Clinical and Virological Heterogeneity of Hepatitis Delta in the Amazonia: More Questions Than Answers

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Abbreviations

Ag

antigen

ALT

alanine aminotransferase

HBV

hepatitis B virus

HDAg

hepatitis delta antigen

HDV

hepatitis Delta virus

HDV‐1

HDV genotype 1

IFN

interferon

IVDU

intravenous drug users

PEG‐IFN

pegylated IFN‐2α

Hepatitis Delta virus (HDV) was described by M. Rizzetto in 1977. It is a 1.7‐kb RNA virus that encodes only one protein. HDV depends on the B virus surface antigen for transmission. This virus, which causes disease in human beings, is unique because it needs the help of another virus to cause liver disease.1

Clinical and Epidemiological Aspects

It is estimated that there are 15 million to 20 million HDV carriers on all continents. In South America, HDV has epidemiological and probably clinical peculiarities that are associated with its genetic variety.1, 2 High prevalence of HDV infection is found in central Africa, the Horn of Africa, the Amazon Basin, Eastern and Mediterranean Europe, the Middle East, and parts of Asia. The highest prevalence is found in the Western Amazon Basin, including regions of Brazil, Peru, Ecuador, Venezuela, and Colombia.1, 2, 3, 4

Usually, HDV causes aggressive disease, although cases of asymptomatic carriers have been described mainly in Eastern Europe.5 There are several putative markers of disease progression, which include biochemical, virological, histological, and biomolecular tools (Fig. 1).

Figure 1.

Hepatitis Delta: markers of disease progression.

Diagnosis of HDV infection is based on clinical, biochemical, serological, histopathological, and virological criteria. The hallmark is immunoglobulin G anti‐HDV, an antibody that usually denotes the contact with the virus, and immunoglobulin M anti‐HDV, an antibody that suggests acute infection or chronic infection in activity. Quantitative HDV RNA is an important tool for therapeutic definition, and HDV genotype is also of fundamental importance to better understand the therapeutic response of the various genotypes to the different regimens.1

In Europe and the United States (countries with low endemicity of HDV infection), HDV infection is almost restricted to groups at risk: Intravenous Drug Users (IVDU) and immigrants from endemic areas. It is a vanishing disease. HDV genotype 1 (HDV‐1) prevails, and HBV DNA is inhibited by HDV. Few patients present with hepatitis B e antigen post status.

In Brazil, and probably in other Amazonian countries, HDV infection is characterized by intrafamilial transmission early in life. Most cases are related to HDV superinfection of HBV carriers.6 Throughout South America, especially in the Amazon Region, HDV infects young patients. IVDU is rarely identified among HDV carriers in Latin America, and most cases are autochthone.4 HDV infection presents with more severe chronic cases and peculiar forms, such as fulminant hepatitis. In some chronic and acute HDV cases, Hepatitis Delta antigen (HDAg) display in liver tissue is abundant and predominantly located in the cytoplasm of hepatocytes, contrasting with European cases (Fig. 2) (R. Paraná, personal communication). In addition, many patients present a disproportional splenomegaly that does not seem to be related to portal hypertension. The factors associated with the enormous splenomegaly in these patients are not well known (Fig. 3) (C. Lobato, personal communication).

Figure 2.

Typical case of chronic HDV infection in Amazonia: HDAg overexpression.

Figure 3.

Voluminous splenomegaly associated with chronic HDV infection in Latin America.

Interferon (IFN), particularly pegylated IFN‐2α (PEG‐IFN), is the only available treatment for HDV, and little information is available about the relative susceptibility of HDV‐3 compared with other HDV genotypes. In a recent study, patients infected with HDV‐3 were treated with PEG‐IFN plus entecavir at a dose of 0.5 mg for 48 weeks, obtaining high sustained response (more than 95%). This study suggests that this pathogenic HDV genotype might be highly susceptible to standard treatment.7

Genetic Heterogeneity

Eight HDV genotypes have been described, with a divergence of 20% between genotypes. Up to four subgenotypes can be defined inside some of these genotypes, with a 10% divergence (Fig. 4).8 HDV‐1 has a worldwide distribution. HDV‐2 and HDV‐4 circulate in Asia, and HDV‐5 to HDV‐7 in Africa.8 HDV‐3 is endemic and highly prevalent in the Amazon, and is associated with outbreaks of severe fulminant hepatitis in the region (Fig. 5).1, 4 HDV‐3 is the most divergent, and it is more frequent among Amerindian populations than in urban ones. Some adaptive mutations might be related to the form of disease. This HDV genotype is frequently found to be associated to the Amerindian HBV genotype F, although coinfection with other genotypes has also been reported.1, 9

Figure 4.

HDV genotypes and subgenotypes. Phylogenetic tree of HDV complete genome sequences (neighbor joining method, distances calculated with Kimura 2 parameters, 500 bootstrap replicas). Sequences are shown in blue with their accession number and country of origin. Numbers in black refer to genotypes and subgenotypes. Numbers in red refer to bootstrap value.

Figure 5.

HDV prevalence and genetic diversity in the Amazon basin.

The coinfecting HBV genotype does not seem to influence the severity of HDV‐3 infection. Other HDV genotypes have been found circulating in specific ethnic groups, like HDV‐1 in Yucpa Amerindians from Venezuela, although HDV‐3 is more prevalent in them, and HDV‐8 in the Maranhão state of Brazil. These later genotypes may have been introduced during slave trade (Fig. 5).9