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Editorial
Board:
Emmet B. Keeffe, MD (Chair); Anna
Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron
Tong, MD; Naoky Tsai, MD; Bruce Tung,
MD |
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HBV Watch™ |
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Timely Information for Practicing Physicians |
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Clinical Study Highlights in
Hepatitis B
39th Annual Meeting of
the European Association for the Study of the Liver
Peginterferons in chronic hepatitis B
(CHB)
Peginterferon
alfa-2a is more effective than lamivudine
for HBeAg-negative CHB. P. Marcellin and
colleagues reported the results of a phase III, partially double-blind study in
adults (n=537) with HBeAg-negative CHB comparing peginterferon
alfa-2a 180 µg weekly plus placebo, peginterferon alfa-2a 180 µg weekly plus
lamivudine 100 mg daily, and lamivudine 100 mg daily for 48 weeks. At the end
of 24-weeks of follow-up, the percentage of
patients with normal alanine aminotransferase (ALT) levels or undetectable HBV
DNA (<20,000 copies/mL) receiving peginterferon alfa-2a plus placebo (59% and
43%, respectively) and peginterferon
alfa-2a plus lamivudine (60% and 44%, respectively) was
significantly higher than in the lamivudine group (44% and 29%,
respectively). A histologic response
occurred in 47% of patients receiving peginterferon alfa-2a plus placebo
compared to 37% and 39% of patients receiving peginterferon alfa-2a plus lamivudine and lamivudine monotherapy,
respectively. HBsAg loss was seen in 12 patients
receiving peginterferon alfa-2a with or
without lamivudine versus no patients receiving lamivudine. (P. Marcellin et al. J Hepatol 2004;39:95)
Combination
therapy with peginterferon
alfa-2b plus
lamivudine suppresses HBV replication. M. van Zonneveld
and colleagues analyzed viral decline in HBeAg-positive
CHB patients (n=36) who completed 24 weeks of peginterferon
alfa-2b alone or combined with lamivudine. Overall, combination
therapy with peginterferon alfa-2b and lamivudine was more effective in
suppressing HBV replication than peginterferon alfa-2b alone. Loss
of serum HBeAg was achieved in 7 patients (39%) in the combination
therapy group and 8 patients (44%) in the monotherapy group. A
significantly more rapid HBV DNA decline was seen with combination therapy
versus monotherapy. The initial decline in HBV DNA was
indicative of loss of serum HBeAg
only for patients treated with combination therapy. (M. van Zonneveld et al. J Hepatol 2004;39:446)
Peginterferon alfa-2b improves liver
histology. M. van
Zonneveld and colleagues
reported a double-blind, randomized, multicenter 52-week
study of the effects on liver histology of peginterferon alfa-2b 100
µg/week in combination with either lamivudine 100 mg/day
or placebo in 266 HBeAg-positive CHB
patients. Paired and evaluable biopsies were available for 110
patients. Necroinflammatory scores improved in both groups; 25
patients (48%) in the combination group and 31 patients (53%) in
the peginterferon monotherapy group showed an improved
inflammatory score. Inflammation score improved
in 65% of responders (n=48; HBeAg-negative at the end
of follow-up) compared to 38% of nonresponders. However, no
significant reduction of fibrosis was found in either treatment
group. (M. van Zonneveld
et al. J Hepatol 2004;39:447)
A new model for describing the dynamics of HBV DNA response. P. Colombatto and colleagues developed a new bio-mathematical model for
describing HBV viral dynamics and computing numbers of infected hepatocytes in
a sub-study of a peginterferon alfa-2a phase III trial. Patients received 48 weeks of either lamivudine (Group A; n=25), peginterferon
alfa-2a 180 µg/week plus lamivudine (Group B; n=23) or peginterferon
alfa-2a 180 µg/week plus
placebo (Group C; n=24).
HBV dynamics with peginterferon alfa-2a monotherapy were
significantly different from those seen with lamivudine monotherapy, and the
mean final virus production per infected cell was lower in groups A and B
versus C (P<.001). The
data support that peginterferon alfa-2a in combination with lamivudine
may accelerate early-phase HBV DNA decay. (P.Colombatto et al. J Hepatol 2004;39:421)
Clinical studies with oral antiviral
agents in CHB
Entecavir 1.0 mg/day shows superiority to lamivudine
100 mg/day. E.R. Schiff and
colleagues reported that the response to entecavir 1.0 gm/day was
consistently superior to continued lamivudine 100 mg/day across multiple
baseline HBV disease characteristics in a phase II study in lamivudine-refractory
patients. Superiority of entecavir to lamivudine was demonstrated within subgroups defined by baseline
characteristics that included HBeAg status, ALT levels, YMDD mutations, and HBV genotype. Mean reduction in HBV DNA at week
48 was 3.60 to 6.99 log10 copies/mL versus 0.46 to 2.73 log10 copies/mL
in subgroups receiving entecavir and lamivudine, respectively. Safety and tolerability of the two drugs were
comparable. (E.R. Schiff et al. J Hepatol 2004;39:442)
Entecavir resistance does not emerge in lamivudine-refractory
patients. R. Colonno and colleagues reported that
three doses of entevcavir (0.1, 0.5
and 1.0 mg) showed superiority to continued lamivudine in reducing HBV DNA over
48 weeks in a phase II study in lamivudine-refractory patients. There
was no evidence of emergence of resistance despite the presence of
lamivudine-resistant mutations at study entry (132 of 181 treated
patients [87%] had isolates with LI80M and M204V/I mutations). No
apparent correlation was seen between virological response to
entecavir and either lamivudine-resistant or novel HBV mutants. Most
patients with lamivudine-resistant HBV at study entry retained
their resistant genotypes over 48 weeks regardless of the treatment regimen.
A comparison of 108 entecavir and 24 lamivudine paired isolates
showed no significant difference in the number of other substitutions.
(R. Colonno et al. J Hepatol
2004;39:43)
Lamivudine-refractory patients can be safely switched directly to
entecavir. R.G. Gish and colleagues reported a
phase II, double-blind, randomized trial in which 181 lamivudine-refractory patients
(87% with YMDD mutations) were switched
directly to entecavir at one of three doses (0.1, 0.5, 1.0 mg daily) or continued on lamivudine therapy (100 mg
daily). ALT flares occurred
infrequently in patients switching therapy (4 patients; 4%) and were not associated with serious adverse
events suggestive of decompensation.
The ALT flares in 2 cases may have been due to an increased immune
response associated with rapid declines in HBV DNA, and 2 other flares resolved
after occurring late in therapy and were not related to emergence of
resistance. These data support that continuation or overlap of lamivudine is not
necessary when switching a
lamivudine refractory/resistant patient to entecavir 1.0 mg daily. (R.G. Gish et al.J Hepatol 2004;39:428)
Prolonged control of viral replication with lamivudine. P.
Lampertico and colleagues reported the effect of 52
(range, 5 to 84) months of continuous lamivudine treatment (100
mg/day) in 44 consecutive patients with HBeAg-negative cirrhosis.
Twenty-one patients (48%) maintained undetectable serum HBV
DNA and normal ALT levels, whereas 22 patients (52%) developed
lamivudine resistance. The 5-yr cumulative probability of
developing lamivudine resistance was 63%, but only 10% for patients
who had undetectable HBV DNA by PCR. Thus,
prolonged
control of viral replication was seen in about one third of HBeAg-negative cirrhotics. Liver-related complications occurred less frequently in responders
than in lamivudine-resistant cirrhotics
(28% vs 64%). The 5-year patient survival of 74% was similar in responders and
nonresponders. (P. Lampertico et al. J Hepatol
2004;39:44)
Early maximal viral suppression with telbivudine correlates with better clinical efficacy. T. Poynard and colleagues reported a randomized multicenter study
comparing the 1-year efficacy and safety of telbivudine 400 or 600 mg/day
plus and minus lamivudine
100 mg/day versus lamivudine 100 mg/day in 104 adults with HBeAg-positive CHB. A direct, continuous relationship
was observed between the degree of early HBV suppression in the first 6 months of therapy and virologic
and clinical efficacy at
1 year. The relationships were evident even at very low levels of viremia. The
best clinical and
virological responses were seen in patients with the most profound early HBV
suppression. (T. Poynard et al. J Hepatol 2004;39:439)
Adefovir dipivoxil added to on-going lamivudine is safe and
effective. R. Perrillo and
colleagues reported results on the 2-year efficacy and safety
of adefovir (10 mg/day) added to ongoing lamivudine (100 mg/day)
versus lamivudine monotherapy in 78 HBeAg-positive CHB patients with YMDD variant
HBV, compensated liver disease, and reduced response to lamivudine. Statistically
significant HBV DNA and ALT responses were seen in the lamivudine
plus adefovir group compared with the lamivudine plus placebo group at week 104
(74% versus 13% and 49% versus 10%, for HBV DNA and ALT responses, respectively).
Increasing duration of therapy enhanced the magnitude of the reductions.
Resistance surveillance is continuing. (R.
Perrillo et al.
J Hepatol
2004;39:438)
HBsAg seroconversion is achieved in adefovir dipivoxil-treated patients. M.
Shiffman and
colleagues reported the effect of adefovir monotherapy on HBsAg loss and
seroconversion to anti-HBs in a retrospective analysis of patients receiving at
least 4 weeks of adefovir monotherapy in 4 clinical trials conducted from
1999-2000. 9/578 patients (7 HBeAg-positive and 2 HBeAg-negative at baseline)
receiving adefovir monotherapy showed HBsAg seroconversion after a median of
72.6 weeks. The seroconversion was associated with loss of HBV DNA and
normalization of ALT. The median time from loss of HBsAg to appearance of
anti-HBs was 32 weeks (range: 16-88). Surveillance in long-term studies is
continuing. (M. Shiffman et al. J Hepatol 2004;39:45)
IN
VITRO STUDY
Combining entecavir with human immunodeficiency virus (HIV) nucleoside
reverse transcriptase inhibitors shows no antagonism. R. Colonno
and colleagues reported studies with in vitro antiviral assays designed to determine whether the inhibition
of HBV or HIV is
adversely affected when entecavir is combined with HIV-1 nucleoside reverse transcriptase
inhibitors (NRTIs) at
clinically relevant doses. The antiviral activity of entecavir was not changed in the presence of the HIV NRTIs
stavudine, didanosine, abacavir, and zidovudine at concentrations up to 5-fold
the Cmax. Tenofovir and zidovudine also did not reduce the entecavir anti-HBV
activity. Conversely, entecavir concentrations up to 4-fold the Cmax determined
for the 1 mg human dose had no effect on the anti-HIV activity of the six NRTIs. These results imply that co-administration
of entecavir with NRTIs is unlikely to result in
antagonism. (R. Colonno et al. J Hepatol 2004;39:366)
This special issue of HBV Watch is
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