Editorial Board:
Anna Lok,
MD; Brian McMahon, MD; Albert Min, MD; Myron Tong,
MD; Naoky Tsai, MD; Bruce Tung, MD
HBV Watch™
Timely Information for Practicing Physicians
Special
Issue Featuring Clinical Study Highlights in Hepatitis B
38th
Annual Meeting of the European Association for the Study of the Liver (EASL)
Impact of HBV genotype on
treatment outcome with peginterferon alfa-2a. W.G.E. Cooksley
and colleagues studied the impact of HBV genotype on treatment outcome in a
phase II study in 191 patients with HBeAg-positive chronic hepatitis B (CHB)
randomized to receive standard IFN α-2a 4.5 MU/wk or PEG-IFN α-2a 90
µg, 180 µg, or 270 µg/wk for 24 wk with follow-up for 24 wk. Predominant
genotypes were C (66%) and B (32%). Combined response rates of both genotypes
were higher in the PEG-IFN α-2a-treated patients
vs those treated with IFN α-2a (24% vs 12%). Response rates were also
significantly higher in genotype B than C. Treatment with PEG-IFN α-2a
resulted in a more than 3-fold higher combined response rate than IFN α-2a
in genotype C patients (21.3% vs 6.3%). (W.G.E. Cooksley
et al. J Hepatology 2003;38:76A)
Predictors of HBeAg loss during
therapy with adefovir dipivoxil (ADV). A.U. Neumann and colleagues reported data on 164 patients treated
for 48 wk with ADV 10 mg/d or placebo. HBV DNA was monitored every 4 wk. HBV
DNA at wk 1 was estimated by log-linear regression. Viral kinetics patterns
were classified and correlated with HBeAg loss and baseline factors. HBV DNA
kinetics during ADV therapy show different patterns that can be used to predict
HBeAg loss: a rapid-flat decline (21% of pts) was
associated with only a 3% HBeAg loss; a rapid-slow-flat decline (32% of pts) was associated with only an 11% HBeAg loss; a
rapid-slow decline below detection (32% of pts) was
associated with a 77% HBeAg loss; and a rapid-slow-acceleration decline (15% of
pts) was associated with a 38% HBeAg loss. Mean HBeAg
loss was 15% on placebo vs 27% on ADV; negative HBV DNA was 0% on placebo vs
21% on ADV. (A.U. Neumann et al. J
Hepatology 2003;38:70A)
Long-term safety of ADV 10 mg daily for CHB: integrated analysis of 2
phase III studies. T.T. Chang et al. reported safety data from 2
well-controlled phase III clinical trials with ADV 10 mg/d. AVD was well
tolerated. ALT elevation leading to study drug discontinuation occurred in 1%
of patients. Serum creatinine elevation >0.5 mg/dL above baseline
occurred in <1% of patients. No hypophosphatemia was observed. No single
type of adverse event led to drug discontinuation in more than 1% of patients.
Hepatic flares (ALT >10x ULN) occurred in 28% of patients. Patients who
discontinue ADV therapy should be closely monitored for several months for ALT
flares. (T.T. Chang et al. J Hepatology
2003;38:454A)
ADV results in consistent efficacy in CHB patients with diverse
baseline characteristics. P. Marcellin et al. compared the
efficacy of ADV 10 mg/d over 48 wk in a broad range of CHB patients (n=692) who
participated in 5 clinical trials. ADV has potent activity against wild-type
and lamivudine (LAM)-resistant HBV as evidenced by HBV DNA suppression, ALT/AST
normalization and HBeAg loss and seroconversion (HBeAg+ pts).
Efficacy was consistent regardless of HBeAg status and liver function. Among
patients with LAM resistance, clinical benefit in pre- and post-liver
transplantation patients with compensated liver function was seen.
Additionally, switching from LAM to ADV monotherapy or adding ADV to ongoing
LAM resulted in significant virological and biochemical improvements. No ADV
resistance mutations were identified in patients treated up to 48 wk, and ADV
was generally well tolerated up to 48 wk. (P. Marcellin
et al. J Hepatology 2003;38:529A)
Two year results of ADV in CHB. S. Hadziyannis et al. reported the results
of a double-blind, placebo-controlled study in 185 patients who had documented
HBsAg+ status for >6 months, compensated liver disease, adequate
renal function, baseline liver biopsy and ALT >1.5-15 x ULN. Patients
were randomized to ADV 10 mg/d (123 pts) or placebo
(62 pts) for 48 wk. After 48 wk, placebo patients
received ADV, and ADV patients were re-randomized (2:1) to ADV or placebo.
Baseline demographics and HBV disease characteristics were similar. Treatment
with ADV 10 mg over 96 wk resulted in significant and persistent reductions in
HBV DNA and continued improvement in ALT levels and histology. Treatment
discontinuation resulted in a loss of HBV DNA and ALT suppression and a
reversal of histologic improvement in most patients. The safety profile of ADV
in the 2nd year of treatment was comparable to the 1st
year. There was a delayed and infrequent emergence of ADV resistance mutations;
0% at wk 48 and 2.5% at wk 96. (S. Hadziyannis et al. J Hepatology 2003;38:492A)
Resistance profile of ADV in
immunocompetent and immunocompromised CHB patients.
C. Westland and colleagues compared the
resistance profile of ADV among immunocompetent CHB patients (n=171 HBeAg+;
n=123 HBeAg-) and immunocompromised CHB patients (n=35 LAM-resistant HIV
coinfected; n=96 LAM-resistant LTx pts receiving immuno- suppressive therapy). There was no HBV
resistance to ADV after 48 wk in either the immunocompetent or
immunocompromised patients. Neither immune suppression nor pre-existing LAM
resistance predisposes patients to ADV resistance. Long-term surveillance, up
to 5 years, is ongoing. (C. Westland et al. J Hepatology 2003;38:627A)
Resistance surveillance of HBeAg-negative CHB patients treated for 2
years with ADV. S. Xiong and colleagues monitored the
emergence of ADV resistance mutations following 96 wk of ADV therapy in the
groups reported above by C. Westland et al. Among the 124 CHB patients who received ADV
for 96 wk, ADV had a favorable resistance profile during long-term
therapy. Emergence of the ADV resistance
mutation was delayed and infrequent (0% of pts at 1
year; 1.6% of pts at 2 years). Patient-derived
ADV-resistant HBV isolates with N236T remained susceptible to LAM in vitro and in vivo. Long-term resistance surveillance in different patient
populations is ongoing. (S. Xiong et al. J Hepatology 2003;38:628A)
Tenofovir (TNV) effectively inhibits viral replication in LAM-resistant
HBV. F. van Bommel et al. conducted a pilot
study in 19 patients to document long-term effectiveness and safety of TNV in
different patient groups with CHB.
Patients included 10 HBV/HIV coinfected, 4 CHB post-renal Tx, and 5 CHB, all of whom
suffered viral breakthrough after 2-3 years of LAM therapy. All patients received 245 mg TNV daily for at
least 24 wk (mean 53.7 wk). During TNV treatment, a mean log decline of 3.7 ±
0.87 of HBV viremia was shown and HBV DNA became undetectable in 17/19
patients. No clinically relevant side
effects were observed. Results showed that TNV has a significant suppressive
effect on replication of LAM-resistant HBV mutants, even in immunosuppressed
patients. (F. van Bommel et al. J Hepatology 2003;38:74A)
Phase I/II dose escalating trial
evaluating clevudine (CLV) in CHB patients. P. Marcellin
et al. reported the results of a multicenter, open-label, dose escalation study
among 30 patients with 10, 50, 100 and 200 mg CLV daily for 28 days. Patients were followed
post-treatment for 6 months. After 28 days of dosing, median log viral load
change from baseline was -2.5, -2.7, -3.0 and -2.6, in the 10, 50, 100 and 200
mg groups, respectively. At 6 months post-dosing,
sustained biochemical responses were observed and median log viral load changes
from baseline were -1.2, -1.4, -2.7 and -1.6, respectively. Seven patients (28%) lost HBeAg; 5 (19%)
seroconverted to anti-HBe. CLV was well tolerated. No treatment emergent
mutations were observed after 5 months of treatment. (P. Marcellin
et al. J Hepatology 2003;38:73A)
Sustained viral load and ALT
reduction after 48 weeks of entecavir (ETV) treatment in LAM failures. R.
Gish and colleagues analyzed the impact of HBeAg status on
response to ETV among 181 patients who had failed prior LAM therapy. Patients
were randomized to ETV 0.1, 0.5, or 1.0 mg, or LAM 100 mg daily for up to 52
wk. Mean HBV DNA decrease from baseline
and normalization of ALT for all ETV doses was superior to LAM at wk 48.
Preliminary analysis demonstrated durable virologic suppression and ALT
normalization through 6 months off treatment follow-up in a substantial portion
of ETV patients. In patients previously failing LAM therapy, HBV DNA reduction
and ALT normalization after 48 wk of ETV therapy were comparable in HBeAg+ and
HBeAg- patients. (R. Gish
et al. J Hepatology 2003;38:93A)
Viral load reduction in response to ETV therapy is not dependent upon
baseline ALT. M. Rosmawati and
colleagues evaluated the effect of baseline ALT on viral load reduction in a
randomized, double-blind phase II dose-ranging trial in 180 patients with CHB comparing 3
doses of ETV (0.01, 0.1, and 0.5 mg QD) to LAM 100 mg QD for 24 weeks. 169
patients were evaluable for efficacy at wk 22. There was a clear dose-response
for ETV, with superior antiviral activity of 0.1 and 0.5 mg doses of ETV
compared to LAM 100 mg. ETV 0.5 mg was highly effective in reducing HBV DNA
(mean change from baseline = -4.31 log10) by PCR regardless of
baseline ALT level. In contrast, there were large differences in response to
LAM depending on baseline ALT: the mean difference in viral load reduction
between high and low ALT groups was 1.64 log10 (p<0.0001). ETV
was well tolerated with a safety profile similar to LAM. (M. Rosmawati et al. J
Hepatology 2003;38:574A)
Summary of phase II clinical and
laboratory safety experience with ETV. E.R. Schiff et al. assessed the incidence of adverse events
occurring with ETV relative to active control (LAM) among 315 patients
receiving ETV monotherapy in 5 phase II dose-ranging trials, with daily doses
ranging from 0.01 to 1.0 mg up to 96 weeks. ETV was well tolerated; the
frequency of adverse events was not different from that of LAM. The most
frequently reported adverse events were headache, rhinitis, fatigue, and
abdominal pain; there was no difference in the ETV dose groups. Large phase III
trials are ongoing to confirm the safety and efficacy of ETV. (E. R. Schiff et al. J Hepatology 2003;38:585)
HBV Watch is produced through educational grants from 
and 
Hepatology Watch is a registered trademark of Market Development Group
Back to Issues Archive