years.More recently, Silva et al. (121) analyzed notifications to the Information System for Notifiable Diseases and estimated that the incidence in 2009 in Brazil and Santa Catarina was 11.5 and 17 infections per 100,000 inhabitants, respectively (121) .Finally, Marcon et al. (122) also studied notifications in the same state and concluded that there was a decrease in incidence starting in 2006 (122) .
The Brazilian official data about hepatitis (SVS/MS, 2012) presents data relating to hepatitis B case notifications from 1999 to 2011 (123) .There is a trend of year-to-year growth.There were fewer notifications among youth <20 years of age in Brazil and in all macroregions.
Figure 1 presents reported case data in Brazil from 2007 to 2013 (SINAN) according to age group, with an increasing number of notifications each year.The majority of the cases are concentrated in the 20-to 59-year-old age group.However, below 20 years of age, the number of reported cases is stable.Reports among this age range were 10% and 5.9% of the total cases in 2007 and 2013, respectively.

DISCUSSION
This review shows an improved epidemiological environment in Brazil compared to the end of the last century, likely due to improved quality of life and the increasingly comprehensive deployment of systematic youth vaccination programs.The results presented in Table 3, which correspond to samples obtained at the end of the 1990s, are similar to reports from previous studies, with carrier prevalence exceeding 7% in some regions, characterizing them as highly endemic (30) (36) (39) .In more recent studies, however, this situation has improved, with low to intermediate-high prevalence and no prevalence rates above 7% (Table 4).
However, there are still foci of intermediate endemicity, especially in areas difficult to access or with low population densities, such as riverine populations in the Amazon Basin and among isolated populations of African descendants (quilombolas) in the Midwest (30) (36) .
Two other findings from this review should be emphasized.First, the disease seems to be under control in the southern region Catarina in the 1990s.Since then, many studies have been conducted, and the states and regional health authorities have worked to identify risk groups and increase vaccine coverage.More recent studies from the Southern regions have reported prevalence rates lower than previously observed, with the exception of pregnant women in Francisco Beltrão (107) .These findings suggest successful vaccination coverage in this region (26) (82) (83) (85) .Second, data from northeast Brazil remain relatively scarce, perhaps because hepatitis B has never been a major problem in this region compared to the Northern and Southern states.However, there may be locations in the interior that require a better approach, as observed by Almeida et al. (34) in the semi-arid region of Bahia during the 1990s (34) .
At-risk groups were not addressed in this review because they are a significant minority of the Brazilian population.However, they are a potential reservoir for dissemination of HBV.Groups such as prisoners, homeless people, drug addicts, people with HIV, and sex workers need specialized approaches to benefit from vaccination and, where appropriate, antiviral therapy.
The data obtained in the SINAN are unreliable as a historical series, as there is no separation between acute and chronic cases, making it impossible to determine when the infection occurred.As a result, the data do not represent incidence rates of new cases.Furthermore, recent infections are added to previous infections that were only recently detected.In addition, the increase in the number of notifications appears to correspond to improvements in the epidemiological surveillance system and notifications for communicable diseases in Brazil.Despite improved socioeconomic conditions and hygiene in a large part of the country, notifications have increased, generating the false impression that the prevalence of many infectious diseases is increasing in Brazil.The same phenomenon has also been observed in hepatitis A. Although analysis of the raw numbers of notifications does not suggest imminent control of hepatitis B in Brazil, the positive trend of decreased or stabilized prevalence among children under 20 years of age indicates the positive effects of vaccination.
Although fewer in number than studies on the prevalence of HBV infection, studies reporting the prevalence of anti-HBs antibodies alone indicate that the levels of coverage offered by vaccination are comparable to those in countries with high vaccine coverage (5) (8) .Similar to reports of reduced HBV incidence and prevalence in these countries, Brazil should detect a similar downward trend in the next decade.It is, however, worrying that vaccine coverage was insufficient in remote communities of the Amazon Region and in the Northeast.Efforts must be made to increase vaccination coverage in these localities.In a remote Amazonian community of the State of Mato Grosso, efforts to increase vaccination coverage resulted in reduced prevalence from the high levels previously reported (17) (42) .
In short, a systematic literature review of 100 studies on hepatitis B prevalence, incidence, and vaccine coverage suggest that Brazil is progressing toward low endemicity, with specific foci of increased fragility, mainly in the interior of the Amazon region and among remote small communities.The National Survey of the last decade captured the declining trend in major urban regions of the country (20) .This review also observed decreasing prevalence in Brazil's innermost part.However, the situation is far from safe.On the contrary, this review underscores the need for increased efforts to control HBV in these specific communities and populations.

references
The author declare that there is no conflict of interest.
cOnfLIcT Of InTeresT Brazilian studies from the early 2000s, including data from the 1990s, according to geographic region.

TABLE 5 -Prevalence of hepatitis B virus infection among pregnant women in Brazilian studies since 2000, according to geographic region.
HBsAg: hepatitis B surface antigen; anti-HBc: antibodies against HBV core antigen.*The HBV infection endemicity classification was based on WHO categorization using HBsAg positivity prevalence.When only anti-HBc results were available, we used previous WHO classifications: ≤20%, low; 21-60%, intermediate; >60%, high.Ref: references.**The study by Santos included seven municipalities bordering the Rio Amazonas: Bragança, Castanhal, Combu, Alenquer, Santarém, Óbidos and Oriximiná.***Article published later in the 2000s but included data from the 1990s.

TABLE 6 -Prevalence of hepatitis B virus infection among blood donors in Brazilian studies since 2005, according to geographic region.
HBsAg: hepatitis B surface antigen; anti-HBc: antibodies against hepatitis B core antigen; WHO: World Health Organization; Ref: references.*The classification of HBV infection prevalence was based on WHO categorization using HBsAg positivity prevalence.When only anti-HBc results were available, we used the previous WHO classification: ≤20%, low; 21-60%, intermediate; >60%, high.

TABLE 7 -Prevalence of vaccine-induced protection profile (anti-HBs-positive only) in Brazilian studies.
Anti-HBs: antibodies against HBV surface antigen; Ref: references.*Average sample age.The study was conducted in a riverside community in the Amazon interior.**Study of university students between 17 and 66 years of age.**Considering any anti-HBs titer.