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发表于 2003-10-7 00:14
Definitions of Response to Treatment
In both HBeAg-positive and -negative CHB, virologic and biochemical
responses (VRs; BRs) may be evaluated during therapy (on-therapy responses)
or after discontinuation of therapy (off-therapy or sustained responses
[SR]).[33,40] Specifically, on-therapy responses may be subdivided into
initial (achieved at any time within the first 12 months of therapy),
maintained (persisting throughout the course of therapy), and end-of-therapy
(EOT; evaluated at the end of a course of therapy with defined duration)
responses.[40] Currently, VRs are preferably evaluated by qualitative
polymerase chain reaction (PCR) assays and are arbitrarily considered to be
achieved when serum HBV-DNA levels fall below 100,000 copies/mL.[12,33]
However, an effective HBV suppression is probably achieved when serum
HBV-DNA levels drop below 400 or even 200 copies/mL, which represents the
cut-off levels of most in-house real-time PCR assays.[41,42] When VR and BR
are maintained for several months, histologic improvement can also be
demonstrated, usually defined as a reduction in the necroinflammatory
(histology activity index [HAI]/Knodell) score by >/= 2 points without
worsening in fibrosis.[12,33] Because on-therapy responses in patients with
HBeAg-negative CHB are not usually durable after termination of treatment,
the efficacy of any drug or combination of drugs should be evaluated both at
the end of the therapeutic course and 12 or more months after the end of
therapy.[32,33]
Indications for Treatment
Ideally, all patients with HBeAg-negative CHB should be treated. Untreated
HBeAg-negative CHB follows an indolent, progressive course frequently
terminating in cirrhosis, portal hypertension, and liver decompensation.[43]
However, patients with minimal or mild histologic liver disease, and usually
minimal increases in ALT level, run a very slowly progressive course or do
not worsen at all -- thus they never reach the cirrhotic stage. In view of
the frequent interferon-alfa-related side effects and the need for very
long-term maintenance therapy with nucleoside/nucleotide analogues, which
often results in viral resistance and relapse of CHB (particularly in the
setting of lamivudine therapy), it is reasonable not to recommend initiation
of therapy in such mild cases, at least for the time being. However,
frequent follow-up is mandatory, and treatment can be administered if there
is deterioration in the biochemical and liver disease profile.
Treatment Strategies
A. Primary treatment of HBeAg-negative CHB:
Currently, there are 3 drugs that are approved for the treatment of both
HBeAg-positive and HBeAg-negative CHB: interferon-alfa, lamivudine, and
adefovir dipivoxil (recently approved for the treatment of CHB both in the
United States and Europe).[40]
Interferon-alfa. Interferon-alfa, an agent with both antiviral and
immunomodulatory activity, was the only available therapeutic option for CHB
until a few years ago. Despite so many years of interferon-alfa
availability, no large randomized, controlled trial has ever been conducted
with this agent in HBeAg-negative CHB. In several relatively small
controlled or uncontrolled studies, interferon-alfa therapy of up to 6
months' duration was found to be associated with high (60% to 90%) EOT
biochemical and virologic response (evaluated by insensitive hybridization
assays) rates but low SR rates due to frequent relapses after termination of
therapy.[40] Longer courses of interferon-alfa therapy were reported to
improve SR rates, reaching 20% to 25%. In a large cohort of 216
treatment-naive patients recently reported on by Manesis and
Hadziyannis,[44] the SR was approximately 11% after 6 months and 22% after
12 months of interferon-alfa therapy; it was not affected by the
interferon-alfa dose (3 or 5 million units [MU]). In a previous small study,
a 24-month course of interferon-alfa given at a dose of 6 MU thrice weekly
was found to achieve biochemical and virologic (by a dot-blot assay) SR in
38% of 21 treated patients compared with 10% of 21 untreated controls.[45]
In a larger study conducted by the same group, the same 24-month course of
interferon-alfa achieved a SR in 30% of 101 patients.[46] Taken together,
these findings indicate that at least 12 months of interferon-alfa given at
a dose of 3-6 MU thrice weekly appears to be the most appropriate
interferon-alfa regimen for patients with HBeAg-negative CHB.[33,40]
All patients treated with interferon-alfa should be followed closely for at
least 2 years after discontinuation of therapy. Only half of relapses occur
within the first 6 months, whereas more than 20% may occur between the 12th
and 24th month after discontinuation of interferon-alfa.[47] Relapses may
sometimes be associated with quite severe, usually transient hepatitis
flares, with ALT levels exceeding those associated with acute hepatitis and
occasionally with even development of liver decompensation.[48,49]
Interferon-alfa therapy is costly, and is associated with several side
effects.[50] Its most common side effects include flu-like symptoms,
fatigue, bone marrow suppression, irritability, and depression.[50] Because
behavioral disturbances and particularly depression as well as bone marrow
suppression (expressed as anemia, neutropenia, and/or thrombocytopenia) may
be potentially severe, interferon-alfa-treated patients should be closely
monitored with monthly clinical examinations, with specific emphasis on
behavior and psychiatric symptoms and monthly full blood counts.[33]
Moreover, patients should be followed-up with regular ALT/AST determinations
in order to monitor the response to therapy. Interferon-alfa therapy is
contraindicated in certain subgroups of patients with HBV-related chronic
liver disease. The most frequent contraindications include decompensated
cirrhosis, anemia (usually hemoglobin < 13 g/dL for men and < 12 g/dL for
women), neutropenia (neutrophils < 1.5 x 109/L), thrombocytopenia (platelets
< 80 x 109/L), major psychiatric diseases (mainly depression), thyroid
diseases, autoimmune diseases, and organ transplantation.[43] Most of the
contraindications are linked to the side effects and the immunologic
activities of interferon-alfa.
The efficacy, safety, and tolerability of the more potent pegylated forms of
interferon-alfa in HBeAg-negative CHB are currently undergoing evaluation in
clinical trials.
Although there are no trials using the detection of a precore mutation as an
inclusion criterion, the effect of the presence of precore mutant or
wild-type HBV strains on the probability of response to interferon-alfa
therapy has been retrospectively evaluated in a few small studies, without
conclusive results. Precore stop-codon mutant strains compared with
wild-type or mixed HBV strains have been associated with worse or similar
response rates, irrespective of HBeAg status,[26,51] and with better
response rates in HBeAg-positive CHB patients.[52] Consequently, the
presence of precore mutant HBV strains has not been definitively associated
with increased or decreased probability of response to interferon-alfa
therapy; the role of additional mutations in the core or core promoter
region has not been studied.[53]
Lamivudine. Lamivudine was introduced in the treatment of chronic HBV
infection in the late 1990s, and has been widely applied in almost any
subset of chronic HBV-related liver disease because of its potent inhibition
of HBV replication, ease of oral administration, rather low associated cost,
and excellent safety and tolerance profile. Moreover, lamivudine offered a
therapeutic option for subgroups of patients with CHB with high risk of side
effects or contraindications to interferon-alfa therapy.
In the HBeAg-negative CHB setting, a 12-month course of lamivudine
administered as a daily dose of 100-150 mg has been shown to achieve
on-therapy BR and VR, even by sensitive PCR assays, in the vast majority
(70% to 90%) of patients, as well as EOT responses in about two thirds of
cases.[54-56] Unfortunately, SRs are rare and both biochemical and virologic
relapses are observed in most patients after discontinuation of a 12-month
lamivudine course.[57]
Long-term lamivudine therapy may be an acceptable alternative therapeutic
option given as maintenance therapy in patients with histologically advanced
CHB. However, only one third of patients with HBeAg-negative CHB may have
long-term benefit from such an approach, because viral resistance due to
YMDD mutations develop in approximately two thirds of patients within 3
years of such long-term lamivudine monotherapy.[56] Such virologic
breakthroughs are almost invariably followed by increasing viremia levels
culminating in biochemical breakthroughs, which ultimately have an adverse
effect on liver histology.[56] The optimal duration of lamivudine therapy
has not been defined and most patients are currently kept on lamivudine for
at least 3-5 years. Moreover, the course of HBeAg-negative CHB after
discontinuation of lamivudine in patients who have remained in very
prolonged complete on-therapy remission is currently unknown. Virologic and
biochemical relapses have occurred in the majority of a series of Greek
patients after discontinuation of a 3-year course of effective lamivudine
therapy (SJ Hadziyannis 2003, unpublished data.
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