Pegylated interferon alpha-2a (40 kDa) in the treatment of chronic hepatitis B

Abstract

Chronic hepatitis B virus (HBV) is a serious and life-threatening disease afflicting 350 million of the world’s population. So far, current monotherapy with conventional interferon-alpha, lamivudine, and adefovir dipivoxil remains unsatisfactory. In addition, the use of conventional interferon-alpha needs to be administered subcutaneously daily or thrice weekly and is associated with frequent adverse events. Although nucleoside–nucleotide analogs such as lamivudine and adefovir dipivoxil are well tolerated and can normalize serum alanine aminotransaminase rapidly, 1-year therapy with either lamivudine or adefovir dipivoxil results in low hepatitis B e antigen (HBeAg) seroconversion rates. In HBeAg negative patients, most of the patients would relapse after lamivudine has been discontinued. Pegylated interferon alpha-2a, an immunomodulatory agent, is a new drug that has just completed phase III clinical trials for the treatment of both HBeAg positive and HBeAg negative chronic HBV infection. The advantage of pegylated interferon alpha-2a in achieving sustained virological response over nucleoside–nucleotide analogs is particularly obvious in the HBeAg negative group. In both of these phase III studies, sustained off-treatment response is superior to the use of lamivudine. These recent data put pegylated interferon alpha-2a as the first choice of anti-HBV therapy, especially in young and motivated patients with chronic HBV infection.

Full text

255
REVIEW
International Journal of Nanomedicine 2006:1(3) 255–262
© 2006 Dove Medical Press Limited. All rights reserved
Abstract: Chronic hepatitis B virus (HBV) is a serious and life-threatening disease afflicting 350
million of the world’s population. So far, current monotherapy with conventional interferon-alpha,
lamivudine, and adefovir dipivoxil remains unsatisfactory. In addition, the use of conventional
interferon-alpha needs to be administered subcutaneously daily or thrice weekly and is associated
with frequent adverse events. Although nucleoside–nucleotide analogs such as lamivudine and
adefovir dipivoxil are well tolerated and can normalize serum alanine aminotransaminase rapidly,
1-year therapy with either lamivudine or adefovir dipivoxil results in low hepatitis B e antigen
(HBeAg) seroconversion rates. In HBeAg negative patients, most of the patients would relapse
after lamivudine has been discontinued. Pegylated interferon alpha-2a, an immunomodulatory
agent, is a new drug that has just completed phase III clinical trials for the treatment of both
HBeAg positive and HBeAg negative chronic HBV infection. The advantage of pegylated
interferon alpha-2a in achieving sustained virological response over nucleoside–nucleotide
analogs is particularly obvious in the HBeAg negative group. In both of these phase III studies,
sustained off-treatment response is superior to the use of lamivudine. These recent data put
pegylated interferon alpha-2a as the first choice of anti-HBV therapy, especially in young and
motivated patients with chronic HBV infection.
Keywords: pegylated interferon alpha-2a, chronic hepatitis B, HBeAg seroconversion, sustained
virological response
Introduction
Hepatitis B virus (HBV) infection is one of the most common viral infections in
humans. Approximately 2 billion people have been infected with HBV and 350 million
of them became chronically infected. Individuals with chronic hepatitis B infection
are at an increased risk of developing liver cirrhosis, hepatic decompensation, and
hepatocellular carcinoma (HCC); 15%–40% of these individuals will develop these
serious sequelae during their lifetime (Beasley 1988; McMahon 1997). Drugs that
are currently approved by the Federal Drug Administration (FDA) for the treatment
of chronic HBV consist of two groups: the immunomodulators such as conventional
interferon alpha and pegylated interferon alpha-2a, and nucleoside–nucleotide analogs
such as lamivudine, adefovir dipivoxil, and entecavir. However, not all patients with
chronic hepatitis B infection respond to these treatments.
The currently approved antiviral regimens, especially the nucleoside–nucleotide
analogs, have been shown to improve the short-term outcome of disease but lack the
ability to provide cure or induce durable remission in most patients with chronic HBV
(Lee 1997). Lamivudine, the first nucleoside–nucleotide analog to be approved for the
treatment of chronic HBV, has a favorable safety profile but long-term therapy with this
drug can lead to the selection of drug-resistant mutants (Wong et al 1993; Niederau
et al 1996). The risk of mutation increases with the duration of treatment. At the end
Lawrence Lai1
Chee-Kin Hui2,3,4
Nancy Leung5
George K Lau2,3,4
1Department of Medicine, Caritas
Medical Centre, Hong Kong SAR, Chi-
na; 2Department of Medicine, Queen
Mary Hospital, The University of Hong
Kong, Hong Kong SAR, China; 3Centre
for the Study of Liver Disease, The
University of Hong Kong, Hong Kong
SAR, China; 4Research Centre for
Infection and Immunity, The University
of Hong Kong, Hong Kong SAR, China;
5Department of Medicine, Alice Ho
Miu Ling Nethersole Hospital, Hong
Kong SAR, China
Correspondence: Chee-Kin Hui
Department of Medicine,
Queen Mary Hospital,
102 Pokfulam Road, Hong Kong,
SAR, China
Tel + 85 2 281 84300
Fax + 85 2 281 84030
E-mail ckhui23@gmail.com
Pegylated interferon alpha-2a (40 kDa) in the
treatment of chronic hepatitis B

International Journal of Nanomedicine 2006:1(3)
256
Lai et al
of the first, second, third, and fourth year of treatment, the
incidences of resistance are: 15%–32%, 38%, 56%, and 67%
respectively (Leung 2002). Adefovir dipivoxil is another oral
nucleoside–nucleotide analog that requires long-term therapy.
Initial reports show that adefovir dipivoxil selects resistant
mutants in only a limited proportion of patients, but adefovir-
resistant mutants do occur at cumulative rate of 18% by 192
weeks (Locarnini et al 2005).
A phase III study on entecavir showed that entecavir is
superior to lamivudine in hepatitis B e antigen (HBeAg)
positive and HBeAg negative nucleoside–nucleotide naïve
patients (Chang et al 2004; Shouval et al 2004). Entecavir,
with its profound suppression of serum HBV DNA, has less
risk of resistance over time with no resistance at 96 weeks in
HBeAg positive lamivudine-naïve patients (Gish et al 2005).
Entecavir resistance in lamivudine-resistant patients is 7%
genotypically and 1% phenotypically at 1 year. But follow-
up studies to determine the resistance rate after 2–5 years
of therapy are required, especially in lamivudine-resistant
patients. Another major limit is the lack of knowledge
on how long nucleoside–nucleotide therapy needs to be
continued, especially in HBeAg negative patients. This group
of patients has been shown to have persistent benefit with
144 weeks of adefovir dipivoxil therapy (Hadziyannis et al
2005). Furthermore, sustained response after withdrawal of
entecavir has also been shown to be less than optimal in both
HBeAg positive and HBeAg negative patients (Chang et al
2005; Lai et al 2005). Therefore, in view of the limitations of
current therapies for chronic HBV, there is a need to develop
new agents for the treatment of chronic HBV infection with
improved efficacy.
Immunomodulators
Conventional interferon alpha
Conventional interferon alpha-2b is the first drug to be
approved by the FDA for treatment of chronic HBV infection.
However, the efficacy of conventional interferon alpha,
defined as sustained loss of HBeAg and HBV DNA, is
limited. In a meta-analysis of 15 randomized, controlled trials,
loss of HBeAg and HBV DNA in HBeAg positive patients
is seen in 33% and 37% on conventional interferon alpha-
treated patients compared with 12% and 17% of untreated
patients, respectively (Wong et al 1993). The studies reviewed
in this meta-analysis employed direct spot hybridization
for the detection of serum HBV DNA. In Caucasians, the
long-term durability of HBeAg is as high as 90% (Niederau
et al 1996), while around 20%–70% of patients with loss of
HBeAg and hepatitis B e antibody (anti-HBe) seroconversion
will eventually lose hepatitis B surface antigen (HBsAg)
(Niederau et al 1996; Lau et al 1997). In those with detectable
HBV DNA after HBeAg seroconversion, the HBV DNA will
be undetectable in 60%–100% of those who lose HBsAg.
In HBeAg negative variants (precore mutants and others),
prolonged interferon at a dose of 3–5 MU thrice weekly
for at least 12 months results in a sustained biochemical
remission in 15%–25% of patients (Manesis and Hadziyannis
2001; Papatheodoridis and Hadziyannis 2001). Factors that
predict a favorable response to conventional interferon alpha
include low pretreatment level of HBV DNA (< 200 pg/ml),
high levels of serum aminotransaminase (> 100 U/L), and
evidence of necroinflammatory activities in the liver (Brook
et al 1989). In contrast, male sex, length of chronic state,
Asian origin, precore mutants, and human immunodeficiency
virus coinfection are factors associated with poor response
to conventional interferon alpha (Schiff 1993). In a recent
study from Taiwan, patients with genotype B were more
likely to respond to conventional interferon alpha than
those with genotype C (Kao et al 2000). A small study on
the use of conventional interferon beta at 3 MU weekly for
24 weeks also showed a 50% HBeAg seroconversion rate
similar to that achieved with conventional interferon alpha
(Kagawa et al 1993). However, conventional interferon beta
has never been recommended for use as a first-line agent for
the treatment of chronic HBV due to a lack of large-scale
randomized studies.
However, conventional interferon alpha is somewhat
tedious and requires daily or 3 subcutaneous injections a
week with a high occurrence of side-effects. Furthermore,
the rate of achieving HBeAg seroconversion in Asian patients
has been low (Conjeevaram and Lok 2003). This difference
between Asian and Caucasian patients is thought to be
related to the duration of the chronic state, the difference in
genotype, and baseline characteristics such as serum alanine
aminotransaminase (ALT) levels.
While Asians acquire HBV perinatally, Caucasians
acquire HBV predominantly in their adolescence or adult-
hood. In perinatally acquired infection, infection is followed
by a lengthy period of immune tolerance during which the
HBV DNA is high while the serum ALT levels are normal
or near normal and liver necroinflammation is minimal (Lai
et al 1987; Lok et al 1989; Conjeevaram and Lok 2003). In
the latter, there is more active host immune response directed
towards clearance of the infection with raised ALT levels
(Perillo 1989). These drawbacks with conventional interferon
alpha therapy have led to the development of pegylated
interferon alpha.

International Journal of Nanomedicine 2006:1(3) 257
Pegylated interferon alpha-2a for hepatitis B
Pegylated interferon
Pegylation
Pegylated interferon alpha-2a (40 kDa) joins a number of
therapeutic agents that are pegylated by the incorporation of a
polyethylene moiety into the active product. Pegylation of the
interferon alpha molecule is undertaken mostly to enhance the
pharmacokinetic properties of unmodified interferon alpha,
which will enable once a week dosing. Although a larger
pegylation molecule can result in better stability and longer
half-life, it will interfere with the active receptor binding
(Youngster et al 2002).
Pegylation may occur at multiple sites of the interferon
molecule, but pegylation at most of them does not retain the
biochemical and therapeutic properties. Therefore it is very
important to strike a balance between the pegylation site, size
of the molecule, steric properties, and biochemical properties
(Youngster et al 2002).
For example, the molecular weight of the pegylation chain
must be greater than 4000 to avoid poisoning by ethylene
glycol (Working et al 1997). The sites of attachment may
be more than one single site, but multiple chains may lead
to steric hindrance and prohibit the binding of the peglyated
interferon to its effector (Harris et al 2001). The bonds must
be strong and resistant to degradation (Wang et al 2000).
The pegylation polymer is usually covalently attached, via
an amide or urethane bond, to a lysine or histidine residue or
the N-terminus of the protein. By controlling the reagents,
condition, and the pH, pegylation of interferon at a specific
site with a defined pegylated polymer can be achieved
(Kozlowski et al 2001; Youngster et al 2002).
The first pegylated interferon alpha-2a to be developed
was 5 kDa in size. However, this drug has limited overall
clinical and laboratory benef its. Since then, pegylated
interferon alpha-2a (40 kDa) and pegylated interferon
alpha-2b (12 kDa) have been developed. As a result of their
difference in size and structure, these two molecules have
different in vivo and in vitro characteristics. Pegylated
interferon alpha-2a (40 kDa) has a longer half-life and is
mainly catabolized in the liver and has active breakdown
products. Pegylated interferon alpha-2b (12 kDa) is a smaller
molecule, has a shorter half-life, and acts as a pro-drug depot
by slowly releasing interferon (Wang et al 2000; Kozlowski
et al 2001).
Pegylated interferon alpha-2a (40 kDa)
The pegylation of interferon alpha-2a involves 2 chains of
20 kDa polyethylene glycol conjugated to the lysine residues
(position 31, 121, 131, and 134) of the interferon alpha-2a
molecule. The plasma level reaches its peak between 72 and
96 hours after administration and the volume of distribution
is 8–12 L, suggesting it is highly compartmentalized in
the intravascular space. The clearance half-life is 40–80
hours. The serum antiviral activity, as measured by the 2’-5’
oligoadenylate synthetase activity, peaks at 24–48 hours after
administration and it remains high for 1 week (Reddy 2004).
Because of its highly intravascular compartmentalization,
dose adjustment according to body weight is not necessary
(Table 1).
Pegylated interferon alpha-2a (40 kDa)
in HBeAg positive patients
When pegylated interferon alpha-2a was tested in a phase
II study at 90, 180, and 270 µg/week for 24 weeks against
conventional interferon alpha-2a, the HBeAg seroconversions
were 37%, 35%, 29%, and 25% respectively (Cooksley et
al 2003). The combined response (HBeAg loss, HBV DNA
suppression < 500 000 copies/mL, ALT normalization) was
higher in all pegylated interferon alpha-2a doses combined
(24% vs 12%). The response was still higher among patients
that were difficult to treat: 27% in patients with < 2 times
upper limit of normal (ULN) of baseline ALT vs 11% of
interferon alpha-2a; 20% vs 0% in patients with HBV
DNA >11.0 log copies/mL. The side-effects seemed to be
dose-dependent and occurred more often in the 270-µg and
180-µg groups. However, no difference in side-effect could
be observed when the 270-µg group was compared with the
180-µg group.
The beneficial effect of pegylated interferon alpha-2a
Table 1 Comparison between conventional interferon alpha-2a and pegylated interferon alpha-2a
Conventional interferon Pegylated interferon
alpha 2a alpha-2a
Time to peak serum level (hours) 7.3–12 80
Absorption half-life (hour) 2.3 50
Volume of distribution (L) 31–73 8–12
Clearance (L/hour) 6.6–29.2 0.06–0.10
Elimination half-life (hours) 3–8 65

International Journal of Nanomedicine 2006:1(3)
258
Lai et al
was further substantiated in 2 multinational phase III studies
(Marcellin et al 2004; Lau, Piratvisuth, et al 2005). In the
phase III HBeAg positive study, 814 HBeAg positive chronic
HBV-infected patients were randomized to receive either
pegylated interferon alpha-2a 180 µg weekly monotherapy,
pegylated interferon alpha-2a 180 µg weekly plus lamivudine
100 mg daily combination therapy, or lamivudine 100 mg
daily for a total of 48 weeks and assessed at 24 weeks after
the end of therapy (Lau, Piratvisuth, et al 2005). More than
85% of patients in this study were Asians, and the mean
HBV DNA was 9.9–10.1 log copies/mL. About 15%–18%
of patients had severe fibrosis or cirrhosis by liver biopsy
at baseline, and 9%–15% had received lamivudine therapy
and 2%–3% of patients had previously been treated with
conventional interferon alpha-2a.
HBeAg seroconversion and suppression of HBV DNA to
less than 100 000 copies/mL were significantly higher with
pegylated interferon alpha-2a monotherapy and pegylated
interferon alpha-2a plus lamivudine combination therapy
when compared with lamivudine monotherapy (Table 2).
More importantly, loss of HBsAg with development of
hepatitis B surface antibody (anti-HBs) was achieved in 8
of the 271 patients (3.0%) on pegylated interferon alpha-2a
monotherapy, 8 of the 271 patients (3.0%) on pegylated
interferon alpha-2a plus lamivudine combination therapy, and
none of the 272 patients (0%) on lamivudine monotherapy
(p=0.004 for both comparisons) (Lau, Piratvisuth, et al 2005).
Pegylated interferon alpha-2a (40 kDa)
in HBeAg negative patients
In another randomized, partially double-blind phase III
controlled study, 537 HBeAg negative chronic HBV patients
were randomized to receive either pegylated interferon alpha-
2a 180 µg weekly, combination pegylated interferon alpha-2a
180 µg weekly plus lamivudine 100 mg daily, or lamivudine
100 mg daily monotherapy for 48 weeks and followed up for
another 24 weeks after therapy (Marcellin et al 2004). Patients
were included into this trial if they had been HBeAg negative
and anti-HBe positive for at least 6 months, had an HBV DNA
of more than 100 000 copies/mL, a serum ALT level greater
than 1 but less than 10 times the upper limit of normal, and
had findings on liver biopsy within the previous 24 months
showing evidence of prominent necroinflammatory activity.
The 2 primary end points assessed at 24 weeks after the
completion of therapy of this study were normalization of
serum ALT and suppression of HBV DNA below 20 000
copies/mL.
After 48 weeks of therapy, suppression of serum HBV
DNA from baseline was the greatest with combination
pegylated interferon alpha-2a plus lamivudine therapy. On
the other hand, suppression of HBV DNA from the baseline
was similar in patients on pegylated interferon alpha-2a
monotherapy and lamivudine monotherapy.
At 24 weeks after therapy, normalization of serum ALT
was higher in patients receiving pegylated interferon alpha-2a
monotherapy (59%) and combination pegylated interferon
alpha-2a plus lamivudine therapy (60%) when compared with
those receiving lamivudine monotherapy (44%). Virologic
response was also higher in patients receiving pegylated
interferon alpha-2a monotherapy (43%) and combination
pegylated interferon alpha-2a plus lamivudine (44%) than
in patients receiving lamivudine monotherapy (29%).
Suppression of HBV DNA to below 400 copies/mL at week
72 was also higher in those receiving pegylated interferon
alpha-2a monotherapy (19%) and combination pegylated
interferon alpha-2a plus lamivudine therapy (20%) when
compared with those on lamivudine monotherapy alone (7%)
(Marcellin et al 2004).
Table 2 Efficacy of pegylated interferon alpha-2a on hepatitis B e Antigen positive chronic hepatitis B virus patients
Pegylated interferon Pegylated interferon Lamivudine
alpha-2a plus alpha-2a plus (n = 272)
placebo lamivudine
(n = 271) (n = 271)
Co-primary endpoints
HBeAg 32% (p < 0.001)a 27% (p = 0.023) 19%
seroconversion
HBV DNA
< 100 000 copies/mL 32% (p = 0.012)a 34% (p = 0.003)a 22%
Secondary endpoints
HBeAg loss 34% (p < 0.001)a 28% (p = 0.043)a 21%
ALT normalization 41% (p = 0.002)a 39% (p = 0.006)a 28%
Adapted from Lau, Piratvisuth, et al (2005).
a compared with lamivudine therapy.

International Journal of Nanomedicine 2006:1(3) 259
Pegylated interferon alpha-2a for hepatitis B
Most importantly, loss of HBsAg occurred in 7 patients
receiving pegylated interferon alpha-2a monotherapy
(5 Asians and 2 Caucasians) and in 5 patients receiving
combination pegylated interferon alpha-2a plus lamivudine
therapy (4 Asians and 1 Caucasian). This was significantly
higher compared with lamivudine monotherapy alone (n = 0)
(p = 0.007 and p = 0.030 respectively). HBsAg clearance with
development of anti-HBs occurred in 8 patients on pegylated
interferon alpha-2a (5 on pegylated interferon alpha-2a
monotherapy and 3 on combination pegylated interferon
alpha-2a plus lamivudine therapy) compared with none
in patients receiving lamivudine monotherapy (p = 0.029)
(Marcellin et al 2004).
Combination pegylated interferon
alpha-2a (40 kDa) plus lamivudine
therapy
Disappointingly, data generated from 2 studies do not
support the use of combination therapy with pegylated
interferon alpha-2a and lamivudine in terms of achieving a
sustained off-treatment response (Marcellin et al 2004; Lau,
Piratvisuth, et al 2005). In both phase III HBeAg positive and
HBeAg negative studies, the degree of viral load suppression
at the end of treatment was higher in those on a lamivudine-
containing regimen than those on pegylated interferon
alpha-2a alone (7.2 log vs 4.5 log respectively in the HBeAg
positive study and 5.0 log vs 4.1 log respectively in the
HBeAg negative study), but the rate of sustained disease
remission was higher in the latter (Marcellin et al 2004;
Lau, Piratvisuth, et al 2005). This finding suggests that the
mechanism of viral load reduction, in addition to the degree
of viral suppression, is an important factor affecting sustained
disease remission. However, one benefit of combination
pegylated interferon alpha-2a plus lamivudine therapy is a
lower YMDD mutation (1%–4%) compared with lamivudine-
only therapy (18%–27%) (Germanidis et al 2004).
Predictors of response
Patients infected with genotype A had the highest HBeAg
seroconversion at 24 weeks after pegylated interferon alpha-
2a (± lamivudine) therapy (52%) compared with patients
infected with genotype B or C (30%–31%), but the rate of
the gentotype C group was still better than with lamivudine-
only therapy (Chow et al 2005).
Patients with a high baseline ALT level and low HBV
DNA are also more likely to achieve sustained response
with pegylated interferon alpha-2a therapy. High baseline
ALT levels (> 5 times ULN) and low HBV DNA (< 9.1 log
copies/mL) achieved HBeAg seroconversion rates of 41%
and 53% respectively (Chow et al 2005). The authors also
found that a more profound HBeAg suppression at week 12
of therapy (less than 10 IU/mL) was associated with a higher
HBeAg seroconversion (53%).
A prior use of other antiviral therapies (lamivudine, or
conventional interferon alpha) does not preclude patients
from treatment with pegylated interferon alpha-2a, as the
response rates were similar to those without such use before
(Lau, Luo, et al 2005).
Durability of off-therapy sustained
response
In a longer follow-up study on the durability of off-therapy
response with pegylated interferon alpha-2a (Marcellin et al
2005), 177 HBeAg negative patients with biochemical and
virological response at 6 months after the completion of 48
weeks of pegylated interferon alpha-2a were rolled over into
a long-term observational study. The rates of biochemical
and virologic response measured 12 months after the end of
treatment with pegylated interferon alpha-2a monotherapy
were similar to those reported 6 months after the end of
treatment: 59% vs 59% for ALT normalization; 42% vs
43% for HBV DNA < 20 000 copies/mL; and 17% vs 19%
for HBVDNA < 400 copies/mL. In a subanalysis of those
patients who responded to pegylated interferon alpha-2a
monotherapy at the end of treatment, more than half (75%)
had HBV-DNA levels < 100 000 copies/mL for most of the
12 month follow-up; 30% had HBV-DNA levels < 20 000
copies/mL, and 15% had HBV-DNA levels permanently
< 400 copies/mL.
Effect on liver histology
The effect of pegylated interferon alpha-2a on liver histology
was analyzed by Lau et al and Cooksley et al (Cooksley
et al 2005; Lau, Cooksley, et al 2005). Both studies found
that pegylated interferon alpha-2a therapy can result in
histological improvement (defined as drop of 2 points in
the Modified Histologic Activity index) (Ishak et al 1995).
Forty-nine percent of HBeAg positive and 59% of HBeAg
negative patients treated with pegylated interferon alpha-2a
had histological improvement on second liver biopsy at 24
weeks after the end of therapy (Cooksley et al 2005).
Histologic improvement is more pronounced in patients
with virological response. Thus, HBeAg positive patients who
had achieved ALT normalization, HBV DNA suppression,

International Journal of Nanomedicine 2006:1(3)
260
Lai et al
and HBeAg seroconversion are more likely to have histologic
improvement. Similarly, HBeAg negative patients with
HBV DNA suppression or ALT normalization also showed
improvement in liver histology. HBeAg negative patients
achieving a combined response (normalization of serum ALT
and suppression of HBV DNA) had a higher histological
response (78% vs 49%) (Lau, Cooksley, et al 2005).
Adverse effects
The drop-out rates were low in both phase III studies
(2%–7%). Most patients (about 80%) finished the prescribed
dose (Lau, Luo, et al 2005). More patients given pegylated
interferon alpha-2a suffered from at least 1 adverse effect
(88%–89% vs 48%–56%). Most of them had fever, fatigue,
headache, myalgia, alopecia, and injection site reaction.
About 4%–6% of patients had serious adverse effects as
a result of pegylated interferon alpha-2a monotherapy and
pegylated interferon alpha-2a plus lamivudine combination
therapy, and 2%–3% of lamivudine monotherapy had a
serious adverse effect. Four deaths occurred in the
combination therapy but 3 of them were not related to the
treatment. The only death that was probably related was the
development of thrombotic thrombocytopenia purpura. Two
patients in the lamivudine monotherapy had liver failure
resulting in 1 liver transplantation and 1 death.
Optimal duration of therapy with
pegylated interferon alpha-2a (40 kDa)
Two studies have demonstrated the efficacy of 48 weeks of
pegylated interferons alpha-2a either as monotherapy or in
combination with lamivudine for the treatment of HBeAg
positive and negative chronic HBV infection (Cooksley et al
2003; Marcellin et al 2004; Lau, Piravisuth, et al 2005), but it
is uncertain if a shorter duration of treatment with pegylated
interferons will affect the sustained virological response rate.
This is because the current licensed duration of therapy with
conventional interferon alpha is 16–24 weeks. At the moment,
no direct comparison between 24 weeks and 48 weeks of
pegylated interferon alpha for chronic HBV infection has
been performed.
In a recent review of our experience in treating HBeAg
positive Chinese patients in Hong Kong with either 48 weeks
of pegylated interferon alpha-2a or 24 weeks of pegylated
interferon alpha-2b, we found that those treated with 48
weeks of pegylated interferon alpha-2a had a higher sustained
virological response, defined as HBeAg seroconversion with
serum HBV DNA less than 105 copies/mL at week 72 (34%
vs 8% respectively, p = 0.04) (Hui et al 2006). However,
owing to the small sample size, the use of different pegylated
interferon alphas and the retrospective nature of this study, the
results should be interpreted with caution and show the need
for a large-scale randomized prospective study comparing
24 with 48 weeks of pegylated interferon alpha in order to
determine its optimal duration of therapy.
Conclusions
Pegylated interferon alpha-2a will have an important role
in the treatment of chronic HBV infection. The choice of
pegylated interferon alpha-2a as a first-line therapy for
chronic HBV is based mostly on its efficacy in inducing off-
therapy sustained disease remission (Marcellin et al 2004;
Lau, Piratvisuth, et al 2005). Newer nucleoside–nucleotide
analogs such as entecavir and telbivudine with a more
pronounced and rapid suppression of HBV replication are
expected to be approved later. Higher or more pronounced
suppression of HBV DNA may be achievable with these
drugs. However, their rates of HBeAg seroconversion after
48 weeks of therapy do not seem to be more pronounced
than that achieved with lamivudine or adefovir dipivoxil. It
is also uncertain if these new nucleoside–nucleotide analogs
can lead to off-therapy sustained disease remission. A finite
course of pegylated interferon alpha-2a with an increased
rate of virologic and biochemical response coupled with its
improved off-therapy response makes pegylated interferon
alpha-2a a first-line therapy for chronic HBV.
In those who do not respond to pegylated interferon
alpha-2a, long-term maintenance therapy with a nucleoside–
nucleotide analog either as monotherapy or combination
therapy may have to be considered. However, drug resistance
and its avoidance is a major obstacle to maintenance therapy.
New nucleoside–nucleotide analogs such as entecavir and
telbivudine have a more pronounced viral suppression of
HBV replication, but their rates of viral resistance during
long-term therapy have yet to be evaluated and may be a
frequent problem, making them unsuitable for effective
long-term therapy (Hadziyannis 2003; Hadziyannis and
Papatheodoridis 2003). Hence, control of chronic HBV may
require long-term therapy consisting of combination therapy.
The challenge is to find the correct combination (Shaw and
Locarnini 2000).

International Journal of Nanomedicine 2006:1(3) 261
Pegylated interferon alpha-2a for hepatitis B
References
Beasley RP. 1988. Hepatitis B virus:the major etiology of hepatocellular
carcinoma. Cancer, 61:1942–56.
Brook MG, Karayiannis P, Thomas HC. 1989. Which patients with chronic
hepatitis B virus infection will respond to alpha-interferon therapy? A
statistical analysis of predictor factors. Hepatology, 10:761–3.
Chang TT, Chao YC, Sollano J, et al. 2005. Sustained response off-treatment
to entecavir and lamivudine after 48 weeks of treatment in nucleoside-
naive, HBeAg(1) patients:24-week follow-up results of Phase 3 Study-
022. Liver Int, 25:AB199.
Chang TT, Gish R, de Man R, et al. 2004. Entecavir is superior to lamivudine
for the treatment of HBeAg (+) chronic hepatitis B:results of phase III
study ETV-022 in nucleoside/nucleotide-naïve patients. Hepatology,
40:193A.
Chow WC, Cooksley G, Chang WY, et al. 2005. Predicting response in a
large, multinational trial of peginterferon α-2a (40 kDa ± lamivudine
vs lamivudine alone for HBeAg-positive chronic hepatitis B α-2a (40
kDa) ± lamivudine vs lamivudine alone for HBeAg-positive chronic
hepatitis B. Liver Int, 25:AB138.
Conjeevaram HS, Lok AS. 2003. Management of chronic hepatitis B.
J Hepatol, 38(Suppl 1):S90–103.
Cooksley G, Marcellin P, Bonino F, et al. 2005. Histologic improvement and
sustained response in patients with HBeAg-positive or HBeAg-negative
chronic hepatitis B treated with peginterferon α-2a (40 kDa) costs of
peginterferon α-2a for the treatment of patients with HBeAg-positive
CHB, compared with LAM treatment for 48. Liver International, 25:
AB134.
Cooksley WG, Piratvisuth T, Lee SD, et al. 2003. Peginterferon alpha-2a
(40 kDa):an advance in the treatment of hepatitis B e antigen-positive
chronic hepatitis B. J Viral Hepat, 10:298–305.
Germanidis G, Lau G, Marcellin P, et al 2004. Profound on-treatment
viral suppression with peginterferon alpha-2a (40 kD) (Pegasys)
plus lamivudine combination therapy limits the develoment of
YMDD mutations, but does not improve sustained response rates
over peginterferon alpha-2a (40 kD) alone. Hepatology, 40(Suppl
1):633A.
Gish RG, Chang TT, De Man RA, et al. 2005. Entecavir results in substantial
virologic and biochemical improvement and HBeAg seroconversion
through 96b weeks of treatment in HBeAg + chronic hepatitis B patients.
Hepatology, 42(Suppl 1):267.
Hadziyannis SJ, Papatheodoridis GV. 2003. Treatment of HBeAg negative
chronic hepatitis B with new drugs (adefovir and others). J Hepatol,
39(Suppl 1): S172–6.
Hadziyannis SJ, Papatheodoridis GV, Vassilopoulos D. 2003. Treatment of
HBeAg negative chronic hepatitis B. Sem Liver Dis, 23:81–8.
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. 2005. Long-term
therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis
B. N Engl J Med, 352:2673–81.
Harris JM, Martin NE, Modi M. 2001. Pegylation:a novel process for
modifying pharmacokinetics. Clin Pharmacokinet, 40:539–51.
Hui CK, Lai L, Lam P, et al 2006. 48 weeks pegylated interferon alpha-2a
is superior to 24 weeks of pegylated interferon alpha-2b in achieving
HBeAg seroconversion in chronic hepatitis B infection. Aliment
Pharmacol Ther. In press.
Ishak K, Baptista A, Bianchi L, et al. 1995. Histological grading and staging
of chronic hepatitis. J Hepatol, 22:696–9.
Kagawa T, Morizane T, Saito H, et al 1993. A pilot study of long-term
weekly interferon-beta administration for chronic hepatitis B. Am J
Gastroenterol, 88:212–6.
Kao JH, Wu NH, Chen PJ, et al 2000. Hepatitis B genotypes and the response
to interferon therapy. J Hepatol, 33:998–1002.
Kozlowski A, Charles SA, Harris JM. 2001. Development of pegylated
interferons for the treatment of chronic hepatitis C. BioDrugs,
15:419–29.
Lai CL, Chang TT, Chao YC, et al. 2005. Sustained response off-treatment
to entecavir and lamivudine after 48 weeks of treatment in nucleoside-
naive, HBeAg(1) patients:24-week follow-up results of Phase 3 Study-
022. Liver Int, 25:AB200.
Lai CL, Lok A, Lin HJ, et al. 1987. Placebo controlled trial of recombinant
alpha 2-interferon in Chinese HBsAg-carrier children. Lancet,
2:877–80.
Lau DT, Everhart J, Kleiner DE et al. 1997. Long-term follow-up of patients
with chronic hepatitis B treated with interferon alpha. Gastroenterology,
113:1660–7.
Lau GK, Cooksley G, Marcellin P, et al. 2005. Predictors of histologic
improvement and relationship between sustained response and histology
in patients with HBeAg positive and HBeAg netaive chronic hepatitis B
treated with Pegintereferon alpha 2a (40kD)(PEGASYS). Hepatology,
42:587A.
Lau GK, Luo KX, Paik SW, et al. 2005. Effect of age, gender, prior anti-
HBV therapy and drug exposure on sustained response in Asian
patients enrolled in a large multinational study of peginterferon α-2a
(40 kDa) ± lamivudine vs lamivudine for chronic hepatitis B. Liver
Int, 25:AB136.
Lau GK, Piratvisuth T, Luo KX, et al. 2005. Peginterferon Alpha-2a,
lamivudine, and the combination for HBeAg-positive chronic hepatitis
B. N Engl J Med, 352:2682–95.
Lee WM. 1997. Hepatitis B virus infection. N Engl J Med, 337:1733–5
Leung N. 2002. Clinical experience with lamivudine. Semin Liver Dis,
22(Suppl 1):15–21.
Locarnini S, Qi X, Arterburn S. 2005. Incidence and predictors of emergence
of adefovir resistant HBV during four years of adefovir dipivoxil therapy
for patients with chronic hepatitis B. J Hepatol, 42:17.
Lok AS, Lai CL, Wu PC, et al. 1989. Treatment of chronic hepatitis B with
interferon:experience in Asian patients. Sem Liver Dis, 9:249–53.
McMahon BJ. 1997. Hepatocellular carcinoma and viral hepatitis. In Wilson
RA (ed). Viral hepatitis: diagnosis, treatment, prevention. New York,
NY: Marcel Deckker. p 315–30.
Manesis EK, Hadziyannis SJ. 2001. Interferon alpha treatment and
retreatment of hepatitis B e antigen-negative chronic hepatitis B.
Gastroenterology, 121:101–9.
Marcellin P, Bonino F, Lau GK, et al. 2005. Factors associated with sustained
virologic response 1 year after teratment with peginterferon alpha-
2a (40kD0( PEGASYS) monotherapy for HBeAg-negative chronic
hepatitis. Hepatology, 42:580A.
Marcellin P, Lau GK, Bonino F, et al. 2004. Peginterferon alpha-2a alone,
lamivudine alone, and the two in combination in patients with HBeAg-
negative chronic hepatitis B. N Engl J Med, 351:1206–17.
Niederau C, Heintges T, Lange S, et al. 1996. Long-term follow-up of
HBeAg-positive patients treated with interferon alpha for chronic
hepatitis B. N Engl J Med, 334:1422–7.
Papatheodoridis GV, Hadziyannis SJ. 2001. Diagnosis and management of
pre-core mutant chronic hepatitis B. J Viral Hepat, 8:311–21.
Perillo RP. 1989. Treatment of chronic hepatitis B with interferon:experience
in Asian patients. Sem Liver Dis, 9:240–8.
Reddy KR. 2004. Development and pharmacokinetics and pharmaco-
dynamics of pegylated interferon alpha-2a (40 kD). Semin Liver Dis,
24(Suppl 2):33–8.
Schiff ER. 1993. Treatment algorithms for hepatitis B and C. Gut, 34
(Suppl 2):S148–9.
Shaw T, Locarnini S. 2000. Combination chemotherapy for hepatitis B virus:
the path forward? Drugs, 60:517–31.
Shouval D, Senturk H, Gish RG, et al. 2004. Entecavir (ETV) demonstrates
consistent responses throughout baseline demographic subgroups for
the treatment of nucleoside-naïve, HBeAg+ and HBeAg- patients with
chronic hepatitis B. J Hepatol, 42:192.
Wang YS, Youngster S, Bausch J, et al. 2000. Identification of the major
positional isomer of pegylated interferon alpha-2b. Biochemistry,
39:10634–40.

International Journal of Nanomedicine 2006:1(3)
262
Lai et al
Wong DK, Cheung AM, O'Rourke K, et al. 1993. Effect of alpha-interferon
treatment in patients with hepatitis B e antigen-positive chronic hepatitis
B. A meta-analysis. Ann Intern Med, 119:312–3.
Working PK, Newman MS, Johnson J. 1997. Safety of poly(ethylene glycol)
and poly (ethylene glycol) derivatives. In Harris JM, Zaplinsky S (eds).
Poly(ethylene glycol): Chemistry and biological Applications. San
Franciso, CA: American Chemical Society. p 45–59.
Youngster S, Wang YS, Grace M, et al. 2002. Structure, biology, and
therapeutic implications of pegylated interferon alpha-2b. Curr Pharm
Des, 8:2139–57.