[Evolution of hepatitis B virus quasispecies during lamivudine-entecavir sequential therapy].
OBJECTIVE
To study the evolution of HBV quasispecies under the pressures of lamivudine (LAM) - entecavir (ETV) sequential therapy and its clinical significance.


METHODS
Consecutive serum samples from 2 patients underwent LAM-ETV sequential therapy were extensively studied for HBV quasispecies composition and evolution, using PCR-cloning-sequencing method. Maximum likelihood trees were built to analyze the genetic relationship between representative sequences. Correlation between HBV quasispecies evolution and serological/virological data was analyzed to determined the clinical significance of the evolution of HBV quasispecies during prolonged nucleotide analog therapy.


RESULTS
Virological breakthrough was observed in both patients. Patient I acquired sustained virological response after switching to ETV rescue therapy, whereas Patient II suffered from virological breakthrough after 72 weeks of ETV therapy. Each virological breakthrough was accompanied with the replacement of previous drug susceptible dominant quasispecies with a drug resistant variant, indicating a close correlation between quasispecies composition and drug susceptibility. The rtL180M+S202G+M204V triple mutant, which was most likely a descendant of the LAM resistant rtL180M+M204V variant, was closely correlated with ETV resistant in Patient II.


CONCLUSIONS
Quasispecies composition of HBV is closely correlated with nucleotide analog susceptibility. ETV resistant variant can emerge from a LAM resistant viral population. Dynamic monitoring of HBV quasispecies composition is of great importance during nucleotide analog therapy.
Liu
Lin
L
Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Tang
Ying-Zi
YZ
Li
Jun-Gang
JG
Zhou
Ji-Jun
JJ
Wang
Xiao-Hong
XH
Wang
Yu-Ming
YM
D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006509:Hepatitis B / Q000188:drug therapy / Q000821:virology*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage* / Q000627:therapeutic use
D000998:Antiviral Agents; D004279:DNA, Viral; D019259:Lamivudine; C413685:entecavir; D006147:Guanine