慢性乙型肝炎现代抗病毒治疗进展

Review article: current antiviral therapy of chronic hepatitis B

W. S. AYOUB & E. B. KEEFFE

From the Division of Gastroenterology and Hepatology,
Department of Medicine,
Stanford University Medical Center,
Stanford, California

Corresponding Author: Emmet B. Keeffe, M.D.
Stanford University Medical Center

SUMMARY

Background
The long-term goals of therapy for chronic hepatitis B are to reduce serum HBV DNA to
low or undetectable levels and ultimately reduce or prevent the development of cirrhosis
and hepatocellular carcinoma.

Aim
To review the current treatment of chronic hepatitis B, with a focus on diagnosis and
management of resistance and active management of suboptimal responses.

Methods
A systematic review of the literature, with a focus on recent guidelines, was undertaken

Results
Among the six drugs licensed for the treatment of chronic hepatitis B in the United
States, the preferred agents in 2008 will include entecavir, peginterferon alfa-2a, possibly
telbivudine, and tenofovir following licensure. When using an oral agent, a major focus
of management is the selection of a drug with high potency and low rate of resistance,
and active on-treatment management to optimize therapy. Preventing the sequelae of
antiviral drug resistance and appropriate management when resistance is initially detected
is also a major focus of current management. The addition of an antiviral agent that is not
cross-resistant is critical to restore suppression of viral replication.

Conclusions
Newer agents and modified treatment strategies, especially using combination therapy,
holds promise to optimize the management of patient with chronic hepatitis B by
achieving the high potency and the lowest rate of resistance.

BACKGROUND
Chronic hepatitis B virus (HBV) infection is a major global cause of morbidity
and mortality. Of 350 million people chronically infected with HBV worldwide, at least
1.25 million individuals live in the United States.1,2 The prevalence of chronic hepatitis B
(CHB) in the United States is under-reported, since epidemiological studies do not
include the prison population or take into consideration the continuous influx of
immigrants from endemic areas with a high prevalence rate of HBV infection.
Individuals with CHB are at risk of premature death from cirrhosis with liver failure or
hepatocellular carcinoma (HCC).2,3 Recent studies have shown that the level of serum
HBV DNA correlates over more than a decade with the risk of developing cirrhosis4 and
HCC (Figure 1).5 For this reason, early diagnosis of chronic HBV infection and treatment
to reduce serum HBV DNA to low or undetectable levels are important in preventing
progression of HBV infection to advanced disease with these complications.
The arsenal of medications to treat CHB continues to increase.3 Compared to two
medications licensed by the United States Food and Drug Administration (FDA) in the
1990s (interferon alfa-2b and lamivudine), four additional agents have now been
licensed: adefovir dipivoxil, entecavir, peginterferon alfa-2a, and telbivudine, with
tenofovir likely to be licensed in the third quarter of 2008. The future management of
CHB appears to be more promising than ever before, with many treatment options
currently available, new drugs in development, and different on-treatment strategies for
optimizing the use of current agents undergoing investigation.

NATURAL HISTORY
An individual’s age and time of infection have a strong impact on the course of
acute HBV infection.2,6 Infection at birth or in early childhood results in the development
of chronic HBV infection in more than 90% of individuals. In contrast, infection in
adulthood is most often self-limited, with more than 95% of infected individuals clearing
the virus.6 The hallmark of acute HBV infection is elevated alanine aminotransferase
(ALT) levels and the presence of hepatitis B surface antigen (HBsAg), IgM antibody to
hepatitis B core antigen (anti-HBc), and hepatitis B e antigen (HBeAg), although the
latter serologic test is not routinely used in practice.

Once chronicity is established, patients infected at birth or early in life typically
enter into an initial immune tolerance phase, which is characterized by high levels of
viral replication (elevated HBV DNA levels and presence of HBeAg) but normal ALT
levels.6 This phase is usually short-lived or absent in adult infection, but long-lived when
infection occurs in infancy or early childhood. Although a liver biopsy is not usually
performed during the immune tolerance phase, studies have shown the presence of
minimal or absent inflammation and fibrosis on histological examination.6-8
The immune clearance phase follows the immune tolerance phase and is
characterized by clearance of infected hepatocytes, which results in elevated or
fluctuating ALT levels and persistently high HBV DNA levels. Inflammation with
varying degrees of fibrosis is characteristic of this stage on a liver biopsy specimen.
Repetitive hepatitis flares and prolonged duration of this phase can lead to advanced
fibrosis or cirrhosis. During this phase, patients may spontaneously seroconvert and
develop antibodies to HBeAg (anti-HBe), which occurs at an annual rate of 5% to 15%
without therapy, but this process can be accelerated by initiation of antiviral therapy.7,8 A
recent study of Alaska Native persons showed that individuals infected with HBV
genotype C, compared to those with genotypes A, B, D, and F, had an increased
likelihood of having persistently detectable serum HBeAg and longer time to
spontaneous HBeAg clearance.9 The age at which 50% of HBV genotype C-infected
individuals cleared HBeAg was 47.8 years, while it was less than 20 years of age in those
with genotypes A, B, D and F. In addition, after losing HBeAg, those with genotypes C
and F were more likely to revert to the HBeAg-positive state. Thus, genotype may have a
strong effect on the outcome of chronic HBV infection as patients with genotype C have
a longer immune clearance phase, and genotype C may also be responsible for most
perinatal transmission, given that seroconversion from HBeAg occurs decades later than
in other genotypes.

Seroconversion from HBeAg to anti-HBe signals the transition to the
nonreplicative phase of infection, and patients in this stage are referred to as inactive
HBsAg carriers, with normal ALT levels, undetectable or low levels of serum HBV
DNA, and the presence of anti-HBe.10 Liver biopsy at this stage may reveal either
resolution or presence of minimal lingering inflammation, with variable amounts of
fibrosis that may have developed during the immune clearance phase. Inactive carriers,
particularly older subjects, may spontaneously lose HBsAg and seroconvert to antibody
to HBsAg (anti-HBs). However, a small amount of serum HBV DNA can often be
detected using sensitive polymerase chain reaction techniques.11
Reactivation of HBV infection may occur in a subgroup of patients despite
HBeAg seroconversion. Reactivation usually occurs close to the time of HBeAg loss, but
can also occur many years later, with high levels of serum HBV DNA and significant
disease on liver biopsy.10,12,13 Emergence of the precore or core promoter mutants of
HBV are responsible for such reactivation.11,13 This phenomenon was first recognized in
the Mediterranean area, but it is becoming more common in the United States.11 Chu and
colleagues14 reported a prevalence rate of 27% for precore and 44% for basal core
promoter variants in a survey of patients with HBV infection in the United States.
HBeAg-negative patients tend to have more severe liver disease than patients who
are HBeAg-positive. Serum ALT levels may remain normal and serum HBV DNA
undetectable for many years before later detection. Patients with HBeAg-negative CHB
are often erroneously labeled as inactive carriers, due to intermittently low or normal
ALT levels and undetectable HBV DNA. However, frequent monitoring of HBV DNA
and ALT can easily detect fluctuation in viremia levels in this group of patients, leading
to early detection and intervention prior to the development of progressive liver disease.15
Serum HBV DNA levels greater than 2,000 IU/mL should raise suspicion for HBeAgnegative
CHB rather than an inactive carrier state.16 Therefore, it is not surprising that
significant inflammatory changes and fibrosis are present in more than 50% of HBeAgnegative
patients. The majority of these patients have a poor long-term prognosis, since
the diagnosis of CHB is made late in the course of the disease, with 25% to 50% having
cirrhosis at time of diagnosis.10,11,17

PREVENTION
Vaccination remains the best prevention against acquisition of HBV infection.
There are 3 hepatitis B vaccines on the market in the United States. Health policies have
advocated hepatitis B vaccination since the 1980s, and recommendations for vaccination
were expanded in the 1990s, resulting in decreased incidence of acute and chronic HBV
infection. During the period from 1990, 8 years after the first set of vaccination
recommendations were issued from the Centers for Disease Control and Prevention
(CDC), to 2005, the incidence of acute hepatitis B declined 78%.18 Currently, HBV
vaccination for infants is nearly universal, and more than 90% of infants under the age of
3 years of age in the United States have been vaccinated.18 Vaccination recommendations
have also been expanded to include all adolescents up to 18 years of age. Furthermore,
three additional strategies have been advocated to prevent dissemination of HBV:
prevention of vertical transmission by screening all pregnant women and immunization
of infants born of infected mothers, routine childhood vaccination and catch-up
vaccination for adolescents, and vaccination of high risk adults (Table 1).

TREATMENT OF CHRONIC HEPATITIS B
Achieving maximum viral suppression without the development of antiviral drug
resistance, reducing progression to cirrhosis, and decreasing the risk of developing HCC
are the primary goals of treatment of CHB. Treatment is recommended for patients in the
immune clearance and reactivation phases, characterized by elevated serum ALT and
HBV DNA levels. The aim of therapy in patients with HBeAg-positive CHB is loss of
HBeAg and/or seroconversion to anti-HBe, normalization of ALT levels, and maximum
suppression of HBV DNA to low or undetectable levels. Accomplishing these goals will
result in improvement of liver histology, reduction in disease progression, and decreased
incidence of HCC, as has been shown in patients with advanced hepatic fibrosis.19
Emerging evidence confirming the relationship between increased liver-related mortality
and ALT levels greater than 20 U/L for females and 30 U/L for males has led to the
conclusion that a lower threshold for elevated serum ALT be used when considering
candidates for treatment.10,20

Indications for treatment differ in patients who are HBeAg-positive versus HBeAgnegative.
10,21 A serum HBV DNA level of at least 20,000 IU/ml (~100,000 copies/mL)
and an ALT level that is elevated10 or 2 times the upper limits of normal (ULN)21 are
indications for treatment in HBeAg-positive CHB. In the setting of an ALT level <2 x
ULN and an elevated HBV DNA level, liver biopsy is usually recommended, since
approximately 20% of individuals over the age of 35 will have significant hepatic fibrosis
on biopsy.10 However, treatment is indicated regardless of the level of HBV DNA if the
liver biopsy reveals inflammatory activity. While therapy in patients with elevated ALT
levels and HBV DNA level can be deferred for 3 to 6 months to assess the development
of HBeAg seroconversion, therapy should be promptly initiated in patients with elevated
serum bilirubin levels or signs of hepatic decompensation.21
The two primary goals for the treatment of patients with HBeAg-negative CHB
are viral suppression and normalization of ALT levels. Chu and colleagues16 have
demonstrated that the presence of significant inflammation on liver biopsy in HBeAgnegative
patients with HBV DNA levels <100,000 copies/mL. Therefore, initiation of
treatment is indicated in the setting of a fluctuating ALT levels with serum HBV DNA
levels >2000 IU/mL(~10,000 copies/mL).10 Similar to HBeAg-positive patients, active
hepatitis found in HBeAg-negative patients on liver biopsy dictates treatment for those
with an elevated HBV DNA level even if the setting of a normal ALT level.
Regardless of HBeAg status, patients with low HBV DNA levels and normal
ALT levels warrant surveillance. Serial monitoring with laboratory testing every 3
months for one year after initial diagnosis and again 6 to 12 months thereafter is usually
recommended. Active inflammation found on liver biopsy indicates the need for
treatment regardless of the low level of the viremia.10,21 Though antiviral therapy is
continued for 6 to 12 months after seroconversion in HBeAg-positive CHB, it is usually
continued indefinitely in HBeAg-negative CHB to prevent relapse.10,21
APPROVED THERAPIES FOR TREATMENT OF CHRONIC HEPATITIS B
Antiviral therapy for CHB includes immunomodulatory agents (interferon and
peginterferon) and oral antiviral agents (the nucleoside and nucleotide analogs).
Nucleoside analogs include lamivudine, telbivudine and entecavir, while nucleotide
analogs include adefovir and tenofovir. While interferon has been limited by its poor
tolerability and significant side effect profile, the efficacy of oral agents has been
hampered by the necessity of prolonged use and emergence of resistance. Six drugs are
currently approved by the FDA for the treatment of CHB: interferon alfa-2b,
peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine.3,10,21
Initiation of therapy requires consideration not only of the potency of individual
drugs, but also the resistance profile of each agent. Lamivudine is not used in most
settings as a first-line agent secondary to a high rate of antiviral drug resistance (65% to
70% after 5 years of therapy).10,21 Similarly, telbivudine is limited to patients who are
able to achieve an undetectable serum HBV DNA by week 24 of therapy, which
minimizes the rate of resistance. The overall rate of telbivudine resistance in pivotal trials
was 22% in patients with HBeAg-positive CHB and 9% in those with HBeAg-negative
CHB.21 Reaching the milestone of an undetectable serum HBV DNA by week 24 results
in a very low rate of resistance and continued efficacy by week 96.22
Peginterferon Alfa-2a
Peginterferon alfa-2a has replaced standard interferon alfa-2b due to its less
demanding injection schedule and its comparable or improved efficacy.10,21 Peginterferon
alfa-2a used for 48 weeks results in a 27% rate of HBeAg seroconversion and 25% rate of
loss of HBV DNA. HBeAg seroconversion is increased to 32% with longer duration of
therapy at week 72. When compared to peginterferon alfa-2a alone, the addition of
lamivudine to peginterferon alfa-2a therapy has no added benefit in HBeAg-positive and
HBeAg-negative CHB.3,23
In patients with HBeAg-negative CHB, 48 weeks of therapy with peginterferon
alfa-2a, with or without lamivudine, resulted in a significantly greater percentage of
patients with HBV DNA <400 copies/mL 24 weeks after the end of treatment compared
with lamivudine monotherapy (19% and 20% versus 7%).24 The combination of
peginterferon alfa-2a plus lamivudine appeared to offer no advantages over treatment
with peginterferon alfa-2a alone. HBsAg seroconversion was reported in 3% of patients
treated with peginterferon alfa-2a, 2% of those treated with peginterferon alfa-2a plus
lamivudine, and in no patients treated with lamivudine alone. In addition, the rate of
emergence of lamivudine-resistant mutations was reduced markedly in the combination
therapy arm. A recent 4-year follow-up study of patients with HBeAg-negative CHB
treated with peginterferon alfa-2a +/- lamivudine versus lamivudine monotherapy
reported significantly higher rates of ALT normalization (27% versus 18%), HBV DNA
<400 copies/mL (17% versus 7%), and HBsAg loss (11% versus 2%) in the peginterferon
alfa-2a–treated patients.25 Among patients who either achieved or did not achieve an
HBV DNA level <400 copies/mL by 48 weeks at the end of treatment, 43% and 0.5%,
respectively, achieved HBsAg clearance.
Hepatitis B genotype predicts response to peginterferon therapy. Genotype A has
a better response than genotype D, and genotype B has a better response than genotype C
in most studies.3,10 Patients with CHB infected with genotypes A and B are therefore the
best candidates for treatment with peginterferon alfa-2a, especially if they are young, lack
comorbidities, have HBV DNA levels less than 109 copies/mL, and also have ALT levels
at least 2-3 times the upper limits of normal.26
The fixed duration of therapy and the lack of antiviral drug resistance distinguish
interferon-based therapy from treatment with available oral agents. However,
administration by injection and the extensive side effect profile have hindered the broader
use of peginterferon therapy in the United States.
Lamivudine
The first breakthrough in oral anti-HBV therapy came with the FDA licensure of
lamivudine in 1998. It has a lower durability of response than interferon in both HBeAgpositive
patients (50-80%) and HBeAg-negative patients (20-25%).3,10 In patients with
HBeAg-positive disease, treatment is continued until HBeAg seroconversion occurs.
Durability of response is further enhanced by extending treatment for an additional six
months.10,21 In addition, treatment of patients with advanced fibrosis is associated with a
lower rate of disease progression as well as lower incidence of HCC.19 Patients who are
HBeAg-negative are usually treated indefinitely, as relapse is invariable if treatment is
stopped after a short duration of treatment even with an undetectable serum HBV DNA.
As with most of the oral agents, prolonged duration of therapy is associated with
an increasing rate of antiviral drug resistance. Lamivudine leads to resistance at a rate of
approximately 20% of patients per year, and can reach 65% to 70% after 4 to 5 years of
therapy. As a result, lamivudine is not considered a first-line agent in the treatment of
CHB.10,21
Patients who develop YMDD mutation with lamivudine therapy were initially
switched to adefovir or entecavir.10,21 However, recent data support the addition of a
nucleotide agent such as adefovir, which avoids an increased rate of subsequent adefovir
resistance.10,21,27 In addition, adefovir resistance can be successfully treated with the
addition of lamivudine to continued adefovir, which is now the preferred approach.10,21,28
Adefovir dipivoxil
Adefovir dipivoxil is the second oral agent approved by the FDA in 2002 for the
treatment of CHB, and is associated with a 12% rate of HBeAg seroconversion, 21% rate
of undetectable serum HBV DNA, and 53% rate of histological improvement in HBeAgpositive
patients after one year of therapy.29 Similar to lamivudine, HBeAg
seroconversion marks the end of therapy with adefovir in HBeAg-positive patients. Once
seroconversion occurs, it is sustained in 91% of patients.10,21
After one year of adefovir therapy in patients with HBeAg-CHB, serum HBV
DNA is undetectable in 51% of patients, who are then treated long-term.30 Histologic
improvement, ALT normalization, and viral suppression have been demonstrated for up
to 5 years of administration of adefovir.31 However, resistance becomes a limiting factor
with prolonged use. Resistance has been demonstrated at 1, 2, 4 and 5 years at a rate of
0%, 3%, 18% and 29%, respectively.31 Furthermore, persistence of high level of HBV
viremia after 48 weeks of adefovir therapy predicts the emergence of resistance.31
Entecavir
Entecavir is a nucleoside analog shown to have greater potency when compared to
other lamivudine. At a dose of 0.5 mg daily, therapy with entecavir results in a 6.98 log10
copies/mL decrease of HBV DNA levels in HBeAg-positive patients.32 When compared
to lamivudine, entecavir achieves increased rates of histological improvement (72% vs.
62%), normalization of ALT (78% vs. 70%), and viral suppression of HBV DNA to less
than 400 copies/mL (69% vs. 38%, respectively).32 However, it has a comparable rate of
HBeAg seroconversion when compared to lamivudine after one year of therapy. In
addition, entecavir achieved greater histological improvement (70% vs. 61%) and viral
suppression (91% vs. 73%) than lamivudine in HBeAg-negative CHB patients.33 The
biochemical and virologic response is further maintained up to 96 weeks on entecavir
therapy.34
The rate of entecavir resistance is minimal (1.2%) in treatment-naïve patient after
5 years of therapy.35 However, in lamivudine-refractory patients, the cumulative
probability of entecavir resistance at years 1 through 5 is 6%, 15%, 36%, 46%, and 51%,
respectively.35
Telbivudine
Telbivudine is a nucleoside analog and a potent inhibitor of HBV DNA
polymerase. The GLOBE trial, a randomized phase III study, established the superiority
of telbivudine to lamivudine in HBeAg-positive and HBeAg-negative patients after 1 and
2 years of therapy.36,37 The rate of HBeAg seroconversion was 22% and viral suppression
was limited to HBV DNA levels of less than 300 copies/mL after 1 year of therapy in
60% of HBeAg-positive patients.38
Resistance to telbivudine has been reported as 4.4% and 21.6% in HBeAgpositive
patients and 2.7% and 8.6% in HBeAg-negative patients after 1 and 2 years of
therapy.37 However, patients who achieved viral suppression of HBV DNA by week 24
of therapy had better rates of HBeAg seroconversion, ALT normalization, and more
importantly, a lower rate of antiviral drug resistance.22
Telbivudine also achieves improved early viral suppression compared to adefovir
at week 24 in HBeAg-positive patients regardless of whether the patients were treated
initially with telbivudine or switched from adefovir to telbivudine.39 The early virologic
suppression resulted in better rates of HBeAg seroconversion, ALT normalization, and
viral suppression.
Tenofovir
Tenofovir is structurally related to adefovir and is likely to be approved by the
FDA for treatment of CHB in the third quarter of 2008. It is more potent than adefovir in
achieving viral suppression defined as less than 400 copies/mL (76% vs. 13%),
histological improvement (67% vs. 12%) and higher rates of HBsAg loss (3.2% vs. 0%)
at 48 weeks in patients with HBeAg-positive CHB.40 In this study design, all eligible
subjects were either continued on tenofovir or switched from adefovir to tenofovir for a
planned additional 4 years. Recent 72 week data show that 89% of HBeAg-positive
patients continued on tenofovir had serum HBV DNA <400 copies/mL, and 78% of
patients who did not achieve complete viral suppression did so after 24 weeks of
tenofovir therapy.41
In a second phase III study in patients with HBeAg-negative CHB, tenofovir was
also superior to adefovir in achieving increased viral suppression (93% vs. 63%),
improved inflammatory score and viral suppression (71% vs. 49%).42 Recent 72 week
data show that 98% of patients continued on tenofovir had serum HBV DNA <400
copies/mL, and 94% of patients who did not achieve complete viral suppression did so
after 24 weeks of tenofovir therapy.43 Both adefovir and tenofovir was well tolerated in
all of the above studies, with no evidence of significant renal toxicity. No resistance to
tenofovir has been detected to date.
Emtricitabine
Emtricitabine is a nucleoside analog structurally similar to lamivudine that is
currently approved for use with other antiretroviral drugs in the treatment of human
immunodeficiency virus (HIV) infection. It demonstrates activity against HBV and
shares the same drug resistance mutation as lamivudine (M204V/I ± L180M). A 48-week
course of therapy with emtricitabine is associated with a 62% improvement in fibrosis
and inflammation compared to 25% in the placebo group. Viral suppression to less than
400 copies/mL was achieved in 54% versus 2% in the emtricitabine and placebo groups
respectively. Resistance development occurred in 9% of patients after one year and 13%
after two years of therapy.44,45 The rate of emergence of resistance and cross-resistance
with lamivudine limits use of emtricitabine as monotherapy in management of CHB.
However, it is a good candidate for use with other antiviral agents and is currently being
tested in combination with tenofovir in the management of CHB.
MANAGEMENT OF RESISTANCE
Recommendations regarding management of CHB once antiviral drug resistance
has emerged have been addressed in guidelines of the American Association for the
Study of Liver Diseases (AASLD) and the U.S. treatment algorithm (Table 2).10,21 The
terminology that has been employed to define antiviral drug resistance has varied in
different publications.46,47 Genotypic resistance is universally defined by the detection of
viral populations bearing amino acid substitutions in the reverse transcriptase region of
the HBV genome that have been shown to confer resistance to antiviral drugs in in vitro
phenotypic assays.46 These genotypic mutations usually are detected in patients who have
developed virologic breakthrough (also called secondary treatment failure), defined as a
≥1 log10 increase in serum HBV DNA above nadir on 2 or more occasions 1 month apart
while receiving treatment, but genotypic mutations can also be present in patients with
persistent viremia and no virologic breakthrough. Biochemical breakthrough is defined as
a rise in ALT levels after achieving normalization while continuing to receive therapy.
Typically, genotypic resistance is followed after some variable time interval with
virologic breakthrough, followed later by biochemical breakthrough and possible clinical
symptoms, sometimes called clinical breakthrough. Others have used the terminology of
phenotypic resistance to refer either to virologic breakthrough (≥1 log10 increase in
serum HBV DNA above nadir, as defined above) or to virologic rebound (increase in
serum HBV DNA to >20,000 IU/mL or to above pretreatment HBV DNA level after
achieving a virologic response) during continued treatment.47 Some experts suggest
limiting the use the term phenotypic resistance to a decreased susceptibility of an HBV
polymerase to an antiviral treatment in vitro.46
Experience derived from HIV drug development and observations from the
current treatment of CHB has identified risk factors for emergence of viral resistance:
monotherapy, long duration of therapy, and inappropriate use of antiviral drugs when not
indicated. Despite advances in HBV genotypic resistance testing, not all mutations can be
detected at present. Therefore, genotypic testing cannot be recommended prior to
initiation of therapy unless the patient is undergoing treatment for CHB.47 Instead,
patients receiving monotherapy need frequent monitoring for emergence of resistance by
checking serum HBV DNA with a sensitive assay on a regular basis. The AASLD
guideline advocates monitoring HBV DNA levels in patients with CHB every 3-6 months
while on treatment.21 Patients receiving lamivudine therapy should be tested every 3-6
months, while patients on adefovir or entecavir every 6 months after the first year of
therapy.47 Patients with cirrhosis should be tested every 3 months.10
Once a patient develops virologic breakthrough, resistance testing is paramount in
identifying mutations and guiding the choice of a different agent.10,21,47 After mutation
analysis results are available, a swift change in therapy will result in more rapid virologic
response than delayed change in therapy. Lampertico et al.48 have demonstrated
improved early virologic suppression at 3 months (100% vs. 46%) and 2 years (100% vs.
78%), and normalization of ALT at 1 year (100% vs. 93%) when adefovir was added at
the time of genotypic resistance (3-6 log10 copies/mL, normal ALT), compared to the
addition at the time of phenotypic resistance (>6 log10 copies/mL, elevated ALT levels).
Patients with lamivudine resistance can be successfully treated by adding or
switching to adefovir,49,50 or by switching to entecavir,51 resulting in viral suppression,
normalization of ALT levels, and histological improvement. However, current guidelines
recommend the adding rather than switching to a nucleotide agent to minimize the
subsequent development of resistance to the new agent. The addition of adefovir to
lamivudine in HBeAg-negative lamivudine-resistant CHB has been shown to result in
effective viral suppression without the development of adefovir resistance.50
Tenofovir is an effective treatment for treatment-experienced patients, especially
those with lamivudine resistance; however, patients with previous therapy with adefovir
and the presence of adefovir resistance mutations have an inferior response to tenofovir.52
In a retrospective analysis of 131 patients from 16 centers in Germany and the
Netherlands treated with tenofovir between 2002 and 2006, 85% of patients overall
achieved HBV DNA <400 copies/mL at the end of follow-up. The rates of undetectable
serum HBV DNA after 12 months of tenofovir was 100% in those with no mutations,
92% in those with YMDD mutations, and only 30% in those with adefovir resistance
mutations.52 Due to high rates of resistance, entecavir is not recommended as
monotherapy in patients with YMMD mutations. In addition, telbivudine and lamivudine
have cross-resistance at codon 204, making a change to telbivudine alone or in
combination with other therapy less desirable.
It is clear from experience with lamivudine and adefovir that monotherapy can be
associated with the development of resistance in the case of drugs with a low genetic
barrier to resistance. A combination of a nucleoside and nucleotide analogs provides
better viral suppression with a higher genetic barrier to the emergence of resistance.
Tenofovir and entecavir are currently the only drugs that have demonstrated a high
genetic barrier to resistance and thus are preferred drugs for monotherapy. The
combination of lamivudine with an immune modulator, peginterferon alfa-2a, results in a
lower rate of resistance when compared to lamivudine monotherapy in a 48 weeks active
treatment trial (1% vs. 18% respectively).24 The combination of adefovir and
peginterferon also results in improved 24-week viral suppression compared to
peginterferon monotherapy (71% vs. 41%).53
ROADMAP FOR ON-TREATMENT MANAGEMENT ON HEPATITIS B
The implications of genotypic resistance in patients with CHB make on-treatment
monitoring vital. The “roadmap” approach, an on-treatment monitoring and management
strategy for patients receiving oral therapy, advocates making treatment decisions based
on the serum HBV DNA levels at 12 and 24 weeks of therapy (Figure 2).54 Treatment
failure is defined as less than 1 log10 IU/mL decrease of serum HBV DNA from baseline
at week 12, presuming that patient noncompliance has been excluded. When treatment
fails, switching to a more potent alternative agent is recommended.
The most important aspect of the roadmap is to assess virologic response at week
24, with categorization of patients receiving oral agents into 3 response groups: complete
response (HBV DNA <60 IU/mL), partial response (HBV DNA 60 to less than 2000
IU/mL), or inadequate response (HBV DNA >2000 IU/mL).54 Frequent monitoring for
virologic breakthrough is recommended every 3 to 6 months. Patients who achieve only a
partial virologic response at week 24 may need to change to a different therapy. For
some, a second drug can be added that is not cross-resistant with the first drug. However,
if they are being treated with a drug with a high genetic barrier to resistance, such as
entecavir, patients can continue treatment to and beyond 48 weeks. In this situation,
patients should undergo viral level testing every 3 to 6 months. Some drugs, such as
adefovir, have a delayed antiviral effect, and these patients can potentially continue
therapy and be monitored every 3 months with further assessment at week 48. If their
virologic response remains partial or becomes inadequate at this time point, as defined by
the roadmap (Figure 2), therapy should be changed. An exception might be a serum HBV
DNA level that has been falling steadily and is nearly undetectable. If the response
becomes complete at week 48, the therapy can be continued.
Patients with an inadequate virologic response at week 24 need to switch to a
different, more effective drug.54 Alternatively, a second drug without cross-resistance can
be added to the first drug. The patient should then be monitored every 3 months up to
week 48. If the serum HBV DNA level falls to undetectable levels at week 48, the HBV
DNA testing can be decreased to every 6 months. However, patients with advanced
disease should continue to be monitored every 3 months, regardless of their response to
treatment.

CONCLUSION
CHB is a disease that is preventable with vaccination. The goal of therapy in
patients with CHB is to prevent progression to cirrhosis, liver failure and HCC. This goal
is best accomplished by achieving a rapid and long-lasting virologic suppression.
Combination therapy, especially with nucleoside/nucleotide analogs, may be the ultimate
and ideal approach to achieve these goals. However, further clinical studies are needed
for confirmation of pilot study results of combination therapy. The proposed roadmap
approach will help clinicians make changes to therapy with the guidance of mutation
analysis results before biochemical or clinical breakthrough occurs. With more drugs in
development and the expected approval of tenofovir in 2008, the arsenal against HBV
continues to expand. Tenofovir is a potent agent with a high genetic barrier, and will
likely emerge along with entecavir as the most effective treatments for patients with
CHB. Although tenofovir monotherapy has not yet been associated with the development
of resistance, results after prolonged use remain to be determined.

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