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Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy

Author(s): Shirvani-Dastgerdi, Elham; Winer, Benjamin Y.; Celià-Terrassa, Toni; Kang, Yibin; Tabernero, David; et al

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Abstract: Background & Aims—Patients chronically infected with the hepatitis B virus (HBV) that are on long-term treatment with nucleoside or nucleotide analogues are at risk of selecting HBV strains with complex mutational patterns. We herein report two cases of HBV-infected patients with insufficient viral suppression despite dual antiviral therapy with entecavir (ETV) and tenofovir (TDF), of which one patient died from aggressive hepatocellular carcinoma (HCC). Methods—Serum samples of the patients from different time-points were analyzed by ultra-deep pyrosequencing analysis. Identified HBV mutations were functionally analyzed after transient transfection of replication-competent HBV vectors into hepatoma cells in vitro. We assessed replication efficacy, resistance to antivirals and potential impact on HBV secretion (viral particles, exosomes). Results—Sequencing analyses revealed the selection of the rtS78T HBV polymerase mutation in both cases that simultaneously creates a premature stop codon at sC69 and thereby deletes almost the entire small HBV surface protein. One of the patients had an additional 261-bp deletion in the preS1/S2 region. Functional analyses of the mutations in vitro revealed that the rtS78T/sC69* mutation, but not the preS1/S2 deletion, significantly enhanced viral replication and conferred reduced susceptibility to ETV and TDF. The sC69* mutation caused truncation of HBs protein, leading to impaired detection by commercial HBsAg assay, without causing intracellular HBsAg retention or affecting HBV secretion. Conclusions—The rtS78T/c69* HBV mutation associated with enhanced replication and insufficient response to antiviral treatment may favor long-term persistence of these isolates. Along with increased production of HBV transcripts and the sustained secretion of viral particles in the absence of antigenic domains of S protein, this HBV mutation may predispose to carcinogenic effects.
Publication Date: Aug-2017
Citation: Shirvani-Dastgerdi, Elham, Winer, Benjamin Y, Celià-Terrassa, Toni, Kang, Yibin, Tabernero, David, Yagmur, Eray, Rodríguez-Frías, Francisco, Gregori, Josep, Luedde, Tom, Trautwein, Christian, Ploss, Alexander, Tacke, Frank. (2017). Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy. Journal of Hepatology, 67 (2), 246 - 254. doi:10.1016/j.jhep.2017.03.027
DOI: doi:10.1016/j.jhep.2017.03.027
ISSN: 0168-8278
Pages: 246 - 254
Type of Material: Journal Article
Journal/Proceeding Title: Journal of Hepatology
Version: Author's manuscript

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