Precore Mutant Chronic Hepatitis B

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MedGenMed Gastroenterology
[B]Precore Mutant Chronic Hepatitis B -- Approach to Management[/B]
Posted 10/01/2003

Stephanos J. Hadziyannis, MD, George V. Papatheodoridis, MD, Dimitrios
Vassilopoulos, MD

Overview and Introduction
Overview
The diagnosis of precore mutant chronic hepatitis B (CHB) can be made with
safety only by sequencing the precore region of the hepatitis B virus (HBV)
genome, a method not widely available. However, in clinical practice,
hepatitis B e antigen (HBeAg)-negative CHB is frequently arbitrarily
referred to as precore mutant CHB, although the 2 terms are not synonymous.
Because no therapeutic trial has specifically addressed the treatment of
precore mutant CHB, all patients with HBeAg-negative CHB are currently
treated in the same way. The aim of therapy in this setting is to induce a
sustained suppression of liver disease activity before cirrhosis or
hepatocellular carcinoma (HCC) develops. This goal may be achieved by
efficient suppression of HBV replication, which represents the main
determinant of underlying liver necroinflammation and fibrosis. Currently
available agents include interferon-alfa, lamivudine, and adefovir
dipivoxil. A 12-month or longer course of interferon-alfa treatment or
re-treatment achieves sustained biochemical responses in 20% to 25% of
patients, with eventual hepatitis B surface antigen (HBsAg) loss and
antibody to HBsAg (anti-HBs) development in a proportion of this population.
Lamivudine induces initial virologic and biochemical responses in 70% to 90%
of patients, but breakthroughs due to lamivudine-resistant mutants
accumulate with continuation of therapy and thus, only one third of patients
may remain in remission after the third year of therapy. Adefovir dipivoxil
also achieves on-therapy responses in the majority of cases. It is effective
against lamivudine-resistant HBV strains and is associated with little, if
any, drug resistance during the first 2 years of therapy -- highlighting its
applicability for long-term treatment of HBeAg-negative CHB. Many other
antiviral agents and immunomodulatory approaches are currently being
evaluated for HBeAg-negative CHB, but, with the exception of
interferon-alfa, none have as yet been shown convincingly to induce
sustained off-therapy responses.

Introduction
Chronic infection with HBV is one of the most common causes of chronic liver
disease worldwide[1] and is associated with high morbidity and
mortality.[2,3] Although the majority of chronic HBV infections may remain
with low viral replication and in biochemical and histologic remission, a
proportion of them exhibit high HBV replication and active histologic
lesions.[3,4] It is estimated that about 15% to 20% of patients with CHB
develop cirrhosis within 5 years[5,6] and only 55% to 85% of patients with
active HBV-related cirrhosis survive 5 years later.[7-9] Moreover, all
patients with chronic HBV infection are at higher risk for HCC when compared
with the general population, but the risk is extremely high when cirrhosis
is present.[10] Thus, it is estimated that over 250,000 patients die
annually from HBV-related liver disease.[1,11]

The first phase of chronic HBV infection is positive for HBeAg and is
characterized by high HBV replication, low aminotransferase levels, and mild
histologic activity. However, during the course of chronic HBV infection,
HBeAg seroconversion and development of the corresponding antibody
(anti-HBe) may occur, an event usually associated with transition from the
phase of high HBV replication to an inactive phase of the infection, with
little residual viral replication and essentially normal liver histology
(the so-called "inactive HBsAg carrier state").[12,13] However, not all
patients who lose HBeAg and seroconvert to anti-HBe antibody go into
sustained remission of HBV replication and liver disease activity. A
variable proportion of the HBeAg-negative and anti-HBe-positive patients,
depending on HBV genotype as well as other factors, retains or redevelops
high serum HBV-DNA levels and persistent or intermittent elevations in
alanine aminotransferase (ALT) activity.[12,13] Such patients harbor
replication-competent HBV variants that are unable to produce HBeAg due to
some mutations either in the precore or the basic core promoter region of
the HBV genome.[14] This form of CHB is also referred to as HBeAg-negative,
or anti-HBe-positive, CHB[12,13]; it represents a potentially severe and
progressive form of liver disease, with frequent development of cirrhosis
and HCC.[15-19]

Because mutations in the precore region of the HBV genome were detected[20]
some years before the detection of the mutations in the basic core promoter
region,[21] HBeAg-negative CHB was initially considered to be identical to
precore mutant CHB. The most common precore mutation is a guanosine (G) to
adenine (A) change at nucleotide 1896 (G1896A), which leads to premature
termination of the translation of the precore region at codon 28, thus
preventing the production of HBeAg.[20] In many cases, a second precore G to
A mutation at nucleotide 1899 is also found, but its significance remains
unknown.[20] HBV variants harboring the 1896 precore stop codon mutation are
mainly responsible for "HBeAg-negative CHB" in the Mediterranean basin and
Far East, and generally in geographical areas where HBV infection is
transmitted vertically or even horizontally in very early life and where the
B and D genotypes of HBV prevail.[13,22] In such areas, HBeAg-negative CHB
is the predominant type of CHB.[13,22]

This review focuses on the practical approach to the management of patients
with HBeAg-negative, precore mutant CHB.

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Diagnosis of Precore Mutant CHB
Confirmation of the presence of precore mutant HBV strains can be reliably
made only by sequencing the precore region of the HBV genome, a method not
widely available. Thus, most frequently, the diagnosis of precore mutant CHB
is made in clinical practice on the basis of established HBeAg-negative CHB,
although the 2 terms, as explained earlier, are not synonymous.
HBeAg-negative CHB is usually associated with precore mutant
HBV,[16,20,22-25] but it may also develop in patients with precore wild-type
HBV strains,[26-28] particularly in infections with HBV genotype A and C,
and be associated with mutations in the basic core promoter (especially with
a double mutation at nucleotides 1762 and 1764).[21,29] Whether these 2
subgroups of HBeAg-negative CHB differ with respect to their clinical
features, natural course, and response to therapy is not known at present.
However, the identification of precore mutations alone is of no clinical
value, because both inactive HBsAg carriers and patients with active
HBeAg-negative infection may carry precore mutant strains[19,24,25,30];
therefore, the differentiation between these 2 phases of chronic HBV
infection is much more crucial than just the detection of precore mutations.

The serologic profile of patients with HBeAg-negative chronic HBV infection
includes (1) positive serum HBsAg for at least 6 months, to establish
chronic HBV infection; and (2) negative serum HBeAg and usually positive
anti-HBe antibody for at least 6, or preferably 12, months, to exclude
patients who are still in the unstable phase of HBeAg seroconversion and
thus who may revert to the HBeAg-positive CHB phase.[31] In such patients,
the diagnosis of HBeAg-negative CHB can be made when the following criteria
are fulfilled (Table):

Increased serum ALT level (ie, ALT levels > 2 x upper limit of normal [ULN]
on 1 occasion, or ALT > 1.5 x ULN on at least 2 monthly determinations), as
a biochemical marker of ongoing hepatocellular damage;

Detectable serum HBV DNA levels, to establish active HBV replication and,
presumably, HBV-induced hepatocellular damage;

Exclusion of other concomitant or superimposed causes of liver disease; and

Moderate-to-severe necroinflammation on liver histology, compatible with
CHB.[32,33]


Common non-HBV causes of liver damage in this setting include
superinfections with other hepatitis viruses (D or C), alcohol abuse,
hepatotoxic drug use, or more rare liver diseases (autoimmune, metabolic,
etc.). Moreover, increased ALT levels may be due to just fatty liver or
steatohepatitis, or due to severe conditions that complicate chronic HBV
infection, such as HCC.

The majority of patients with HBeAg-negative CHB fulfill all of the above
criteria and therefore can be safely differentiated from individuals in the
inactive chronic HBsAg carrier state, who have an identical serologic
profile.[32] However, not all patients with HBeAg-negative CHB fulfill all
of the above diagnostic criteria because the pattern of virologic and
biochemical activity may be intermittent instead of continuous, and the
intervening periods of biochemical and virologic remission may be quite
long-lasting (Figure). In studies with frequent assessments of ALT and serum
HBV DNA levels, major fluctuations in viremia and serum aminotransferase
levels were observed in more than 40% of cases.[34] According to our data,
20% to 30% of patients with histologically documented HBeAg-negative CHB
first presented with normal ALT levels and low HBV DNA levels (below the
cut-off value of 105 -- and even 104 -- copies/mL), and were thus initially
misclassified as inactive HBsAg carriers.[35] These findings demonstrate
that the diagnosis of HBeAg-negative CHB and its differential diagnosis from
the inactive state of chronic HBV infection cannot be reliably made on the
basis of cross-sectional (single time-point) determinations, and that
therefore, lengthy follow-up assessments of several months' duration may be
required in many patients.[32,34]

Figure. (click image to zoom) Patterns of ALT activity in patients with
HBeAg-negative chronic HBV infection. Pattern A: Persistently increased ALT
activity; Pattern B: ALT flares without ALT normalization in the intervening
period; Pattern C: ALT flares with intervening long periods of normal ALT
activity; Pattern D: Persistently normal ALT activity. Patterns A-C
represent patients with HBeAg-negative CHB; pattern D represents inactive
chronic HBsAg carriers.



Because both the high cost and the lack of an accurate established cut-off
level preclude very frequent estimations of serum HBV DNA levels, sequential
ALT/aspartate aminotransferase (AST) determinations remain, in clinical
practice, the basis for a reliable differentiation between HBeAg-negative
CHB and the inactive HBsAg carrier state of chronic HBV infection.[32]
ALT/AST determinations are also useful in the follow-up of clear-cut
asymptomatic HBsAg carriers, as a percentage of these patients may
eventually develop HBV reactivation and thus progress to the HBeAg-negative
CHB phase[16,22,36] (Figure).

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Management of Precore Mutant CHB All patients with precore mutant CHB are candidates for therapy; however, no therapeutic trial conducted in patients with HBeAg-negative and/or anti-HBe-positive CHB has ever applied the detection of a precore stop codon mutation as an entry criterion. Therefore, the management of HBeAg-negative CHB will be reviewed here, keeping in mind that this form of CHB is presumed to be related to precore mutant HBV, which is not always the case.[26-29] Goals/Endpoints of Treatment It is now becoming clear that complete viral eradication cannot be a realistic therapeutic endpoint, either in HBeAg-positive or HBeAg-negative CHB. Sensitive virologic assays have documented that residual amounts of replicating HBV are detectable in many patients with a sustained virologic and biochemical response, even in those who lose HBsAg and develop its antibody (anti-HBs).[37] Thus, sustained seroconversion of HBeAg to anti-HBe or sustained biochemical and virologic remission are considered to be the most realistic therapeutic goals in HBeAg-positive and HBeAg-negative CHB, respectively.[32,33] In fact, in the subset of patients with HBeAg-positive CHB, HBeAg loss and seroconversion to anti-HBe is usually associated with a decrease in serum HBV-DNA levels to nondetectability by the branched DNA (bDNA) assay (<\= 0.7x106 viral equivalents/mL), biochemical remission, and improved long-term outcome.[37,38] Moreover, for the subset of HBeAg-negative CHB, we have recently shown that a sustained biochemical remission after therapy with interferon-alfa, usually accompanied with low residual viremia levels, is associated with reduced risk of development of liver decompensation and/or HCC and with improved survival.[39] Therefore, induction of sustained normalization of liver enzymes irrespective of the presence of low viremia levels should probably be the main therapeutic goal in this setting.

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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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Whether there is a difference in the sensitivity or resistance to lamivudine
therapy between HBeAg-negative CHB patients with and without precore mutant
HBV strains is currently unclear.[32] Precore mutant strains have been found
to be replaced by precore wild-type strains when YMDD mutants are selected
under lamivudine therapy.[58,59] Such observations might suggest that
precore wild-type HBV compared with mutant HBV strains are more resistant to
lamivudine and therefore "escape" during therapy. However, this hypothesis
does not seem to be valid, because reappearance of precore mutant strains
after their initial replacement, as well as reversion of precore wild-type
strains to mutant strains, have also been reported.[59,60] Thus, no clear
relationship between the presence of precore or even core promoter mutant
strains and the efficacy of lamivudine therapy can be supported.[32]

Finally, it is noteworthy to point out that when precore HBV mutant strains
of genotype D become YMDD-resistant, their replicative efficacy increases,
whereas the contrary appears to be true for YMDD mutants with a wild-type
precore region.[61] This observation may explain the frequent occurrence of
severe virologic and biochemical breakthroughs in patients with
HBeAg-negative CHB under lamivudine treatment that have been reported in
studies from Greece, where there is a 95% predominance of HBV genotype
D.[55,56,62]

Because lamivudine is a safe drug[33,54-56] with a safety profile similar to
placebo,[54] specific follow-up for prompt detection of possible adverse
events has not been decided. In many clinical trials,[54-56]
lamivudine-treated patients were followed up with amylase, creatine
phosphokinase, and lactate dehydrogenase determinations at least every 3
months (in order to monitor potential pancreatic reactions and mitochondrial
toxicity) without any evidence of toxicity. The most disturbing event seen
on lamivudine therapy is the occurrence of exacerbations of hepatitis, as
expressed by significant elevations in ALT/AST levels.[33] Such
exacerbations may develop during therapy due to emergence of
lamivudine-resistant HBV strains[55,56] or after discontinuation of
lamivudine therapy due to relapse of wild-type HBV.[33] When hepatitis
exacerbations occur in patients with advanced liver disease, they may be
associated with development of hepatic decompensation.[33] Thus,
lamivudine-treated patients should be closely monitored (at least every 3
months) with ALT/AST determinations during therapy and for at least 1 year
after discontinuation of therapy. Monitoring patients on lamivudine with
frequent serum HBV-DNA determinations by sensitive PCR assays is useful,
because it permits early recognition of virologic and subsequent biochemical
breakthroughs.[56] However, the cost-benefit of such a monitoring approach
has not been clarified as yet.

Adefovir dipivoxil. Adefovir, a nucleotide analogue of adenosine, is a new
anti-HBV agent that is administered orally as adefovir dipivoxil. The
prodrug, adefovir dipivoxil, is adefovir esterified with 2 pivalic acid
molecules and has good oral availability.[63] The "48-week results" from 2
large phase 3, randomized, placebo-controlled, clinical trials of adefovir
dipivoxil therapy in patients with HBeAg-positive and -negative CHB were
published recently.[64,65] In both trials, the 10-mg adefovir dipivoxil
daily dose was found to be very well tolerated and to have a safety profile
similar to placebo,[64,65] whereas a higher daily dose of 30 mg was found to
be associated with an increased risk of renal damage without a significant
benefit in efficacy.[64] Thus, the recommended dose of adefovir dipivoxil
for CHB is 10 mg daily, irrespective of HBeAg status. Adefovir dipivoxil can
be safely administered at the daily dose of 10 mg in patients with hepatic
or mild renal impairment, but dosing interval adjustments are recommended
for patients with creatinine clearance of < 50 mL/min and patients requiring
hemodialysis.[66]

In the HBeAg-negative CHB setting, adefovir dipivoxil was found to
effectively suppress biochemical activity and HBV replication during the
first 48 weeks of therapy.[65] Most specifically, ALT levels normalized in
72% and 29% (P < .001), and serum HBV-DNA was undetectable by PCR in 51% and
0%, of the 123 adefovir dipivoxil- and the 61 placebo-treated patients,
respectively (P < .001). Median serum HBV-DNA levels dropped at 48 weeks
compared with baseline by 3.9 log10 copies/mL in the adefovir dipivoxil
group and by 1.35 log10 copies/mL in the placebo group (P < .001) .
Moreover, at 48 weeks, histologic improvement was observed in 64% of
adefovir dipivoxil-treated and in 33% of placebo-treated patients (P <
.001).[65]

Whether a defined course of adefovir dipivoxil may achieve SR maintained
after drug discontinuation in a sizeable proportion of patients with
HBeAg-negative CHB is currently not known. However, the majority of
on-therapy responders are expected to relapse soon after discontinuation of
a 48-week course of adefovir dipivoxil therapy, and therefore, long-term
adefovir dipivoxil treatment will likely be needed to maintain on-therapy
responses. Data on the efficacy of long-term adefovir dipivoxil therapy are
available from a single phase 2 extension study including 39 patients with
HBeAg-positive (n = 28) and HBeAg-negative (n = 11) CHB,[67] and from the
second year of the study by Hadziyannis and colleagues.[68] Two-year
adefovir dipivoxil therapy was found to maintain on-therapy biochemical and
virologic remission activity in both patients with HBeAg-positive
and -negative CHB without significant toxicity and without evidence of
significant viral resistance (< 2%),[67,68] likely signaling the start of a
new era in the treatment of CHB. Studies with long-term adefovir dipivoxil
therapy are under way. However, similar to lamivudine therapy, the optimal
duration of adefovir dipivoxil therapy in patients with HBeAg-negative CHB
is currently unknown.

Adefovir dipivoxil given at the recommended dose of 10 mg daily is a safe
drug with a safety profile similar to placebo.[64,65] However, careful
monitoring is required during its use in clinical practice. Renal toxicity
appears to be a potential hazard, at least in patients taking more than 10
mg daily, or in those with impaired renal function,[64] and therefore
patients treated with adefovir dipivoxil should be closely monitored with
frequent determinations of serum creatinine and phosphorus levels. Moreover,
patients should be monitored with ALT/AST determinations, while surveillance
for viral resistance should continue -- particularly with long-term use of
the drug.

B. Re-treatment of HBeAg-negative CHB:

Patients with HBeAg-negative CHB who fail to achieve SR after 1 course of
interferon-alfa therapy may be re-treated with a second interferon-alfa
course, with lamivudine, or with adefovir dipivoxil. Re-treatment with
interferon-alfa has been shown to have the same efficacy as that of
interferon-alfa therapy in treatment-naive patients.[44] The on-drug or
on-treatment efficacy of lamivudine or adefovir dipivoxil does not differ
between treatment-naive and previously interferon-alfa-treated patients with
HBeAg-negative CHB, but the rate of SR is negligible.

Patients who do not initially respond to lamivudine may be treated with
interferon-alfa or adefovir dipivoxil or referred for treatment in clinical
trials with other antiviral agents. Patients who relapse after
discontinuation of lamivudine without having developed YMDD mutants may be
re-treated with lamivudine[69] or even with a course of interferon-alfa or
adefovir dipivoxil. In contrast, lamivudine re-treatment is ineffective in
patients who have developed YMDD mutant HBV strains during a previous course
of lamivudine therapy because rapid reemergence of the lamivudine-resistant
strains will inevitably occur.[70]

C. Treatment of HBeAg-negative CHB with resistance to lamivudine:

Although adefovir dipivoxil is the only approved agent for the treatment of
patients who have developed resistance to lamivudine, entecavir is a
potential candidate in this setting.[40,71] Moreover, interferon-alfa given
as monotherapy or in combination with lamivudine may be used against
lamivudine-resistant HBV mutant strains.[40] However, the efficacy of
interferon-alfa has not yet been evaluated in any well-designed study in
this setting, therefore no conclusion can de drawn.

In recent clinical trials, the addition of adefovir dipivoxil was shown to
achieve significant reduction in serum HBV-DNA levels and improvement in
liver function tests and Child-Pugh score in patients with decompensated
cirrhosis or in post-liver transplant patients with resistance to
lamivudine, irrespective of HBeAg status.[72-75] Adefovir dipivoxil was also
found to have similar antiviral efficacy against all types of
lamivudine-resistant YMDD mutant HBV strains.[76] Moreover, in a small
randomized study including patients with HBeAg-positive CHB and lamivudine
resistance, adefovir dipivoxil monotherapy was reported to demonstrate
similar efficacy as the combination of adefovir dipivoxil and
lamivudine.[77]

Entecavir, a carboxylic analogue of guanosine, has potent and selective
inhibitory activity against all HBV polymerase functions.[78] Entecavir has
demonstrated efficacy against lamivudine-resistant YMDD mutant HBV
strains.[79] In a recent large randomized clinical trial of entecavir
treatment, at 24 weeks serum HBV-DNA levels were undetectable by the bDNA
assay in approximately 50% to 75% of patients given 0.5 or 1.0 mg entecavir
daily. The median serum HBV-DNA log10 drop at 24 weeks was 3.9 and 4.4 for
the 0.5- and 1.0-mg entecavir doses respectively, whereas a biochemical
response was observed in approximately 60% of patients at 24 weeks.[80]

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New Drugs -- Combination Therapies and Concluding Remarks
The development of lamivudine (and recently adefovir dipivoxil) has offered
the hepatologist new therapeutic options against HBV infection besides
interferon-alfa. Several newer antiviral agents, mainly nucleoside
analogues, immunomodulatory agents, or combinations thereof, are currently
undergoing evaluation for the treatment of CHB. Newer antiviral agents, such
as emtricitabine (the 5-fluorinated derivative of lamivudine), clevudine (a
pyrimidine analogue), and L-nucleosides (natural nucleosides in
beta-L-configuration), particularly L-deoxythymidine, have yielded promising
results in preliminary phase 1/2 trials. In contrast, initial data regarding
the efficacy of immunomodulatory approaches, such as interleukin-2 or -12,
interferon-gamma, or vaccine-based therapies, have been relatively
disappointing.[40]

Besides interferon-alfa therapy, which may achieve SRs in a small proportion
(15% to 25%) of HBeAg-negative CHB patients,[32] monotherapy with
nucleoside/nucleotide analogues is unlikely to result in clearance of HBV
from infected hepatocytes and thus SR, despite a strong initial antiviral
effect.[71] Therefore, the use of combinations of therapeutic agents seems
to be the next reasonable step in the treatment of such difficult-to-manage
patients.[81] However, the efficacy of such regimens cannot be easily
extrapolated from in vitro or small preliminary clinical studies and must be
documented in well-designed clinical trials. Combination regimens involving
lamivudine with pegylated interferon-alfa or immunomodulatory agents,
including a therapeutic vaccine, are currently undergoing evaluation in
phase 3 clinical trials.

Thus, the development of more effective combination antiviral regimens
appears to be a challenging task. Ideally, drugs with complementary
mechanisms of antiviral activity should be used concurrently and/or
sequentially, and drug resistance should be avoided. It should be kept in
mind, however, that patients with CHB do not represent a homogeneous
population for global evaluation of new antiviral therapies; response rates
may differ between patients with HBeAg-positive and HBeAg-negative CHB, or
between treatment-naive patients and those who have failed to respond to
different antiviral agents in the past. Therefore, the new therapeutic
approach may need to tailor treatment to different patient characteristics.