Selection of the highly replicative and partially multidrug resistant rtS78T polymerase mutation in two patients with chronic hepatitis B virus infection during tenofovir-entecavir combination therapy.

TitleSelection of the highly replicative and partially multidrug resistant rtS78T polymerase mutation in two patients with chronic hepatitis B virus infection during tenofovir-entecavir combination therapy.
Publication TypeJournal Article
Year of Publication2017
AuthorsShirvani-Dastgerdi, E, Winer, BY, Celia-Terrassa, A, Kang, Y, Tabernero, D, Yagmur, E, Rodríguez-Frías, F, Gregori, J, Luedde, T, Trautwein, C, Ploss, A, Tacke, F
JournalJ Hepatol
Date Published2017 Apr 06
ISSN1600-0641
Abstract

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). Ultra-deep pyrosequencing analyses revealed the selection of the rtS78T polymerase mutation in both cases that 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 a reduced susceptibility to ETV and TDF. This partial resistance to antiviral treatment favoring 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, may predispose carcinogenic effects.

LAY SUMMARY: Long-term treatment with antiviral drugs carries the risk of selecting mutations in the hepatitis B virus (HBV). We herein report two cases of patients with insufficient response to dual tenofovir and entecavir therapy. Molecular analyses identified a distinct mutation, rtS78T/sC69∗, that abolishes HBsAg detection, enhanced replication, sustained exosome-mediated virion secretion and decreased susceptibility to antivirals, thereby representing a potential high-risk mutation for HBV-infected individuals.

DOI10.1016/j.jhep.2017.03.027
Alternate JournalJ. Hepatol.
PubMed ID28392234