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The evolution and clinical impact of hepatitis B virus genome diversity


The global burden of hepatitis B virus (HBV) is enormous, with 257 million persons chronically infected, resulting in more than 880,000 deaths per year worldwide. HBV exists as nine different genotypes, which differ in disease progression, natural history and response to therapy. HBV is an ancient virus, with the latest reports greatly expanding the host range of the Hepadnaviridae (to include fish and reptiles) and casting new light on the origins and evolution of this viral family. Although there is an effective preventive vaccine, there is no cure for chronic hepatitis B, largely owing to the persistence of a viral minichromosome that is not targeted by current therapies. HBV persistence is also facilitated through aberrant host immune responses, possibly due to the diverse intra-host viral populations that can respond to host-mounted and therapeutic selection pressures. This Review summarizes current knowledge on the influence of HBV diversity on disease progression and treatment response and the potential effect on new HBV therapies in the pipeline. The mechanisms by which HBV diversity can occur both within the individual host and at a population level are also discussed.

Key points

  • Hepatitis B virus (HBV) is an ancient virus with deep ancestry in the animal kingdom.

  • HBV seems to undergo very little long-term mutational variation despite multiple host–virus factors driving short-term viral variations.

  • Viral diversity is generated by features of the unique replication cycle of HBV as well as by cellular host factors.

  • A possible bottleneck in the establishment of new viral variants could be the limited number of HBV-susceptible hepatocytes in the chronically infected liver.

  • HBV viral diversity contributes to variations in natural history, disease progression and treatment response in those with chronic infection.

  • Viral diversity must be considered in the development of new therapeutic regimens.

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Fig. 1: Phylogenetic trees of Hepadnaviridae.
Fig. 2: A proposed model for evolution of the Hepadnaviridae genome.
Fig. 3: Mechanisms for the generation and constraint of HBV diversity.
Fig. 4: Hepatitis delta replication cycle.


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T.T. is financially supported by the German Centre for Infection Research (DZIF), TTU Hepatitis Projects 5.807 and 5.704, the Deutsche Forschungsgemeinschaft (DFG) TRR179 (TP 15 and the Australian Centre for HIV and Hepatitis Virology Research). The authors thank R. Schinazi for providing helpful information on capsid inhibitors.

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Correspondence to Margaret Littlejohn.

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Hepatitis B surface antigen

(HBsAg). HBV encodes three surface (envelope) proteins: large (L), middle (M) and small (S) HBsAg, which share the C-terminal domain but differ in their N-terminal extensions.

HBV genotypes

Based on >7.5% nucleotide divergence, HBV has been phylogenetically classified into nine genotypes (A–I) and one putative genotype (J).

HBV sub-genotypes

HBV genotypes have been further classified into >35 sub-genotypes based on approximately 4–8% nucleotide divergence.

Hepatitis B e antigen

(HBeAg). A secreted protein of the nucleocapsid gene of HBV. Seroconversion to HBeAg-negative is an important clinical marker in the natural history of HBV infection.


Occurring or sampled at different times.

BCP variant

A variant with nucleotide changes in the basal core promoter of HBV that result in reduced expression of HBeAg.

PC variant

A variant with nucleotide changes in the pre-core region of the HBeAg that result in loss of expression of HBeAg.

HBV variants

Changes in the virus sequence that may or may not have consequences.

Splice variants

Variants produced as a result of splicing of HBV pregenomic RNA. These are incapable of autonomous replication but replicate in the presence of wild-type HBV.


Insertions or deletions of bases in the virus genome.

Hepatitis B core antigen

(HBcAg). The nucleocapsid (core) protein of HBV. A phosphoprotein that associates with the viral polymerase, DNA and RNA.

HBV quasi-species

The population of related viral species occurring within a patient.


Generation of viruses (or viral vectors) in combination with foreign viral envelope proteins.

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Revill, P.A., Tu, T., Netter, H.J. et al. The evolution and clinical impact of hepatitis B virus genome diversity. Nat Rev Gastroenterol Hepatol 17, 618–634 (2020).

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