Selection of multiresistant hepatitis B virus during sequential nucleoside-analogue therapy.
Hepatitis B virus (HBV) drug resistance to lamivudine is always accompanied by mutations in the viral polymerase gene at position 550, termed group 1 (M550V with L526M) or group 2 (M550I) mutations. The latter mutation has not been associated with famciclovir resistance. Thus, the addition of famciclovir to lamivudine therapy in persons with group 2 lamivudine resistance may lead to virus suppression. The effect of lamivudine/famciclovir combination therapy on HBV infection was monitored in 5 lamivudine-resistant patients by quantitative polymerase chain reaction and polymerase gene sequencing of serum virus. No patients treated with combination therapy had a decline in HBV load >1 log10. Continual evolution of the viral polymerase was detected in association with virologic resistance to both drugs. Cloning experiments identified the preexistence of these multidrug-resistant virus variants as minority species prior to addition of famciclovir therapy. HBV resistance to lamivudine monotherapy is associated with a complex mixture of variants that limit the efficacy of second-line nucleoside-analogue therapy. First-line potent combination therapy may reduce the emergence of HBV drug resistance.
Mutimer
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D
Public Health Laboratory Service Antiviral Susceptibility Reference Unit, Divisions of Medical Sciences, University of Birmingham Medical School, Edgbaston, Birmingham, United Kingdom.
Pillay
D
D
Cook
P
P
Ratcliffe
D
D
O'Donnell
K
K
Dowling
D
D
Shaw
J
J
Elias
E
E
Cane
P A
PA
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D000077595:Famciclovir; D006509:Hepatitis B / Q000188:drug therapy* / Q000821:virology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019562:Viral Load
D000998:Antiviral Agents; D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015075:2-Aminopurine; D004259:DNA-Directed DNA Polymerase; D000077595:Famciclovir