The clinical practice guidelines for the management of chronic hepatitis B (CHB) were
first presented in 2004 by the Korean Association for the Study of the Liver (KASL),
and were revised in 2007 and 2011. The American Association for the Study of Liver
Diseases (AASLD) published their guidelines in 2015, the European Association for
the Study of the Liver (EASL) in 2012, the Asian Pacific Association for the Study
of the Liver (APASL) in 2015 and the World Health Organization (WHO) in 2015. These
guidelines carry some variations due to ethnic differences and different medical environments.
Therefore, there is a demand for Korean practice guidelines which reflect medical
practice in Korea. Problems with emergence of drug resistant mutation are eminent
in Korea and the KASL updated their guidelines regarding the management of antiviral
resistant mutation in 2014.
In 2015, the objective of this manuscript was to update the recommendations for management
of CHB, including epidemiology, prevention, natural history, diagnosis, treatment,
monitoring, drug resistance mutations and treatment of special populations discussed
herein based on current evidences or if, evidences lack, on expert opinions after
The main targets of this guideline are patients both newly diagnosed with CHB and
those being followed up or treated for CHB. This guideline is also intended to facilitate
management of patients under the following special circumstances: malignancy, transplantation,
kidney dysfunctions, co-infection with other viruses, pregnancy, and children.
This revised CHB guideline is designed as a resource for all Korean clinicians caring
for patients with CHB. It also provides physicians undertaking training courses with
practical information on the management of CHB.
Developer and funding
The CHB Clinical Practice Guideline Revision Committee (CPGRC) comprising 17 hepatologists
and 1 pediatrician was formed with support from the KASL. All of the required funding
was provided by the KASL. Each member of the CHB-CPGRC collected and evaluated evidence,
and contributed to writing the manuscript.
Conflicts of interest of the CHB-CPGRC members are summarized in Conflicts of interest.
Relevant evidences obtained from a comprehensive literature search using MEDLINE (up
to 2015) were systematically reviewed and selected. The languages were limited to
English and Korean. In addition to published articles, abstracts of important meetings
published before 2015 were also evaluated. The following search terms were used: “hepatitis
B”, “hepatitis B virus”, “HBV”, “chronic hepatitis”, and other key words related to
clinical questions (see below). These clinical questions covered a variety of pertinent
topics ranging from epidemiology, natural course, prevention, diagnosis, treatment,
antiviral resistance, and special situations.
Levels of evidence and grades of recommendation
The evidence and recommendations were graded according to Grading of Recommendations,
Assessment, Development and Evaluation (GRADE) system with minor modifications (Table
1). The levels of evidence were determined as the possibility of change in the estimate
of clinical effect by further research, and were described as high (A), moderate (B)
or low (C). The grades of recommendation were either strong (1) or weak (2), as determined
by the quality of evidence as well as patient-important outcomes and socioeconomic
List of the clinical questions
The committee considered the following questions as key components to be covered in
1. How does this guideline differ from previous guidelines?
2. What is the updated knowledge on the epidemiology?
3. What is the updated knowledge on the natural course of CHB?
4. How should the infection be prevented?
5. How are patients evaluated prior to treatment?
6. When should treatment be considered?
7. What are the goals and endpoints of treatment?
8. What are the optimal first-line treatments for different disease status?
9. How should the treatment be monitored?
10. When can we consider stopping treatment?
11. What are the predictors of a treatment response?
12. What are the definitions of treatment failure?
13. How should we manage drug-resistant CHB patients?
14. What are the definitions of recurrence after treatment completion and how should
these be managed?
15. How should we manage the following special groups:
- acute hepatitis B
- liver transplantation
- chronic kidney disease
- coinfection [with hepatitis C virus (HCV), hepatitis D virus (HDV), and/or human
immunodeficiency virus (HIV)]
16. How can we reduce vertical transmission in pregnant CHB patients?
17. What is the optimal management of CHB in children?
Review of the manuscript
Drafts of the revised guideline were thoroughly reviewed at separate meetings of the
committee. A revised manuscript was reviewed at a meeting of an external review board,
and at a symposium open to all KASL members, and was modified further prior to publication.
The external review board comprised of 18 specialists in CHB who are members of the
KASL. The final manuscript was endorsed by the board of executives of the KASL.
Release of the guidelines
The revised CHB guidelines of KASL were released on November 26, 2015 (http://www.kasl.org).
Plan for updates
Updates or full revision will be planned when major new evidence regarding the diagnosis
and/or treatment of CHB becomes available. Detailed plans for updates will be posted
on the KASL website at a later date.
Hepatitis B virus (HBV) infection, as a causative factor of liver disease of 240 million
patients globally and death of 600 thousand patients annually , is a major cause
of acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. It
has been recognized as an important public health problem in Korea since the 1970s
 and was designated a third-class communicable disease by law in 1982 and is now
the target of a national vaccination program as a second-class communicable disease
The prevalence of HBV infection in the Korean population as estimated by positivity
rates for hepatitis B surface antigen (HBsAg) was 8–9% for males and 5–6% for females
before commercialization of an HBV vaccine in the early 1980s ; thereafter, the
prevalence of HBV infection tended to decline gradually due to the initiation of a
vaccination program for newborn infants in 1991 and a national vaccination program
in 1995. For example, in 2006 the prevalence of HBV among children aged 4 to 6 years
had decreased to 0.2% . Nevertheless, according to the 2005 National Health and
Nutrition Examination Survey, the HBsAg positivity rate was 4.0% at 2009 . The
Ministry of Health and Welfare reported that the HBsAg positivity rate was 3.4% for
males and 2.6% for females, with 3.0% of the total population being infected with
HBV in 2012 . Positivity rates for HBsAg among pregnant females, which represents
a major infection route for hepatitis B, declined steadily after 2004, as did the
positivity rates among females in the childbearing period . Given that HBsAg is
detected in approximately 70% of patients with chronic hepatitis or cirrhosis ,
and in 65–75% of HCC patients [9,10], it can be concluded that CHB infection is a
matter of importance for public health in Korea. Most Korean CHB patients are infected
with HBV genotype C2 , and tend to have lower hepatitis B e antigen (HBeAg) seroconversion
rates, more rapid progression to cirrhosis and HCC, reduced efficacy of interferon
treatment, and are subject to higher rates of relapse after antiviral treatment, compared
to those infected with other HBV genotypes [12,13].
The progression of CHB may be divided into the following five clinical phases: the
immune-tolerant phase, immune-active phase, immune-control phase, immune-escape phase,
and HBsAg-clearance phase. Individual patients do not necessarily experience these
clinical phases in a continuous manner, and clinical phases are not always correlated
with criteria or indications of antiviral therapy [14,15]. HBV DNA positivity indicates
an acute or chronic HBV infection, and negativity indicates resolution of infection.
For this reason, the WHO decided to delete the term ‘hepatitis B carrier.’ The natural
history of CHB is outlined below (Table 2).
1. Immune-tolerant phase
In cases of perinatal infection, the immune-tolerant phase is characterized by HBeAg
positivity, high levels of serum HBV DNA (generally ≥107 IU/mL), normal levels of
aspartate aminotransferase/alanine aminotransferase (AST/ALT), and mild or no liver
necroinflammation [16-19]. Elevation of ALT level was detected in 16% of patients
in the immune-tolerant phase during 5 years of follow up .
This phase may continue for more than three decades in patients infected with HBV
genotype C, which is common among Korean patients, and the rate of spontaneous HBeAg
loss is very low . Therefore, many females infected with this genotype are in
the HBeAg-positive immune-tolerant phase when they are of childbearing age. The absence
of, or only mild histologic liver damage, despite high levels of HBV DNA, is attributed
to immune tolerance to HBV .
2. Immune-active HBeAg-positive CHB
Most patients in the immune-tolerant phase will experience immune responses to HBV
as they grow older, and finally reach the immune-active phase, which is characterized
by HBeAg positivity, lower serum HBV DNA levels, and increased or fluctuating ALT
levels [22,23]. Histologic findings in this phase include moderate-to-severe liver
inflammation and, in some patients, rapid progression of fibrosis . Such changes
are due to enhancement of hepatitis B core antigen (HBcAg) or HBeAg-specific cytotoxic
T-lymphocyte activity and the resulting destruction of infected hepatocytes .
Sustained HBV DNA suppression occasionally accompanies HBeAg seroconversion.
Once HBeAg seroconversion occurs, the natural course of the disease may have one of
three clinical features: (1) repeated HBeAg reversion and seroconversion, (2) inactive
state, or (3) HBeAg-negative CHB [26,27]. Typically, 10–40% of patients who experience
seroconversion revert to HBeAg positivity and then experience recurrence of seroconversion
at least once with progression of hepatitis activity [24,28,29]. In particular, reversion
frequently occurs in patients with HBV genotype C, and the rate decreases with age
. Hepatic decompensation, which occurs in 5% of patients with acute exacerbation,
may be fatal .
3. Immune-control inactive CHB
Most patients who seroconvert during the immune-active phase progress to the immune-control
phase, which is characterized by HBeAg negativity, persistent normal ALT levels, and
HBV DNA levels of <2,000 IU/mL [31-33]. Typical histologic findings in this phase
are mild liver inflammation and fibrosis ; however, patients who have suffered
from previous severe inflammation and fibrosis may continue to experience moderate-to-severe
inflammation and fibrosis. This may result in even biochemical and histologic tests
not being useful for differentiating these patients from those with cirrhosis who
require antiviral treatment .
This phase persists for a long time in most patients, but with a relatively good prognosis;
however, an estimated 20% of them will reactivate to the HBeAg-negative or HBeAg-positive
immuneactive phase, and might experience recurring periods of reactivation and inactivation
throughout their lives, which can lead to cirrhosis or HCC [34,35]. This is why the
ALT levels of patients in the immune-control phase must be measured at least every
6 months for life because currently there are no predictors of which patients will
remain in the inactive phase and which will revert to HBeAg-negative active hepatitis
4. Immune-escape HBeAg-negative CHB
Approximately 20% of patients who experience HBeAg seroconversion during their immune-active
phase maintain HBeAg negativity and hepatitis B e antibody (anti-HBe) positivity but
progress to the immune-escape phase, with findings of HBV DNA levels ≥2,000 IU/mL,
increased ALT levels, and active liver necroinflammation . These patients show
HBeAg negativity since they harbor HBV variants in the precore (PC) or basal core
promoter (BCP) regions of HBV DNA, resulting in failure to produce HBeAg [36-38].
HBeAg-negative CHB is associated with low rates of prolonged spontaneous disease remission,
and most patients in this phase will experience persistent hepatocellular inflammation
and progress to hepatic fibrosis and cirrhosis [38-40]. Severe fluctuations of HBV
DNA and ALT levels can make it difficult to differentiate these patients from those
in the immune-control phase . Accordingly, for the first year after a patient
is diagnosed as being in the immune-control phase, HBV DNA and ALT levels should be
measured every 3 months to identify HBeAg-negative CHB patients who require antiviral
5. HBsAg-clearance phase
Patients in the immune-control phase subsequently progress to the HBsAg clearance
phase at a rate of 1–2% annually [41,43,44]. According to Liaw’s data, HBsAg loss
occurs in 1.9% of CHB patients, and 0.8% of those with chronic HBV infection regardless
of gender and virus genotype, with age being the only known influencing factor [45,46].
It has been reported that Korean patients experience a relatively low rate of HBsAg
loss (0.4% annually) . HBV DNA is not detectable in the serum during this phase,
while hepatitis B core antibody (anti-HBc) with or without hepatitis B surface antibody
(anti-HBs) is detectable. HBsAg loss is associated with a reduced risk of cirrhosis
but a sustained, significant risk of HCC development [34,43,48-53].
Risk factors that influence the natural history of CHB
The accumulated incidence of cirrhosis developing from CHB is generally reported to
be 8–20% [54,55]. In Korea, the reported annual and 5-year accumulated incidences
of cirrhosis are 5.1% and 23%, respectively, while those for HCC are 0.8% and 3% .
The risk factors for hepatitis B progressing to cirrhosis or HCC can be divided into
demographic, environmental, social, and viral factors (Table 3) .
Regarding demographic factors, the risk of developing HCC is three- to fourfold higher
for males than for females, and the risk of HCC and cirrhosis is low among those younger
than 40 years, then increases exponentially with increasing age after the fourth decade
of life [33,57-59]. Those with a family history of HCC also have a higher risk of
contracting HCC [60,61]. Environmental and social risk factors for progression to
cirrhosis or HCC are alcohol consumption, exposure to aflatoxin , and smoking
. It is suggested that obesity, metabolic syndrome, and fatty changes in histologic
tests increase the risk of CHB patients progressing to hepatic fibrosis or HCC [64-67].
Many epidemiological research studies have found that coffee exerts protective effects
against the development of hepatic fibrosis and HCC [68-72].
Viral factors that may influence the progression of CHB patients to cirrhosis or HCC
include high levels of serum HBV DNA (≥20,000 IU/mL), genotype C, BCP variants, and
coinfection with other viruses [57,59,73-75]. According to the Taiwanese Risk Evaluation
of Viral Load Elevation and Association Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV)
study, the risk of developing HCC during the study period among subjects aged at least
40 years was significantly higher in those with an HBV DNA level of ≥104 copies/mL
(cpm) at the start of observation and 105 cpm 11 years later than among those with
an entry HBV DNA level of <104 cpm. Likewise, the incidence of cirrhosis was significantly
associated with HBV DNA levels higher than 104 cpm at study entry [58,59]. If the
HBV DNA level decreased during the follow-up period, the risk of developing HCC or
cirrhosis decreased. Subsequent research highlighted the clinical importance of careful
evaluation of patients with an HBV DNA level >2,000 IU/mL who are older than 40 years
(especially those HBeAg positive) for the development of fibrosis  and HCC [74,75].
Therefore, intervention with antiviral therapy should be performed when appropriate,
as recommended by established practice guidelines .
Unlike HCV infection, the HBV genotype exerts a profound effect on the clinical outcome
but—with the exception of interferon—little effect on the treatment outcome .
Eight HBV genotypes have been identified, and that with the worst prognosis is genotype
C, which is the most common in Korean CHB patients . Genotype C is associated
with delayed natural seroconversion and rapid progression to liver cirrhosis and HCC.
Therefore, it is an independent risk factor for HCC development. According to a cohort
study in Alaska, patients infected with A-, B-, and D-genotype hepatitis B typically
experience seroconversion from HBeAg to anti-HBe before the age of 20 years, whereas
in those infected with the C genotype this occurs at a mean age of 47 years .
This implies that those infected with genotype C would on average experience a much
longer period of infection with high HBV viral loads, and may in part explain why
the risks of HCC and cirrhosis are so high in patients infected with genotype C.
Two important genetic mutations of HBV that affect the natural history of CHB infection
are the BCP and PC mutations [42,45,75,77-79]. BCP mutations are A1762T and G1764A
mutations in the HBV BCP regions, and multiple cross-sectional and prospective studies
have indicated that they increase the risks of cirrhosis and HCC [42,45,77,78]. According
to the results of the REVEAL-HBV study, 359 and 1,149 individuals without and with
BCP mutations, respectively, developed HCC among a population of 100,000 . PC
mutation typically appears near the time of HBeAg seroconversion. The mutation results
in an amino-acid change that creates a stop codon at site 1896 on the HBV genome,
which results in the virus being able to transcribe hepatitis B core protein but not
HBeAg . Patients infected with PC mutants are characterized by HBeAg negativity
and HBeAg positivity, but high levels of HBV DNA [81,82]. However, the observed effects
of PC mutants on the natural history of CHB have been inconsistent; a recent analysis
of the role of PC in the prospective population-based REVEAL-HBV study revealed the
opposite to the findings of cross-sectional clinic-based studies—that the presence
and absence of the PC mutation decreased and increased, respectively, the subsequent
annual incidence of HCC (269 and 996 per 100,000, respectively) .
Because HBV infection is endemic in Korea, any person at high risk of liver disease
or has suspected liver disease is recommended to have their HBsAg and anti-HBs statuses
checked . CHB patients can transmit virus to others, and hence they should be
counseled regarding how to modify their lifestyle so as to prevent HBV transmission.
Epidemiologic studies found that the daily consumption of 40–80 g of alcohol is associated
with liver damage and the progression of liver disease [83-88], and a long-term prospective
cohort study of patients with chronic HBV infection showed that alcohol consumption
increases the risks of liver cirrhosis and HCC development [57,59]. No data are available
on the threshold level of alcohol consumption required to significantly increase the
risks of liver cirrhosis and HCC in patients with chronic HBV infection. In the general
population, a daily alcohol intake of 24 g in males and 12 g in females significantly
increases the risk of liver cirrhosis . So, abstinence or a very limited consumption
of alcohol is recommended in patients with chronic HBV infection . According to
a long-term prospective study of patients with chronic HBV infection, smoking also
increases the risks of liver cirrhosis and HCC, and so non-smoking is recommended
in patients with chronic HBV infection [57,59,90].
Vertical infection is the most important route of HBV transmission. Following initiation
of the HCV vaccination program, the HBsAg positivity rate among pregnant females was
3.32% (308/9281) and the vertical transmission rate was 1.59% (4/252) in 2014. Therefore,
the vaccination program is effective for control of vertical transmission . HBV
immunoglobulin and vaccination after delivery can prevent 90-95% of vertical transmission
to newborns from HBsAg-positive mothers [92-94]. Therefore, such infants should receive
0.5 mL HBIG and scheduled HBV vaccination within 12 hours of birth and after. Adding
immunoglobulin is more effective than vaccination only. The introduction of HBV vaccination
did not result in the rate of HBV infection among newborns differing between breast-
and formula-feeding HBsAg-positive mothers (0% vs. 3%, respectively) .
In patients negative for HBsAg and anti-HBs, vaccination is recommended. Isolated
anti-HBc positive patients negative for HBsAg and anti-HBs should consider vaccination,
especially if liver function results are abnormal. As HBV is endemic in Korea, patients
negative for HBsAg and anti-HBs should be vaccinated [92,93], particularly the household
members and sexual partners of patients with chronic HBV infection, as such persons
are at increased risk of HBV infection [96,97]. Patients with chronic HBV infection
are not candidates for vaccination because of its lack of effectiveness. Sexual partners
who have not been tested for HBV serologic markers, have not completed the full immunization
series, or who are negative for anti-HBs should use barrier protection methods, such
as condoms. The three doses constituting the hepatitis B vaccine series administered
intramuscularly at 0, 1, and 6 months induce a protective antibody response (anti-HBs
>10 mIU/mL) in >90% of recipients. Most non-responders (44–100%) subsequently respond
to a further three-dose revaccination [92,93].
Although serologic testing for anti-HBs is not necessary after routine vaccination
in immunocompetent adults, post-vaccination testing of anti-HBs status is recommended
in some subjects, such as newborns of HBV-infected mothers or 9-18 months old young
infants whose family members has CHB. Healthcare workers, dialysis patients, workers
in dialysis units and operation rooms, immunocompromised subjects (e.g., HIV infection,
hematopoietic stem cell transplants, patients with chemotherapy), and sexual partners
of patients with chronic HBV infection should be tested 1-2 months after their completion
of the HBV immunization series [92,93]. While anti-HBs levels can decline or disappear
over several decades, vaccinated subjects remain protected against HBV infection and
there is no need for booster vaccination in immunocompetent individuals. However,
an anti-HBs level of <10 mIU/mL in dialysis patients indicates an increased risk of
HBV infection, and so a booster vaccination is needed if annual testing reveals an
anti-HBs level of <10 mIU/mL . This also applies to immunocompromised patients
[92,93]. A person without protective anti-HBs exposed to HBV-contaminated blood or
body fluids should receive hepatitis B immunoglobulin (HBIG, 0.06 mL/kg) and hepatitis
B vaccine as soon as possible; preferably within 24 h, otherwise postexposure prophylaxis
should be initiated within 7 days for percutaneous exposure or within 14 days for
sexual exposure .
Coinfection with hepatitis A in HBV carriers increases the risk of mortality by 5.6-
to 29-fold . Therefore, hepatitis A vaccination is recommended for persons negative
for the protective hepatitis A virus antibody (anti-HAV) .
1. HBV vaccination is recommended for persons negative for HBsAg and anti-HBs. (A1)
2. Abstinence from alcohol and smoking is recommended for patients with chronic HBV
3. Newborns of HBV-infected mothers should receive HBIG and hepatitis B vaccine at
delivery and complete the recommended vaccination series. (A1)
4. Hepatitis A vaccine should be given to patients with chronic HBV infection negative
for anti-HAV. (A1)
DIAGNOSIS AND INITIAL EVALUATION
CHB is defined as the presence of HBsAg for longer than 6 months. The initial evaluation
of CHB patients should include a thorough history-taking and physical examination,
with emphasis on risk factors such as alcohol consumption or drug use, HAV, HCV, HDV
coinfection, and family history of HBV infection and HCC. The causal relationship
between HBV infection and liver disease has yet to be established. Appropriate longitudinal
long-term follow-up is crucial for patients with CHB. Serologic tests, virologic tests,
biochemical tests and/or liver biopsy are used to assess HBV replication and the degree
of liver injury in patients with CHB.
HBsAg immunoassay is a necessary and accurate test for diagnosis of CHB. By definition,
patients who remain positive for HBsAg for longer than 6 months have progressed to
chronic infection. Quantitative measurement of HBsAg is now possible and the combination
of HBsAg quantification and HBV DNA level is an integral component of monitoring the
response to antiviral therapy. Serologic tests, including anti-HBs and anti-HBc, can
assist in screening of populations for HBV infection and differentiating among acute,
chronic, and past infections. In acute HBV infection, HBsAg appears 1-10 weeks after
exposure to HBsAg and disappears 4-6 months after recovering from HBV infection .
Acute HBV infection is diagnosed by being HBsAg positive and anti-HBc IgM positive.
Anti-HBc IgM is the only marker present during the window period, the interval between
disappearance of HBsAg and appearance of anti-HBs.
Anti-HBc typically persists for life, but IgM anti-HBc is detectable for 6 months,
and anti-HBc is detectable thereafter in patients with resolved acute HBV infection.
IgM anti-HBc can be detected at low levels during chronic HBV infection . Persistently
positive anti-HBc is shown when anti-HBs titer from the past HBV infection becomes
undetectable over time or in cases with occult hepatitis B infection [102-105]. Measurement
of the serum HBV DNA level might be helpful in these settings. Patients with these
serologic patterns should be followed with repeated testing of HBsAg, anti-HBs, and
anti-HBc for 3–6 months. Patients who recover from HBV infection will test negative
for HBsAg and positive for anti-HBs and anti-HBc. Patients who respond adequately
to hepatitis B vaccines will test negative for anti-HBc and positive for antiHBs,
since anti-HBc emerges only after HBV infection and persists for life.
Laboratory tests for patients with CHB should include HBeAg and anti-HBe. HBeAg positivity
generally indicates a high level of viral replication, and anti-HBe positivity a low
level. Serum HBV DNA and AST/ALT levels are important parameters in HBeAg-negative
patients. HBeAg-negative, anti-HBe-positive patients with a normal ALT level and an
HBV DNA level of <2,000 IU/mL (<10,000 cpm) may be in the inactive phase. These patients
usually have mild or no liver necroinflammation and no or slow progression of fibrosis,
but some patients with severe liver damage during the immune-active phase may present
with a cirrhotic liver. HBeAg-negative CHB patients have an elevated ALT and an HBV
DNA level of >2,000 IU/mL. HBe-negative CHB is associated with viral mutants in the
PC and/or BCP regions that are unable to produce or produce only low levels of HBeAg
. They have severe liver necroinflammation with a low rate of prolonged spontaneous
disease remission and a high risk of subsequent complications, such as decompensated
cirrhosis and HCC .
Acute hepatitis A co-infection in chronic hepatitis B patients can result in increased
icteric manifestation, longer recovery time, and increased risk of fulminant hepatic
failure. Underlying chronic liver disease is an important risk factor for fulminant
hepatic failure and death in patients with acute HAV infection [106-108]. Therefore,
CHB patients younger than 50 years should undergo testing for IgG anti-HAV, and all
patients with a negative immune status for hepatitis A should receive HAV vaccine.
Laboratory tests should include tests for coinfection with HCV and/or HIV in those
Serum HBV DNA test
Serum HBV DNA testing provides a direct measure of the level of viral replication.
This quantification is essential for characterizing the status of infection, diagnosing
the disease, making the decision to treat, and subsequent monitoring of patients.
It is also important for predicting the risks of cirrhosis and HCC. Therefore, it
should be applied to all patients diagnosed with CHB. The introduction of the international
unit (IU) (1 IU is equivalent to 5.6 HBV DNA copies) as a recommended reporting unit
for HBV DNA has facilitated standardized reporting and comparison of serum HBV DNA
levels . The methods used to quantify HBV DNA levels have evolved rapidly. Real-time
PCR-based assays have been introduced and demonstrate both high sensitivity and a
broad linear range (10–108 IU/mL) of quantification . The same test should be
specified each time when monitoring HBV DNA levels for a given patient in clinical
practice to ensure consistency.
HBV genotypes appear to influence the progression of disease, risk of HCC, and response
to therapy (including interferon therapy) [75,111,112]. Some studies in Asia have
suggested that genotype C is associated more frequently with HBV reactivation, severe
liver disease, and HCC than is genotype B [111,113-115]. The specific genotype has
also been shown to affect the response to interferon therapy, with the rate of an
antiviral response to pegylated interferon (peginterferon) therapy being higher for
genotypes A and B than for genotypes C and D . In CHB, examination of genotyping
is recommended selectively to help identify patients who might be at greater risk
of disease progression, and routinely to determine the most appropriate candidates
for peginterferon therapy . However, genotyping is recommended as being unnecessary
in Korea because Korean patients are almost exclusively infected with genotype C.
Assessments of the severity of liver disease should include biochemical markers such
as AST, ALT, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), prothrombin
time (PT), and serum albumin. A progressive decline in the serum albumin level and
prolongation of the PT, often accompanied by a decrease in the platelet count, are
characteristically observed after cirrhosis develops. The serum ALT level has been
commonly used in assessments of liver disease and as an important criterion for defining
which patients are candidates for therapy . The ALT level is usually higher than
that of AST, but the ratio may be reversed when the disease progresses to cirrhosis.
HBV-infected patients with normal or mildly elevated ALT levels have been thought
to have mild-to-no or significant necroinflammation on liver biopsy, respectively.
However, there is no correlation between the degrees of liver cell necrosis and ALT
level . ALT activity might also be affected by other factors such as body mass
index, gender, abnormal lipid and carbohydrate metabolism, and uremia [119,120]. Therefore,
relying solely on the finding of elevated ALT as a prerequisite for treatment candidacy
has limitations. Data from clinical studies have shown that the true normal level
of ALT is significantly lower than the previously established limits: 40 IU/mL for
males and 30 IU/mL for females. Moreover, data from cohort studies indicate that the
upper limit of normal (ULN) ALT and AST levels should be decreased to 30 IU/mL for
males and 19 IU/mL for females [119,120]. Clinical studies have shown that patients
with ALT levels of 40–45 IU/mL have a high risk of significant liver disease and mortality
from complications . According to the treatment algorithm for CHB suggested by
Keefee et al., serum ALT levels of 30 and 19 IU/mL for males and females, respectively,
should be used as the ULN levels when deciding to commence treatment . Further
prospective studies are needed to clarify this issue.
A recent prospective study in Korea involving 2,000 liver donors suggested that healthy
serum ALT values should be 33 IU/L for males and 25 IU/L for females . Ninety
thousand males and 40,000 females aged 35 to 59 years in the prospective NHS cohort
exhibited upper limits of AST and ALT values for prediction of liver diseases of 31
IU/L and 30 IU/L, respectively .
A liver biopsy is recommended for determining the degree of necroinflammation and
fibrosis in patients with elevated ALT, an HBV DNA positive or both, because liver
histology is useful when deciding whether or not to commence treatment. A liver biopsy
is invasive but the rate of serious complications is very low (1/4,000-10,000) .
Several recent clinical studies found that 12–43% of patients with persistent normal
ALT levels had histologic evidence of significant fibrosis or inflammation in a biopsy,
particularly those older than 35-40 years [116-121,124]. A retrospective study of
the relationship between ALT level and fibrosis in CHB patients reported similar results:
of the 59 patients with persistent normal ALT levels, 18% had stage 2 fibrosis and
34% had grade 2 or 3 inflammation, with 37% of all patients with persistent normal
ALT levels having significant fibrosis and inflammation . Subgroup analysis also
demonstrated that most of the patients with fibrosis had high normal ALT levels. These
results indicate that the ALT level in CHB patients with high normal ALT levels should
be interpreted in conjunction with the serum HBV DNA level, age, and liver histology
results when deciding to commence treatment. Therefore, in HBsAg-positive patients
with HBV DNA levels of ≥20,000 IU/mL and normal ALT levels, a liver biopsy should
be considered in those older than 35 years since they are less likely to be in the
immune-tolerance phase of infection. Treatment should be considered if a liver biopsy
reveals fibrosis at stage 2 or greater and/or necroinflammation. When deciding whether
to commence treatment in this patient population, it must be recognized that long-term
therapy is likely to be needed due to the low probability of HBeAg seroconversion
occurring within 1 year. A liver biopsy is usually not required in patients with clinical
evidence of cirrhosis or when treatment is indicated irrespective of the grade of
activity or the stage of fibrosis. This is because only a small portion of the liver
is sampled, and the low intra/interobserver reliabilities. Therefore, the efficacy
of noninvasive methods such as the Fibroscan device or serum markers in assessing
fibrosis in CHB has increased.
Noninvasive fibrosis test
The severity of liver fibrosis and determination of ALT and HBV DNA levels have essential
roles in treatment decisions. Noninvasive methods to estimate liver fibrosis have
been developed and used. These methods include the aspartate aminotransferase-platelet
ratio index (APRI), AST/ALT ratio (AAR), Forns’ fibrosis index (age, platelets, GGT,
cholesterol), FIB-4 (platelets, ALT, AST, Age). Also, the FibroTest that uses indirect
markers (α-2 macroglobulin, haptoglobin, r-globulin, apolipoprotein A1, and GGT),
the FibroSpect II Enhanced Liver Fibrosis test that uses direct markers (Hepascore,
FibroMeter, hyaluronic acid and tissue inhibitor of matrix metalloproteinase-1, 2)
are available . The age-spleen-platelet ratio index (ASPRI) is the most accurate
in predicting liver fibrosis in chronic HBV infection . APRI is useful for diagnosis
of not only for liver fibrosis but also liver cirrhosis, while FIB4 is useful for
mild fibrosis. However FIB4 has limitations in terms of predicting fibrosis of stage
F2 and above as it has low sensitivity and specificity .
Transient elastography using Fibroscan® has a high degree of accuracy for assessment
of advanced liver fibrosis. It is the most commonly used method for chronic liver
diseases because of its noninvasiveness and high reproducibility .
Fibroscan® can be perform rapidly (5 min) in the outpatient clinics of hospitals and
produce a result immediately after the test [129,130]. However, only procedures involving
≥10 successful measurements are considered reliable. Moreover, a success rate (SR)
of at least 60% and an interquartile range (IQR) of less than 30% of the median value
are required (Interquartile range/median value (IQR/M) , Fibroscan® has limitations
in subjects with ascites, obesity, or narrow intercostal spaces. Moreover, the system
may yield false-positive results in subjects with acute hepatitis and extrahepatic
biliary tract obstruction [132-134].
Fibroscan® has greater diagnostic accuracy than APRI or FIB-4 for liver cirrhosis
in a study that compared liver biopsy, AAR, APRI, Fibroscan®, and FIB-4 in patients
with chronic hepatitis [135,136]. Also, Fibroscan® was more predictive of liver fibrosis
and liver cirrhosis in a study that compared Fibroscan® and APRI in 567 subjects with
chronic hepatitis (Area under Receiver Operating Characteristic: F3 0.849 vs. 0.812,
F4 0.902 vs. 0.707) .
Screening for hepatocellular carcinoma
The initial evaluation of patients with CHB should include tests for HCC. Periodic
surveillance is also needed in these patients to ensure early detection of HCC during
follow-up. The issue of HCC is treated in detail in the “Practical Guidelines for
Management of Hepatocellular Carcinoma 2014 .” Standard tools for HCC screening
include measuring the α-fetoprotein level and ultrasound. Magnetic resonance imaging
and computed tomography might be preferred for some patients with severe cirrhosis
or obesity, since ultrasound has poor sensitivity in those conditions. Patients at
a high risk of HCC include those older than 40 years , patients with cirrhosis,
those with a family history of HCC, and any carriers older than 40 years exhibiting
persistent or intermittent ALT elevation, a high HBV DNA level (>2,000 IU/mL), or
both . Keeffe et al. recently recommend earlier screening (at 30–35 years of age
or even younger) in Asian patients with presumed infection at the time of birth or
in early childhood due to the higher risk of HCC in this patient population.
The use of antiviral therapies improves liver function and increases survival rates
of patients with liver failure (liver decompensation).
Consistent inhibition of HBV replication with antiviral therapies delays progression
of liver fibrosis, induces reversal of advanced liver fibrosis, reduces the incidence
of liver cirrhosis, and prevents diseases including hepatocellular carcinoma in patients
with advanced liver fibrosis or liver cirrhosis .
Recently developed treatments can decrease the incidence of liver diseases or delay
their progression but cannot prevent all possible complications. Therefore, surveillance
and screening for hepatocellular carcinoma are required at regular intervals for early
diagnosis and a complete recovery.
1. The initial evaluation of patients with CHB should include a thorough history-taking
and physical examination, with emphasis on risk factors such as coinfection, alcohol
consumption, and the family history of HBV infection and liver cancer. (A1)
2. Laboratory tests to assess liver disease should include the complete blood count
(CBC), AST/ALT, ALP, GGT, bilirubin, albumin, creatinine, and PT. (A1)
3. Tests for HBV replication include HBeAg/anti-HBe and quantitative serum HBV DNA
levels. A real-time PCR quantification assay is strongly recommended for quantifying
the HBV DNA level. (A1)
4. An anti-HCV test is necessary to rule out coinfection with HCV. (B1)
5. An anti-HAV test is necessary in CHB patients younger than 50 years. (A1)
6. Liver biopsy is useful for determining the degree of liver inflammation and fibrosis.
7. Noninvasive tests such as serum markers and liver elasticity are used for diagnosis
of the degree of liver fibrosis. (B1)
8. Standard tools for HCC screening include ultrasound and serum α-fetoprotein measurement.
The goals of hepatitis B treatment are to decrease the mortality rate and increase
the survival rate by alleviating hepatic inflammation and preventing the development
of fibrosis, which ultimately reduces the frequency of progression of hepatitis to
liver cirrhosis or HCC [141-145]. The optimal treatment result would be the loss or
seroconversion of HBsAg, but since intranuclear cccDNA persists despite treatment,
complete clearance of HBV is almost impossible to achieve . This is why indices
such as ALT level normalization, undetectable HBV DNA, loss or seroconversion of HBeAg,
and histologic improvement are used (rather than the loss or seroconversion of HBsAg)
to predict the treatment response in the clinical context. Therefore, a realistic
virologic goal of anti-HBV therapy is the suppression of viral replication.
Most guidelines state that antiviral treatment is required for patients with acute
liver failure, decompensated liver cirrhosis or in the acute phase of severe chronic
HBV hepatitis regardless of HBV DNA and ALT levels, and the treatment has almost no
complications, although few controlled studies have been performed . Antiviral
therapy decreases the rate of recurrence of viral infection in patients who require
liver transplantation . The HBV DNA and HBeAg levels in CHB are indices of viral
replication and active hepatitis, respectively, and patients with HBeAg-positive hepatitis
B with high levels of HBV DNA have an increased risk of developing liver cirrhosis
or HCC [57,59,74]. Patients with disappearance or conversion of serum HBeAg have a
low risk of liver cirrhosis and hepatocellular carcinoma, and so have a good prognosis
The loss or seroconversion of HBeAg during the natural course of hepatitis B or after
IFN-α treatment indicates a favorable long-term outcome with a decreased probability
of liver cirrhosis or HCC development [26,53,149,150]. Therefore, clearance or seroconversion
of HBeAg is an important goal of antiviral treatment in patients with HBeAg-positive
active hepatitis. A decrease in the HBV DNA level has recently been suggested to be
even more important. The decrease in the HBV DNA level after antiviral treatment in
active hepatitis with elevated HBV DNA levels results in histologic improvement, seroconversion
of HBeAg, and normalization of ALT levels, and thus a slowing of the progression of
hepatitis [151,152]. However, even in cases with HBV DNA levels of less than 104 copies/mL,
which is considered to be inactive hepatitis, the hepatitis can still progress to
liver cirrhosis and HCC. Therefore, a decrease in HBV DNA to an undetectable level
is recommended for patients on antiviral treatment .
1. The treatment goals in hepatitis B are to decrease the mortality rate and increase
the survival rate by alleviating hepatic inflammation and preventing the development
of fibrosis, which would ultimately reduce the frequency of progression of hepatitis
to liver cirrhosis or HCC. (A1)
2. To achieve HBsAg clearance, which is the ideal treatment goal, long-term maintenance
of an undetectable HBV DNA level is recommended. (B1)
3. The ultimate treatment goals in patients with HBeAg-positive hepatitis are normalization
of the ALT level, undetectable HBV DNA level, and the clearance or seroconversion
of HBsAg and HBeAg. In patients with HBeAg-negative hepatitis the treatment goals
are normalization of the ALT level, an undetectable HBV DNA level, and the clearance
or seroconversion of HBsAg. (B1)
TREATMENT INDICATIONS AND STRATEGIES
Long-term viral suppression by drugs with potent antiviral activity and high genetic
barrier to resistance is a current paradigm of antiviral treatment for CHB aimed at
the prevention of disease progression and improvement of survival. Since eradication
of HBV infection is rarely achieved with currently available drugs, long-term treatment
is necessary in most cases. Treatment protocol should be individualized according
to various factors: host factors such as mode of infection, disease status, and immunity;
viral factors such as genotypes, prior antiviral treatment, mutation, and susceptibility
level; and drug factors such local availability, cost, and reimbursement policy .
The durations of currently available antiviral trials are insufficient to assess the
effects of treatment on long-term survival . Long-term treatment with oral nucleos(t)ide
analogs (NAs) ameliorates histologic abnormalities such as necroinflammation and/or
fibrosis, both in HBeAg-positive [35,154,155] and HBeAg-negative [155-158] CHB. Therefore,
long-term antiviral therapy may prevent disease progression and reduce the risk of
liver cirrhosis .
Immune tolerance phase
Antiviral therapy is not indicated for patients in the immune-tolerant phase despite
HBeAg positivity and a high level of HBV DNA, because of the benign natural course
of the disease and such treatment results in minimal histologic changes .
Patients in the immune-tolerant phase (HBeAg positive and persistently normal ALT
level as recommended by this guideline rather than local laboratory ULNs) are not
indicated for antiviral therapy. (B1)
Chronic hepatitis B
CHB patients with active viral replication and significant inflammation and/or fibrosis
are appropriate targets for antiviral treatment. Early guidelines generally agreed
that antiviral treatment could be recommended for CHB patients (especially those without
liver cirrhosis) with serum HBV DNA level > 20,000 IU/mL and serum ALT level> 2 ULN
[160,161]. However, recent guidelines suggest that the indications of antiviral treatment
should be expanded to those with lower serum HBV DNA levels and/or lower serum ALT
Serum HBV DNA level is a marker of viral replication and an indicator of the efficacy
of antiviral treatment in individuals with CHB. Progression to cirrhosis in HBV-infected
patients is reported to be strongly correlated with the level of circulating virus
[57,59]. However, an HBV DNA level of 105 cpm or 20,000 IU/mL was arbitrarily chosen
by early guidelines as the cut-off level for indication of antiviral treatment. Some
patients with lower serum HBV DNA levels (300–105 cpm), especially those with HBeAg
negative hepatitis and/or cirrhosis, frequently show progression of liver disease
and hence may need treatment [35,161,164]. A serum HBV DNA level of ≥20,000 IU/mL
has been suggested as the cut-off for HBeAg-positive CHB . However, the distinction
between HBeAg-negative CHB and inactive carriers is not clear due to the fluctuating
course of HBeAg-negative CHB . A population-based cohort study revealed increased
risks of liver cirrhosis and HCC when the serum HBV DNA level exceeds 2,000 IU/mL
[57,59,165], therefore this level is widely accepted as the cut-off for indicating
Serum ALT has been used as a convenient surrogate marker for liver injury, and elevated
serum ALT is indicated as a risk factor for disease progression in CHB . A serum
ALT level > 2 ULN was suggested as a suitable indication of antiviral treatment for
CHB by early guidelines, especially in CHB patients without cirrhosis [160,161,166].
However, an increased risk of developing liver cirrhosis and HCC has been documented
in patients with mildly elevated serum ALT and even in those with serum ALT levels
in the upper normal range [119,121,167]. About two-thirds of CHB patients with mildly
elevated ALT (1–2 ULN) show significant hepatic fibrosis (F2 or higher) , and
CHB patients with persistently normal ALT levels and HBV DNA levels of >20,000 IU/mL
may actually have significant fibrosis or inflammation [125,168,169], which are indications
for antiviral therapy. A cohort study in Hong Kong demonstrated that the risk of liver-related
complications in CHB patients was higher for ALT levels of 0.5–1 ULN and 1–2 ULN than
for those <0.5 ULN. Thus, previous ALT criteria might exclude some patients with existing
or potentially significant disease [170,171].
Liver biopsy has three major roles: diagnosis, assessment of prognosis (disease staging),
and assistance in making therapeutic decisions . In CHB, liver biopsy is especially
useful for patients who do not meet definite criteria for treatment but still have
a possible risk of significant disease . Age of the patient, serum HBV DNA level,
serum ALT level, and family history of HCC should be considered before deciding whether
to perform a biopsy. ALT and HBV DNA levels may miss cases of histologically significant
disease , and so histologic confirmation should be considered, especially in
patients of advanced age with serum AST/ALT levels in the upper normal range or higher.
Peginterferon-α and NAs including lamivudine, adefovir, clevudine, telbivudine, entecavir,
and tenofovir, have been used for antiviral treatment of CHB. Drug of choice can differ
according to various factors, including effectiveness, safety, risk of resistance,
and cost of drugs, preference of patients and physicians, and any plans for pregnancy
Lamivudine and telbivudine are not preferred due to their weak antiviral potency and
high frequency of drug resistance, unless a good response is predicted or the anticipated
duration of treatment is short. Adefovir is not an ideal option due to its weak anti-viral
activity and high frequency of drug resistance after 48 weeks. There are insufficient
long-term follow-up data on the efficacy and safety of clevudine. Entecavir and tenofovir
are safe agents with potent antiviral effects and low frequency of drug resistance.
Due to convenience of usage, peginterferon-α is preferred over interferon-α. To date,
there has been no report confirming the superiority of combination therapies over
monotherapy in treatment-naïve patients.
Currently, monotherapy with entecavir, tenofovir, or peginterferon-α is the preferred
initial therapy for CHB. Other NAs might be used in patients with good predictors
of response, and can be continued or modified according to on-treatment response.
In patients treated with lamivudine, the predictive factors for a good response to
therapy are increased initial serum ALT level and high histologic activity index score
. During telbivudine treatment, a combination of pretreatment characteristics
(low HBV DNA level; HBV DNA < 109 copies/mL (HBeAg positive CHB) or HBV DNA < 107
copies/mL (HBeAg negative CHB) and ALT level ≥ 2 ULN) plus non-detectable serum HBV
DNA at treatment week 24 is suggested to be the strongest predictor of optimal outcomes
at 2 years . Of CHB patients receiving lamivudine or telbivudine treatment, those
with a virologic response at week 24 (< 300 copies/mL) achieved a high rate of HBeAg
seroconversion at week 52 . Less resistance was reported in patients with low
serum HBV DNA levels (< 1,000 copies/mL) at week 48 during long-term therapy with
1. HBeAg positive CHB patients with HBV DNA ≥ 20,000 IU/mL, plus serum AST or ALT
≥ 2 ULN or significant histologic changes such as inflammation or fibrosis (≥ moderate
necroinflammation; ≥ periportal fibrosis) on biopsy should be considered for treatment.
(A1) Treatment can be delayed for 3–6 months if spontaneous HBeAg seroconversion is
expected. (B2) However, patients with apparent or anticipated liver failure (i.e.,
those with jaundice, prolonged PT, hepatic encephalopathy, and ascites) should be
treated promptly. (B1)
2. For those with HBV DNA ≥ 20,000 IU/mL and serum AST or ALT < 2 ULN, observation
or liver biopsy can be considered. Antiviral treatment is recommended for those showing
subsequent elevation of serum ALT or AST, or significant histologic changes such as
inflammation or fibrosis on biopsy. (A1)
3. Monotherapy with tenofovir, entecavir, or peginterferon-α is preferred. (A1)
1. HBeAg negative CHB patients with HBV DNA ≥ 2,000 IU/mL plus serum AST or ALT ≥
2 ULN or significant pathologic changes such as inflammation or fibrosis on biopsy
should be considered for treatment. (A1)
2. For those with HBV DNA ≥ 2,000 IU/mL and serum AST or ALT < 2 ULN, observation
or liver biopsy can be considered. Anti-viral treatment is recommended for those showing
subsequent elevation of serum ALT or AST, or significant pathologic changes such as
inflammation or fibrosis on biopsy. (A1)
3. Monotherapy with tenofovir, entecavir, or peginterferon-α is preferred. (A1)
Compensated liver cirrhosis
Liver biopsy has been considered the gold standard for diagnosis of liver cirrhosis.
Whereas use of liver biopsy is limited in real clinical practice; imaging studies
such as CT, abdominal ultrasound, and MRI are helpful for the diagnosis of liver cirrhosis.
Typical image findings of liver cirrhosis include nodular liver surface, splenomegaly,
and the presence of intra-abdominal collateral vessels, which indicate increased portal
venous pressure. If esophageal or gastric varices is observed in upper gastrointestinal
endoscopy, liver cirrhosis can be diagnosed . With imaging studies, laboratory
findings such as albumin, bilirubin, or prothrombin time and platelet values are helpful
for the diagnosis of liver cirrhosis.
Patients with compensated cirrhosis and elevated serum HBV DNA (HBV DNA ≥ 2,000 IU/mL)
can benefit from treatment with long-term oral NAs, because such treatment may prevent
disease progression  and the development of HCC [144,145,175-178]. Compensated
cirrhosis patients with a low viral load, although HBV DNA < 2,000 IU/mL, are at considerable
risk for HCC, and antiviral treatment in these patients was suggested to reduce the
risk of HCC . Antiviral therapy is recommended in CH-B patients with significant
hepatic fibrosis regardless of AST/ALT levels [35,162,163,180]. The levels of AST/ALT
should not be used as criteria for starting antiviral therapy in patients with liver
cirrhosis, because they already have significant hepatic fibrosis and frequently have
nearly normal AST/ALT levels.
In a cohort of HBeAg-positive liver cirrhosis patients, long-term follow-up data after
interferon-α therapy showed that the HBeAg seroconversion rate was similar (67% vs.
60%, respectively) but the ALT normalization rate (62% vs. 47%) and HBsAg loss rate
(23% vs. 3%) were better in the interferon-α treated group than in the control group
. Interferon-α treatment in cirrhotic patients requires careful monitoring because
it may cause acute exacerbation of hepatitis, which leads to hepatic failure .
After treating CHB patients with peginterferon-α-2b alone or in combination with lamivudine
for 52 weeks, the virologic response rate (as indicated by HBeAg seroconversion and
an HBV DNA level of <10,000 copies/mL) was superior in those with cirrhosis than in
those without cirrhosis (35% vs. 14%, respectively) . However, acute exacerbation
of hepatitis (33% vs. 12%, respectively) and requirement for dose reduction (63% vs.
30%) were more common in cirrhotic patients than in noncirrhotic patients . Therefore,
interferon-α can be used with caution in cirrhotic patients with preserved liver function.
In patients with decompensated liver cirrhosis, long-term lamivudine treatment significantly
reduced the complications and hepatocellular carcinoma compared to placebo. However,
the benefit was less in patients with lamivudine resistance . Entecavir treatment
of patients with advanced hepatic fibrosis or cirrhosis for 48 weeks showed improvements
in the liver histology in 57%, 59%, and 43% of patients with HBeAg-positive, HBeAg-negative,
and lamivudine-resistant CHB, respectively . A study including a small number
(n=40) of patients showed that telbivudine effectively decreased HBV DNA levels in
patients with compensated liver cirrhosis, and HBV DNA was undetectable after 48 weeks
of telbivudine treatment in 92.5% . A study comparing the effects of clevudine
treatment for 48 weeks found that the virologic response rate (HBV DNA <1,000) (87.1%
vs. 71.4%, respectively) and biochemical response rate (83.9% vs. 80.9%) did not differ
significantly between patients with CHB (n=21) and those with liver cirrhosis (n=31)
. A phase III clinical trial of tenofovir adopting paired liver biopsy at baseline
and at week 240 revealed that, of the 96 (28%) patients with liver cirrhosis (Ishak
score 5 or 6) at baseline, 71 (74%) no longer had liver cirrhosis (≥1 unit decrease
in score) at follow-up biopsy .
Since long-term antiviral therapy is generally required in patients with liver cirrhosis,
the AASLD and EASL guidelines recommend the use of entecavir or tenofovir due to their
potent antiviral efficacy and high genetic barrier to drug resistance.
Decompensated liver cirrhosis
Decompensated liver cirrhosis is defined as liver cirrhosis complicated with ascites,
variceal bleeding, hepatic encephalopathy, or jaundice . Patients with decompensated
liver cirrhosis should be treated at an institution that can provide appropriate management
for complications of liver cirrhosis. Liver transplantation should be considered in
patients with decompensated liver cirrhosis. Oral NAs may improve hepatic function
 and decrease the need for liver transplantation in Child-Turcotte-Pugh (CTP)
class C cirrhosis . The use of interferon-α in patients with decompensated liver
cirrhosis is contraindicated due to the risk of serious complications, such as infection
or hepatic failure . Lamivudine treatment for longer than 6 months was shown
to improve or stabilize liver function and prolong the time to liver transplantation
in patients with decompensated liver cirrhosis [190-192]. A study comparing the effects
of telbivudine and lamivudine in patients with decompensated liver cirrhosis found
a higher rate of HBV DNA undetectability (47% vs. 36%, respectively) and a lower viral
breakthrough rate (29% vs. 39%, respectively) in the telbivudine group than in the
lamivudine group . A study of the effect of adefovir in lamivudine-resistant
cirrhotic patients (n=101) found that the virologic response rate was lower in decompensated
cirrhotic patients (n=53) than in compensated cirrhotic patients (n=48) (50.9% vs.
83.3%, respectively), whereas ALT normalization and HBeAg loss did not differ between
the two groups .
A randomized study comparing the effects of entecavir (1 mg/day) and adefovir (10
mg/day) in patients with decompensated liver cirrhosis found that the rates of HBV
DNA undetectability at weeks 24 and 48 were higher in the entecavir group than in
the adefovir group (week 24, 49% vs. 16%, respectively; week 48, 57% vs. 20%), while
HBeAg seroconversion at week 48 did not differ significantly between the two groups
(6% vs. 10%) . Entecavir therapy showed improvement of the CTP score (to ≥2)
in almost half (27/55) of treatment-naïve patients with decompensated liver cirrhosis
(n=55) and a 1-year transplantation-free survival rate of 87.1% .
A randomized trial comparing the effects of tenofovir (n=45), tenofovir plus emtricitabine
(n=45), and entecavir (n=22) in patients with decompensated liver cirrhosis showed
that the requirement for early withdrawal of drug (6.7%, 4.4%, and 9.1%, respectively)
and elevation of serum creatinine (8.9%, 6.7%, and 4.5%) did not differ among the
three groups. The rates of HBV DNA undetectability at week 48 were 70.5%, 87.8%, and
72.7%, respectively, and those of HBeAg loss/seroconversion were 21%/21%, 27%/13%,
and 0%/0% .
Because prompt treatment is required in patients with decompensated liver cirrhosis,
oral antiviral therapy is the treatment of choice if HBV DNA is detectable by PCR
tests [35,162,180]. An antiviral drug with a potent antiviral efficacy and high genetic
barrier to drug resistance should be used. Since clinical improvement often requires
3–6 months of antiviral therapy, progression to hepatic failure is possible even during
antiviral therapy in some patients. Hence, liver transplantation should be considered
together with antiviral treatment . Pre- and post-transplantation antiviral therapy
has been reported to reduce the risk of reactivation of hepatitis after liver transplantation.
Compensated liver cirrhosis
1. Antiviral therapy should be performed if HBV DNA level is ≥2,000 IU/mL regardless
of AST/ALT levels. (A1)
2. Antiviral therapy can be considered when HBV DNA is HBV DNA is <2,000 IU/mL to
reduce the risk of decompensation regardless of AST/ALT levels. (C1)
3. Oral antiviral therapy is recommended. Monotherapy with tenofovir or entecavir
is preferred. (A1)
4. Peginterferon-α may be used with careful monitoring of impairment of liver function
and drug side effects in patients with compensated liver cirrhosis with preserved
liver function. (B2)
Decompensated liver cirrhosis
1. Prompt antiviral therapy is recommended if HBV DNA is detectable by PCR test regardless
of AST/ALT levels. (B1)
2. Oral antiviral therapy is recommended. Monotherapy with tenofovir or entecavir
is preferred. (A1)
3. The use of peginterferon-α is contraindicated due to the risk of serious complications,
such as hepatic failure. (A1)
4. Liver transplantation should be considered. (B1)
Monitoring prior to antiviral treatment
After diagnosis and initial evaluation of patients with CHB, their serum HBV DNA,
ALT, HBeAg, and anti-HBe levels should be regularly monitored until they are considered
for treatment [35,168,196,197]. The HBV genotype test is not recommended in Korea
because most Korean patients are known to have HBV genotype C [198,199].
Applying a quantitative HBsAg (qHBsAg) assay before or during antiviral treatment
may assist prediction of the treatment response [200-203]. HBsAg is generated by transcription
and translation of cccDNA or HBV DNA integrated into the genome, and can be detected
on the surface of infective virions and on circular and linear non-infective particles.
The quantity of HBsAg (qHBsAg) showed a positive correlation with the amount of cccDNA
in hepatocytes, which enabled a standardized qHBsAg assay [204,205]. HBsAg quantity
is highest during the immune-tolerant phase (4.5–5.0 log10 IU/mL), starts to decrease
during the immune-active phase (3.0–4.5 log10 IU/mL), and decreases gradually after
HBeAg seroconversion. The HBsAg quantity is lowest in the immune-control phase (1.5–3.0
log10 IU/mL), and starts to increase in HBeAg-negative CHB (2.5–4.0 log10 IU/mL) [206-208].
During long-term lamivudine treatment, a low level before treatment and large decrement
during treatment of qHBsAg were predictors of HBsAg seroconversion. Several studies
reported that the decrement of qHBsAg correlated with the decrement of HBV DNA level
1. Chronic hepatitis (HBeAg positive or negative)
1) In patients with persistently normal AST/ALT levels, liver function should be tested
and serum HBV DNA should be measured by real-time PCR at 2–6-month intervals, plus
HBeAg status (HBeAg and anti-HBe) should be checked every 6–12 months. (C1)
2) If AST/ALT levels increase above the normal limit, liver function should be tested
every 1–3 months, and serum HBV DNA should be measured by real-time PCR plus HBeAg
status should be checked every 2–6 months. (C1)
2. Compensated liver cirrhosis Liver function should be tested every 2–6 months, and
serum HBV DNA should be measured by real-time PCR plus HBeAg status should be checked
every 2–6 months. (C1)
3. Decompensated liver cirrhosis Liver function should be tested every 1–3 months,
and serum HBV DNA should be measured by real-time PCR plus HBeAg status should be
checked every 2–6 months. (C1)
Monitoring during antiviral treatment
In a compliant patient with a primary non-response (decrease in serum HBV DNA of <2
log10 IU/mL after 6 months or more of NA treatment), changing to or adding a more-potent
drug should be considered. Serum HBV DNA should be measured every 1 to 3 months for
the first few months to ascertain the virologic response, and then every 3 to 6 months.
Serum HBV DNA reduction to an undetectable level by real-time PCR (i.e., <10–15 IU/mL)
should ideally be achieved to avoid resistance. Serum HBV DNA monitoring is thus critical
to detect treatment failure.
Peginterferon therapy resulted in a more significant reduction in qHBsAg levels than
NA therapy [211,212]. However, a low pretreatment qHBsAg level and greater qHBsAg
decline were reported to be positive predictors of a sustained virologic response
[213,214]. In CHB patients receiving 10 years of NA therapy, low baseline qHBsAg levels
(<1,000 IU/mL) and a greater rate of HBsAg reduction (>0.166 log10 IU/mL/year) were
predictive of qHBsAg seroclearance, strengthening the prognostic role of HBsAg measurements
during NA therapy . Compliance and antiviral-resistance mutations should be monitored
in patients who develop virologic breakthrough while receiving NA, and an appropriate
rescue therapy should be initiated if necessary [215-219].
Most NAs are excreted through the kidney, and hence dose adjustment is required in
patients with renal insufficiency (Table 4) , and regular monitoring of renal
function should be performed in patients receiving adefovir or tenofovir. Several
reports have associated tenofovir with bone loss in patients with HIV, although there
was no consistent report during tenofovir monotherapy [220-222].
Studies of entecavir-related carcinogenicity are in progress. There have been few
reports on telbivudine-related myositis; however, monitoring of the serum creatine
kinase (CK) level is recommended due to the possibility of CK elevation [223-226].
For clevudine prescription, serum CK level and related symptoms should be monitored
due to clevudine-related myositis and CK elevation [227-229].
The serum CBC and ALT level of patients receiving peginterferon-α should be tested
monthly. Serum HBV DNA should be measured after 3–6 months of treatment to verify
the primary response. For response prediction, qHBsAg assay can be used before the
treatment and at 12 and 24 weeks of treatment. All patients treated with peginterferon-α
should be checked for the known adverse effects of interferon at every visit.
Patients should be tested for HBeAg and anti-HBe at 6 and 12 months during the treatment,
and at 6 months post treatment. After cessation of treatment, patients should be monitored
for 6–12 months to check if additional treatment is required. There is a high probability
of HBsAg loss if serum HBV DNA becomes undetectable during treatment. HBeAg-positive
patients who achieve HBeAg seroconversion with peginterferon-α require a long follow-up
due to the possibility of HBeAg reversion or development of HBeAg-negative CHB. HBsAg
loss should be checked at 6-month intervals after HBeAg seroconversion if serum HBV
DNA is undetectable. The qHBsAg assay assists in predicting the treatment response
[230,231]. In case of a primary non-response (failure to achieve a 1 log10 reduction
in serum HBV DNA from baseline after 3 months of peginterferon-α treatment), peginterferon-α
treatment should be stopped and replaced by a NA. Several studies recommend that peginterferon-α
treatment should be stopped if qHBsAg does not decrease below 20,000 IU/mL after 24
weeks of treatment, which is predictive of non-response [230,231].
HBeAg-negative patients should be monitored similarly to HBeAg-positive patients during
48 weeks of treatment. A virologic response with a serum HBV DNA level of <2,000 IU/mL
is generally associated with remission of the liver disease . Undetectable serum
HBV DNA by real-time PCR is the ideal off-treatment sustained response, with a high
probability of HBsAg loss in the longer term. HBsAg should be checked at 6-month intervals
if HBV DNA is not detectable. qHBsAg levels after 12 and 24 weeks of treatment as
well as serum HBV DNA levels can be major predictive factors of a treatment response
[210,232,233]. Several studies recommend treatment interruption when qHBsAg after
12 weeks of treatment does not decrease, together with a < 2 log10 serum HBV DNA level
1. During treatment with NAs, liver function should be tested and serum HBV DNA should
be measured by real-time PCR every 1–3 months, plus HBeAg status (HBeAg and anti-HBeAg)
should be checked every 3–6 months. (C1) qHBsAg assay may assist prediction of the
treatment response and identification of cases in which discontinuation of antiviral
therapy may be attempted. (C1)
2. During treatment with peginterferon-α, CBC and ALT level should be measured monthly.
Serum HBV DNA should be measured by real-time PCR at 1- to 3-month intervals, plus
HBeAg and anti-HBe should be checked at 6 and 12 months during the treatment and at
6 months post-treatment. (C1) qHBsAg assay should be performed before, at 12 and 24
weeks during the treatment and at the end of treatment. (B1)
3. After identification of a complete virologic response, serum HBV DNA should be
measured by real-time PCR after 3–6 months and then retesting should be performed
at 2–3 months after HBeAg seroclearance is achieved. (C1)
4. Patients who develop virologic breakthrough while receiving a NA should be monitored
for compliance and antiviral-resistance mutations. (A1)
5. During antiviral therapy, close monitoring for side effects of each drug is mandatory.
Monitoring after antiviral treatment
The response to antiviral treatment persists in some patients, while others relapse.
Non-responders should prepare for the deterioration of liver function. Therefore,
regular monitoring is needed to check for the durability of the treatment response,
relapse, and liver function.
1. During the first year after the cessation of antiviral treatment, liver function
should be monitored and serum HBV DNA should be measured by real-time PCR every 1–3
months, plus HBeAg and anti-HBe should be checked at 3- to 6-month intervals. Beyond
1 year after the cessation of antiviral treatment, liver function and serum HBV DNA
by real-time PCR should be tested every 3–6 months to detect viral relapse. (C1)
2. For early detection of HCC, ultrasound and serum α-fetoprotein measurement should
be performed regularly. (A1)
CESSATION OF TREATMENT
Although the ideal goal of treatment is to achieve HBsAg loss, the primary endpoint
when treating patients with HBeAg-positive hepatitis is to achieve HBeAg seroconversion.
Undetectable serum HBV DNA by real-time PCR and HBeAg seroconversion are strongly
correlated with favorable biochemical and histologic responses. NA can be stopped
when HBeAg seroconversion is achieved and antiviral treatment has been maintained
at least for 12 months . However, cessation should be decided carefully since
40–90% of patients developed reactivation of HBeAg-positive or -negative hepatitis
after HBeAg seroconversion induced by NA treatment [237-240]. HBsAg should be tested
at 6-month intervals after HBeAg seroconversion. HBsAg loss is rarely observed after
NA therapy; however, low baseline qHBsAg levels and greater rate of HBsAg reduction
were highly predictive of HBsAg seroclearance . Peginterferon-α is generally
administered for 48 weeks, and its efficacy was confirmed in a recent double-blind,
randomized controlled study [241,242].
The recommended duration of peginterferon-α treatment in patients with HBeAg-negative
hepatitis is 48 weeks, but the optimal treatment duration for NA is unknown, and cessation
of treatment should be individually decided according to the clinical treatment response
and the baseline severity of the liver disease. Treatment with NA should be continued
until the loss of HBsAg. Treatment discontinuation can be considered if undetectable
serum HBV DNA has been documented on three separate occasions 6 months apart .
However, close follow up is required due to the high probability of reactivation (29.7–91.0%)
after treatment discontinuation [239,243-245]. Peginterferon-α administration for
48 weeks is recommended.
Long-term treatment is required in patients with cirrhosis. In HBeAg-positive patients
with compensated cirrhosis, treatment discontinuation can be considered when NA is
administered for at least a further 12 months after HBeAg seroconversion. Treatment
discontinuation can be considered after achievement of HBsAg loss in HBeAg-negative
patients. Monitoring for viral relapse and acute exacerbation of disease is mandatory
after discontinuation. Long-term treatment should be planned in patients with decompensated
cirrhosis, including the possibility of liver transplantation.
1. HBeAg-positive CHB
1) The optimal duration of treatment with a NA is unclear, although the ideal goal
is HBsAg loss, and alternative goals are HBeAg loss and seroconversion. NAs should
be administered at least 12 months after serum HBV DNA is undetectable and HBeAg seroclearance
or seroconversion is attained. (B1)
2) Peginterferon should be administered for 48 weeks. (A1)
2. HBeAg-negative CHB
1) Although the optimal duration of treatment with NA is unclear, discontinuation
of NA treatment may be considered when HBsAg loss is demonstrated. (A1)
2) Peginterferon-α should be administered for at least 48 weeks. (B1)
3. Liver cirrhosis
Patients require long-term treatment. (B1)
DEFINITIONS OF RESPONSE AND PREDICTORS OF RESPONSE
Definitions of treatment responses (Table 5)
The definitions of responses to antiviral therapy vary according to the type of therapy.
A primary non-response to NA is defined as a decrease of less than 2 log10 IU/mL in
serum HBV DNA from baseline after 6 months of therapy. A complete virologic response
is defined as undetectable serum HBV DNA by real-time PCR. A partial virologic response
is defined as a decrease in serum HBV DNA of more than 1 log10 IU/mL but with serum
HBV DNA still being detectable by real-time PCR . A partial virologic response
should be assessed to determine whether to modify the current therapy after 24 weeks
of treatment for moderately potent drugs or drugs with a low genetic barrier to resistance
(lamivudine and telbivudine), and after 48 weeks of treatment for highly potent drugs,
drugs with a high genetic barrier to resistance, and drugs with late emergence of
resistance (e.g., entecavir, adefovir, and tenofovir).
Virologic breakthrough is defined as a confirmed increase in serum HBV DNA of more
than 1 log10 IU/mL relative to the nadir serum HBV DNA during therapy. This usually
precedes a biochemical breakthrough, which is characterized by an increase in ALT
level after an initial normalization. If a virologic breakthrough develops in a compliant
patient, antiviral-resistant mutations should be tested for.
Genotypic resistance is defined as the presence of HBV mutations in serum that confers
resistance to the antiviral agent, and phenotypic resistance is defined as the presence
of HBV mutations that decrease susceptibility to antiviral drugs in an in vitro test.
Cross-resistance is defined as an HBV mutation induced by one antiviral agent that
confers resistance to other antiviral agents.
HBV resistance to NAs is characterized by the presence of HBV variants with amino-acid
substitutions that confer reduced susceptibility to the administered NA. Such resistance
may result in primary treatment failure or virologic breakthrough during therapy.
A primary non-response to peginterferon-α is defined as a decrease of less than 1log10
IU/mL in serum HBV DNA from baseline after 3 months of therapy. A virologic response
is defined as an HBV DNA level of less than 2,000 IU/mL after 6 months of therapy.
A serologic response is defined by HBeAg seroconversion in patients with HBeAg-positive
Predictors of treatment responses
Certain baseline and on-treatment predictors of the subsequent treatment response
have been identified. The predictors of the responses to existing antiviral therapies
at various time points vary according to the agent.
Pretreatment factors predictive of HBeAg seroconversion are a low viral load (serum
HBV DNA of <107 IU/mL), high ALT level (<3 ULN), and high inflammatory activity score
in a liver biopsy (at least A2)  A high pretreatment ALT level is the most important
predictor of the outcome of treatment with lamivudine, adefovir, or telbivudine .
During treatment with lamivudine, adefovir, or telbivudine, a virologic response at
24 or 48 weeks (undetectable serum HBV DNA by a real-time PCR assay) is associated
with lower incidences of antiviral resistance (i.e., higher probability of a sustained
virologic response) and HBeAg seroconversion in HBeAg-positive patients [156,225,248].
HBV genotype does not influence the response to any NA. In a study of the ability
of qHBsAg assay to predict a treatment response, both HBsAg ≤2 log IU/mL and reduction
by >1 log from baseline at the end of treatment had a 78% positive predictive value
and 96% negative predictive value for a 12-month sustained post-treatment response
(HBV DNA ≤200 IU/mL) to lamivudine in HBeAg-negative patients . During telbivudine
treatment, a decline in serum HBsAg levels (≥ 1 log10 IU/mL) in the first year was
related to a greater likelihood of achieving HBsAg clearance at year 3 . Serum
HBsAg levels ≤2 log IU/mL at treatment week 104 are highly predictive of sustained
virologic response to telbivudine at 2 years off-treatment .
Pretreatment factors predictive of HBeAg seroconversion in HBeAg-positive patients
are a high ALT level, low viral load, a high inflammatory activity score in a liver
biopsy, and HBV genotype [183,251]. There is no consensus among previous reports for
patients with HBeAg-negative hepatitis, but generally a pretreatment high ALT level,
young age, and female gender are reported to be associated with a favorable treatment
A decrease in serum HBV DNA to less than 20,000 IU/mL after 12 weeks of treatment
is associated with a 50% probability of HBeAg seroconversion in HBeAg-positive patients
and with a 50% probability of a sustained response in HBeAg-negative patients [124,253].
A decrease in HBeAg at week 24 may predict HBeAg seroconversion [118,253]. In HBeAg-positive
patients, HBsAg levels <1,500 IU/mL at week 12 during peginterferon alfa-2a therapy
were associated with high rates of posttreatment response, but treatment discontinuation
is indicated in all patients with HBsAg >20,000 IU/mL at week 24 [230,231]. In HBeAg-negative
patients, at week 12 of peginterferon-α treatment, the combination of a decline in
serum HBV DNA <2 log10 copies/mL and absence of a decrease in HBsAg levels is predictive
of a poor response [234,235]. HBV genotypes A and B are associated with a better response
to interferon-α than genotype C, in terms of HBeAg seroconversion and HBsAg loss [254-257].
However, knowledge of the HBV genotype has a poor predictive value in individual cases,
and currently genotype alone should not determine the choice of treatment.
Both entecavir and tenofovir are highly potent antivirals with an excellent resistance
profile, and to which antiviral resistance develops rarely. Nonetheless, the development
of antiviral resistance is one of the most important factors predicting the success
or failure of CHB treatment. The emergence of antiviral resistance results in resumption
of active viral replication that had been suppressed after the initiation of antiviral
therapy, and can impair biochemical or histologic improvement . Therefore, the
prevention, early diagnosis, and management of antiviral resistance may significantly
affect the long-term prognosis of CHB patients undergoing antiviral therapy .
Mechanism of antiviral resistance and definitions
It is estimated that more than 10  new virions are produced daily in a human body
with active HBV replication . Some of the HBV mutants that emerge naturally during
active replication are selected by the selection pressure exerted by the human immune
system or antiviral therapy. Those mutants with maximal replication become predominant
during antiviral therapy. Primary antiviral-resistant mutants usually have a low replication
capacity, but recover to the level of the wild-type virus when compensatory mutations
appear . In addition, a higher fold resistance to antiviral therapy allows increased
replication of the mutant virus. A genetic barrier is defined as the number of genetic
mutations needed to develop antiviral resistance, with a higher genetic barrier indicating
a lower risk of resistance . The antiviral potency of drugs also influences the
development of resistance. Drugs with a lower antiviral potency or potent antiviral
activity have lower risks of antiviral resistance, because the former is associated
with a lower selection pressure and the latter with complete suppression of the virus.
However, drugs with intermediate potency have an increased risk of resistance because
residual viremia during treatment may result in selection of mutants with good replication
fitness . Clinically, the HBV DNA level, history of prior antiviral treatment,
duration of treatment, serum drug concentration (peak and trough), and patient compliance
are the most important factors influencing the development of resistance. Definitions
of terms associated with antiviral resistance are provided in Table 5.
Mutations conferring resistance to antiviral agents
Antiviral agents for the treatment of HBV infection are classified into two groups:
NAs and nucleotide analogues. Cyclopentenes (entecavir) and L-nucleoside analogues
(lamivudine, telbivudine, and clevudine) are NAs, while acyclic phosphonates (adefovir
and tenofovir) are nucleotide analogues . The incidences of resistance to individual
antiviral drugs are shown in Table 6.
1. Nucleoside analogues
1) L-nucleoside analogues (lamivudine, telbivudine, and clevudine)
Mutations at rtM204 are the primary resistance mutations to lamivudine, telbivudine,
and clevudine [264-267]. The rtM204V and rtM204I mutations involve the substitution
of methionine with valine and isoleucine, respectively, at codon 204 of the reverse
transcriptase gene. Originally these were termed YMDD mutations, but that terminology
is no longer recommended . rtM204V emerges during lamivudine treatment, but rtM204I
can develop during the administration of lamivudine, telbivudine, or clevudine [225,226,269,270].
An rtM204V mutant may commonly accompany rtL180M but not rtM204I . These mutants
are sensitive to adefovir and tenofovir, but they exhibit cross-resistance to entecavir
and show an eightfold decrease in sensitivity. The rtA181T mutation has been detected
in 5% of lamivudine-resistant patients . The mutants exhibit cross-resistance
to adefovir but remain sensitive to entecavir .
2) Cyclopentene (entecavir)
Resistance to entecavir develops via a two-hit mechanism. rtL180M and rtM204V first
develop as background mutations, and then additional mutations such as rtT184L/F/A/M/S/I/C/G,
rtS202G/I/C, or rtM250V/I/L develop as primary resistance mutations to entecavir,
resulting in a marked decrease in drug susceptibility [261,273]. rtI169T is a compensatory
mutation that increases the fold resistance of rtT184, rtS202, and rtM250 mutants.
Since multiple genetic mutations are needed to develop high-level resistance to entecavir
(high genetic barrier), the resistance rate in treatment-naïve subjects is very low.
However, a resistance rate as high as 51% has been reported after 5 years of treatment
in lamivudine-refractory subjects .
2. Nucleotide analogues
rtN236T and rtA181V/T are the primary resistance mutations to adefovir [157,275].
The levels of resistance of rtN236T and rtA181T to adefovir are 7- to 10-fold and
2.5- to 5-fold, respectively, compared to the wild-type virus [263,272]. rtA181T can
be detected in subjects receiving lamivudine monotherapy or combination therapy comprising
adefovir plus lamivudine [276,277].
Clinically significant resistance mutations to tenofovir have not been reported in
patients with HBV monoinfection. However, rtA194T can decrease the susceptibility
to tenofovir 10-fold in the presence of rtL180M+rtM204V, according to a case study
of a patient with HBV and HIV coinfection .
Management of antiviral resistance
Prior antiviral resistance predisposes individuals to subsequent viral mutations and
limits the choice of rescue therapies due to the presence of cross-resistance [263,279].
Although antiviral agents without cross-resistance may be selected, the resistance
to the rescue therapy is greater than that of treatment-naïve subjects [279-281].
It is therefore critical to initially choose the antiviral agent with the lowest resistance
Appropriate monitoring during treatment is needed to detect virologic and biochemical
breakthroughs as early as possible. Anti-viral resistance testing is required when
a virologic or biochemical breakthrough is detected in subjects with good compliance.
If genotypic resistance is confirmed, rescue therapy should be initiated before the
clinical situation deteriorates .
General principles of antiviral resistance management:
1. An antiviral resistance test should be performed when virologic breakthrough occurs,
especially in cases with good compliance. (A1)
2. Rescue antiviral therapy should be started as soon as possible upon emergence of
resistant variants, especially when viral breakthrough is detected and genotypic resistance
is confirmed. (A1)
MANAGEMENT OF ANTIVIRAL-RESISTANT CHB
Management of lamivudine resistance
Tenofovir shows potent antiviral activity against lamivudine-resistant HBV [284-287].
In a retrospective study that compared a tenofovir monotherapy group with a tenofovir-plus-lamivudine
combination-therapy group for 197 patients (105 naïve patients and 92 patients resistant
to lamivudine), the HBV undetectable rate (HBV DNA <20 IU/mL) was not different significantly
in the HBeAg-negative group (94% vs. 96%, respectively) and HBeAg-positive group (67%
vs. 83%, respectively) . One comparative study involving lamivudine-resistant
CHB patients coinfected with HIV found that the HBV DNA level after 48 weeks was <105
cpm in 100% of patients in the tenofovir group but in only 44% of patients in the
adefovir group, with the difference being statistically significant . In a study
that compared a tenofovir monotherapy group with a tenofovir-plus-emtricitabine combination-therapy
group including 280 patients with lamivudine-resistant HBV, the HBV undetectable rate
(69 IU/mL) was not significantly different (85.8% vs. 83.5%, respectively) and tenofovir-resistant
HBV was not detected in either group after 96 weeks . No prospective study has
compared tenofovir monotherapy with tenofovir-plus-lamivudine combination-therapy.
However, in a retrospective study that compared a tenofovir monotherapy group (n=71)
with a tenofovir-plus-lamivudine combination-therapy group (n=54) among 125 patients
with a history of antiviral treatment, the cumulative HBV undetectable rate (<20 IU/mL)
differed significantly after 3 years (90.7% vs. 96.0%, respectively) .
Adefovir has shown antiviral activity against lamivudine-resistant HBV. The development
of resistance to adefovir was significantly less frequent in the adefovir-plus-lamivudine
combination-therapy group than in the adefovir-monotherapy group in long-term studies
[288,289]. No comparative study of tenofovir monotherapy and adefovir plus NA combination
therapy has been performed. However, combination therapy with lamivudine plus adefovir
results in a higher adefovir resistance rate (2.2-13.3%) compared to tenofovir (0%)
[290-293]. Few studies of combination therapy with adefovir plus other NAs such as
entecavir, telbivudine, and clevudine instead of lamivudine are available; moreover,
the studies reported to date have involved small populations. One retrospective study
involving 91 lamivudine-resistant CHB patients consisted of adefovir monotherapy (n=29),
adefovir and lamivudine combination therapy (n=30), adefovir and entecavir 1 mg combination
therapy (n=32) found that the HBV DNA undetectable rate (<60 IU/mL) was not significantly
different (48.2% vs. 76.7% vs. 87.5%, respectively) but the adefovir resistance rate
differed significantly (27.6% vs. 13.3% vs. 0%, respectively) after 24 months .
In a small prospective study that compared an adefovir-plus-telbivudine combination-therapy
group (n=21) with an adefovir-monotherapy group (n=21), the HBV undetectable rate
(<300 copies/mL) was 38.5% and 0%, respectively, and adefovir resistant virus was
detected in 9.6% of patients in the adefovir-monotherapy group after 96 weeks .
Two small prospective studies revealed that the reduction in HBV load was greater
in the adefovir-plustelbivudine combination-therapy group than the adefovir-plus-lamivudine
combination-therapy group [295,296].
Entecavir at a dose of 1.0 mg exhibits antiviral activity in lamivudine-resistant
CHB patients [297,298]. In a study of monotherapy with 1.0 mg entecavir compared with
adefovir-plus-lamivudine combination therapy in patients with lamivudine resistance,
monotherapy showed a significantly higher viral breakthrough rate (17.6% vs. 2.0%)
but comparable antiviral efficacy [291,299-301]. Two retrospective studies of combination
treatment with adefovir and entecavir 1 mg in patients with lamivudine resistance
revealed a significantly lower viral breakthrough rate (0-2.6%) than adefovir combination
therapy with another NA or entecavir 1 mg monotherapy [292,302].
4. Peginterferon alpha
In a study that compared a group receiving peginterferon alpha group for 48 weeks
(n=155) with a group receiving adefovir for 72 weeks (n=80) among patients with compensated
liver disease, the HBV DNA undetectable rate (<80 IU/mL) was lower (10.6% vs. 22.5%),
but the HBeAg seroconversion rate was higher (14.8% vs. 3.8%) significantly in the
peginterferon alpha group . There was no significant difference in the HBeAg
seroconversion rate and HBV undetectable rate in another study that compared the efficacy
of peginterferon alpha between patients with wild-type virus and lamivudine-resistant
1. Switch to tenofovir or combine tenofovir with a nucleoside analogue. (A1)
2. Consider combination of adefovir and a nucleoside analogue if use of tenofovir
is contraindicated. (B1)
3. Stop lamivudine and consider treatment with peginterferon-α if the patient has
compensated liver function. (B2)
Management of telbivudine resistance
Few data related to telbivudine resistance are available. In a study in which telbivudine-
resistant patients or viral breakthrough patients without resistance (n=68) were treated
with adefovir, over 70% of patients had an HBV level of ≤300 copies/mL after 12 months
. Treatment based on tenofovir could be a therapeutic option, but comparative
data for telbivudine and lamivudine are insufficient. The general principles of management
of telbivudine resistance are similar to those for the management of lamivudine resistance.
1. Follow the recommendations for the management of lamivudine-resistant CHB. (B2)
Management of adefovir resistance
The HBV mutations rtN236T and rtA181V/T result in primary resistance to adefovir [157,275].
rtA181T can also be detected in subjects receiving lamivudine monotherapy or combination
therapy of adefovir plus lamivudine [272,275-277,306]. rtN236T and rtA181T result
in 7- to 10-fold and 2.5- to 5-fold, respectively, greater resistance to adefovir
relative to the wild-type virus [263,272]. The double mutation (rtA181T/V and rtN236T)
results in a 5.2- to 18-fold reduction in sensitivity to adefovir . Patients
with persistent drug-resistant HBV viremia are more likely to suffer hepatitis flares,
disease progression, and death than those without drug-resistant HBV .
The rate of adefovir-resistance is 20% and 29% after 5 years of adefovir treatment
in HBeAg-positive and HBeAg-negative treatment naïve patients, respectively [157,308].
The risk of genotypic resistance to adefovir increases in patients resistant to lamivudine
compared to treatment-naïve patients. After 48 weeks of adefovir treatment, the rate
of resistance was 18% and 0% in lamivudine-resistant and treatment-naïve patients,
respectively . Moreover, the rate of adefovir resistance can reach 22-25% after
2 years of treatment in lamivudine-resistant patients [281,309].
In vitro studies showed that the rtN236T mutant remained sensitive to lamivudine,
while the rtA181/V mutant exhibited reduced susceptibility to lamivudine .
In adefovir-resistant patients without prior exposure to lamivudine , the combination
of telbivudine/adefovir and monotherapy with entecavir was associated with virologic
response rates of 73.3% and 57.1%, respectively, and HBeAg seroconversion rates of
only 20% and 0%, respectively.
In patients who developed adefovir resistance in the presence of lamivudine resistance,
the combination of lamivudine/adefovir resulted in a virologic breakthrough rate of
7.3% and primary nonresponse rate of 51.2% at 1 year, and a very low virologic response
rate (HBV DNA <60 IU/mL) of 12.2% .
In vitro studies have shown that HBV with adefovir-mono-resistant mutations may be
susceptible to entecavir . However, HBV with lamivudine-resistance mutations
have cross-resistance to entecavir. Thus, in patients resistant to both adefovir and
lamivudine, entecavir monotherapy was associated with a suboptimal virologic response
(42%) and high rate of additional resistance to entecavir (17%) at 1 year. In these
patients, even the combination of entecavir/adefovir resulted in a very low virologic
response rate of 31.1% and 44.7% at 1 and 2 years, respectively [302,312,313].
Tenofovir has about 30-fold higher antiviral efficacy than adefovir [314-316]. However,
in vitro studies show that HBV strains expressing the adefovir resistance-associated
substitutions, rtA181T/V and/or rtN236T, demonstrate reduced susceptibility to tenofovir,
ranging from 2.9- to 10-fold that of the wild-type virus [276,317-319]. Nonetheless,
several studies have suggested that tenofovir disoproxil fumarate (TDF) monotherapy
is efficacious in patients with lamivudine-resistant, entecavir-resistant, adefovir-refractory,
and adefovir-resistant HBV [287,315,316,320,321]. An European trial comparing TDF
and emtricitabine (FTC) plus TDF in patients with adefovir-refractory CHB demonstrated
that the rate of virologic response did not differ between TDF and FTC/TDF therapies;
82% vs. 84% at 3.5 years [315,316]. A randomized trial comparing TDF monotherapy and
TDF/entecavir combination therapy in patients with adefovir-resistant HBV showed a
similar virologic response rate of 62% and 63.5%, respectively, at 48 weeks .
However, in a subgroup of patients who had double adefovir-resistance mutations; i.e.,
both rtA181T/V and rtN236T, the decrease in serum HBV DNA levels tended to be less
in the TDF group than in the TDF/entecavir group (-3.03 log10 IU/mL vs. -3.31 log10
1. Switch to tenofovir or combine tenofovir with entecavir. (B1)
2. Combination therapy with tenofovir and a nucleoside analogue other than entecavir.
3. Consider combination of adefovir and a nucleoside analogue if use of tenofovir
is contraindicated. (B2)
Management of entecavir resistance
In patients with lamivudine-resistant HBV, the rate of entecavir resistance increases
to 51% after 5 years of entecavir treatment, in contrast to a 1.2% resistance rate
in NA-naïve patients [273,274]. The difference is because the entecavir resistance
barrier is lowered by the initial selection of the lamivudine-resistance HBV mutation,
rtM204V/I . In vitro studies have shown that susceptibility to entecavir is decreased
by 10-250-fold when one of the entecavir resistance-associated substitutions at rtT184,
rtS202, or rtM250 is present in combination with rtM204V/I, and by >500-fold when
two or more of these mutations are present [273,323].
In vitro studies suggest that entecavir-resistant HBV mutants are susceptible to adefovir
and TDF [324,325]. A few cohort studies have reported the efficacy of adefovir or
TDF in patients with entecavir-resistant HBV [326-329].
No randomized trial of adefovir treatment in patients with entecavir resistance has
been performed. Adding adefovir to entecavir would be more reasonable for reducing
adefovir resistance and improving the antiviral efficacy . Combination therapy
of adefovir plus lamivudine could also be considered . However, small retrospective
cohort studies demonstrated that the virologic response rate was 24-51% at 1 or 2
years of treatment with the combination of adefovir and entecavir or lamivudine [326-328,332].
Tenofovir does not show cross-resistance to entecavir in vitro and has excellent potency
. A Korean multicenter randomized trial was performed in HBV patients with entecavir
resistance-associated mutations comparing TDF monotherapy and TDF and entecavir combination
therapy for 48 weeks . All patients had at least one entecavir-resistance mutation:
rtT184A/C/F/G/I/L/S, rtS202G, and rtM250L/V, in addition to rtM204V/I. At week 48,
the proportion of patients with HBV DNA <15 IU/mL, the primary efficacy endpoint,
was not significantly different between the TDF and TDF+entecavir groups (71% vs.
73%; P=0.81). Virologic breakthrough occurred in one patient on TDF, which was attributed
to poor drug adherence. At week 48, six and three patients in the TDF and TDF+entecavir
groups, respectively, retained their baseline resistance mutations (P>0.99). None
developed additional resistance mutations. Safety profiles were comparable in the
1. Switch to tenofovir or combine tenofovir with entecavir. (B1)
2. Consider combination of adefovir and a nucleoside analogue if use of tenofovir
is contraindicated. (B2)
Management of tenofovir-resistance
No tenofovir-resistant patients have been reported to date. A prospective study found
no HBV strain resistant to TDF after up to 8 years of treatment . An in vitro
study reported that A194T in combination with lamivudine resistance mutations, rtL180M
and rtM204V, might account for TDF resistance in HBV . However, other in vitro
studies have reported inconsistent results [336,337].
Management of multiple drug resistance
Multidrug resistance is defined as resistance to two or more groups of antiviral drugs;
i.e., L-nucleoside (lamivudine, telbivudine, clevudine), cyclopentane (entecavir),
or nucleotide analogue (adefovir and tenofovir) [279,318].
Interferon has not been used for the management of patients with multidrug-resistant
HBV. However, there is also no suggestion that such patients have decreased susceptibility
In vitro clonal analyses showed that multidrug-resistance mutations usually reside
in the same viral genome [279,318], and replicating clones with lamivudine- and adefovir-
associated mutations had >50-fold reduced susceptibility to combination of lamivudine
and adefovir [338,339]. In fact, a cohort study demonstrated that in patients with
HBV resistant to lamivudine and adefovir, combination therapy with these two drugs
was not effective and indeed was inferior to entecavir monotherapy in terms of suppressing
HBV DNA . However, the response to entecavir monotherapy was not optimal. Entecavir
was markedly less effective in patients refractory to both lamivudine and adefovir
than in those with lamivudine monoresistance , or treatment-naïve patients .
In patients with multidrug-resistant HBV, a combination of the two most potent drugs,
TDF and entecavir, would likely prevent the emergence of resistance to TDF .
However, two randomized trials in patients with resistance to entecavir and/or adefovir
in addition to lamivudine resistance showed no difference in virologic response between
TDF monotherapy and TDF and entecavir combination therapy, and no emergence of additional
resistance mutations [322,334]. Based on their comparable antiviral efficacy, extremely
low risk of TDF resistance, lower cost, and potentially better safety profile, TDF
monotherapy would be a reasonable option for the treatment of entecavir-resistant
1. Switch to tenofovir or combine tenofovir with entecavir. (B1)
2. Consider combining adefovir with a nucleoside analogue if use of tenofovir is contraindicated.
RESPONSE-GUIDED THERAPY DURING ORAL ANTIVIRAL DRUG TREATMENT FOR CHB
Once antiviral-resistant HBV mutants have been selected, they are persistently archived
(retained in the virus population) in ccc-DNA in the nucleus of infected cells, even
if treatment is stopped, which can limit future therapeutic options [341,342]. Preventing
the development of resistance is important to ensure long-term therapeutic efficacy.
Persistence of viral replication during antiviral treatment is associated with the
emergence of drug resistance [225,343,344]. Therefore, evaluation of the treatment
response using sensitive PCR assays to measure serum HBV DNA levels every 3-6 months
The response patterns of oral antivirals during treatment are classified as complete
response, partial response and primary non-response. Complete response is defined
as undetectable serum HBV DNA by PCR during treatment. Partial virologic response
is defined as detectable serum HBV DNA with a more than 2 log10 IU/mL reduction in
HBV DNA level from baseline . A primary non-response is defined as a reduction
in the serum HBV DNA level of less than 2 log10 IU/mL at week 24 . Virologic breakthrough
is defined as an increase in serum HBV DNA level of more than 1 log10 IU/mL from nadir.
Although virologic break-through is generally associated with emergence of resistance
mutations, up to 30% of the cases of virologic breakthrough in clinical trials are
related to medication noncompliance . Therefore, compliance should be checked
in all patients with a sub-optimal response.
In patients with a complete virologic response, treatment should be continued until
the endpoint is achieved, which should be evaluated by measuring the serum HBV DNA
level every 3–6 months [117,347]. Primary non-response is very rare in oral antiviral
therapy, with the exception of adefovir. Therefore, few studies of primary non-response
patients have been performed. In patients with primary non-response with good compliance,
switching to a drug with a high genetic barrier is indicated if the patient is taking
a drug with a low genetic barrier, due to the possibility of immanent resistance [117,347].
However, a recent study of entecavir for treatment-naïve CHB reported a primary non-response
rate of 1.3-1.7%, and all patients achieved a virologic response after continuing
entecavir therapy during follow up [348,349]. Therefore, if the patient is taking
a drug with a high genetic barrier, such as entecavir or tenofovir, treatment could
either be switched to another high-genetic-barrier drug or be continued using the
same high genetic barrier drug with monitoring for virologic response at 3-6-month
intervals in patients with primary non-response.
The rate of emergence of lamivudine or telbivudine-resistant HBV was directly proportional
to the HBV DNA level after 24 weeks of treatment [225,343,344]. Yuen and colleagues
found that these rates were 8%, 13%, 32%, and 64% for patients with 24-week HBV DNA
levels of <200, 3 log10, 4 log10, and 4 log10 or higher, respectively, after a median
follow-up of 29 months . Although few studies on this issue have been conducted,
a partial response should be evaluated at 6 months after therapy and switching to
a drug with a higher genetic barrier should be considered if lamivudine or telbivudine
is used [117,347]. A prospective study of switching to entecavir 1 mg in patients
with a partial response to lamivudine reported a virologic response rate of 67.6%
and a resistance rate of 3% at 96 weeks . However, a history of exposure to lamivudine
is associated with a high rate of emergence of entecavir resistance during entecavir
therapy . Therefore, switching to entecavir should be considered carefully. The
response to tenofovir monotherapy was influenced by neither a previous history of
lamivudine treatment nor resistance [287,333,352-354]. The incidences of adefovir
resistance at 114 weeks of adefovir therapy in patients with an HBV DNA level of less
than 1,000 copies/mL, 103-106 copies/mL or more than 106 copies/mL at 48 weeks of
adefovir therapy were 4%, 26% and 67%, respectively . A partial virologic response
to adefovir should be evaluated at 12 months after adefovir therapy and switching
or adding anti-virals is recommended for patients with a partial virologic response.345
Although a prospective controlled study reported that the virologic response rates
were 81% and 88% after 12 months of therapy with adding lamivudine or telbivudine
in patients with a partial virologic response to adefovir at 48 weeks , these
combination therapies have a substantial risk of emergence of resistance during long-term
treatment . Switching to entecavir 1.0 mg needs to be done with upmost caution
since the incidence of entecavir resistance was as high as 25.7% in patients with
adefovir resistance . In a prospective controlled study of treatmentnaïve CHB
patients, the virologic response rate during adefovir therapy at 48 weeks was 63%
but increased to 90% after switching to tenofovir for a further 48 weeks . Tenofovir
is an effective alternative for patients with a suboptimal response to adefovir and
adefovir resistance mutations , and no report of tenofovir resistance has been
Partial virologic response to entecavir and tenofovir (which have a high genetic barrier)
should be evaluated at 12 months after therapy due to the high potency and low incidence
of resistance . Although some studies suggested that a partial virologic response
to entecavir could be defined as a serum HBV DNA level of 1,000 IU/mL or 35 IU/mL
at 12 months after therapy [246,358], it is generally defined as detectability of
HBV DNA by PCR. The incidence of a partial virologic response to entecavir therapy
has been reported to be 10% to 28% and that of a virologic response to maintenance
entecavir therapy after a partial virologic response have been reported to be 45%
to 95% [349,358-361]. Although switching therapy to tenofovir in 14 patients with
a decline in HBV DNA level of less than 1 log10 during more than 6 months of entecavir
therapy achieved a virologic response in all patients during a mean of 50 weeks of
tenofovir therapy , further studies are needed to determine the optimal treatment
strategy for patients with a partial virologic response to entecavir. Although a partial
virologic response has been found in patients with a high genetic barrier, continuing
the antiviral agent, especially in cases with a continuous decrease in HBV DNA level,
could be recommended as the incidence of resistance during long-term treatment is
low . However, switching to another high genetic barrier antiviral is another
1. In patients with a complete virologic response, treatment should be continued until
the treatment endpoint is achieved, and monitored by measuring the serum HBV DNA level
every 3–6 months. (B1)
2. Drug compliance should be checked thoroughly in patients with a partial virologic
response or primary non-response. For patients treated with a drug with a low genetic
barrier, treatment should be switched to a drug with a higher genetic barrier. (B1)
For patients treated with a drug with a high genetic barrier, treatment could either
be switched to another drug with a high genetic barrier or be continued with monitoring
for a virologic response at 3-6-months intervals. (C1)
3. In the event of viral breakthrough, rescue therapy should be implemented according
to the genotypic resistance profile. (A1)
4. The treatment strategy should follow the recommendations for treating drug-resistant
HBV when genotypic resistant mutations are identified. (A1)
TREATMENT OF SPECIAL POPULATIONS
Acute hepatitis B
Acute hepatitis B resolves spontaneously and does not progress to the chronic stage
in more than 95% of patients, so antiviral therapy is generally not recommended [363,364].
Early initiation of antiviral therapy has been reported to interfere with the normal
protective immune response and suppresses production of neutralizing antibodies against
hepatitis virus, increasing the risk of chronic hepatitis . However, acute hepatitis
B infection seldom progresses to serious hepatitis and may lead to hepatic failure
. According to a randomized controlled trial in 71 patients with severe acute
hepatitis B, HBV DNA levels were significantly lower in the lamivudine-treated group
(n=31, 3.7 log10 copies/mL) compared with the control group (n=40, 4.2 log10 copies/mL)
after 4 weeks. However, the rate of HBsAg loss after 12 months was similar in the
two groups (93.5% in the lamivudine group and 96.7% in the placebo group) . In
this study, the rate of development of protective anti-HBs after 1 year was 67.7%
in the lamivudine group and 85% in the placebo group; the difference was not significant.
A recent, small, prospective, controlled study also reported no significant benefit
of lamivudine in severe acute hepatitis B . In contrast, Tillman et al. reported
that lamivudine is safe in patients with severe acute or fulminant hepatitis B, leading
to rapid recovery with the potential to prevent liver failure and liver transplantation
when administered sufficiently early . However, only a few case reports of antiviral
agents as treatment for acute hepatitis B other than lamivudine have been published
to date [369-371].
1. For patients with acute hepatitis B, oral antiviral therapy might be considered
in cases of persistent serious hepatitis or acute liver failure. (C1)
Liver transplant patients
In the past, severe liver damage and a low survival rate due to HBV recurrence after
liver transplantation in HBV-related liver disorder patients were major problems [372-379].
However, in an extensive cohort study of 372 patients who received liver transplants
in the early 1990s and were positive for HBsAg, the study group treated with HBIG
therapy for more than 6 months showed a significantly lower rate of hepatitis B recurrence
than the group treated with HBIG therapy for less than 6 months or those who were
not treated. The study group also had a higher long-term survival rate than the other
groups . Since then, several studies have reported hepatitis B recurrence rates
ranging from 16% to 35% after liver transplantation in groups receiving high-dose
HBIG (10,000 IU) therapy [381-383].
Lamivudine and HBIG combination therapy reduces the rate of HBV recurrence to less
than 10% after 1–2 years and is superior to high-dose HBIG therapy with respect to
cost and effectiveness [384-387]. In a meta-analysis of six independent studies, lamivudine
and HBIG combination therapy was found to reduce the rates of HBV recurrence and death
12-fold compared with HBIG therapy alone [388,389]. A meta-analysis of 46 studies
in which 2,161 HBV-infected patients received liver transplants found that adefovir
and HBIG combination therapy significantly reduced the rate of hepatitis B recurrence
to 2% compared to 6% with lamivudine and HBIG combination therapy .
In patients who received lamivudine monotherapy without HBIG, the hepatitis B recurrence
rate after 4 years of liver transplantation was ~40% [391,392]. In contrast, a study
of lamivudine and adefovir combination therapy reported no recurrence in CHB patients
during the 22-month observation period . In patients who received entecavir monotherapy
without HBIG [394,395], the rate of HBsAg loss was 88-91% and negative viremia was
maintained in more than 98% during a 26-53-month follow up; moreover, the rate of
HBV recurrence was lower than that with lamivudine monotherapy .
In a meta-analysis of 19 studies, lamivudine or adefovir with HBIG significantly reduced
HBV recurrence compared to monotherapy with either lamivudine or adefovir . However,
in a meta-analysis of 17 studies with 519 patients, those treated with lamivudine
and HBIG (6.1%) combination therapy showed a rate of HBV recurrence comparable to
that of those treated with either entecavir or tenofovir monotherapy (3.9%, P=0.52),
and significantly higher than that of those treated with the combination of HBIG and
either entecavir or tenofovir therapy (1%, P<0.001) . To date, few studies regarding
entecavir or tenofovir monotherapy for the prevention of HBV recurrence after liver
transplantation have been reported. Therefore, the combination of an antiviral and
HBIG is recommended to prevent HBV recurrence after liver transplantation.
To reduce the cost of HBIG, studies of low-dose HBIG in combination with an antiviral
or conversion to antiviral monotherapy after short-term HBIG combination therapy have
been performed. In a study of 147 patients who received liver transplants, Gane et
al. showed that lamivudine and low-dose HBIG (400–800 IU) combination therapy effectively
suppressed the recurrence of hepatitis B at a moderate cost, as the 5-year recurrence
rate of hepatitis B was 4% . Furthermore, patients with HBV DNA levels of less
than 2.5 pg/mL before liver transplant and treated with lamivudine and HBIG (2,000
IU) combination therapy for 1 month after liver transplant were randomly assigned
to either a combination therapy maintaining group or lamivudine monotherapy group.
The rates of HBV recurrence and patient survival did not differ between the two groups
. Two other retrospective studies reported no recurrence of HBV when lamivudine
and HBIG combination therapy or HBIG therapy alone for 2 years after liver transplantation
was replaced with lamivudine monotherapy [400,401]. In a recent study by Angus et
al., lamivudine and low-dose HBIG (800 IU) combination therapy was continued for at
least 12 months after liver transplantation. The group in which HBIG was replaced
by adefovir and the group in which HBIG was continuously administered showed similar
rates of hepatitis B recurrence . Lamivudine and adefovir combination therapy
with initial short-term low-dose HBIG (400-800 IU) did not show HBV recurrence during
the 57-month follow-up period .
Few studies with a small number of patients have evaluated entecavir- or tenofovir-based
therapy to reduce HBIG usage. The HBV recurrence rate was reported to be 10% (1/10)
 and 0% (0/11)  when combination entecavir and HBIG therapy was converted
to entecavir monotherapy; there was no HBV recurrence after converting to tenofovir
monotherapy in 9 patients  and 17 patients . The rates of recurrence were
5.9% (1/17)  and 4.8% (1/21)  in a study of conversion to tenofovir and
emtricitabine (Truvada®); however, HBIG withdrawal had an economic benefit. Although
these studies suggested the possibility of reducing the dose and duration of HBIG
treatment, further work is needed to determine the optimal duration, amount and type
of antiviral treatment.
If hepatitis B recurs after preventive HBIG therapy following liver transplantation,
lamivudine therapy could effectively inhibit the virus. However, it has been reported
that long-term lamivudine therapy is associated with a resistance rate of >50% after
3 years [407-409]. Such lamivudine resistance causes inflammatory changes and hepatic
fibrosis in the transplanted liver; indeed, death following hepatic failure is possible
in severe cases [408,410,411].
A few studies have reported the effects of tenofovir and entecavir on hepatitis B
recurrence after liver transplantation; however, further research is required .
Several studies have reported relatively good efficacy of lamivudine and adefovir
in patients with recurrent hepatitis B who exhibit lamivudine resistance after liver
transplantation. The most extensive study administered the combination therapy to
241 patients with recurrent hepatitis B. The rate of reduction in HBV DNA was 65%,
whereas the rate of lamivudine resistance at 96 weeks after the initiation of therapy
was 2% . Although these studies were conducted for a short period in small groups,
it was recently reported that tenofovir is effective against mutants with lamivudine
resistance [411,414]. However, a high rate of emergence of entecavir resistance has
been reported when entecavir is administered as a rescue therapy to patients with
lamivudine resistance . Therefore, entecavir is not recommended in patients with
lamivudine resistance after liver transplantation.
If HBsAg seronegative patients receive liver transplants from positive anti-HBc donors,
~50% will develop new hepatitis B . When HBIG therapy was administered to these
patients after liver transplantation, hepatitis B occurred in >20%. However, when
lamivudine therapy was applied, hepatitis B developed only in 2–3% of patients. Nevertheless,
lamivudine and HBIG combination therapy had no additional preventive effects compared
to lamivudine therapy alone [415-417]. The protective effect against HBV recurrence
was similar between lamivudine and entecavir or tenofovir . Lamivudine was more
cost-effective than entecavir or tenofovir according to a Markov model .
1. Pre-transplant therapy with a NA is recommended for all HBsAg-positive patients
undergoing liver transplantation to achieve the lowest possible level of HBV DNA before
2. Antiviral therapy before liver transplantation should comply with the guidelines
for chronic hepatitis B therapy. (B1)
3. Therapy with a NA and HBIG should be administered for the lifetime of the patient
to prevent recurrence of hepatitis B after liver transplantation, until more evidence
regarding alternative treatment regimens is accumulated. (B1) If serum HBV DNA becomes
negative before the liver transplant, withdrawal of HBIG may be considered in certain
patients after long-term monitoring. (B1)
4. In case of HBV recurrence after liver transplantation, a potent NA with a high
barrier to resistance is recommended. (B1) Upon emergence of drug-resistant variants,
the CHB treatment guidelines should be followed. (B1)
5. When an HBsAg-negative recipient receives an HBsAg-negative but anti-HBc-positive
graft, the recipient should take oral antivirals indefinitely. (B1)
Immunosuppression and chemotherapy
The clinical course of individual patients with chronic hepatitis B is affected by
the interaction between the virus and the host immune system. Impaired host immunity
due to chemotherapy or immunosuppressive treatment increases the risk of HBV reactivation
. Previously, HBV reactivation referred to the reappearance of necroinflammatory
disorders in patients with either inactive CHB or with resolved hepatitis , and
was commonly defined as an increase in the serum HBV DNA of >10-fold the baseline
level or an absolute level of >108 IU/mL together with elevated serum ALT (higher
than 3× ULN or an absolute increase of >100 IU/L) [422,423]. However, most studies
of HBV reactivation used their own definition of HBV reactivation, and so the exact
incidence of HBV reactivation during immunosuppressive therapy or chemotherapy was
unclear. In addition, several terms such as “preventive”, “prophylactic” and “preemptive”
were used but not clearly defined, which resulted in confusion in scientific communications.
In this guideline, “prophylactic” therapy means starting antiviral therapy simultaneously
with initiation of immunosuppressive therapy or chemotherapy. Meanwhile, “preemptive”
therapy means deferring antiviral therapy until the HBV DNA level increases. We prefer
the term “preventive” therapy, which means not only starting antiviral therapy upon
initiation of immunosuppressive therapy or chemotherapy but also deferring antiviral
therapy until the HBV DNA level increases.
Two definitions of HBV reactivation are in use . One is exacerbation of chronic
HBV infection, and the other is relapse of past HBV infection. Exacerbation of chronic
HBV infection is defined ≥2log10 increase of HBV DNA level from the baseline level
or a new appearance of HBV DNA to a level of ≥100 IU/mL. Relapse of past HBV infection
is defined among HBsAg negative, IgG anti-HBc positive and HBV DNA negative patients
as reappearance of HBsAg or detectable HBV DNA. The diagnosis of HBV reactivation
requires the exclusion of other conditions such as chemotherapy-related hepatic injury,
hepatic metastases, and other types of viral hepatitis. The reactivation rate has
been reported to be 20-50%, although the ranges varied among studies. Many patients
with HBV reactivation are asymptomatic, but the clinical course varies widely from
jaundice to decompensation or even death [422,425-427]. In typical cases, HBV DNA
appears in the serum during immunosuppressive treatment, followed by elevation of
ALT after treatment cessation. If HBV reactivation occurs during chemotherapy, treatment
disruption or premature termination may adversely affect the outcome of chemotherapy
[428-430]. Predictive factors for HBV reactivation include the pretreatment HBV DNA
level, HBeAg positivity, cccDNA in hepatocytes and PC/BCP mutation as viral factors,
type of malignancy, male and young age as host factors, and type or intensity of immunosuppression
or chemotherapy and hematopoietic stem cell or organ transplantation as environmental
therapeutic factors .
The reported reactivation rate in lymphoma patients ranges from 24% to 67%, possibly
due to intense chemotherapeutic regimens against lymphoma and higher HBsAg positivity
rates in these patients [426,432-434]. Rituximab, which is commonly administered with
corticosteroid for lymphoma, further increases the risk of HBV reactivation [435,436].
One retrospective study reported a 27.8% (45/162) HBV reactivation rate among HBsAg-positive
lymphoma patients, with a lower rate of HBV reactivation in the preventive antiviral
therapy group compared to the non-preventive antiviral therapy group (22.9% [32/140]
vs. 59.1% [13/22]; P<0.001) . In this study, entecavir reduced the rate of HBV
reactivation to a greater degree than lamivudine (6.3% vs. 39.3%; P<0.05). In HBsAg
negative/anti-HBc positive patients, the rate of HBV reactivation was 2.4% in this
retrospective study. Another prospective study of HBsAg negative/anti-HBc-positive
lymphoma patients reported a higher rate of HBV reactivation and hepatitis aggravation
(10.4 and 6.4 per 100 person-years, respectively) during rituximab plus cyclophosphamide,
doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy . In this study,
close monitoring of HBsAg and HBV DNA with immediate antiviral therapy usually overcame
the complications of HBV reactivation; however, some cases showed marked aggravation
and progression of severe hepatitis, which was associated with reappearance of HBsAg
compared to reappearance of HBV DNA without HBsAg (100% vs. 28%). A rituximab-containing
regimen increased the risk of HBV reactivation among HBsAg-positive and HBsAg-negative/anti-HBc-positive
lymphoma patients (relative risk 2.14, 95% CI 1.42–3.22, P=0.0003), especially in
HBsAg-negative/anti-HBc-positive lymphoma patients (relative risk 5.52) . Preventive
anti-viral therapy in lymphoma reduced the rate of HBV reactivation significantly
compared to a non-preventive group (13.3% vs. 60%) . Pretreatment screening for
HBsAg and anti-HBc before R-CHOP chemotherapy in lymphoma and preventive antiviral
therapy enhanced survival and cost-effectiveness by reducing the rate of HBV reactivation
The risk of reactivation is also elevated when high-intensity chemotherapy is applied
prior to hematopoietic stem-cell transplantation in hematologic malignancies [442,443].
Similarly, preventive anti-viral therapy with lamivudine or entecavir reduced the
rate of HBV reactivation . Although the reactivation rate was 14-21% in solid
tumors, higher rates of 41-70% were reported in breast cancer, possibly related to
the use of high-dose chemotherapy with anthracycline agents and steroids [430,445,446].
The rate of HBV reactivation during transcatheter arterial chemoembolization (TACE)
as a therapeutic option for HCC was 4-40% [447-450]. Preventive lamivudine therapy
compared to non-preventive group reduced the rates of HBV reactivation (2.8% vs. 40.5%),
hepatitis aggravation (2.8% vs. 29.7%) and hepatic failure (0% vs. 8.1%) significantly
. Preventive antiviral therapy can be considered in cases undergoing TACE for
HCC treatment to reduce HBV reactivation; however, the rates of HBV reactivation during
TACE differed according to procedure method, interval, frequency and the TACE agents
[447,448,451]. Therefore, further studies are required to elucidate the criteria for
preventive antiviral therapy in TACE. Sorafenib, which was approved for advanced HCC,
seems not to cause HBV reactivation  but this should be confirmed in further
investigations. Steroids can suppress the host immune system but also induce HBV replication
directly, which increases the risk of HBV reactivation. Other risk factors for reactivation
include the use of anti-TNF agents for inflammatory bowel diseases or rheumatologic
diseases (e.g., infliximab, etanercept, and adalimumab), the HBV genotype or specific
mutations in the HBV genome, and recovery from neutropenia [453-462]. The rate of
HBV reactivation was 12.3% among HBsAg-positive patients receiving an anti-TNFα antibody
or disease-modifying antirheumatic drug (DMARD), which are used in rheumatologic diseases
. Other study reported a rate of HBV reactivation of 39% among HBsAg-positive
patients and 5% among isolated anti-HBc-positive patients receiving anti-TNFα antibody
therapy. Preventive antiviral therapy decreased the rate of HBV reactivation significantly
(23% vs. 62%, P=0.003) .
Because HBV reactivation is associated with the risk of hepatic failure and death,
prevention is of utmost importance. This necessitates screening for HBsAg and IgG
anti-HBc . Vaccination should be considered if there is no evidence of (past) HBV
infection (i.e., negative for both HBsAg and IgG anti-HBc). Preventive antiviral therapy
is recommended in HBsAg-positive patients regardless of the serum HBV DNA level .
Preventive lamivudine therapy has significantly reduced the rates of HBV reactivation,
hepatic failure, and mortality in randomized controlled studies of lymphoma patients
in Hong Kong and Taiwan [433,443,465,466]. Therefore, it is recommended that preventive
antiviral therapy be started simultaneously with the initiation of chemotherapy rather
than deferring until the HBV DNA level increases, and should be maintained for certain
period after the termination of chemotherapy (e.g., at least 6 months) [466,467].
However, evidence that can be used to determine the duration of preventive antiviral
therapy remains limited. Elevated risk of reactivation was reported with cessation
of preventive lamivudine therapy at 3 months following the termination of chemotherapy,
especially in cases with a high HBV DNA level before chemotherapy (≥2,000 IU/mL) .
Therefore, the duration of preventive antiviral therapy could be determined based
upon treatment guidelines for CHB if the pre-treatment HBV DNA level is high. In contrast,
attention should be paid to reports of reactivation after more than 6 months irrespective
of the pre-treatment HBV DNA level. Although there is limited information about the
efficacy of preventive treatment with other antiviral agents—such as adefovir, telbivudine,
clevudine, entecavir, and tenofovir—these agents could be administered for preventive
purpose considering their mechanisms of action and therapeutic results. Since resistance
was reported in preventive lamivudine therapy, other antiviral agents with lower resistance
rates should be considered in cases with prolonged treatment (e.g., >1 year) .
A retrospective study reported that the risks of hepatitis and chemotherapy disruption
due to HBV reactivation in lymphoma patients were lower for entecavir than for lamivudine
. However, data on the relative efficacy and cost-effectiveness of antiviral
agents are scarce. Prospective studies to determine the appropriate antiviral agents
and optimal treatment duration in various types of malignancy are needed, as most
previous studies involved only lymphoma patients. If cost is ignored, entecavir and
tenofovir are appropriate choices based on their potency and resistance rate. Interferon-α
is contraindicated for preventive use due to its bone marrow suppression and exacerbation
of underlying hepatitis.
In some cases, HBV reactivation occurs not only in HBsAg-positive patients but also
in IgG anti-HBc-positive patients without HBsAg . The latter cases correspond
to either occult HBV infection in which HBV DNA is detected in the hepatocytes or
even in the serum, or reverse seroconversion (seroreversion) of HBsAg in which HBV
replication resumes after immunosuppression with reappearance of HBsAg [422,471,472].
The rate of HBV reactivation is higher in patients with isolated anti-HBc than in
patients with both anti-HBc and anti-HBs . IgG anti-HBc-positive patients (HBsAg-negative)
have a risk of HBV reactivation irrespective of anti-HBs, but a uniform treatment
recommendation cannot be provided because the effects of the type of malignancy or
immunosuppressive/chemotherapeutic agents used on the reactivation risk are unclear.
However, preventive therapy should be started if serum HBV DNA is positive in high-risk
groups such as patients with lymphoma under a rituximab-containing regimen or those
with leukemia who undergo hematopoietic stem cell transplantation; preventive treatment
may be started together with immunosuppressive/chemotherapy or determined with periodic
monitoring (e.g., every 1-2 months) of the HBV DNA level in patients with no detectable
serum HBV DNA at baseline.
1. It is recommended to screen for HBsAg and IgG anti-HBc prior to initiation of immunosuppressive
treatment or chemotherapy. If either is positive, serum HBV DNA should be tested.
2. Patients without evidence of HBV infection should be vaccinated. (B1)
3. Consider preventive antiviral therapy simultaneously with the initiation of immunosuppressive
treatment/chemotherapy if HBsAg or HBV DNA is positive. (A1) Although selection of
a NA requires consideration of the serum HBV DNA level, the intensity and duration
of immunosuppressive treatment/chemotherapy and the cost, entecavir or tenofovir can
be preferentially considered if the baseline HBV DNA level is high or long-term treatment
is anticipated. (C1)
4. If IgG anti-HBc is positive without HBsAg or HBV DNA, irrespective of anti-HBs,
serum HBV and HBsAg should be tested regularly and preventive antiviral therapy should
be considered if either reappears during immunosuppressive treatment/chemotherapy.
(A1) Preventive antiviral therapy in patients with isolated anti-HBc can be initiated
in high-risk groups such as patients with lymphoma under a rituximab-containing regimen
or those with leukemia who undergo hematopoietic stem cell transplantation. (B2)
5. Serum HBV DNA should be monitored periodically during and after preventive antiviral
6. Preventive antiviral therapy should be maintained for at least 6 months after the
termination of immunosuppressive treatment/chemotherapy. (C1)
Patients with chronic kidney disease and under dialysis
Patients under dialysis are relatively prone to being exposed to HBV infection, which
might exert a negative influence on their long-term prognosis. Exacerbation of hepatitis
B is of particular importance for immunosuppression after renal transplantation .
Fortunately, the incidence of HBV infection in dialysis patients has decreased due
to surveillance of blood products, enhanced infection control, and widespread use
of erythropoietin. The prevalence of HBV infection based on HBsAg positivity in this
population is 0-6.6% in Western countries, and ~5% in Korea in recent reports [475-477].
The prevalence of occult HBV infection was higher than the HBsAg-positivity rate in
one report , but this was not the case in Korea . The standard precautions
to avoid nosocomial transmission are of the highest priority for preventing new HBV
infections in dialysis patients . Vaccination against HBV is widely recommended
in these patients; the efficacy is higher with earlier vaccination because the antibody
production rate is 50-60% compared with ~90% in the general population, and decreases
as residual renal function declines [481-483]. Data on antiviral treatment in dialysis
patients are insufficient. Although a randomized controlled study of interferon-α
in HBV-infected patients with glomerulonephritis has been performed , it is difficult
to recommend its use due to the increased adverse events in this population due to
pharmacodynamic changes [485,486]. Several small studies have reported the effectiveness
of lamivudine [487-489]. Resistance to lamivudine was 39% at 16.5 months of treatment,
which was similar to the rate in patients with normal renal function . Entecavir
or tenofovir may be preferentially used, given their potency and resistance profile
in patients with normal renal function . Careful dose adjustment is required for
adefovir and tenofovir due to their potential nephrotoxicity in patients with residual
renal function [491-494]. Tenofovir is less nephrotoxic than adefovir. Two of 426
patients with chronic hepatitis B who underwent tenofovir therapy for 144 weeks showed
elevation of serum creatinine to >0.5 mg/dL compared to baseline with no reduction
in glomerular filtration rate to <50 mL/min .
1. Vaccination is recommended for patients under dialysis negative for HBsAg and anti-HBs.
2. Oral NAs such as entecavir and tenofovir are preferable to interferon therapy in
patients under dialysis. (B1) NAs should be dose-adjusted according to residual renal
CO-INFECTION WITH OTHER VIRUSES
In patients with CHB the anti-HCV antibody positivity rate varies from 0.1% to 22%,
depending on the region [496-499] with it being very low in Korea (0.1%) . Patients
with HBV/HCV co-infection have an increased risk of severe or fulminant infection,
and high incidences of cirrhosis and HCC [500-503]. The scarcity of data makes it
impossible to recommend a treatment for HBV/HCV co-infection [504-506]. However, it
is necessary to determine which virus is dominant by means of serologic or virology
tests. If HCV RNA is positive with a low or undetectable serum HBV DNA level, HCV
infection should be considered dominant and the patient treated as for HCV monoinfection.
Combination therapy of pegIFN-α-2a plus ribavirin is equally effective in patients
with HCV monoinfection and HBV/HCV co-infection [507,508]. HBV treatment should be
added when HBV reactivates, which can reportedly occur during or after combination
therapy of pegIFN-α plus ribavirin for HCV .
The role of direct-acting agents (DAAs) in HBV/HCV co-infection needs to be elucidated.
1. After confirming the dominant cause of liver disease in HBV/HCV coinfection, treatment
following the same strategy as that for the dominant virus is recommended. (B1)
2. HBV treatment should be initiated when HBV proliferation is identified during or
after treatment for HCV. (B1)
It is estimated that ~20 million people are infected with HDV worldwide . HDV
infection is prevalent in Mediterranean countries, the Middle East, central Africa,
and South America . The HDV co-infection rate in CHB patients has been reported
to be 0-3.6% in Korea [512-514]. The incidences of cirrhosis and HCC are higher in
patients with HBV/HDV coinfection than in those with HBV monoinfection [515,516].
HDV infection can be diagnosed by detecting anti-HDV antibody or HDV RNA in the serum
or by detecting HDV antigen in liver tissue by immunohistochemistry. The treatment
goals are to inhibit HDV replication, normalize ALT, and improve histology findings.
IFN-α (conventional or pegylated) is the only drug that can inhibit HDV replication
[517-521]. The biochemical, virologic, and histologic responses to high-dose IFN-α
therapy (9 MU, three times per week) were better than those to the conventional dose
of IFN-α (3 MU, three times per week), with the high-dose therapy producing an HDV
RNA negativity rate of 43% at 6 months after the end of 48 weeks of treatment .
PegIFN-α showed HDV RNA negativity rates of 17-43% at 6 months after the end of 48
or 72 weeks of treatment [517,521,522]. No head-to-head comparison trial between high-dose
IFN-α and pegIFN-α therapies has been performed and hence either pegIFN-α or high-dose
IFN-α therapy for longer than 1 year is recommended for patients with HBV/HDV co-infection
. The treatment response can be evaluated by measuring the serum HDV RNA level
at week 24. Both lamivudine and adefovir were found to be ineffective in terms of
inhibiting HDV replication [524,525]. Combination therapy of lamivudine plus IFN-α
was not superior to IFN-α monotherapy , and adefovir plus pegIFN-α therapy did
not improve the response rate compared to pegIFN-α monotherapy . In addition,
the rates of HDV DNA negativity at 24 weeks after therapy with the combination of
adefovir plus pegIFN-α or pegIFN-α monotherapy for 48 weeks were superior to those
following adefovir monotherapy for 48 weeks (26%, 31% and 0%, respectively) .
1. CHB patients with HDV co-infection should be treated with peginterferon-α or high
dose interferon-α (9 MU, three times per week) for >1 year. (B1)
The incidences of cirrhosis and HCC are reportedly higher in patients with HBV/HIV
coinfection than in those with HBV monoinfection [528,529]. HBV should be treated
in HBV/HIV-coinfected patients who exhibit ALT elevation due to HBV. Before such treatment
it is necessary to determine whether treatment for HIV is also required . Patients
who are not indicated for HAART should receive the standard treatment for CHB. In
such cases anti-viral agents (e.g., IFN, adefovir, or telbivudine) that do not affect
HIV proliferation should be selected, to prevent the future development of HIV cross-resistance.
Entecavir or tenofovir monotherapy should not be used in patients with HBV/HIV co-infection
due to the development of resistant HIV. Patients who need treatment for both HIV
and HBV should be treated with antiviral agents that are effective against both viruses,
such as tenofovir/emtricitabine, tenofovir or lamivudine, as highly active anti-retroviral
therapy (HAART) [531-533]. When HAART regimens are altered, antiviral agents that
are effective against HBV should be included to avoid HBV reactivation, except in
patients who meet the criteria for discontinuation of anti-HBV treatment.
1. HBV/HIV-coinfected patients who exhibit ALT elevation due to HBV should be considered
for HBV treatment. (B1)
2. Patients who are not indicated for HAART at present or in the near future should
receive the standard treatment for CHB. In such cases, NAs that do not affect HIV
proliferation should be used to prevent the future development of HIV cross-resistance.
3. Patients who need treatment for both HIV and HBV should be treated with HAART agents
effective against both viruses; e.g., tenofovir/emtricitabine or tenofovir plus lamivudine.
Female patients of childbearing age
1. Treatment before pregnancy
When planning treatment for females of child-bearing age, special considerations for
the fetus and the duration of treatment are needed in addition to the aforementioned
general considerations. For example, IFN preparations are preferred in female patients
who are planning pregnancy as the period of treatment is more clearly defined. However,
the IFN side effect of fetal malformations makes it contraindicated during pregnancy,
and so it must be recommended in combination with contraception during the therapy
and until 6 month after cessation of therapy. Females who want to be pregnant should
be treated with antiviral agents that belong to pregnancy category B drugs (which,
according to the results of animal studies, carry no teratogenic or embryogenic risk
and for which there have been no controlled human studies or for which animal studies
may indicate a risk, but controlled human studies refute the findings). Tenofovir
and telbivudine belong to pregnancy category B, while entecavir, adefovir and lamivudine
belong to pregnancy category C drugs (drugs that exert teratogenic or embryocidal
effects in animals and for which there are no controlled studies in humans) .
2. Treatment during pregnancy
Pregnant females with chronic HBV infection are usually in the immune-tolerance phase
, and changes in the maternal immune system during pregnancy, such as a shift
in the Th1-Th2 balance toward a Th2 response, lead to an increase in the HBV DNA level
and a reduction in the ALT level . These immune responses are restored after
delivery, thereby causing a reduction in the HBV DNA level and ALT elevation, and
so careful monitoring is needed [535-537].
The optimal antiviral treatment strategy during pregnancy is based on the aforementioned
general principles for the treatment of CHB. However, all decisions regarding the
timing and duration of treatment in pregnancy should include an analysis of the risks
and benefits for both the mother and fetus. In addition, pregnant females often experience
worsening of liver disease unrelated to HBV infection (e.g., acute fatty liver of
pregnancy), which is difficult to discriminate from an HBV flare-up. Thus, antiviral
treatment should be considered when liver disease is present (e.g., jaundice or prolongation
of PT), and the HBV DNA level meets the general criteria for antiviral treatment.
When starting antiviral therapy during pregnancy, category B drugs are recommended.
Safety data of antiviral agents during pregnancy can be found at the Antiretroviral
Pregnancy Registry (APR; http://www.apregistry.com). The APR is an international,
voluntary, prospective registry that reports the rate of birth defects of newborns
born to mothers receiving antiretroviral therapy, and it contains a considerable amount
of data on lamivudine and tenofovir. According to the APR, the rates of birth defects
among females exposed to lamivudine and tenofovir in the first trimester (3.1% and
2.4% of live births, respectively) are similar to that in the general population (2.7%),
as reported by the CDC birth defect surveillance system. Few cases related to other
drugs such as telbivudine and entecavir have been reported. However, since the APR
is designed to report only defects identified at birth, it may not contain accurate
data on developmental anomalies (e.g., cardiac or neurologic defects).
Oral antiviral agents may cause mitochondrial toxicity by inhibiting mitochondrial
DNA replication. It is difficult to estimate their effects on the fetus, especially
in the developmental stages . Thus, based on considerations of fetal safety oral
antiviral agents should not be administered, especially in the first trimester of
pregnancy. However, the decision about whether to discontinue drugs in patients receiving
treatment with oral antiviral agents should be individualized. One retrospective study
showed that ~14% of pregnant females with active chronic hepatitis B without antiviral
therapy can progress to hepatic failure and have a risk of maternal or fetal death,
so appropriate antiviral therapy should be considered in pregnant females in the active
phase of chronic hepatitis B .
In childbearing females who require treatment with an oral antiviral agent against
HBV, pregnancy category B drugs such as tenofovir can be considered if the patient
wants to become pregnant. In females already receiving antiviral therapy with a category
C drug who want to become pregnant, the category C drug should be changed to a category
B drug, such as tenofovir.
In the first trimester of pregnancy, pregnant females with mild chronic hepatitis
B and undetectable HBV DNA (<60 IU/mL) may be considered for temporary drug discontinuation
with careful monitoring for HBV reactivation. Meanwhile, females who become pregnant
while on category C drugs should change to category B drugs if continuous antiviral
therapy is needed .
As little about whether or not antiviral agents are secreted into breast milk is known,
and the effects on babies of antiviral agents in breast milk is unclear, breast-feeding
is not currently recommended.
Prevention of vertical transmission with antiviral drugs
A high maternal HBV DNA level is associated with a high rate of failure of neonatal
passive-active immunoprophylaxis [540-543]. In a double-blind, randomized controlled
trial, pregnant females with high serum HBV DNA levels (>103 Meq/mL [~109 cpm]) were
given lamivudine from week 32 of gestation to week 4 postpartum in addition to neonatal
passive-active immunoprophylaxis. HBsAg positivity was present in 18% and 39% of 1-year-old
infants from lamivudine- and placebo-treated mothers, respectively (P=0.014) 
No safety concerns were noted in the lamivudine-treated mothers and their newborns.
However, these data should be interpreted with caution due to the high dropout rates,
especially in the placebo group (13% in the lamivudine group and 31% in the placebo
group). A prospective study included pregnant females with HBeAg-positive and high
serum HBV DNA levels (>107 copies/mL) who were treated with lamivudine from week 24
to week 32 in addition to neonatal passive-active immunoprophylaxis as the treatment
group. The HBsAg-positivity rates of infants at 1 year after birth were significantly
different: 0% (0/94) in the treatment group and 7.7% (7/91) in the placebo group 
Another prospective study included pregnant females with high serum HBV DNA levels
(>106 copies/mL) treated with telbivudine from week 12–30 to birth in addition to
neonatal passive-active immunoprophylaxis as the treatment group. The HBsAg-positivity
rates of infants at 6 months after birth were significantly different: 0% (0/54) in
the treatment group and 8.6% (3/35) in the placebo group . Another prospective
controlled study included pregnant females with high serum HBV DNA levels (>107 copies/mL)
treated with telbivudine from weeks 20 to 32 of gestation to week 4 postpartum in
addition to neonatal passive-active immunoprophylaxis. HBsAg positivity was present
in none (0/132) of the 6-month-old infants from telbivudine-treated mothers, whereas
it was present in 8% (7/88) of those from placebo-treated mothers . Another prospective
study included pregnant females with high serum HBV DNA levels (>107 copies/mL) treated
with tenofovir or lamivudine from week 32 to week 4–12 postpartum in addition to neonatal
passive-active immunoprophylaxis as the treatment group. The HBsAg-positivity rates
of infants at 9 months after birth were significantly different: 1% (1/87) in the
treatment group and 20% (2/10) in the placebo group . The prevalence of safety
issues did not differ significantly between the two groups. These studies imply that
antiviral medication in the late stage of pregnancy is likely to reduce the rate of
vertical transmission. However, the decision about whether or not to treat should
be individualized in patients not indicated for the treatment of HBV, based on the
treatment duration, stopping point, possible appearance of drug-resistant strains,
and the patient’s preferences.
1. Peginterferon-α has an advantage in female patients who are planning pregnancy
due to its finite treatment duration. (C1) However, the side effects pertaining to
fetal malformations make peginterferon-α treatment contraindicated during pregnancy,
and it should be recommended in combination with contraception. (A1)
2. When antiviral treatment is needed during pregnancy, pregnancy category B NAs are
3. The antiviral treatment strategy during pregnancy is based on the general principles
of CHB treatment; however, decisions should be based on analysis of the risks and
benefits for both the mother and fetus. (C1)
4. Breastfeeding is not recommended in females receiving treatment with NAs. (C1)
Children and adolescents
Providing HBIG and HBV vaccine to newborns of HBsAg-positive mothers within 12 h of
birth can prevent 90–95% of cases of perinatal infection. Ninety percent of infants
infected as a neonates progress to chronic infection. Most children remain in the
immune-tolerant phase until late childhood or adolescence. However, some children
progress to the immune-reactive phase. The spontaneous HBeAg seroconversion rate in
immune-tolerant Korean children was 4.6%, 7.1%, and 28.0% for patients aged <6, 6-12,
>12 years, respectively . A Taiwanese study reported annual spontaneous HBeAg
seroconversion rates of 2% and 4–5% in children younger than 3 years and older than
3 years, respectively . Children who are in the immune-reactive phase—with increased
ALT levels and histologic findings of liver inflammation and fibrosis—are usually
asymptomatic. Long-term treatment in children with CHB is expected, and a prudent
decision should be made based on the adverse effects of the drugs and the potential
for viral resistance to affect future therapies. The treatment window should not be
missed because cirrhosis can occur in their 20s and HCC later in life. The goals of
therapy are to suppress viral replication, reduce liver inflammation, reverse liver
fibrosis, and prevent cirrhosis and HCC.
Treating children in the immune-tolerant phase is not beneficial, and there is a high
risk of development of drug resistance, which would limit treatment options in later
life. Children with a persistent elevated serum ALT level should be evaluated for
viral active replication, including measurement of HBV DNA levels. HBeAg-positive
children should be considered for treatment when their serum ALT levels are above
2 ULN for at least 6 months and their HBV DNA levels are above 20,000 IU/mL .
Acute elevation of liver enzymes with an ALT level of >5 ULN may be followed by spontaneous
HBeAg seroconversion. It is therefore reasonable to delay treatment for an observation
period of at least 3 months if there is no concern regarding hepatic decompensation.
Children with moderate-to-severe necroinflammation or periportal fibrosis in a liver
biopsy are recommended for treatment. The decision to treat is based on factors such
as age, liver biopsy findings, and family history of HBV-associated cirrhosis or HCC.
In obese children it is important to remember that ALT elevations may be due to fatty
liver disease . The responses to interferon-α and lamivudine are better in children
with higher activity scores in a liver biopsy [553,554].
A randomized controlled trial of interferon-α therapy involving children aged 1 to
17 years found that 36% of those with a baseline ALT level of at least 2 ULN became
negative for HBeAg at the end of treatment. HBsAg seroconversion occurred in 10% of
the treated children . Factors predictive of a positive response among children
are being younger than 5 years , having a low serum HBV DNA level, and having
active inflammation in a liver biopsy . After 5 years of observation, the rate
of HBeAg seroconversion did not differ between the treatment and control groups. However,
loss of HBsAg occurred in 25% of children who responded to treatment, but in none
of the children in the nonresponse and control groups . The recommended treatment
regimen for interferon-α is 6 MU/m2 three times per week by subcutaneous injection
for 6 months. Interferon-α is approved in children older than 12 months, and its advantages
include the finite duration of treatment and no development of viral resistance. The
adverse effects include fever, flu-like symptoms, bone marrow suppression, depression,
and transient growth suppression. Interferon-α is contraindicated in children with
decompensated cirrhosis and autoimmune disease. Clinical trials of peginterferon in
children with CHB are ongoing. The efficacy and safety of peginterferon were demonstrated
in children with chronic hepatitis C, and an update of the Swedish national recommendations
for the treatment of CHB recommends the use of peginterferon (100 μg/m2 weekly) in
A randomized controlled study of lamivudine involving children aged 2–17 years found
that loss of HBeAg at 52 weeks of treatment occurred in 34% of those with a baseline
ALT level of at least 2 ULN, and that the resistance rate was 18% . The HBeAg
seroconversion rate after 2 years of therapy was 54% in children without lamivudine-resistant
virus. The resistance rate was 64% in children who received lamivudine for 3 years.
Lamivudine treatment for >3 years did not significantly increase seroconversion rates
and increased the incidence of viral resistance . Studies of Korean children
found that the HBeAg seroconversion rates after 2 and 3 years of treatment were 65%
and 70%, respectively [560,561]. Loss of HBsAg was observed in 20% of children after
2 years of lamivudine treatment, and the resistance rates at 1 and 2 years of treatment
were 10% and 23%, respectively. Factors associated with a response were elevated baseline
ALT, high baseline histology-activity-index score , and being younger than 7
years . Long-term durability of HBeAg seroconversion was observed in more than
90% of the subjects after they had taken lamivudine for at least 2 years . Lamivudine
is orally administered at a dose of 3 mg/kg/day, with a maximum of 100 mg/day .
Lamivudine treatment should be continued for at least 1 year, and it is desirable
to continue treatment for 1 year after HBeAg seroconversion. If lamivudine resistance
develops, it should be treated in accordance with the guidelines for antiviral resistance
management in adults.
A randomized controlled study of 173 HBeAg-positive children aged 2–17 years showed
undetectable HBV DNA and a normal ALT level after 48 weeks of adefovir treatment in
23% of 12- to 17-year-old subjects, but there was no significant difference between
adefovir and placebo in those aged 2–11 years. The HBeAg seroconversion rate in the
adefovir group and placebo group was 16% and 5%, respectively (P=0.051). No subject
developed adefovir resistance . Continuation of adefovir treatment for a further
4 years was safe. Resistance to adefovir was observed in one child .
Entecavir and tenofovir are potent HBV inhibitors with a high barrier to resistance.
Entecavir is considered the first-line therapy in children older than 2 years and
tenofovir in those older than 12 years. A randomized controlled trial of tenofovir
in adolescents aged 12 to 17 years reported that the rate of a virologic response
(HBV DNA <400 copies/mL) at week 72 was significantly higher in patients (n=52) who
received tenofovir than those (n=54) who received placebo (89% vs. 0%) . No resistance
to tenofovir developed through week 72. The rate of grade 3/4 adverse events was higher
among patients treated with placebo (24%) than those treated with tenofovir (10%).
In a randomized controlled study involving 180 children aged 2 to 17 years with HBeAg-positive
CHB, the HBeAg seroconversion and HBV DNA <50 IU/mL rates at week 48 were significantly
higher with entecavir than placebo (24.2% versus 3.3%). The cumulative probability
of entecavir resistance at 1 and 2 years was 0.6% and 2.6%, respectively. Entecavir
showed no difference in safety compared with placebo .
1. HBeAg-positive CHB children with an HBV DNA level >20,000 IU/mL and HBeAg-negative
CHB children with an HBV DNA level >2,000 IU/mL should be considered for treatment
when the AST or ALT level is > 2 ULN for at least 6 months, or moderate-to-severe
necroinflammation or periportal fibrosis is evident in a liver biopsy. (A1)
2. Tenofovir, entecavir or interferon-α is the first-line therapy in children with
CHB. (B1) Data on peginterferon are currently scarce, but its use in children can
be based on the results of studies involving adults. (C1)
3. If antiviral resistance develops, it should be treated in accordance with the guidelines
for antiviral resistance management in adults. (B1)