Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy

Abstract

Structurally modified nucleotide/nucleoside analogues can exert potent inhibitory effect on HBV polymerase activities. Some of these agents have been approved for the treatment of chronic hepatitis B. Because of a high risk of reactivation upon drug withdrawal, continuous long-term therapy is recommended to maintain maximal viral suppression. Consequently, drug resistance has developed in a significant proportion of patients. During long-term therapy, mutations occur not only in the polymerase gene but also in the S gene, resulting in the emergence of surface protein mutants. Two types of surface protein mutants are recognized. The first type arises as a result of amino acid substitutions caused by primary and compensatory resistance mutations in the polymerase gene, which concomitantly generate S gene mutations owing to overlapping S and polymerase genes. The second type occurs because of prolonged viral suppression leading to seroclearance of HBV surface antigen, where vaccine-escape-like mutants might be selected. The second type of mutants does not possess primary resistance mutations in the polymerase gene. Some drug-related S gene mutations are nonsense mutations, leading to truncation of the surface proteins. Among them, the rtA181T/sW172* mutant has a dominant negative secretion effect as well as an increased oncogenic potential. The clinical consequences of infection by these S gene mutants demand further clarification. Judicious selection of the antiviral agents and vigilant monitoring of viral mutants during the course of therapy are advised.

Clinical implications of hepatitis B virus mutations: Recent advances

“…Antiviral-drug-associated S gene mutations (ADASMs) can lead to three different consequences [112] : amino acid substitution mutations in the surface proteins, nonsense mutations resulting in truncated surface proteins and silent mutations. Also, there are ADASMs that cannot be explained by gene overlapping but which are probably the result of lower or reverse ratio of HBsAg to anti-HBs during long-term efficient viral suppression.…”

Hepatitis B e Antigen and Hepatitis B Surface Antigen Seroclearance with the Emergence of Lamivudine-associated and Core Mutations Following CD4 Elevation in a Patient with Hepatitis B and HIV

“…Furthermore, the rtL180M mutation emerged at time point 3 in correlation with the rtS143T mutation, which corresponds to the S gene sF134L mutation. Because the S gene is overlapped by the polymerase gene, whenever a nucleotide mutation occurs in the polymerase gene, a concomitant nucleotide mutation develops in the S gene (14). The mutation in sF134L/rtS143T emerged based on the following two main possible explanations: the sF134L mutation induced by host immune pressure forced the development of the rtS143T mutation and the lamivudine-resistant rtS143T mutation forced the development of the sF134L mutation.…”

Possible Involvement of Multidrug-Resistant Hepatitis B Virus sW172* Truncation Variant in the ER Stress Signaling Pathway during Hepatocarcinogenesis

“…This point mutation was recently reported in CHB patients with viral breakthrough after LMV or ADV treatment (5)(6)(7)(8)(9). Recent studies have indicated that the rtA181T/sW172* mutant has a dominant negative secretion effect as well as an increased oncogenic potential through its transactivation activity (4,(10)(11)(12)(13). It can also be speculated that is these truncated proteins cause endoplasmic reticulum (ER) stress and cell damage by intracellular retention (12,14).…”

“…Consequently, mutations in the polymerase gene may produce changes in the overlapping S gene, which confer resistance against NAs. Widespread treatment of CHB infection with NAs results in the selection of these resistant HBV mutants, thus causing serious public health implications (3,4).…”