标题: Impact of hepatitis B e antigen-suppressing mutations on the replication efficie [打印本页] 作者: StephenW 时间: 2011-10-15 06:54 标题: Impact of hepatitis B e antigen-suppressing mutations on the replication efficie
Summary. Hepatitis B e antigen (HBeAg)-negative hepatitis B commonly
requires long-term treatment with nucleos(t)ide analogues aiming at
persistently suppressing hepatitis B virus (HBV) replication to halt
progression of liver disease and prevent complications. Entecavir (ETV) is
widely used in HBeAg-negative hepatitis B, but distinct HBV polymerase
mutations can confer resistance against ETV, in conjunction with lamivudine
resistance. Precore (PC) and basal core promoter (BCP) mutations that
underlie HBeAg-negativity enhance replication of lamivudine-resistant
mutants. To comprehensively analyse the impact of PC or BCP mutations on
viral replication of ETV-resistant HBV mutants, replication-competent HBV
constructs were generated harbouring lamivudine resistance
(rtM204V/rtL180M, rtM204I) plus ETV resistance (rtS202G, rtS202I or
rtT184G) on wild-type (WT)-, PC- and BCP-backgrounds. Functional
consequences on viral fitness and susceptibility to antivirals were
assessed in vitro. The presence of any ETV resistance drastically reduced
viral replication when compared to WT HBV. In rtS202G mutants (plus
lamivudine resistance), addition of either PC or BCP mutations moderately
enhanced the reduced replication, without reaching WT HBV levels. In
rtS202I or rtT184G mutants, PC and BCP mutations did not significantly
improve viral fitness. All ETV-resistant constructs, independently of PC or
BCP mutations, showed resistance towards ETV and lamivudine, but remained
susceptible to tenofovir. Our data demonstrate that HBeAg-suppressing PC or
BCP mutations cannot restore the strongly reduced replicative capacity of
ETV-resistant HBV mutants to WT level, although they moderately increase
replication of rtS202G combination mutants. ETV resistance thereby differs
from lamivudine resistance alone, corroborating that ETV is in short term a
safe option for HBeAg-negative patients.