The rtA194T polymerase mutation impacts viral replication and susceptibility to tenofovir in hepatitis B e antigen-positive and hepatitis B e antigen-negative hepatitis B virus strains.
Tenofovir is a new effective treatment option for patients with chronic hepatitis B, but could be potentially hampered by mutations in the hepatitis B virus (HBV) polymerase conferring drug resistance. Drug resistance may occur preferentially if long-term administration is required, for example, in patients with hepatitis B e antigen (HBeAg)-negative HBV infection bearing precore (PC) and basal core promoter (BCP) mutations. The rtA194T polymerase mutation has been found in HBV/HIV coinfected patients during tenofovir treatment and may be associated with tenofovir resistance. We generated replication-competent HBV constructs harboring rtA194T alone or in addition to lamivudine (LAM) resistance (rt180M + rtM204V), PC mutations, and BCP mutations and assessed their replicative capacity after transient transfection in human hepatoma cells. The rtA194T polymerase mutation alone or in conjunction with LAM resistance reduced the replication efficiency as compared with wild-type (WT) HBV. In contrast, combination of rtA194T (+/- LAM resistance) with HBeAg-negative PC or BCP mutants increased the replication capacity of the drug-resistant polymerase mutants, thereby restoring the viral replication to similar levels as WT clones. Clones harboring rtA194T showed partial resistance to tenofovir in vitro and also to LAM but remained susceptible to telbivudine and entecavir.


CONCLUSIONS
The rtA194T polymerase mutation is associated with partial tenofovir drug resistance and negatively impacts replication competence of HBV constructs. Viral replication, however, can be restored to WT levels, if these polymerase mutations occur together with precore or basic core promoter substitutions as found in HBeAg-negative hepatitis B. Patients with HBeAg-negative chronic HBV infection may therefore be at particular risk when developing drug resistance to tenofovir. Telbivudine or entecavir should be considered as effective alternative treatment options for these patients.
Amini-Bavil-Olyaee
Samad
S
Department of Medicine III, RWTH-University Hospital Aachen, Germany.
Herbers
Ulf
U
Sheldon
Julie
J
Luedde
Tom
T
Trautwein
Christian
C
Tacke
Frank
F
D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics*; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006509:Hepatitis B / Q000188:drug therapy / Q000276:immunology; D006513:Hepatitis B e Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000201:enzymology / Q000235:genetics* / Q000502:physiology; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D009154:Mutation; D009705:Nucleosides / Q000627:therapeutic use; D063065:Organophosphonates / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000627:therapeutic use; D000077712:Telbivudine; D000068698:Tenofovir; D013936:Thymidine / Q000031:analogs & derivatives; D014764:Viral Proteins / Q000235:genetics*; D014779:Virus Replication
D019380:Anti-HIV Agents; D006513:Hepatitis B e Antigens; D009705:Nucleosides; D063065:Organophosphonates; D011744:Pyrimidinones; D014764:Viral Proteins; D000077712:Telbivudine; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir; D004259:DNA-Directed DNA Polymerase; D000225:Adenine; D013936:Thymidine