Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir.
Mutations within the hepatitis B virus (HBV) polymerase gene conferring drug-resistance are selected during prolonged lamivudine (3TC) or adefovir dipivoxil (ADV) treatment. Because there is no other approved drug against HBV, treatments with 3TC or ADV are used either sequentially or in addition, depending on treatment response or failure. Considering the use of de novo or add-on 3TC+ADV bitherapy, we investigated the possibility of the emergence of an HBV strain harboring polymerase mutations conferring resistance to both 3TC (rtL180M+M204V) and ADV (rtN236T). We constructed the L180M+M204V+N236T mutant and determined its replication capacity and its susceptibility to different nucleos(t)ide analogs in transiently transfected hepatoma cell lines. The triple mutant replicates its genome in vitro, but less efficiently than either the wild-type (wt) HBV or L180M+M204V and N236T mutants. Phenotypic assays indicated that the L180M+M204V+N236T mutant is resistant to pyrimidine analogs (3TC, -FTC, beta-L-FD4C, L-FMAU). Compared with wt HBV, this mutant displays a 6-fold decreased susceptibility to ADV and entecavir and a 4-fold decreased susceptibility to tenofovir. Interferon alfa inhibited equally the replication of wt and L180M+M204V+N236T HBV. In conclusion, the combination of rtL180M+M204V and rtN236T mutations impairs HBV replication and confers resistance to both 3TC and ADV in vitro. These results suggest that the emergence of the triple mutant may be delayed and associated with viral resistance in patients treated with 3TC+ADV. However, other nucleos(t)ide analogs in development showed an antiviral activity against this multiresistant strain in vitro. This provides a rationale for the clinical evaluation of de novo combination therapies.
Brunelle
Marie-Noëlle
MN
INSERM U271, Laboratoire des virus hépatiques et pathologies associées, Lyon, France.
Jacquard
Anne-Carole
AC
Pichoud
Christian
C
Durantel
David
D
Carrouée-Durantel
Sandra
S
Villeneuve
Jean-Pierre
JP
Trépo
Christian
C
Zoulim
Fabien
F
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics*; D016679:Genome, Viral; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D009154:Mutation; D009705:Nucleosides / Q000494:pharmacology; D009711:Nucleotides / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013678:Technology, Pharmaceutical; D014779:Virus Replication
D000998:Antiviral Agents; D009705:Nucleosides; D009711:Nucleotides; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; C053001:adefovir; D000225:Adenine