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Combination
of Nucleoside Analogues in the Treatment of Chronic Hepatitis B
Long-term
antiviral therapy is therefore required in most patients with
chronic hepatitis B who do not mount a vigorous immune response,
to avoid relapse of viral replication after treatment withdrawal.
However,
the major drawback of prolonged therapy is the selection
of drug-resistant mutants generated by the spontaneous
error rate of the viral polymerase. Therefore, one of
the major research areas is the evaluation of combination
anti-HBV therapy to delay or prevent the occurrence of drug-resistant mutants.
Owing
to the persistence of hepatitis B virus (HBV) and the selection
of drug-resistant mutants, a new concept of antiviral therapy
for chronic hepatitis B relies on the combination of nucleoside
analogues. In experimental models of HBV infection, several
key points concerning these combinations were addressed:
(i) Is
it possible to achieve a synergic antiviral effect with polymerase
inhibitors?
(ii) Is
it possible to impact on intracellular viral covalently
closed circular DNA?
(iii) What
is the impact of the cross-resistance patterns of the
different nucleoside analogues?
(iv) What
is the effect of viral load suppression on the restoration
of specific antiviral cellular responses?
The
clinical impact of these key issues is discussed in the perspective
of new clinical trials.
It is important to note that most of
the nucleoside analogues administered in monotherapy
may select for drug-resistant mutants, as this was shown
with HIV. It was shown that lamivudine
(Epivir-HBV) and
emtricitabine share the same cross-resistance profile with
the selection of the M204V or M204I polymerase mutants that
are susceptible to adefovir (Hepsera).
To date, telbivudine is
associated with the emergence of the M204I mutant, which
is resistant to lamivudine and emtricitabine.
Adefovir selects for the A181V
and N236T mutants, which are susceptible to lamivudine.
Entecavir is less active against lamivudine-resistant
strains and selects for specific resistance mutations
on a genetic background of lamivudine resistance mutations.
Clevudine is not active against the
lamivudine-resistant strains and was shown to select for the
same resistant mutants in woodchucks chronically infected with
WHV. It also exhibits some antiviral activity against
the adefovir-resistant strains in vitro.
Elvucitabine is not active against the
lamivudine-resistant mutants but is active against the
adefovir-resistant strains.
Tenofovir
shows a good antiviral efficacy against the lamivudine-resistant
strains and slightly decreased activity against the adefovir-resistant
mutants. A tenofovir-resistant mutant was also recently described.
Given the cross-resistance profile
of these drugs, the rationale is to combine the drugs
that would inhibit the emergence of drug-resistant strains
to one or the other drug. This may lead to an improved
management of antiviral therapy of chronic HBV infection
in the long term.
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 seroconvert anti-HBeAg antibodies
should first receive a course of pegylated
interferon alfa.
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 replication 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 profile, 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 these combination
strategies will need to rely on accurate endpoints and
timing for such analysis.
06/15/05
Reference
F
Zoulim and others. Combination of nucleoside analogues
in the treatment of chronic hepatitis B virus infection: lesson
from experimental models. Journal of Antimicrobial Chemotherapy
2005 55(5): 608-611. May 2005
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