Geographical and genetic diversity of the human hepatitis B virus.

Ten hepatitis B virus (HBV) genotypes (A-J) and 34 HBV subgenotypes have been identified so far. HBV genotypes and subgenotypes have distinct geographical distributions, and have been shown to differ with regard to clinical outcome, prognosis, and response to interferon treatment. Infection with subgenotype A2 is frequently associated with high viral load, resulting in acute infection via horizontal transmission. Genotypes A and B are more sensitive to interferon treatment than genotypes D and C, respectively. Genotype B is more frequent in acute hepatitis than genotype C, whereas genotype C (C2) is more frequently associated with an increased risk of hepatocellular carcinoma (HCC), mostly cirrhotic, as compared with genotype B (B2). Genotype mixture is associated with high viral load and worse outcome of HBV infection. HBV mutations in the S genes, especially amino acids substitution at position 145 (G145R), are associated with immune escape, whereas mutations in the PreS or S genes which impair HBsAg secretion could present a risk to blood safety. HBV variants harboring mutations in the viral polymerase gene that confer resistance to nucleoside analogs may be selected during antiviral therapy. Different genotypes have distinct mutation patterns in the PreS and EnhII/BCP/Precore regions. PreS deletions, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. HCC-associated HBV mutants may not transmit via mother-to-child transmission, and are likely generated during HBV-induced pathogenesis. Examination of HBV mutations alone or in combination and host genetic susceptibility will be helpful in classifying the HBV-infected subjects who will develop HCC and need active anti-viral treatments.

Clinical relevance and public health significance of hepatitis B virus genomic variations

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.26079

Dating the origin and dispersal of hepatitis B virus infection in humans and primates.

Acute hepatitis B virus (HBV) infection has been increasing through promiscuous sexual contacts, and HBV genotype A (HBV/A) is frequent in patients with acute hepatitis B (AHB) in Japan. To compare the geographic distribution of HBV genotypes in patients with chronic hepatitis B (CHB) in Japan between 2005 and 2006 and between 2000 and 2001, with special attention to changes in the proportion of HBV/A, a cohort study was performed to survey changes in genotypes of CHB patients at 16 hospitals throughout Japan. Furthermore, we investigated the clinical characteristics of each genotype and examined the genomic characteristics of HBV/A isolates by molecular evolutionary analyses. Of the 1,271 patients, 3.5%, 14.1%, and 82.3% were infected with HBV/A, -B, and -C, respectively. In comparison with our previous survey during 2000 and 2001, HBV/A was twice as frequent (3.5% versus 1.7%; P = 0.02). The mean age was lower in the patients with HBV/A than in those with HBV/B or -C. Based on phylogenetic analyses of 11 full-length genomes and 29 pre-S2/S region sequences from patients, HBV/A isolates were imported from Europe and the United States, as well as the Philippines and India. They clustered with HBV/A from AHB patients and have spread throughout Japan. HBV/A has been increasing in CHB patients in Japan as a consequence of AHB spreading in the younger generation through promiscuous sexual contacts, aided by a tendency of HBV/A to induce chronic hepatitis. The spread of HBV/A infection in Japan should be prevented by universal vaccination programs.

Distribution of Hepatitis B Virus Genotypes among Patients with Chronic Infection in Japan Shifting toward an Increase of Genotype A

The Hepatitis B Virus (HBV) has a worldwide distribution and is endemic in many populations. It is constantly evolving and 10 genotypic strains have been identified with varying prevalences in different geographic regions. Numerous stable mutations in the core gene and in the surface gene of the HBV have also been identified in untreated HBV populations. The genotypes and viral variants have been associated with certain clinical features of HBV related liver disease and Hepatocellular carcinoma. For example Genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion, and more advanced liver disease. Genotype A is associated with a greater risk of progression to chronicity in adult acquired HBV infections. Genotype D is particularly associated with the precore mutation and HBeAg negative chronic hepatitis B (CHB). The genotypes prevalent in parts of West Africa, Central and South America, E, F and H respectively, are less well studied. Viral variants especially the Basal Core Promotor mutation is associated with increased risk of fibrosis and cancer of the liver. Although not currently part of routine clinical care, evaluation of genotype and viral variants may provide useful adjunctive information in predicting risk about liver related morbidity in patients with CHB.

Genotypes and viral variants in chronic hepatitis B: A review of epidemiology and clinical relevance.

Eight genotypes (A to H) and nine subtypes (adw2, adw4, ayw1, ayw2, ayw3, ayw4, adrq+, adrq−, and ayr) of hepatitis B virus (HBV) have been identified worldwide. They appear to be associated with geographical distribution, virological characteristics, and possibly clinical outcomes. We performed sequence analysis of part of the S gene and the entire precore/core gene of HBV isolates obtained from HBsAg-positive blood donors in Papua Province, Indonesia. Phylogenetic analysis of the S gene sequences revealed that 23 (85.2%) of the 27 HBV isolates tested belonged to genotype C (HBV/C) and 2 (7.4%) each to HBV/B and HBV/D. Interestingly, 19 (82.6%) of the 23 isolates of HBV/C clustered in a branch that was distinct from the previously reported subgenotypes C1 to C5 (HBV/C1 to HBV/C5). Similarly, two isolates of HBV/D clustered in a branch distinct from the reported subgenotypes HBV/D1 to HBV/D5. Phylogenetic analysis of the entire precore/core gene confirmed the consistent presence of the distinct branches in HBV/C and HBV/D. We therefore propose novel subgenotypes designated HBV/C6 and HBV/D6. The majority of HBV/C6 isolates in Papua had alanine at positions 159 and 177 (A159/A177) in the HBsAg. A159/A177 is different from the determinants for adrq+ (A159/V177), found throughout Asia, and adrq− (V159/A177), found in New Caledonia and Polynesia, possibly representing a unique antigenic group (provisionally referred to as adrq indeterminate). In conclusion, we have identified two novel HBV subgenotypes, HBV/C6 and HBV/D6, the first of which is the most prevalent subgenotype of HBV in Papua, Indonesia.

https://jcm.asm.org/content/jcm/46/7/2160.full.pdf

Novel Subgenotypes of Hepatitis B Virus Genotypes C and D in Papua, Indonesia

Each hepatitis B virus (HBV) genotype and subgenotype is associated with a particular geographic distribution, ethnicity, and anthropological history. Our previous study showed the novel HBV subgenotypes C6 (HBV/C6) and D6 (HBV/D6), based on the S gene sequences of isolates in Papua, Indonesia. The present study investigated the complete genome sequence of 22 strains from Papua and subjected them to molecular evolutionary analysis. A phylogenetic analysis revealed that 9 out of 22 strains were classified as HBV/C6, 3 strains as HBV/D6, and 9 strains as HBV/B3. A particular strain positioned between HBV/B3 and HBV/B5 remained unclassifiable into any known subgenotypes. This strain showed high homology with HBV/C5 from the Philippines in the core region and was thought to have undergone genetic recombination with HBV/C5. Further studies are needed to determine whether this strain belongs to a new subgenotype of HBV/B. Based on the amino acid alignment, HBV/C6 has subgenotype specific variations (G18V and V47M) in the S region. HBV/C6 strains were more closely related in terms of evolutionary distance to strains from the east Asia and Pacific regions than those found in southeast Asia. HBV/D6 strains were most closely related to strains from the Western countries (HBV/D3) rather than those from Asia and Papua New Guinea. In conclusion, we have confirmed by complete sequence analysis that two novel HBV subgenotypes, HBV/C6 and HBV/D6, are prevalent in Papua, Indonesia.

Complete Genome Sequence and Phylogenetic Relatedness of Hepatitis B Virus Isolates in Papua, Indonesia

Hepatitis B virus (HBV) genotypes and subtypes have been identified worldwide. As HBV genotypes/subtypes, the HBV subgenotypes seem to be associated with their geographical distribution and ethnic origin. A previous study showed the novel HBV subgenotype C6 based on the complete genome sequences of isolates in Papua, Indonesia. In the present study, further characterization of HBV in Jayapura (capital of Papua Province), particularly from native people of Papua originating from the highland (highland Papuans) and those from the lowland (lowland Papuans) were examined. Of 32 HBV isolates from both highland and lowland Papuan blood donors with HBsAg positive, part of the S gene and the core gene sequences were analyzed. Analyses of some isolates from highland Papuans were confirmed by the complete genome sequences. Most HBV isolates were classified into genotype C (78.1%), followed by genotype B (18.8%), and genotype D (3.1%). The subtype adr was predominant (71.9%), followed by adw2 (25.1%), and ayw2 (3.1%). As with previous findings, phylogenetic analyses revealed that most HBV isolates from Papuans, C/adr, belonged to subgenotype C6. Interestingly, some C/adr isolates from highland Papuans formed a distinct cluster from all reported subgenotypes of HBV/C, and they differed from HBV/C1-C10 by 4.2-7.2% over the complete genome. SimPlot analysis showed no evidence of recombination with HBV/C1-C10. The isolated life and closed social systems of highland Papuans, even though some have been moving to Jayapura, likely contribute to the formation of this unique cluster of infection with a novel subgenotype of HBV, named C11.

/pdf/another-novel-subgenotype-of-hepatitis-b-virus-genotype-c-b17nzpj597.pdf

Another novel subgenotype of hepatitis B virus genotype C from papuans of Highland origin.

The genotypes (A-H) and subtypes (adw2, adw4, adrq-, adrq+, ayw1-4, ayr) of HBV show distinct geographical distributions, which have been associated with anthropological history. The novel finding of the HBV subgenotypes C6 and D6 from Papuans formed a specific cluster distinct from the previous HBV subgenotypes C1-C5 and D1-D5. In this study we determined the most recent genotype-subtype patterns of the HBV from non-Papuan blood donors who live in Jayapura and their phylogenetic relatedness, especially with the Papuan clusters. Fifteen HBsAg-positive serums were obtained from non-Papuan blood donors including from people in Java (46.7%), Maluku (26.7%), Sulawesi (20%) and East Nusa Tenggara (6.7%). S gene of all HBV serum isolates were partially sequenced and analyzed. Most HBV isolates (53.3%) were classified as genotype B, followed by genotype C(26.7%) and D (20.0%). The subtype adw2 (33.3%) was predominant, followed by adrq+ (26.7%) and ayw1/ayw2 (20.0%). All HBV isolates with subtype adw2 and ayw1 belonged to genotype B, while adrq+ belonged to genotype C and ayw2 belonged to genotype D. The most predominant HBV genotype-subtype (B/adw2) was consistent with the ethnic background (mostly from Java people). Nevertheless, based on the phylogenetic relatedness, many non Papuan isolates (40%) were classified into HBV/C6 and HBV/D6 of the Papuan clusters. Other isolates were classified into HBV/C1, HBV/B3 and HBV/B7. In conclusion, many HBV isolates from non-Papuans in Jayapura belonged to the Papuan clusters, but others had different genotype-subtype patterns with frequencies dependent on ethnicity.

/pdf/the-relatedness-between-hepatitis-b-virus-from-non-papuan-2r93dmzk7y.pdf

Victor Eka Nugrahaputra

Papers

Novel Subgenotypes of Hepatitis B Virus Genotypes C and D in Papua, Indonesia

Complete Genome Sequence and Phylogenetic Relatedness of Hepatitis B Virus Isolates in Papua, Indonesia

Another novel subgenotype of hepatitis B virus genotype C from papuans of Highland origin.

The Relatedness between Hepatitis B Virus from Non-Papuan Blood Donors in Jayapura and the Papuan Clusters