Molecular identification of hepatitis B virus genotypes/subgenotypes: Revised classification hurdles and updated resolutions

Abstract

The clinical course of infections with the hepatitis B virus (HBV) substantially varies between individuals, as a consequence of a complex interplay between viral, host, environmental and other factors. Due to the high genetic variability of HBV, the virus can be categorized into different HBV genotypes and subgenotypes, which considerably differ with respect to geographical distribution, transmission routes, disease progression, responses to antiviral therapy or vaccination, and clinical outcome measures such as cirrhosis or hepatocellular carcinoma. However, HBV (sub)genotyping has caused some controversies in the past due to misclassifications and incorrect interpretations of different genotyping methods. Thus, an accurate, holistic and dynamic classification system is essential. In this review article, we aimed at highlighting potential pitfalls in genetic and phylogenetic analyses of HBV and suggest novel terms for HBV classification. Analyzing full-length genome sequences when classifying genotypes and subgenotypes is the foremost prerequisite of this classification system. Careful attention must be paid to all aspects of phylogenetic analysis, such as bootstrapping values and meeting the necessary thresholds for (sub)genotyping. Quasi-subgenotype refers to subgenotypes that were incorrectly suggested to be novel. As many of these strains were misclassified due to genetic differences resulting from recombination, we propose the term “recombino-subgenotype”. Moreover, immigration is an important confounding facet of global HBV distribution and substantially changes the geographic pattern of HBV (sub)genotypes. We therefore suggest the term “immigro-subgenotype” to distinguish exotic (sub)genotypes from native ones. We are strongly convinced that applying these two proposed terms in HBV classification will help harmonize this rapidly progressing field and allow for improved prophylaxis, diagnosis and treatment.

Keywords: Hepatitis B virus; Hepatitis; Classification; Genotype; Subgenotype; Phylogenetic tree

Core tip: Hepatitis B virus (HBV) eradication could be achieved through three important points: (1) efficient universal vaccination; (2) accurate diagnostic assays; and (3) effective treatment of HBV carriers. Undoubtedly, these critical measures are not possible without fully understanding the genetics of the virus and being able to differentiate the isolates. In this review article we provide an update of HBV virology, focusing on classification and its impact on diagnosis, clinical outcomes, therapy, prophylaxis, evolution and epidemiology. Subsequently, the role of correct classification in describing HBV is highlighted, and misclassifications together with their causes are recounted. Finally, through the proposal of novel terms, HBV strains are reclassified.