Hepatitis
B
Zadaxin Plus Nucleoside Analogues Combination
Treatment for Chronic Hepatitis B
In contrast to the disease in the West, the natural history
of CHB in Asia is characterized by an initial active viral replicative
state with minimal liver damage (immune tolerance phase). Immune-tolerant
patients are usually asymptomatic and have normal or near-normal
ALT. This phase is followed by an active immune clearance phase
with chronic active hepatitis. However, most patients do not
clear HBV DNA, which then becomes integrated into the host’s
genome. Many of these patients will eventually progress to develop
cirrhosis and hepatocellular carcinoma (HCC).
The main aim of treatment is to suppress HBV replication before
there is any significant irreversible liver disease. As most
of the liver damage occurs during the immune clearance phase
(when HBV replication is being suppressed spontaneously), it
would be optimal to suppress HBV replication in the earlier,
immune tolerant phase. Unfortunately, patients in the immune
tolerant phase do not respond to current therapies, and an effective
therapy remains elusive.
The response rate to interferon in Asian patients is low: Only
15% to 20% will clear HBeAg and HBV DNA, and most of these responders
are already in the immune clearance phase and, thus, would have
eventually spontaneously cleared their infection without any
treatment. However, in immune-tolerant patients, response to
interferon is even lower, with less than 5% of patients clearing
HBV DNA. One of the factors that impair the antiviral effect
of immunomodulatory agents is a high pretreatment HBV DNA level.
Recently, second-generation nucleoside analogues such as lamivudine
and famciclovir have been shown effective in suppressing HBV
replication. It would, therefore, be logical to use a combination
of immunomodulatory agents and second-generation nucleoside
analogues in the treatment of CHB in the immune-tolerant phase.
Pilot Hong Kong study (Zadaxin plus famciclovir)
(101)
This study was populated with patients whose ALT levels made
them highly unlikely to undergo spontaneous seroconversion to
negative HBV DNA and HBeAg.
| Patients and
protocol: |
| • |
32 immune-tolerant adult
Chinese patients with vertically transmitted CHB |
| |
| – |
ALT <2.5 times
upper limit of normal |
| – |
High HBV DNA load:
HBV DNA titers > 4000 mEq/mL (Chiron Quantiplex
bDNA assay) |
|
| • |
6-month treatment |
| |
| – |
Zadaxin (1.6 mg SC
BIW) |
| – |
Famciclovir (500
mg TID) |
|
| • |
12-month follow-up |
| • |
Complete virological response
defined as disappearance of HBV DNA and HBeAg |
| • |
Significant improvement in liver histology
characterized by improvement =2 points, Knodell hepatitis
activity index (HAI) |
| Results: |
| • |
Virological and histological
response evaluated |
| • |
3 patients (9.09%) demonstrated
a sustained complete virological response after treatment
and follow-up |
| • |
27.3% patients had significant
improvement in liver histology |
| • |
Combination was well tolerated |
| • |
No side effects reported |
These results are highly promising since immunetolerant patients
usually do not respond to any available drug therapy.
Unfortunately, therapy with nucleoside analogues leads to the
selection of HBV mutants that are resistant to these drugs.
Lamivudine-treated patients develop lamivudineresistant mutants
at a cumulative rate of approximately 20% per treatment year.82
HBV mutants are also induced by famciclovir therapy. However,
famciclovirinduced HBV mutants do not show cross-resistance
to lamivudine. Therefore, it may be possible that the use of
a combination of famciclovir and lamivudine may decrease the
risk of emergence of HBV mutants.
Pilot Hong Kong study (Zadaxin plus lamivudine
plus famciclovir) (102)
| Patients and
protocol: |
| • |
11 Chinese patients with
vertically transmitted CHB |
| |
|
| • |
12-month treatment period
|
| |
| – |
Zadaxin (1.6 mg BIW
for 6 months) |
| – |
Lamivudine (100 mg/day
for 12 months) |
| – |
Famciclovir (500
mg TID for 12 months) |
|
| • |
12-month posttreatment
follow-up |
| • |
Complete virological response
defined as disappearance of HBV DNA and HBeAg |
| Results: |
| • |
64% (7/11) complete virological
response |
| • |
ALT normalized in all patients |
| • |
91% (10/11) HBV DNA negative |
| • |
Drugs were well tolerated |
| • |
No side effects noticed |
These data support the hypothesis that a combination of Zadaxin
and nucleoside analogues may be a safe and effective therapy
for CHB, especially in difficult-to-treat cases such as patients
with vertically transmitted diseases and nonresponders to previous
therapy.
Pilot Turkish study (Zadaxin plus lamivudine
in pediatric patients unresponsive to previous treatment). (103)
| Patients and
protocol: |
| • |
10 pediatric patients with
vertically transmitted CHB |
| • |
Nonresponders to previous
IFNα or IFNα
plus lamivudine |
| • |
12-month treatment period
|
| |
| – |
Zadaxin (1.6 mg/m2
BIW for 6 months) |
| – |
Lamivudine (3 mg/kg/day
for 12 months) |
|
| • |
12-month posttreatment
follow-up |
| Results: |
| • |
70% (7/10) HBV DNA negative |
| • |
Drugs were well tolerated |
| • |
No side effects noticed |
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