Emergence of hepatitis B virus quasispecies with lower susceptibility to nucleos(t)ide analogues during lamivudine treatment.
OBJECTIVE
We studied the impact of hepatitis B virus (HBV) polymerase/reverse transcriptase (Pol/Rt) heterogeneity on adefovir rescue therapy in 34 consecutive chronic hepatitis B patients with viral breakthrough during lamivudine monotherapy.


METHODS
The Pol/Rt A-F domains were directly sequenced in all patients at baseline, and 12 and 24 months. Response to therapy was evaluated at 3, 6, 12 and 24 months by quantitative HBV-DNA.


RESULTS
Primary treatment failures did not occur. At 6 months 24/34 (70.6%) patients had viraemia<10(4) copies/mL [initial viral response (IVR)]; at 12 and 24 months 23 (71.9%) and 26 (81.3%) of 32 had HBV-DNA<200 copies/mL [complete viral response (CVR)]. IVR or CVR patients did not show viral breakthroughs, which occurred in one of the six remaining patients. All but three patients had baseline rtM204I/V substitutions associated with rtL180M in 23, rtL80I/V in 14, rtV173L in 4, rtT184S in 3, rtQ215S in 2 and rtA181S in 2 cases. rtA181S without rtM204I/V was found in one patient. Four of the six patients (67%) without 24 month CVR showed rtA181S or rtT184S substitutions either alone or with typical lamivudine resistance profiles. Baseline HBV-DNA levels were negatively associated with IVR (univariate analysis, P=0.023). At least one of rtA181S and rtT184S substitutions correlated negatively with IVR and CVR (univariate analysis, P=0.001) and was independently associated with absence of CVR (P = 0.016).


CONCLUSIONS
Lamivudine monotherapy favours the emergence of viral quasispecies that influence the response rate to adefovir rescue therapy independently from baseline viraemia and lower the susceptibility to other nucleos(t)ide analogues.
Moriconi
F
F
UO Gastroenterologia ed Epatologia Ospedaliera, University Hospital of Pisa, Pisa, Italy.
Colombatto
P
P
Coco
B
B
Ciccorossi
P
P
Oliveri
F
F
Flichman
D
D
Maina
A M
AM
Sacco
R
R
Bonino
F
F
Brunetto
M R
MR
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004279:DNA, Viral / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; 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; D008875:Middle Aged; D008969:Molecular Sequence Data; D009705:Nucleosides / Q000494:pharmacology; D009711:Nucleotides / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014766:Viremia / Q000821:virology
D000998:Antiviral Agents; D004279:DNA, Viral; D009705:Nucleosides; D009711:Nucleotides; D063065:Organophosphonates; D019259:Lamivudine; C053001:adefovir; D012194:RNA-Directed DNA Polymerase; D004259:DNA-Directed DNA Polymerase; D000225:Adenine