Jibatuat. 2017 Apr 6.论坛 pii: S0168-8278 (17) 30198-8. Doi: 10.1016 / j.jhep.2017.03.027. [Epub ahead of print]
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.
Shirvani-Dastgerdi E1, Winer BY2, Celia-Terrassa A2, Kang Y2, Tabernero D3, Yagmur E4, Rodríguez-Frías F3, Gregori J5, Luedde T6, Trautwein C6, Ploss A2, Tacke F7.
Author information
1
Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany .; Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
2
Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
3
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain The
4
Medical Care Center, Dr Stein and Colleagues, Mönchengladbach, Germany.
5
Roche Diagnostics SL, Sant Cugat del Vallès, Spain
6
Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany.
7
Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany .. Electronic address: [email protected].
Abstract
Patients with 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 here report two cases of HBV- 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, greatly enhanced viral replication and conferred a reduced susceptibility to ETV and TDF. This partial resistance to antiviral favouring 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:
1德国亚琛亚琛大学医院第三医学系;普林斯顿大学分子生物系,普林斯顿,新泽西州,美国。
2普林斯顿大学分子生物系,普林斯顿,新泽西州,美国。
3 Centro deInvestigaciónBiomédicaen Red de EnfermedadesHepáticasy Digestivas(CIBERehd),Instituto de Salud Carlos III,Madrid,Spain;肝脏单位,Vall d'Hebron研究所(VHIR),巴塞罗那自治大学(UAB),西班牙巴塞罗那
4医疗中心,Stein博士和同事,德国门兴格拉德巴赫。
5 Roche Diagnostics SL,Sant Cugat delVallès,西班牙
6德国亚琛亚琛大学医院第三医学系。
7德国亚琛亚琛大学附属医院三医院电子地址:[email protected]。