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INTRODUCTION
Viral dynamics during and after entecavir therapy 177
In patients with chronic hepatitis B infection, annual clearance of HBsAg and HBeAg is
estimated at 1 and 10%, respectively. HBeAg clearance, which is immune mediated, is
improved by alpha interferon therapy resulting in HBeAg seroconversion in 30–40% of
patients. 1–4 In particular, those patients with an immune-tolerant status, a large part of
which is originating from Asian countries, do not show a favourable response to alpha
interferon therapy. 5 Recently, lamivudine has been registered as a second option for the
treatment of chronic hepatitis B patients. Whereas HBeAg seroconversion is a solid endpoint
for alpha interferon therapy, durability of HBeAg seroconversion after withdrawal
of lamivudine therapy needs to be evaluated. Reports on this end-point are contradictory.
6–8 Recurrence of viral activity is attributed to the remnant covalently closed circular
DNA (cccDNA) inside the nucleus of hepatocytes which is not affected by lamivudine. 9–10
Entecavir, a new guanine nucleoside analogue which is currently under investigation
in phase II studies, is believed to be capable of interfering with cccDNA. 11–13 This consideration
is based on observations in woodchucks chronically infected with the woodchuck
hepatitis B virus (HBV). Short-term entecavir therapy markedly reduces cccDNA
levels in the liver of woodchucks14 and rebound of virus after withdrawal of therapy in
woodchucks. 15 Moreover, maintenance therapy in woodchucks with once weekly dosing
regimens is able to reduce cccDNA in the liver to undetectable levels. 16
Mathematical modelling can be used to evaluate the mechanism of action of entecavir
on both viral decline during and the return of virus after withdrawal of therapy. In previous
modelling studies on the effect of nucleoside analogues in a chronic hepatitis B infection,
it has been shown that viral decline can be divided into two phases: a fi rst phase
of turn-over of free virus and a second phase of death of infected hepatocytes. 17–18
Return of virus after withdrawal of therapy has never been evaluated in detail, but may
be helpful in clarifying the mechanisms that take place during viral replication.
We therefore conducted a study to model viral decline during entecavir therapy and
viral return after withdrawal of entecavir therapy.
PATIENTS AND METHODS
Study design
All patients who were treated in the Academic Hospital Rotterdam, The Netherlands,
in a study on the safety and effi cacy of entecavir were recruited for a study on viral
dynamics. Patients were treated in a 1 month, double-blind, placebo-controlled dose
escalating study on the safety and effi cacy of entecavir (0.05, 0.1, 0.5, 1.0 mg) vs. placebo
with a follow-up of 6 months. During the fi rst month of therapy, HBV DNA was measured