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Viral dynamics during and after entecavir therapy 185
Although the results of this study are based on a small number of patients, the antiviral
activity during short-term therapy with entecavir seems somewhat greater than during
lamivudine therapy27 and lower than during adefovir dipivoxil therapy, 17 although
it should be realized that this is a head-to-head comparison and randomized studies
are needed to identify the actual differences in parameters between these nucleoside
analogues. Our analysis is based on four low doses of entecavir during the fi rst study
in chronic hepatitis B patients; some of these doses might have been insuffi cient for
the optimal treatment of HBV. Moreover, the majority of our patients had previously
failed lamivudine therapy which could also result in a less favour-able response to reintroduction
of another antiviral agent. Entecavir did show continuing activity in patients
with detectable lamivudine-induced mutant virus. Theoretically, the second phase of
more gradual decline in viral concen tration may be infl uenced by death of infected
hepatocytes and turn-over of cccDNA harbouring cells. After the fi rst 28 days of therapy,
the decline of viral concentration can be either slower than, equal to, or faster than
observed during the second phase. We do not observe a difference in the slope of
the second phase between lamivudine-and entecavir-treated patients in a head-to-head
comparison. We could therefore speculate that in both lamivudine and entecavir treated
patients, this second phase is primarily infl uenced by death of infected hepatocytes. If
entecavir exhibits a direct effect on cccDNA, this effect may surface only during a longer
treatment period.
All nine patients who were evaluated after withdrawal of therapy showed a bi-phasic
pattern with an initial fast increase of viral replication followed by a more or less steady
state. This initial fast return of viral replication, which was calculated to last 30 days,
could refl ect the production capacity of the reservoir of hepatocytes that is still infected
with HBV, as well as infection of non-infected hepatocytes leading to a larger productivity.
The part of the cccDNA pool which is not affected by entecavir can be used as a
template from which the virus can re-initiate replication once the inhibitor has been
removed. This implies that a larger pool of still infected hepatocytes could result in
a faster return of viral replication to baseline level. The second phase of this model
represents a steady state of viral production, counteracted by turn-over of free virus and
infected hepatocytes.
Patients who were treated with the two higher doses of entecavir (0.5 and 1.0 mg) showed
a more gradual increase in HBV DNA to baseline levels than those patients who were
treated with lower doses, even though viral load was suppressed to the same extent in
all dose groups. Slower return of viral replication in the high dosed groups may therefore
be due to a smaller remnant pool of infected hepa tocytes and not to the extent of viral