Restoration of specific anti-HBV immune response
Several studies have shown that the decrease in viral load
induced by lamivudine therapy is associated with the subsequent
restoration of the CD4 and then the CD8 cellular immune
response against HBV.
25,26
Another recent study showed that the
activation of the specific cellular immune response depends on a
relatively low level of viral load.
27
However, the recent results
of clinical trials with entecavir and telbivudine, which showed a
stronger inhibition of viral load compared with lamivudine, did
not show a statistical difference in the rate of hepatitis B e anti-
gen (HBeAg) seroconversion.
In our study in the woodchuck model, the intrahepatic deliv-
ery of recombinant adenovirus vectors encoding the woodchuck
interferon-gdid not lead to an added benefit to the combination
of emtricitabine and clevudine, suggesting that chronically
infected woodchuck hepatocytes may be refractory to the anti-
WHV activity of interferon-g.
5
This has been confirmed by other
teams, one study showing that interferon-ahad more antiviral
efficacy than interferon-gin the woodchuck model.
28,29
Perspectives for the treatment of chronic hepatitis B
The current understanding of chronic HBV infection and its
treatment suggest that the patients who are more likely to sero-
convert anti-HBeAg antibodies should first receive a course of
pegylated interferon-a.
30
In this setting, pegylated interferon
therapy may be the best option because of the possibility of
short-term therapy and the absence of selection of resistant
mutants. On the other hand, the majority of patients who are
non-seroconverters or are infected with a pre-core mutant will
require long-term maintenance therapy to control viral replica-
tion and liver disease. In this view, the development of clevudine
and emtricitabine opens new avenues in the management of
these patients. Clevudine, with its unusual antiviral activity pro-
file, may be the first nucleoside analogue to be used as a relative
short-term treatment and to achieve sustained control of viral
replication even after treatment withdrawal. On the other hand,
emtricitabine, as well as other drugs in development, offers a
new option for combination of nucleoside analogues that do not
share the same cross-resistance profile. For instance, it may be
used in combination with adefovir or tenofovir. The evaluation
of such combination strategies will need to rely on accurate end-
points and timing for such analysis.
Acknowledgements
This work was supported in part by fundings from the European
Community (HepBvar project, contract QLRT2001-00977; and
viRgil network contract LSHM-CT-2004-503359).
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