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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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APRIL 2005
REVIEW: PEGINTERFERON THERAPY FOR
CHRONIC HEPATITIS B
Interferon has
been a treatment option for chronic hepatitis B since the early 1990s, and
several large trials have now shown improved results using peginterferon. Several lines of evidence suggest that
induction of host immune responses, which can be achieved with immunomodulatory
therapy such as interferon, is important for achieving sustained response to
antiviral therapy for chronic HBV infection.
Sustained response, with clearance of HBeAg and HBV DNA, to standard
interferon has been reported to occur in 20% to 35% of patients with chronic
hepatitis B. There have been several recent reports on the treatment of chronic
HBV infection, including patients with HBeAg-positive and HBeAg-negative
disease, using peginterferon alfa-2a and alfa-2b, either alone or in
combination with lamivudine. Two of the
studies of peginterferon alfa-2b are reported in detail below. Summarized here
are the results from 3 studies of peginterferon alfa-2a in patients with
chronic hepatitis B. ♦ A phase II study showed that peginterferon alfa-2a
yielded superior outcomes to standard interferon in patients with HBeAg-positive
chronic hepatitis B (28% vs 19% achieved a complete response, with loss of
HBeAg, reduction of HBV DNA <500,000 copies/mL, and normalization of ALT). (Cooksley WG. J Viral Hepat. 2003;10:298–305) ♦ Subsequently, a
multinational study was conducted in which 814 patients with HBeAg-positive
chronic hepatitis B were randomized to receive peginterferon alfa-2a (180
μg once weekly) plus lamivudine (100 mg
daily), peginterferon alfa-2a plus placebo, or
lamivudine alone for 48 weeks (results published in abstract form). (Lau G. Hepatology. 2004;40:171A) On follow-up at
24 weeks after completion of therapy,
greater percentages of patients treated with combination therapy and peginterferon alfa-2a
alone, as compared with lamivudine alone, achieved HBeAg seroconversion (27%,
32%, and 19%, respectively), serum HBV DNA levels <100,000 copies/mL (34%,
32%, and 22%, respectively), serum HBeAg loss (28%, 34%, and 21%,
respectively), and normalization of serum ALT (39%, 41%, and 28%,
respectively). It was disappointing that
the addition of lamivudine to peginterferon alfa-2a did not improve response
rates over those achieved with peginterferon alfa-2a
alone. ♦ Peginterferon alfa-2a has also been studied in
patients with HBeAg-negative chronic hepatitis B. In a recent large, multicenter study
comparing peginterferon alfa-2a, peginterferon alfa-2a
plus lamivudine, and lamivudine alone for 48 weeks, the respective
percentages of patients with sustained HBV DNA levels <20,000 copies/mL
after 24 weeks of follow-up were 43%,
44%, and 29%. (Marcellin P. N Engl J Med. 2004;351:1206–1217) Rates of sustained suppression of HBV DNA
<400 copies/mL were 19%, 20%, and 7%, respectively, in the 3 treatment
groups. There was a low frequency of depression (3% and 4%) with use of peginterferon alfa-2a in
this study. Thus, pivotal trials of both peginterferon alfa-2a
and alfa-2b in patients with HBeAg-positive and HBeAg-negative chronic
hepatitis B show good efficacy with reasonable tolerability. In all of these
trials, the addition of lamivudine to peginterferon did not result in higher rates
of sustained response.
COMBINATION PEGINTERFERON ALFA-2b AND
LAMIVUDINE THERAPY
Staggered regimen of peginterferon
alfa-2b and lamivudine in patients with HBeAg-positive chronic hepatitis
B. Henry Chan and others evaluated
whether the combination of peginterferon alfa-2b and lamivudine improves the
virologic response rate more than lamivudine monotherapy in patients with
HBeAg-positive chronic hepatitis B and moderately elevated serum ALT
levels. In a single-center, open-label
study, 100 patients were randomized to receive either peginterferon alfa-2b
(1.5 μg/kg weekly by subcutaneous injection) for 32 weeks plus lamivudine (100 mg daily by
oral administration) for 52 weeks or lamivudine monotherapy for 52 weeks. In the combination-therapy arm,
peginterferon alfa-2b was started 8 weeks before lamivudine was
initiated. Patients who received
combination therapy had a greater median decrease in serum HBV DNA (3.91 log10
copies/mL vs 2.83 log10 copies/mL) and a higher rate of
sustained virologic response, defined as HBeAg seroconversion and HBV DNA
<500,000 copies/mL (36% vs 14%; P =
0.011) than patients who were given lamivudine alone. Lamivudine-resistant mutants also developed
less frequently in the combination-therapy
group (21% vs 40%). No differences in
the rates of ALT normalization or histologic improvement were observed between the treatment groups. The occurrence of influenza-like symptoms,
alopecia, and local erythematous reactions was more frequent in the
combination-therapy group. These data indicate that combination peginterferon
alfa-2b and lamivudine may be associated with greater antiviral efficacy than
lamivudine monotherapy. (Chan HL, et al.
Ann Intern Med 2005;142:240–250)
Peginterferon alfa-2b alone or with
lamivudine in patients with HBeAg-positive chronic hepatitis B. Harry Janssen and coworkers conducted a multicenter study in
which 307 HBeAg-positive patients were randomized to receive peginterferon
alfa-2b (100 μg/week) plus lamivudine (100 mg/day) or peginterferon
alfa-2b plus placebo for 52 weeks to investigate whether the combination of an
immunomodulatory and an antiviral agent would increase the rate of sustained
response. At the end of treatment (week 52), serum HBeAg became
undetectable and serum HBV DNA was suppressed to <200,000 copies/mL in
greater percentages of combination-treated patients than monotherapy-treated
patients (44% vs 29%, P = 0.01, and 74%
vs 29%, P < 0.0001, respectively).
However, at the end of the 26-week follow-up period, these differences were not
sustained, and similar percentages of patients in the combination-therapy and the
peginterferon alfa-2b monotherapy groups had undetectable serum levels of HBeAg
(36% vs 35%) and suppression of serum levels of HBV DNA (32% vs 27%). HBeAg loss was found to vary by HBV genotype: 47% for
genotype A patients, 44% for genotype B patients, 28% for genotype C patients,
and 25% for genotype D patients (P =
0.01). These findings demonstrated that
peginterferon alfa-2b was an effective treatment for patients with
HBeAg-positive chronic hepatitis B and that the addition of lamivudine did not
enhance efficacy over that achieved with peginterferon alfa-2b alone. In
addition, HBV genotype was a predictor of response to interferon-based therapy.
(Janssen HL, et al. Lancet
2005;365:123–129)
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