Review
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CONTENTS
HBV: summary of
viral characteristics
Chronic hepatitis B
treatment: view of
current drugs
Combination treatment
with analogues
Characteristics of patients
under treatment, predictive
factors of response &
monitoring of treatment
Five-year view
Expert commentary
Acknowledgments
Key issues
References
Affiliations
† 3200 bp in length. The virus has an envelope
Author for correspondence
Second University Naples, Internal
Medicine and Hepatology C/O
Ospedale Gesù e Maria,
Via Cotugno, 1 80135 Napoli,
Italy
Tel.: +39 081 566 6274
Fax: +39 081 566 6230
rosa.zampino@unina2.it
KEYWORDS:
adefovir, entecavir, hepatitis B
treatment, interferon, lamivudine
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reprints@future-drugs.com
Treatment of chronic hepatitis B:
efficacy of current drugs and
prospects for the future
Rosa Zampino†, Aldo Marrone, Luigi Elio Adinolfi and
Giuseppe Ruggiero
Chronic hepatitis B is an important clinical problem often leading to severe complications.
In this review, the results obtained in the last few years with the use of current drugs, such as
interferon and nucleo(t)side analogues, are summarized and the problems of obtaining a
sustained remission, which is only achieved in a small number of patients, are discussed.
The new approaches, such as the use of combinations of drugs, to optimize long-term
tolerable treatment are also considered.
Expert Rev. Clin. Immunol. 2(6), 915–929 (2006)
Hepatitis B virus (HBV) infection is a world- for the X protein that functions as a transactivat-
wide health problem, with more than ing protein, but its complete range of functions
350 million people with a chronic infection. is not yet clear [4]. During replication, the HBV
Chronic HBV infection represents an impor- genome translocates to the nucleus and is con-
tant risk for developing more serious stages of verted into a covalently closed-circular DNA
liver disease. It progresses to cirrhosis in up to (cccDNA), an intermediate of HBV replication
25% of cases in endemic areas and to hepato- that serves as template for viral transcript syn-
cellular carcinoma (HCC) in 5–10% of cases thesis and also represents a pool of HBV DNA
[1–3]. Furthermore, approximately 1 million hidden in the hepatocytes.
people die every year from complications of A total of eight HBV genotypes (A–H) are
chronic hepatitis B. known each of which has a different geographic
Effective antiviral treatment should be distribution:
administered to interrupt the progression of • Genotype A – North America and Northern
liver disease and the development of its com- Europe
plications before the onset of irreversible
• Genotype B and C – The Far East
liver damage.
• Genotype D – the Mediterranean area
HBV: summary of viral characteristics • Genotype E – Africa
HBV is a hepadnavirus; its genome is partially • Genotype F – Central and South America
double-stranded circular DNA of approximately and Alaska
• Genotype G – France, Germany and USA
that incorporates the hepatitis B surface antigen
(Ag) (HBsAg), inside there is a nucleocapsid • Genotype H – Central and South America
core in containing DNA. HBV encodes its pro- These HBV genotypes show diverse viru-
teins from partially overlapping open reading lence, mutation prevalence and response to
frames (ORFs): the preS/S ORF for the enve- treatment [5].
lope glycoproteins, the precore/core ORF for One of the first HBV mutations to be identi-
the precore protein, from which the HB soluble fied was the precore stop-codon mutation
e antigen (HBeAg) is derived, and the core pro- (G1896A), which prevents HBeAg synthesis, as
tein, the polymerase region (POL) ORF for the a result of the presence of a premature termina-
polymerase and, finally, the ORF that encodes tion codon [6]. On the basis of the presence or
10.1586/1744666X.2.6.915 © 2006 Future Drugs Ltd ISSN 1744-666X 915
Zampino, Marrone, Adinolfi & Ruggiero
absence of HBeAg in serum, patients are defined as HBeAg-posi-
tive or -negative. These two patient populations differ for the
HBV-DNA levels, number of hepatic flares, progression of
chronic hepatitis and response to treatment.
The prevention of HBeAg synthesis can also be related to muta-
tions in the core promoter region (A1762T/G1764A), which
plays a central role in HBV replication [7]. Mutations in various
positions of the core promoter and precore regions have been
largely associated with the natural course of chronic hepatitis, the
HBeAg status, the severity of liver disease, acute exacerbation and
even with fulminant liver failure [7–9].
Goals of treatment
The treatment of chronic hepatitis B has three main goals:
• Durable suppression of HBV DNA
• Alanine transaminase (ALT) normalization
• Remission of liver disease with prevention of more severe
stages of disease and complications, such as HCC.
In HBeAg-positive chronic hepatitis, anti-HBe seroconversion
is an additional goal that permits the suspsension of therapy and
generally indicates a stable response to treatment.
A clearance of HBsAg with anti-HBs seroconversion is a very
important goal of treatment, but is unfortunately rarely achieved.
Chronic hepatitis B treatment: view of current drugs
Two main classes of drugs currently exist for chronic hepatitis B
treatment: immunomodulators (e.g, interferon [IFN]) and viral
replication inhibitors (e.g., nucleos(t)ide reverse transcriptase
inhibitors [NRTIs] or nucleos(t)ide analogues). However, only
five drugs are currently licensed, with different modalities in dif-
ferent countries, for hepatitis B treatment: IFN-α, conventional
and pegylated forms, lamivudine, adefovir, and entecavir.
Interferon
IFN-α was the first drug to be used to achieve suppression of
HBV replication and remission of chronic hepatitis owing to its
immunomodulatory and antiviral properties and was recently
largely replaced by its pegylated forms. These have been used in
controlled investigational studies to improve the rate of sustained
virological response and reduce the emergence of mutant strains
of HBV resistant to analogues when used in combination with
them. Pegylated (Peg)-IFN-α2a (Pegasys, Roche; dosage
180 µg/week), the only one licensed for chronic hepatitis B, con-
sists of IFN-α2a with a side branch of 40-kD polyethylene glycol,
which reduces fluctuating drug exposure by modifying IFN
pharmacokinetics. This structure allows a weekly administration
and a better outcome than conventional IFN.
Peg-IFN-α2b (PegIntron, Schering-Plough; dosage
1.5 µg/kg/week) consists of IFN-α2b with a linear side branch
of 12-kD polyethylene glycol. It is not licensed for chronic
hepatitis B and has been used only in one controlled trial.
Peg-IFNs are administered subcutaneously and their side
effects during treatment are generally not well tolerated by
patients: influenza symptoms, which can be improved with
916
paracetamol, hair loss and leukopenia. More serious, but less
frequent side effects include depression, even suicidal tendan-
cies, and the development or worsening of autoimmune dis-
eases (i.e., thyroiditis). Peg-IFNs are not indicated in patients
with decompensated liver disease, but in selected well-com-
pensated cirrhotic patients with careful monitoring it can be
used. However, Peg-IFNs do not induce resistant mutant
emergence and, although more expensive than the NRTIs,
require shorter treatment (12–24 vs 24–48 months or longer,
respectively).
IFN & Peg-IFN monotherapy or in combination for
HBeAg-positive patients
In HBeAg-positive patients, a response to IFN treatment,
namely, anti-HBe seroconversion, has been reported in
25–40% of cases; however, as the spontaneous rate of HBeAg
clearance in controls is approximately 10–15%, the real
response rate is therefore approximately 15–25% [10–12].
Response to IFN is lost in only 10–20% of cases, particularly
during the first year after stopping treatment. HBsAg loss has
been reported in 5–10% of patients within 1 year of the start of
therapy and after 5 years increases to 11–20%. These results
have been reported in European and American studies, but not
in Asian studies [12]. It has been demonstrated that patients
treated with IFN have a reduced risk of developing hepatic
decompensation and liver-related death, but no certain data are
available on the development of HCC [12].
Different combinations of IFN and lamivudine have been
tried in HBeAg-positive patients in diverse schedules. High
HBV-DNA levels and an almost normal ALT are negative
predictive factors of response to IFN. Treatment with lamivu-
dine in the attempt to decrease HBV-DNA levels prior to
immunomediated IFN action, was tested with poor results in
a small number of patients (TABLE 1) [13]. Other studies, on
patients with more active chronic hepatitis, found combined
or sequential treatment with lamivudine and IFN superior in
achieving sustained response in terms of anti-HBe seroconver-
sion, HBV-DNA clearance and ALT normalization [14–16], and
also found a reduction in the occurrence of lamivudine resist-
ance (TABLE 1). Differences in the patient populations regarding
the number of patients, histological activity and baseline
HBV-DNA levels make any comparison between the studies
difficult.
Peg-IFN-α2a and -α2b, monototherapy or in combination
with lamivudine, have recently been used in two studies for the
treatment of HBeAg-positive patients [17,18]. In both studies the
patients were predominantly Asian. The authors concluded
that Peg-IFN monotherapy or in combination with lamivudine
was superior to lamivudine monotherapy in terms of HBeAg
seroconversion, HBV-DNA clearance and histological improve-
ment (a reduction of at least 2 points of the histological activity
index [HAI] score in a percentage ranging between 34 and 60%
of patients in the two studies) (TABLE 2). Furthermore,
rtM204V/I mutations emerged less frequently in patients with
combination treatment (4–21 vs 27–40%).
Expert Rev. Clin. Immunol. 2(6), (2006)
 Chronic hepatitis B treatment

Table1. IFN and lamivudine combination treatment in HBeAg-positive patients: main studies.
Author Treatment Duration Patients Patients with HBeAg loss Patients with HBeAg loss HBsAg Ref.
(weeks) (n) HBV-DNA at E-T (%) HBV-DNA at E-FU (%) loss (%)
clearance at clearance at
E-T (%) E-FU (%)
Schalm IFN–Lam 52 76 36* 35 31* 33 - [14]
IFN monotherapy 70 29* 23 29* 29
Lam monotherapy 84 60* 23 32* 21
Serfaty Lam 20 weeks+ 48 14 64† 45 57† 45 21 [15]
IFN–Lam 4 weeks + 11 (HBeAg+)
IFN monotherapy
24 weeks
Marrone Lam 12 weeks + 72 11 0§ 18 0§ 0 0 [13]
IFN–Lam 24 weeks
+ Lam 36 weeks
Sarin Lam 8 weeks + 52 38 26¶ 39.5 39.5¶ 36.8 - [16]
Lam–IFN 16 weeks 37 13¶ 38 16.2¶ 10.8
+ Lam 28 weeks
Lam monotherapy
*Serum HBV–DNA level limit for clearance: 3 pg/ml; †2.5 pg/ml; §<400 cps/ml; ¶<1.4 x 105cps/ml.
E-FU: End-follow-up; E-T: End-treatment; HBV: Hepatitis B virus; HBeAg: Hepatitis B e Ag; HBsAg: Hepatitis B surface antigen; IFN: Interferon; Lam: Lamivudine.

IFN & Peg-IFN monotherapy or in combination in
HBeAg-negative patients
IFN was administered to HBeAg-negative patients at a dosage
of 6–10 MU twice weekly for 6–12 months. An end-of-treat-
ment response was achieved in approximately 40–90% of
patients, but a sustained virological response was maintained
in only 15–25% [10], mostly in patients who underwent treat-
ment for more than 1 year [19]. Patients with a sustained viro-
logical response attained HBsAg clearance in approximately
32% of cases [19], and showed an improved long-term out-
come than untreated patients [20]. Treatment with IFN at a
dosage of 6 MU twice weekly for 24 months showed a sus-
tained response in 30% of patients, as seen by normal ALT
and undetectable HBV DNA by non-PCR assays; in this
group no progression of the liver disease was observed, but no
difference in the development of HCC was reported com-
pared with nonresponders [21]. Predictive factors of response
were young age and high immunoglobin (Ig)M anticore lev-
els. In a recent study Manesis and colleagues showed that a
combination of lamivudine and IFN-α2b for 36 patients for a
variable duration of time obtained a sustained response (ALT
normalization, HBV DNA ≤ 30000 cps/ml) in 22% of
patients, which was a response similar to that observed in a
historical control group treated with IFN monotherapy [22].
Long-term treatment with IFN and lamivudine (combination
for 12 months followed by lamivudine indefinitely) showed a
virological response (HBV DNA < 400 cps/ml) in 97% of
patients at the end of the combination treatment, but a break-
through in the following 4 years of follow up was observed in
36% of responders. Anti-HBs seroconversion was achieved in
11% of patients [23].
These two studies on a small number of patients and demon-
strating a low rate of sustained response to treatment, do not
allow definitive conclusions to be drawn.
Peg-IFN-α2a monotherapy was recently used in an interna-
tional trial or in combination with lamivudine versus lamivu-
dine monotherapy [24]. A sustained virological response
(HBV-DNA < 20,000 cps/ml) was more frequent in patients
treated with Peg-IFN-α2a (43%) or Peg-IFN-α2a plus lamivu-
dine (44%) than in those treated with lamivudine mono-
therapy (29%). HBV-DNA was persistently under
400 cps/ml in 19, 20 and 7% of cases in the Peg-IFN-α2a,
Peg-IFN-α2a plus lamivudine and lamivudine monotherapy
groups, respectively; furthermore, in the Peg-IFN-α2a groups,
HBsAg clearance was observed (TABLE 3). The emergence of
resistant mutants to lamivudine was significantly lower in the
combination group (TABLE 3).
Nucleos(t)ide reverse transcriptase inhibitors or
nucleos(t)ide analogues
These molecules are able to mimic natural nucleosides and
are incorporated into the synthesized DNA, leading to chain
termination. Furthermore, after conversion into triphosphate
counterparts, some competitively inhibit the HBV reverse
transcriptase/DNA polymerase (rt-polymerase). They effec-
tively suppress HBV-DNA levels, but on suspension, viremia
can rebound to baseline levels. Optimal duration of treat-
ment has not yet been established, but long-term therapy,
perhaps indefinitely, appears to be the best option. Emer-
gence of resistance to these drugs is a limit to their use. For
the sake of brevity from here on they will be referred to
as analogues.

www.future-drugs.com 917
Zampino, Marrone, Adinolfi & Ruggiero

Table 2. Recent clinical trials on HBeAg-positive patients.

Author Treatment Duration Patients Patients with HBeAg loss Patients HBeAg loss HBsAg Ref.
(weeks) (n) HBV DNA at E-T (%) with HBV at E-FU loss
clearance at DNA (%) (%)
E-T (%) clearance at
E-FU (%)
Lau Peg-IFNα2a 48 271 52*, 25† 30 32* , 14† 32 2 [17]
Peg-IFNα2a–Lam 271 86*, 69† 27 34*, 14† 27 2
Lam monotherapy 272 62*, 40† 22 22*, 5† 19 0
Chan Peg-IFNα2b –Lam 52 50 50§ 20 36§ 20 2 [18]
Lam monotherapy 50 28§ 11 14§ 11 0
Marcellin Adefovir 10 mg 48 172 21¶ 12 ND ND – [52]
Adefovir 30 mg 173 39¶ 14
Placebo 170 0¶ 6
Chang Entecavir 52 314 67# 22 ND ND 2 [60]
Lam 314 36# 20 1
*Serum HBV DNA level limit for clearance: <100000 cps/ml; †<400 cps/ml; §<500000 cps/ml; ¶<400 cps/ml; #<300 cps/ml.
E-T: End treatment; E-FU: End-follow-up; HBeAg: Hepatitis B e anigen; HBsAg: Hepatitis B surface Ag; HBV: Hepatitis B virus; IFN: Interferon; Lam: Lamivudine;
Peg: Pegylated; ND: Not determined.

Lamivudine [33].The appearance of lamivudine-resistant mutants during treat-

Lamivudine (Zeffix, GlaxoSmithKline) is a nucleoside analogue
and acts particularly on the YMDD motif in the C subdomain
of HBV polymerase, which is conserved in all reverse tran-
scriptase isolates, including the hepadnavirus. Lamivudine is
very effective in controlling HBV replication, but during pro-
longed treatment, mutations in the YMDD motif can emerge,
decreasing the sensitivity of the virus to the drug. Methionine is
replaced by valine or isoleucine and these mutations are now
known as rt-M204V/I, according to the new nomenclature
recently proposed by Stuyver and colleagues [25]. These muta-
tions are often associated with another mutation, the
rt-L180M, also involved in lamivudine resistance. The develop-
ment of lamivudine resistance has been associated with dura-
tion of treatment, high body-mass index (BMI), high pre-treat-
ment serum HBV-DNA levels, insufficient serum HBV DNA
suppression and elevated ALT during treatment [26,27]. A strict
and consistent adherence to the lamivudine dosage is important
to reduce the transmission of resistant mutants [28].
Lamivudine is administered orally at a dosage of 100 mg/day
adjusted only in the case of renal failure [29]. Lamivudine is very
well tolerated and an increase in ALT or creatine phosphokinase
(CPK) values have rarely been reported.
Lamivudine in HBeAg-positive patients
After 1 year of lamivudine treatment, HBeAg seroconversion was
reported in 16–18% of cases, increasing with the duration of
treatment (27, 40, 47 and 50% after 2, 3, 4, 5 years of therapy,
respectively) [12,30,31]. The loss of HBeAg was more frequent in
patients with elevated baseline ALT [32]. A histological improve-
ment (a reduction of at least 2 points of the HAI score), a decrease
in HBV DNA (undetectable by non-PCR methods) and ALT
normalization were also reported during lamivudine treatment
ment was associated with breakthrough to pre-treatment levels of
HBV DNA and ALT, a severe ALT flare or the onset of rapid liver
failure have occasionally been observed [34]. rtM204V/I muta-
tions emerged during treatment with frequencies of approxi-
mately 14, 38, 49, 66 and 74 % at 1, 2, 3, 4 and 5 years, respec-
tively [35,36]. In patients with cirrhosis or advanced fibrosis, the
risk of liver disease progression and the appearance of complica-
tions, including the development of HCC was significantly
reduced by continuous treatment with lamivudine [37].
Lamivudine in HBeAg-negative patients
Biochemical and virological responses in HBeAg-negative
patients treated with lamivudine range between 70 and 96%
after 1 year of therapy, while histology improvement is reported
in approximately 20–90% of patients [38]. Unfortunately, the
relapse rate after stopping treatment is high (∼90%) and the
breakthrough during long-term treatment is frequent and corre-
lated with the emergence of lamivudine resistant mutants, a fre-
quency that increases with longer treatment (∼30, 44, 60 and
74% at 1, 2, 4 and 5 years, respectively) [33,36]. Furthermore,
breakthrough during treatment can be a cause of significant hep-
atitis flares [39,40], particularly dangerous in cirrhotic patients, and
at times of the development of HCC [41,42].
Adefovir
Adefovir dipivoxil (Hepsera, Gilead Sciences, CA, USA) is a
DNA-chain terminator, but can also stimulate the production of
endogenous IFN and promote natural killer cell activity [43]. It is
effective in HBV replication control and is active against lamivu-
dine-resistant mutants [44–47]. An oral dose of adefovir of
10 mg/day is generally well tolerated with minimal renal toxic
effect [48].

918 Expert Rev. Clin. Immunol. 2(6), (2006)


Table 3. Recent clinical trials on HBeAg-negative patients.
Author Treatment Duration Patients (n)
(week)
Marcellin Peg–IFNα2a 48 177
Peg–IFNα2a–Lam 179
Lam 181
Hadziyannis Adefovir 10 mg 48 123
Placebo 61
Lai Entecavir 52 325
Lam 313
*Serum HBV DNA level limit for clearance: <20000 cps/ml; †< 400 cps/ml; §< 0.7 MEq/ml.
Ag: Antigen; E-T: End-treatment; E-FU: End-follow-up; HBV: Hepatitis B virus; HBeAg: Hepatitis B e Ag; IFN: Inteferon; Lam: Lamivudine; ND: Not determined;
Peg: Pegylated.
Resistance to adefovir has not been described during the first
year of treatment, but appears relatively late, after a mean dura-
tion treatment time of 20 months [49,50]. Mutations that confer
resistance to adefovir are the A181V and N236T, located in the B
and D polymerase subdomains, respectively. A recent study eval-
uated the risk of resistance after 192 weeks of adefovir therapy;
this risk was higher (>25%) in patients with HBV-DNA levels of
more than 3 log10 cps/ml than in patients with HBV-DNA levels
of less than 3 log10 cps/ml after 48 weeks of treatment [51].
Adefovir in HBeAg-positive patients
Adefovir treatment was evaluated in a randomized trial, at a
dosage of 10 versus 30 mg/day versus placebo [52]. With both
dosages, treatment was effective in decreasing HBV DNA to
less than 400 cps/ml (21 vs 39%, 10 vs 30 mg, respectively)
and achieving HBeAg seroconversion in 12 vs 14%. A histolog-
ical improvement, that is, a reduction of at least 2 points of the
Knodell score, was also reported in more than 50% of patients,
and after 1 year of treatment no resistant mutants were
observed. The dosage of 10 mg/day was associated with less fre-
quent side effects, particularly regarding renal function, and
was found to be the best dosage for long-term treatment.
Adefovir in HBeAg-negative patients
Adefovir dipivoxil was demonstrated to be effective in normaliza-
tion of HBV DNA (51%) and ALT (71%) levels after 1 year of
treatment and resulted in a histological improvement in 64% of
patients versus 33% of controls (TABLE 3) [53]. In this study, no
mutations correlated to adefovir treatment were reported and no
important side effects were registered. The effect of long-term
treatment with adefovir in HBeAg-negative patients was
described by Hadziyannis and colleagues [54]. The benefits
obtained during the first year of treatment were lost if therapy
was discontinued, and were maintained, with a low emergence of
mutants (∼7% at 144 weeks of treatment), if continued. HBV
DNA levels of less than 1000 cps/ml were detected in 71 and
79% of patients after 2 and 3 years of treatment, respectively. At
4 years of therapy the incidence of resistant mutants was 18%
www.future-drugs.com
Chronic hepatitis B treatment
Patients with HBV DNA Patients with HBV HBsAg loss Ref.
clearance at E-T (%) DNA clearance at (%)
E-FU (%)
81*, 63† 43*, 19† 4 [24]
92*, 87† 44*, 20† 3
85*, 73† 29*, 7† 0
51† ND – [53]
0†
90§ ND 0.3 [61]
72§ 0.3
and at 5 years 28% [28,54]. As is the case for lamivudine, the
emergence of adefovir resistance can be associated with severe
flares of ALT and hepatic decompensation [50]. It has been shown
that adefovir is effective in controlling HBV replication in
HBeAg-negative patients with HBV strains resistant to lamivu-
dine [55]; the efficacy of adefovir was greater when it was started
after the emergence of genotypic resistance versus phenotypic
resistance (p < 0.001), so adefovir should be added to lamivudine
soon after the appearance of genotypic resistance.
A cost–effective analysis of lamivudine and adefovir in the
treatment of patients with HBeAg-negative chronic hepatitis B
showed that long-term treatment with adefovir was a
cost-effective strategy for this group of patients [56].
Entecavir
Entecavir (Baraclude®, Bristol-Myers Squibb Co) is a potent
inhibitor of HBV polymerase. It has been shown to be active in
chronic hepatitis B, in HBeAg-positive and -negative patients
with proven resistance to lamivudine; a dosage of 1.0 mg/day is
better than 0.5 mg/day after 24 weeks of treatment [57,58]. Ente-
cavir is also effective for adefovir-resistant HBV [59]. Optimal
duration of treatment is not known at present. As is the case
with the other analogues, entecavir is very well tolerated.
Two Phase III studies were recently published on the treat-
ment of chronic hepatitis B with entecavir in HBeAg-positive
and -negative patients by Chang and colleagues, and Lai and
colleagues, respectively [60,61]. In both trials, the patients who
were naïve for analogue treatment received entecavir
(0.5 mg/daily) or lamivudine (100-mg/daily) for at least
52 weeks; the primary end-point was a histological improve-
ment (a decrease of at least 2 points in the Knodell score, with
no worsening of fibrosis). In the 715 HBeAg-positive patients,
a histological improvement was significantly higher in the ente-
cavir than in the lamivudine group (72 vs 62%; p = 0.009);
indeed, in the entecavir group more patients presented
undetectable serum HBV-DNA (67 vs 36%; p < 0.001) and
ALT normalization (68 vs 60%; p = 0.02) [58]. At week 48 of
treatment, the mean reduction in serum HBV-DNA was
919
Zampino, Marrone, Adinolfi & Ruggiero
6.9 versus 5.4 log10 cps/ml (p < 0.001) with entecavir and lam-
ivudine, respectively. No differences in terms of anti-HBe sero-
conversion were observed and no emergence of resistance to
entecavir was registered (TABLE 2). Resistance to entecavir of
approximately 9% has been observed in HBeAg-positive
patients refractory to lamivudine treatment [62].
In the 648 HBeAg-negative patients, the histological
improvement was significantly higher in the entecavir than the
lamivudine group (70 vs 61%; p = 0.01); indeed, in the ente-
cavir group more patients presented undetectable serum HBV
DNA (90 vs 72%; p < 0.001) and ALT normalization (78 vs
71%; p = 0.045) (TABLE 3) [61]. At week 48 of treatment, the
mean reduction in serum HBV-DNA was 5.0 versus
4.5 log10 cps/ml (p < 0.001) with entecavir and lamivudine,
respectively (TABLE 3). In both studies, the safety profile was
similar for entecavir and lamivudine. No emergence of resist-
ance to entecavir was registered. However, the addition of
entecavir in HBeAg-positive patients refractory to lamivudine
treatment was associated to the emergence of virological ente-
cavir resistance in 1.4% of patients and to genotypic resistance
in approximately 7% of patients [58].
The advantages and disadvantages of Peg-IFN and analogues
for the treatment of chronic hepatitis B are summarized in
TABLE 4.
Other drugs
Other HBV-polymerase inhibitors have been tried in the treat-
ment of chronic hepatitis B, but they have been used in short-
term clinical studies and their efficacy and safety need to be
evaluated on a wider scale. Their resistance profiles are impor-
tant to evaluate cross-resistance phenomena. Emtricitabine
(FTC), clevudine (L-FMAU) and telbivudine (LdT) are
L-nucleoside analogues, (e.g., lamivudine), whereas tenofovir
and alamifovir are nucleotide analogues (e.g., adefovir). After
1 year of treatment, resistance mutations were observed for
emtricitabine and telbivudine [28] and exacerbation of the dis-
ease after discontinuation of therapy was reported for emtricit-
abine [63]. The efficacy of the new antiviral agents versus lami-
vudine resistant strains has been evaluated [64], in an in vitro
study acyclic phosphonate nucleotides (adefovir, tenofovir and
Table 4. Advantages and disadvantages of pegylate-interferon and analogues in chronic hepatitis B treatment.
Pegylate-interferon
Advantages
Treatment for a defined period of time
In responders, response is mantained in approximately 25% of cases
No resistance emergence
Disadvantages
Poor tolerability
Higher cost
920
alamifovir) were demonstrated to be effective against lamivu-
dine resistant strains and all L-nucleoside analogues (emtricit-
abine, clevudine, telbivudine and torcitabine) completely
ineffective, with a high level of cross resistance [47].
The following paragraphs contain a synthesis of the studies
conducted with these drugs.
Clevudine
Clevudine used in a Phase II escalating-dose clinical trial in
patients with chronic hepatitis B showed a change in the HBV-
DNA levels from baseline of 2.5, 2.7, 3.0 and 2.6 log10 at the
daily dosage of 10, 50, 100, 200 mg, respectively, for 28 days
[65]. No toxicity or important side effects were registered.
In a recent study the safety and efficacy of clevudine were
evaluated in a 12-week course of treatment at a daily dosage of
30 and 50 mg versus placebo in 98 HBeAg-positive patients
[66]. At week 12, the HBV-DNA levels had decreased from
baseline by 4.49, 4.45 and 0.20 log10 in the 30-, 50-mg and
placebo group, respectively (p < 0.001). The antiviral activity
and ALT normalization were maintained in the 6 months fol-
lowing the 12 weeks of treatment. The incidence of adverse
effects was similar in the three groups of patients.
Emtricitabine
The antiviral activity and safety of a daily dose of emtricitabine
of 25, 100, 200 mg for 48 weeks was evaluated in chronic hep-
atitis B patients in a double-blind, randomized trial [67]. All the
patients were subsequently treated for another 48 weeks at a
dosage of 200 mg/day. After 2 years, the HBV DNA levels were
4700 cps/ml or less in 53% of patients, 33% of them serocon-
verted to anti-HBe and 85% had normal ALT. Emtricitabine
resistance was observed in 18% of patients who received
200 mg throughout the course.
Another multicenter, double-blind study compared emtric-
itabine treatment (200 mg daily) with placebo for 48 weeks in
chronic hepatitis B patients [68]. Liver histology was assessed
before starting and after the end of treatment. A histological
improvement (2-point reduction in the Knodell necro-
inflammatory score) was observed in 62% of treated patients
versus 25% of placebo (p < 0.01), with significant evidence in
Analogues
Advantages
Good tolerability
Lower cost (for same duration of treatment)
Disadvantages
Long-term treatment (maybe forever)
Emergence of resistance
Expert Rev. Clin. Immunol. 2(6), (2006)

both HBeAg-positive and -negative patients. HBV DNA of
less than 400 cps/ml was detected in 54% of treated and 2%
of placebo patients (p < 0.001), whereas normal ALT values
were found in 65 and 25% of patients (p < 0.001), respec-
tively. At the end of treatment, emtricitabine resistance was
observed in 13% of patients with detectable HBV DNA.
Post-treatment reactivation of the disease was observed in
23% of emtricitabine treated patients. No significant side
effects were found.
Telbivudine
The first clinical study assessed the safety and efficacy of a high
dosage of telbivudine (400 and 800 vs 25, 50, 100 and
200 mg/daily) in HBeAg-positive chronic hepatitis B patients
for 4 weeks of treatment. In the 800-mg/daily group, the mean
HBV-DNA reduction was 3.75 log10 cps/ml after 4 weeks of
treatment, with a 99.98% reduction in the serum viral load.
Indeed, the post-treatment rebound of viremia was slower in
the high-dose groups [69]. In HBeAg-positive patients, telbivu-
dine exhibited significantly grater and more consistent antiviral
efficacy than adefovir after 24 weeks of treatment (HBV-DNA
negative in 38.6 vs 12.4%, respectively) [70]. A pharmaco-
kinetics evaluation with a single dose of telbivudine found that
it could be used in the treatment of chronic hepatitis B patients
with decompensated cirrhosis [71], but further studies on the
safety and efficacy are needed.
Alamifovir
The safety and efficacy of alamifovir were tested in a rand-
omized study, with dose escalation (2.5–20 mg/day, in a single
or divided doses) for 28 days in 66 patients with chronic hepa-
titis B. The serum HBV-DNA levels decreased by 1.5–2.6 log10
after 28 days [72]. No differences were observed in the various
drug regimens, but viral suppression during the 12 weeks of
follow up after treatment was dose-dependent. No significant
adverse events were registered.
Tenofovir
Tenofovir has been used in clinical trials mostly in HBV–HIV
coinfected patients. In this population, tenofovir showed a
good antiviral effect (HBV-DNA baseline 7.95 log10; 3.1 and
4.3 log10 after 12 and 24 weeks, respectively) in patients who
had failed to respond to previous IFN and lamivudine therapy
Table 5. HBV polymerase mutations during antiviral treatment.
V173L L180M A181V A184G
LAM LAM ADV
ETV ETV ETV
*Only M204I.
ADV: adefovir; ETV: entecavir; FTC: emtricitabine; LAM: lamivudine; LdT: telbivudine; TDF: Tenofovir.
www.future-drugs.com
Chronic hepatitis B treatment
[73].In a recent retrospective study, tenofovir was effective on
HBV-infected patients who had been treated with tenofovir
for at least 6 months as part of antiretroviral treatment [74]. In
the HBeAg-positive patients, the median reduction in the
HBV-DNA levels from baseline was of 4.56 log10 cps/ml and
in the HBeAg-negative of 2.53 log10 cps/ml. The efficacy of
tenofovir was demonstrated on wild-type and precore mutant
HBV [75]. Tenofovir was also active on lamivudine-resistant
HBV strains and was better than adefovir in reducing HBV-
DNA levels to under 105 cps/ml. However, in two HBV–HIV
coinfected patients treated with lamivudine and tenofovir for
more than 12 months, a novel mutation, rt-A194T, was
described in association with rt-L180M and rt-M204V; these
three mutations reduced the susceptibility to tenofovir and
increased the IC50 over tenfold for tenofovir compared with
the wild-type strain [76].
In vitro and in vivo tenofovir was effective versus a rare HBV
variant with primary resistance to adefovir (rt-I233V) [77].
The HBV polymerase mutations during antiviral treatment
are reported in TABLE 5.
Combination treatment with analogues
Combination treatment has been tested to improve HBV-DNA
suppression and to limit the emergence of mutants resistant to
nucleoside analogues.
Particularly problematic are patients with advanced or
decompensated cirrhosis who cannot receive Peg-IFN owing to
its side effects and, therefore, need long-term treatment with
analogues. The best combination treatment may include mole-
cules with different mechanisms of resistance (e.g., a nucleotide
and nucleoside analogue, drugs without cross-resistance may
be able to prevent or delay the emergence of resistant viruses,
but the efficacy and safety of such a combination should be
carefully assessed.
In vitro, adefovir in combination with lamivudine, telbivu-
dine or emtricitabine showed an additive antiviral effect and
in combination with tenofovir, and entecavir a moderate
synergistic effect [78].
The combination of adefovir and lamivudine was evaluated
in patients who presented lamivudine-resistant HBV infec-
tions. The efficacy and safety of the combination (adefovir
added to ongoing lamivudine vs lamivudine monotherapy) was
observed in patients with compensated and decompensated
A194T S202I M204V/I N236T M250V
TDF LAM ADV
ETV ETV ETV
FTC
LdT*
921
Zampino, Marrone, Adinolfi & Ruggiero
HBeAg-positive chronic hepatitis; the virological (HBV-DNA
levels <105 cps/ml or > 2 log10 reduction from baseline at weeks
48 and 52) and biochemical (ALT normalization) responses
were significantly higher in the group treated with the combi-
nation than in the lamivudine monotherapy group; indeed
HBeAg loss was observed in 15% of patients treated with com-
bination and in 2% of patients treated with lamivudine
monotherapy [79].
In another study, Peters and colleagues treated HBeAg-pos-
itive patients with lamivudine-resistant mutants with adefovir
monotherapy, or adefovir and ongoing lamivudine or lamivu-
dine monotherapy [80]. Furthermore, adefovir afforded a
greater decrease in the HBV-DNA levels (median change
from baseline at 48 weeks in lamivudine monotherapy, adefo-
vir/lamivudine and adefovir monotherapy groups were 0.0, -
3.59 and -4.04 log10, respectively), and more frequent HBeAg
loss (16 and 17% adefovir monotherapy or in combination,
respectively, versus 0% lamivudine monotherapy).
Only two short reports describe the use of lamivudine plus
adefovir in combination in naïve HBeAg-positive patients
[81,82]. The combination provided a more potent inhibition of
the HBV-DNA levels than adefovir monotherapy (baseline
HBV-DNA 8.6 and 8.01 log cps/ml in the combination and
adefovir groups, respectively; after 1 year the HBV-DNA levels
were 2.62 and 4.13 log cps/ml in combination and adefovir
groups, respectively) [82], but did not enhance the antiviral
effect compared with lamivudine monotherapy [81]. However,
after 1 year of treatment a significant reduction in the emer-
gence of lamivudine resistance (2%) in the combination group
versus the lamivudine group (20%) was observed [77]. HBeAg
loss was similar in the combination and monotherapy groups.
Other combination treatments have recently been tested.
In a multicenter, double-blind study patients treated in a
Phase III study with emtricitabine were randomized to
receive emtricitabine (200 mg/day) monotherapy or plus cle-
vudine (10 mg daily) for 24 weeks [83]. No significant differ-
ences were observed between the two groups of patients in
terms of change in the serum HBV-DNA levels or ALT nor-
malization. However, in the subsequent 24 weeks of follow-
up, post-treatment reacutizations were less frequent in the
combination group.
In a Phase II 1-year randomized, double-blind multicenter
trial telbivudine (400 or 600 mg/day), lamivudine
(100 mg/day) and combination (five groups in total) were com-
pared in HBeAg-positive patients [84]. Telbivudine treatment
obtained a greater reduction in the HBV-DNA levels (telbivu-
dine 400, 6.43 log10 cps/ml; telbivudine 600, 6.09 log10 cps/ml)
than lamivudine (4.66 log10 cps/ml); furthermore, telbivudine
was more effective in terms of ALT normalization (86 vs 63%;
p < 0.05), HBeAg seroconversion and viral breakthrough
(p = not signigicant for both). Combination treatment was not
superior to telbivudine monotherapy.
New studies with longer treatment and follow-up are needed
to confirm the advantage of combination treatment on viral
suppression and the emergence of mutants.
922
Characteristics of patients under treatment, predictive factors
of response & monitoring of treatment
The eligibility of chronic hepatitis B patients to antiviral treat-
ment is generally evaluated on the basis of three parameters:
serum ALT levels, serum HBV-DNA levels and liver histology.
Alanine aminotransferase
Elevated ALT is a pre-requisite for treatment; however, ALT
levels do not always correlate with the severity of the liver dis-
ease. Other factors, such as BMI or metabolic disorders can be
associated with an ALT increase. Rather than being indicative
of liver disease in need of treatment, elevated ALT values is a
predictive factor of response to treatment. Patients with normal
ALT, HBV-DNA levels of less than 105 cps/ml in HBeAg-posi-
tive and less than 104 cps/ml in HBeAg-negative and histologi-
cally proven mild-chronic hepatitis should be monitored and
therapy started if the disease becomes more active.
HBV-DNA level
HBV-DNA levels are variable during the natural history of
chronic hepatitis B. HBeAg-positive patients are generally char-
acterized by higher HBV-DNA levels (>105 cps/ml) and the
HBeAg-negative by lower HBV-DNA levels (>104 cps/ml); fur-
thermore, in the latter population, fluctuations in the serum
HBV-DNA levels are often found. Evidence of significant int-
rahepatic HBV-DNA and cccDNA levels is present even with
HBV-DNA levels of less than 105 cps/ml [85]. Antiviral agents
do not clear HBV-DNA in the cccDNA form.
After 1 year of treatment with lamivudine, the HBV-DNA
levels should be monitored every 3 months, as an increase, gen-
erally correlated with the emergence of lamivudine-resistant
strains, precedes an ALT flare. The emergence of resistance dur-
ing adefovir treatment is less frequent than during lamivudine
treatment and, therefore, HBV DNA should be measured every
6 months.
Any chronic HBV patient with cirrhosis, irrespective of
HBV-DNA level, should receive treatment to prevent future
decompensation and liver failure secondary to flare.
Liver histology
Baseline liver histology is a precise indicator of the state of the
disease; the discrimination between chronic hepatitis and
cirrhosis is important for the choice of treatment.
Genotype
The HBV genotype generally correlates with the IFN response
(genotype B responds better than C, and A better than D), but
no clear data are available for treatment with Peg-IFN, no cor-
relation has been observed between the response to treatment
and nucleo(t)side analogues [5].
In summary, HBeAg-positive or -negative patients with ele-
vated ALT, positive HBV DNA and liver histology of moder-
ate-to-severe chronic hepatitis have favorable predictive factors
of antiviral response and should be treated. The first-line treat-
ment depends particularly on the severity of the histological
Expert Rev. Clin. Immunol. 2(6), (2006)
 Chronic hepatitis B treatment

to liver damage, as HBV-infected hepato-

cytes are targeted and ALT flares may
HBeAg-positive chronic hepatitis B occur [87].
Lamivudine is one of the drugs used in
HBV DNA <105 HBV DNA > 105 HBV DNA > 104–105 HAART; HIV positive patients prospec-
ALT normal ALT elevated ALT elevated tively followed during HAART treatment
Mild disease Moderate-severe Advanced disease
disease containing lamivudine presented undetect-
able HBV DNA (by hybridization) and
anti-HBe seroconversion in 35% of
Regular follow-up Peg-IFN Analogs treatment
treatment
patients. Patients treated for longer (21 vs
(every 3 months at
diagnosis and every 13 months) showed the emergence of lam-
6–12 months ivudine resistance [88], so lamivudine
Liver transplantation
thereafter) Sustained No response should be avoided as initial treatment
response owing its high resistance rate.
In a recent study, adefovir (10 mg/daily)
Long-term was added to antiretroviral therapy for
No treatment patients with lamivudine resistance and
analogs treatment
resulted in a significant decrease in the
HBV-DNA levels (median baseline
HBeAg-negative chronic hepatitis B HBV-DNA 9.76 log10; median HBV-
DNA at 48, 96, 144 weeks of treatment,
HBV DNA < 104 HBV DNA > 104 HBV DNA > 103–104 4.68, 5.24, 5.90 log10 cps/ml, respectively;
ALT nornal ALT elevated ALT elevated p < 0.0001 at all time points) [89].
Mild disease Moderate-severe Advanced disease
disease
The efficacy of tenofovir in HIV
patients is described in the paragraph on
Regular follow-up tenofovir in the ‘Other drugs’ section.
(every 3 months Peg-IFN Analogs treatment
at diagnosis treatment
HBV–hepatitis C virus coinfection
and every
6–12 monhts
HBV–hepatitis C virus (HCV) coinfection
Liver transplantation generally leads to more severe liver disease
thereafter) Sustained No response
response with a higher risk of complications (e.g.,
HCC), than a single infection [90]. The dif-
No treatment Long-term ferent patterns of molecular replication and
analogs treatment
immunity stages make it difficult to find an
optimal and homogeneous therapeutic
approach; furthermore, few studies, often
Figure 1. Treatment suggestion for chronic HBeAg-positive and -negative patients.
ALT: Alanine transaminase; HBV: Hepatitis B virus; IFN: Interferon; Peg: Pegylated. with a small number of patients, have
focused their attention on the treatment of
this dishomogeneous group of patients. In
damage; patients with advanced or decompensated liver disease the treatment of HBV–HCV-coinfected patients it is important
cannot be treated with IFN owing to its side effects, but can to identify the dominant virus. When HBV replication is preva-
improve with analogues. lent, IFN is the treatment of choice, perhaps with lamivudine
Recommendations for treatment in HBeAg-positive and [91,92]; when HCV replication is prevalent IFN plus ribavirin has
-negative patients are given in FIGURE 1. shown a similar rate of response to HCV monoinfected patients
[93,94]. No data on the use of Peg-IFN and other analogues, such
Particular groups of patients as adefovir or entecavir, are available at present for this popula-
HBV–HIV coinfection tion. It must be borne in mind that during treatment, an imbal-
The prevalence of HBV infection in HIV-positive patients is ance in the viral replication of HBV and HCV can cause a flare
approximately 9%; chronic HBV infection is reported to sig- of hepatitis and an exacerbation of the liver disease [95]. Larger
nificantly increase liver-related mortality, but does not influ- trials are warranted to clarify treatment for this group of patients.
ence progression to AIDS or the response to highly active
antiretroviral therapy (HAART) [86]. In this type of coin- Transplanted patients
fected-patient treatment has the principal goal of preventing HBV reinfection after liver transplantation is one of the principal
cirrhosis and decompensation. During anti-HIV treatment events affecting the long-term survival of transplanted patients.
the immune reconstitution of HBV-specific T cells can lead Prophylaxis has decreased the rate of reinfection and ameliorated

www.future-drugs.com 923
Zampino, Marrone, Adinolfi & Ruggiero
the recipient’s outcome; the advent of hepatitis B Ig in the pro-
phylaxis, associated with analogues, such as lamivudine before
transplant, has reduced the reinfection rate. Unfortunately, the
incidence of resistance to lamivudine is high, approximately
25–30% at 2 years post-transplantation. In patients with lamivu-
dine resistance, adefovir has been demonstrated to be as effective
as salvage treatment before transplant. [96–98].
In recipients of solid organs other than the liver or of bone-
marrow transplantation, a pre-existing silent HBV infection
can be reactivated by immunosuppression treatment [29,99],
but antiviral therapy with analogues has favorably changed
the outcome in these patients. HBV infection can also be
acquired after transplantation, for example, as a consequence
of endomyocardial biopsy after heart transplant [100].
Pregnancy
Although the immunoprophylaxis of babies from HBsAg posi-
tive mothers is effective, the vertical transmission of HBV during
pregnancy is possible, especially in women with a high viral load
(108–109 cps/ml) [101]. Lamivudine has been used in the attempt
to avoid the vertical-transmission of HBV. The administration of
lamivudine in the last 4 weeks of pregnancy has proved to be safe
and prevents vertical transmission of HBV and vaccination
breakthrough in children of mothers with high viremia [102,103].
Su and colleagues retrospectively evaluated the efficacy and safety
of lamivudine treatment in HBsAg/HBeAg-positive pregnant
woman who volunteered to continue lamivudine treatment for
HIV during pregnancy [104]. Lamivudine therapy was not found
to be correlated with pregnancy complications and showed a
block of vertical transmission of 100%, which was significantly
higher than the block of transmission obtained with active vac-
cine immunization (∼70%). Unfortunately, the number of cases
was low and the control values were taken from the literature.
However, despite good prevention following the administration
of lamivudine, cases of inefficacy have been described [105], there-
fore, warranting evaluation in larger studies. Breast-feeding of
infants from chronic HBV carriers poses no additional risk for
transmission of HBV when appropriate immunoprophylaxis has
been carried out [106].
Children
Chronic hepatitis B can be treated in children with IFN-α
(6 MU/m2 twice weekly subcutaneously, for 6–12 months) or
with lamivudine (3 mg/kg/day orally, for 12 months). When
exposure to the virus occurs during childhood, it is generally fol-
lowed by a long period of immune tolerance characterized by
HBeAg positivity, high HBV-DNA levels, normal ALT and min-
imal liver damage. A subsequent activation of the immune sys-
tem can clear the virus, with anti-HBe seroconversion and at
times anti-HBs seroconversion. In children, the response to IFN
is similar to that observed in adults, ranging between 10% in
patients with normal ALT to 30% in those with elevated ALT
[35]; HBeAg clearance is approximately 30% in treated compared
with 10% in untreated patients [107]. A recent study found IFN
treatment at the age of 5 years or less more effective than in older
924
children [108]. Lamivudine treatment is effective in inducing anti-
HBe seroconversion in children, especially those with a more
active liver disease at baseline [109]; lamivudine resistance develops
in 16–33% per year [110]. The combination of IFN and lamivu-
dine is as effective in children as in adults and also reduces the
frequency of the emergence of lamivudine resistance [111].
Five-year view
The advent of new treatments has transformed chronic hepatitis B
in a treatable disease, with better results in terms of viremia sup-
pression, ALT normalization and progression to more serious
stages of disease. Unfortunately, current therapies, particularly the
analogues that do not eradicate HBV, can reappear after stopping
treatment. Indeed, HBV mutations, responsible of resistance to
analogues, can emerge during therapy, making duration of treat-
ment with these drugs still unclear. New approachs with combina-
tion of drugs have been tried and others are certainly coming. It
must be taken in mind that long-term safety of these drugs in
monotherapy and in combinations needs to be better evaluated.
In this complicated view, new therapeutic approaches for
chronic hepatitis B have been studied; at present they are
experimental but may be implemented in future clinical studies.
Therapeutic vaccination
The aim of therapeutic vaccination is to stimulate the T-cell
immune response in chronic HBV carriers, therefore, breaking
the immune tolerance of these patients. Commercial vaccines
or others with different adjuvants may be effective for this pur-
pose [35]. At present the relative data are controversial. No good
results have been obtained with standard vaccines in a control-
led study [112], however, preliminary studies with alternative
adjuvants have reported some encouraging data [113]. A vaccine
containing a T-helper epitope from tetanus toxoid and a CTL
epitope from the HBV core was unable to stimulate an immune
response capable of clearing the infection in chronic hepatitis B
patients [114]. Similar experiments in woodchucks produced
anti-woodchuck hepatitis virus, but the side effects were severe
and one animal died [115].
DNA-based vaccines
DNA-based vaccines are plasmids encoding HBV antigens that
can express proteins in their native form in vivo, with the exact
post-translational modification. The results of experiments in ani-
mals are encouraging [116], but in healthy volunteers the anti-
HBsAg response using the PowderJect system, which delivers gold
particles coated with plasmid DNA to the skin cells, was weak [117].
Antisense oligodeoxynucleotides
Antisense oligodeoxynucleotides are synthetic DNA that inhibit
gene expression by binding to complementary mRNA, which
proved effective in inhibiting HBV replication and protein
expression [35]. They have been used in HepG2.15 cells to down-
regulate asialoglycoprotein receptor 1, which is upregulated by
HBV. As a consequence, reduced levels of HBV DNA, HBsAg
and HBeAg were observed in the cell medium [118].
Expert Rev. Clin. Immunol. 2(6), (2006)
 Chronic hepatitis B treatment

Ribozymes in combination, can be suggested. In advanced and decompen-

Ribozymes (ribonucleic acid enzymes) are able to cleave HBV-
mRNA in vitro [35]. Recently ribozymes delivered by modified
hepatitis D virus (HDV) showed a higher level of inhibition
activity on HBV than ribozymes alone in transfected cells [119].
Expert commentary
The primary aim of treatment of HBV infection is the control
of viral replication, as high HBV-DNA levels correlate with a
progression of liver damage and a risk of complications.
IFN, lamivudine and adefovir are all able to control viral rep-
lication with varying side effects and costs. A pre-treatment
evaluation of the patients is crucial in order to decide whether
or not he/she should be treated and, if so, which therapy is the
most appropriate. Age, HBeAg status, stage of liver disease
(more or less active chronic hepatitis or cirrhosis), HBV DNA,
anticore IgM and ALT levels must be studied before treatment
is applied. Therapy with analogues is easy and no important
side effects have been registered in short-term studies; however,
stopping treatment is almost always associated to a rebound of
the viremia levels and to a new progression of the liver disease,
so the duration of treatment with analogues in HBV chronic
infection is not clear, and might even be indefinite; the devel-
opment of resistance, occurring earlier for lamivudine than for
adefovir and entecavir, needs to be monitored so that treatment
can be modified. Furthermore, the effects after long-term treat-
ment are not known at present.
In patients with a mild, slowly progressive liver disease and
normal ALT, treatment can be postponed; in patients with a
mild-active liver disease IFN treatment can be suggested as first
choice, as it can be resolutive; if a patient does not respond to
IFN treatment, long-term treatment with analogues, possibly
sated cirrhotic patients and in patients awaiting transplanta-
tion, IFN therapy is not recommended owing to its side effects;
these patients can be treated safely with analogues but strict
monitoring of HBV DNA (every 3 months) is necessary to
identify at an early stage the emergence of mutants that could
generate dangerous hepatitis flares.
Hopefully, the introduction of new molecules and the com-
bined use of the drugs available will offer more efficient strate-
gies in the management of chronic hepatitis B treatment in the
not too distant future.
Acknowledgment
The authors would like to thank Dr Peter Karayiannis for his
critical review of the manuscript.
Key issues
• Role of chronic hepatitis B treatment in the control of liver
disease progression.
• Treatment results obtained with drugs currently in use
(interferon, lamivudine, adefovir and entecavir), with
particular reference to the last few years.
• Indication of treatment in patients with different stages of
liver disease and with different serological and molecular
hepatitis B virus pattern.
• Management of particular groups of patients, for example,
these coinfected with hepatitis C virus or HIV, transplant
patients, pregnant women and children.
• Future approaches in the treatment of chronic hepatitis B.

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Via Cotugno, 1 80135 Napoli, Italy
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Fax: +39 081 566 6230
rosa.zampino@unina2.it
Second University Naples, Internal Medicine
and Hepatology C/O Ospedale Gesù e Maria,
Via Cotugno, 1 80135 Napoli, Italy
Tel.: +39 081 566 6225
Fax: +39 081 566 6230
aldo.marrone@unina2.it
Second University Naples, Internal Medicine
and Hepatology C/O Ospedale Gesù e Maria,
Via Cotugno, 1 80135 Napoli, Italy
Tel.: +39 081 566 6229
Fax: +39 081 566 6230
luigielio.adinolfi@unina2.it
• Giuseppe Ruggiero, MD
Second University Naples, Internal Medicine
and Hepatology C/O Ospedale Gesù e Maria,
Via Cotugno, 1 80135 Napoli – Italy
Tel.: +39 081 566 6270
Fax: +39 081 566 6230
giuseppe.ruggiero@unina2.it

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