Around 250 million persons are chronically infected with hepatitis B virus (HBV) worldwide, and this infection may lead to cirrhosis and Hepatocellular carcinoma (HCC). HBV can circulate as an occult infection (OBI), with the absence of the classical surface antigen marker characteristic of active infection. OBI can also lead to (HCC). HBV infection is highly endemic in Indigenous populations from the Americas. This review intends to summarize the knowledge on HBV infection, with particular reference to OBI in indigenous populations from Latin America. OBI has already been described in Indigenous populations from Latin America and seems a frequent presentation of this disease in these vulnerable populations.
 

Pujol FH, Cardona N, Loureiro CL, Jaspe R, Chemin I (2016) Hepatitis B Occult Infection in Indigenous Populations from Latin America. JSM Hepat 1(1): 1004.

HBV: Hepatitis B Virus; HCC: Hepatocellular Carcinoma; OBI: Occult Hepatitis B Virus Infection; ORF: Open Reading Frame; Pre-S: HBV Pre-surface Protein; S: HBV Surface Protein; HBsAg: HBV Surface Antigen; Pol: HBV Viral Polymerase; HBx: HBV X Protein; preC/C: HBV Precore/core; HBeAg: HBV e Antigen; HBcAg: HBV Core Antigen; EnhI: Enhancer I; EnhII: Enhancer II; BCP: Basal Core Promoter; LA: Latin America; anti-HBc: Antibody to Core Antigen; anti-HBs: Antibody to Surface Antigen ; HDV: Hepatitis Delta Virus

Around 250 million persons are chronically infected with hepatitis B virus (HBV) worldwide [1]. HBV chronic infection leads in many cases to cirrhosis and Hepatocellular carcinoma (HCC) [1,2]. HBV infection is highly endemic in Sub - Saharan Africa, Asia, and Indigenous populations from the Americas [1]. In addition to the classical (overt) HBV infection, HBV can circulate as an occult infection (OBI), with the absence of the classical surface antigen marker characteristic of active infection but detection of HBV DNA in the serum and/or liver biopsies [3]. It has been shown that occult HBV infection can also lead to HCC [3]. This review intends to summarize the knowledge on HBV infection, with particular reference to OBI in indigenous populations from Latin America.

HBV biology and variability

HBV belongs to the Hepadnaviridae family and shares with these viruses a circular genome of approximately 3.2 kb in length. It contains four overlapping open reading frames (ORF) encoding: ORF preS1/preS2/S the surface antigens (HBsAg), ORF P the viral polymerase (Pol), ORF X the transactivator X protein (HBx) and ORF precore/core (preC/C) the e Antigen (HBeAg) and Core protein (HBcAg) (Figure 1A). Two viral enhancers (EnhI and EnhII) positively regulate transcription of the HBV promoters, including basal core promoter (BCP) that controls the transcription of the pre core and core regions. The partially double stranded DNA is generated from an intermediate RNA through reverse transcription. The absence of proof reading capacity of the HBV Pol leads to a high mutation rate. On the other hand, the extreme overlapping of the ORFs of this viral genome represents a constraint for natural selection that limits the possibility of fixation of many of these mutations [4].

Up to 10 genotypes has been described for HBV (A-J), exhibiting a minimum divergence of 8% in the complete genome sequences [5]. Genotypes A and D are also widely distributed, genotypes B and C circulate mainly in South East Asia and the Far East, while genotype E circulates in sub - Saharan West Africa. Genotype G has been reported in the US, Mexico and Europe, but its distribution is not fully known. HBV genotype F is the most divergent of the HBV genotypes, autochthonous to South America and highly predominant in the region. HBV genotype H is closely related to genotype F and is prevalent Central and North America. The most recently described genotypes I and J circulate mainly in Asia [5,6].

Although HBV genotypes F and H are indigenous to America, their prevalence varies markedly among different countries. In the Southern region of South America, HBV genotype A prevails over genotype F, while in the Northern region genotype F is highly predominant. In Brazil, the genotype distribution is related with the immigration pattern, and a high prevalence of genotype A can be seen in African - Brazilians. HBV genotype H has only been found in Central America and is found circulating either with genotype A or F. The relative frequency of HBV genotype F in Latin America is in close correlation with the degree of admixture of the general population with Amerindians, in many cases through the maternal contribution to the genetic pool. For example, in Colombia and Venezuela, the frequency of HBV genotype F is around 80% in the general population [7], while in Brazil, HBV genotype A is more common than HBV genotype F [8].

The error - prone reverse transcriptase mechanism of replication of HBV lead to quasi species, that is, a population of not identical viruses sharing a consensus sequence but. HBV quasi species diversity is associated with response to antiviral therapy, disease severity and long - term clinical outcomes. Mutations have been described in the whole HBV genome, including the S, Pre - S and promoter region. Specific mutants (genetic variants or deletion variants) have been associated with antiviral drug resistance, immune escape, liver fibrosis development and tumorigenesis [9].

HBV in Latin America

Latin America (LA) displays a variable degree of endemicity for HBV infection, ranging from low prevalence (less than 2% HBsAg prevalence) to intermediate (2-8% HBsAg), with some clusters of high exposure in Amerindians [10]. With a total population of 400 million persons, HBV incidence reaches up to 140,000 to 400,000 cases per year, of which two thirds are found in South America [11]. Regarding chronic carriers, the projection is 6 to 12 million persons infected [12]. No sex difference has been found in general in HBV prevalence in Latin America. In contrast, the prevalence increases progressively with age [13].

Seroprevalence studies in LA generally are limited to blood banks, through the detection of HBsAg, with little information on stratification by age or socioeconomic group. HBV in the Amazon basin of Brazil, Peru, Colombia and Venezuela, Haiti and the Dominican Republic is high (> 8%). The current rate of infection is considered intermediate (2-7%) in Guatemala, Honduras and Cuba, and low in the rest of Central America, including Mexico (< 2%) [14]. In South America the number of HBV carriers increases from South to North. The prevalence in Argentina, Uruguay, Chile and southern Brazil varies from 0.2 to 1.1% to 2.1% HBsAg and anti-HBc [13,15], while in the Center and Northeast Brazil is estimated at between 1.5 and 3.0%, with anti-HBc prevalence of 7.9% [13]. The prevalence of HBV in Central America is low to moderate (1 to 3%), like the Caribbean (1 to 2%). In the Dominican Republic, the prevalence reaches 4.1% and anti-HBc 21.4% [13,14].

In the general population of Colombia, the prevalence of HBsAg is 2-5% [14,16], being the country considered as intermediate endemicity. Peru is also considered of intermediate endemicity, although the regional distribution is very variable, with higher prevalence among adult population of the Amazon [17]. Venezuela has an intermediate prevalence: 1-5% HBsAg, 0.94% HBsAg and 4-5% anti-HBc in Blood Banks [18]. However, again, there are at least 3 clusters of high endemicity in Amerindians [4].

Amerindian populations exhibit high HBV exposure, particularly the AmazonBasin [10,19]. Studies in indigenous communities in Bolivia, Brazil, Colombia, Peru and Venezuela have shown a high endemicity for HBV infection (Table 1) [6,20]. However, a great variation of HBV is observed between different indigenous communities, with anti-HBc prevalence from 2.2% to 100%. Differences in socio - cultural practices between communities may influence the degree of HBV exposure among these groups. Differences in anti-HBc acquisition have been well documented between Yanomami and Piaroas [41] (Table 1). Effective vaccination campaigns may also contribute to the reduction of HBV infection in some ethnic groups.

Relatively high vaccine coverage is documented throughout LA [43]. However, remoteness of Indigenous communities often hampered the access of HBV vaccine to these populations [44]. Vaccination has proved to be effective in reducing HBV incidence in indigenous populations from LA [45], with the added benefit of preventing fulminant hepatitis due to co - infection with HDV.

HBV occult infection

Occult hepatitis B virus (HBV) infection is defined to have persistence of HBV DNA in serum or liver tissue without the presence of detectable HBsAg of circulating blood [46]. Occult HBV infection was first reported in patients receiving a blood transfusion 37 years ago [47] and it has been recognized in an increasing number of clinical settings with the advent of highly sensitive detection methods [3].

For instance, occult HBV infection was found in a considerable proportion of patients with hepatitis C virus (HCV) infection [48] and also in Non-B and Non-C (HBsAg and anti - HCV antibody negative) chronic liver diseases [49,50]. Highest rates of occult HBV infections have been reported in patients with HCC, in particular among HCV carriers [48,49] suggesting that occult HBV worsen the course of HCV infection [50-52].

HBV reactivation incidence is increasing worldwide, in relation with the increasing of efficient immunosuppressive drugs used in different clinical settings such as cancer therapy or grafts [53]. The clinical significance of OBI is related with the risk of HBV transmission, reactivation, progression to chronic liver disease and development of Hepatocellular cancer. OBI may reactivate in oncohematological patients undergoing immunosuppression by aggressive chemotherapy or hematopoietic stem cell transplantation [54]. Particularly severe presentations may be expected from HBV reactivations after oncological complications, requiring antiviral treatment to prevent even fatal outcomes [55,56].

Prevalence and molecular status of occult HBV in patients with HCC has been investigated in a number of studies in patients from different region of the world [4,57,58]. In these HBsAg - negative HCC patients, HBV DNA was detected in tumorous and/ or in adjacent non - tumorous liver tissue using polymerase chain reaction (PCR) in almost half of the patients, being anti - HCV positive or not [59]. Some of the patients are positive for anti - HBc antibodies as the only marker of HBV infection, but not all. Covalently closed circular HBV DNA may be detected in the liver of some of these patients indicating the persistence of the template for viral genome transcription and replication. Observational cohort study showed that, among the HBsAg - negative patients with chronic hepatitis C, HCC develops for the most part in carriers of occult HBV.

One of the markers in HBsAg (-) HCC cases has been the presence of the HBV - X gene expression in HCC since positivity for the HBV - X protein in liver tissue in several studies reached half of the liver tissues specimens [60-62]. In all studies, the significant association of occult HBV with HCC was irrespective of age, sex, and may be contemporary with hepatitis C virus infection. Both integrated viral DNA and covalently closed circular HBV genomes were detected in patients with occult HBV [4,63]. Moreover, the presence of episomal HBV genomes was associated with persistence of viral transcription and replication; there are evidences that occult HBV is a risk factor for the development of HCC and that the potential mechanisms whereby overt HBV might induce tumor formation are mostly maintained in cases of occult infection. In parallel to the development of new, efficient treatments against HBV infection, the number of occult HBV infection will probably increase.

HBV occult infection in indigenous population from Latin America

Prevalence of occult hepatitis B virus infection (OBI) in LA varies according to geographical region, is related to the prevalence of HBV in the country, the type of study population and the sensitivity of HBV-DNA PCR assays used for diagnosis. In LA, OBI has been reported mainly in blood donors, human immunodeficiency virus (HIV) -infected patients, hemodialysis patients and with liver disease. However, OBI has not been studied thoroughly in Amerindian populations (Table 2).

In LA occult HBV infection prevalence is widely divergent, ranging from 0% among blood donors [75] to 88% among children with clinical hepatitis [83], with ranges of 0%-8.2% in blood donors, 5.6%-49% in HIV - infected patients and 6.5%- 35% in Amerindian (Table 2).

In Argentina, although the frequency of HBV infection is low in Amerindians (1.1%) [21] (Table 1), when it is compared to that reported for HIV - infected patients (3.7%) [64], the frequency of OBI in these populations was very similar (6.5% and 5.6%, respectively) (Table 2). This OBI prevalence in Amerindians from Argentina is the lowest reported in LA to date.

Studies in Colombia, a country with intermediate HBV endemicity pattern, reported a low prevalence of OBI in blood donors (0%-1.98%), intermediate in HIV - infected patients (8.3-%-17%), but higher in the Amerindian communities, where the frequency of OBI was similar among Amerindian vaccinated children and their mothers (23.5% and 25%) [80], although the HBV infection is extremely different between them, 0.6 % and 16% respectively (Table 2).

In Brazil, a country with differences of HBV endemicity between Northern and Southern states, the OBI frequency is similar in blood donors (2.7-6%) [65-68] and hemodialysis (1.5-5%) [67,72] patients; and between HIV - infected patients (14-19%), [67,69-71] and residents of rural area (18%) [73]. To the best of our knowledge, no information is available on OBI in Brazilian Amerindians.

Mexico is considered a low HBV prevalence region, with the higher OBI prevalence in HIV - infected patients reported in LA (49%) [81]. This prevalence was more frequent in patients with detectable HIV RNA, and less frequent in patients who were undergoing HIV - ARV treatment with drugs active against HBV. The prevalence of OBI in blood donors is a bit higher (6.4% and 8.2%), [81,82] than that found in other LA countries, and lower in native Mexican communities (14.2%) [86], with respect to Amerindians communities in Colombia or Venezuela, although these are located in regions of high prevalence for HBV infection.

In Venezuela, the frequency of OBI in blood donors and HIV - infected patients is quite similar compared with other studies carried out in other LA countries with similar epidemiological pattern of HBV infection (Table 2). In the Piaroa community, an Amerindian group which exhibits significant evidence of exposure to HBV but relatively low presence of HBsAg [40], the prevalence of OBI is higher than that reported in others Amerindian communities in LA (34%) [41]. In this study, the OBI isolates displayed a restrained variability and were similar to the isolates causing overt HBV infection in other Venezuelan Amerindian groups. The findings suggested that the prevalence of occult HBV was significantly higher in subjects with either anti - HBs or anti - HBc positivity, while those without anti - HBc or anti - HBs positivity remained lower.

The wide range of OBI prevalence observed in different population groups may be explained not only by the individual prevalence of HBV in the each population, but might be also due to differences in the sensitivity and specificity of the diagnostic tests used in different studies. In addition, inclusion of more sensitive HBV DNA detection assays in the last years has improved the detection of OBI.

Table 1: Prevalence of HBV infection among autochthonous populations from South America.

Table 2: Prevalence of occult hepatitis B virus infection (OBI) in Latin America.

Since the last decade, OBI is a recognized as a HBV manifestation which can also lead to severe sequels of the disease and HCC. In general, the frequency of OBI in Amerindian communities from LA seems to be higher than that found in blood donors, HIV - infected patients and hemodialysis patients. This difference may be due to differences in the genetic constitution of these particular ethnic groups, as well as the frequent immune compromised observed in Amerindians, due to multiple parasitic and bacterial infections. The frequent presence of OBI in Amerindians stresses the importance of addressing this particular presentation of this disease in order to reinforce the control measures aimed to reduce the burden of HBV infection in these vulnerable groups.

This work was supported by Project ECOS-Nord FranceVenezuela: 2009-2017.

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