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. Hepatitis B virus (HBV) infection remains a global public health issue. This Review provides insights into the evolution of HBV and discusses the mechanisms by which HBV and hepatitis delta virus diversity occurs and the influence of this diversity on disease progression and treatment response. 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.