REVIEW

NATURAL HISTORY OF HEPATITIS B VIRUS INFECTION

Natural History of Hepatitis B Virus Infection:

An Update for Clinicians
SURAKIT PUNGPAPONG, MD; W. RAY KIM, MD; AND JOHN J. POTERUCHA, MD
Hepatitis B virus (HBV) is a common viral pathogen that causes a
substantial health burden worldwide. Significant progress has
been made in the past few decades in understanding the natural
history of HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of
liver disease. In immunocompetent adults, most HBV infections
spontaneously resolve, whereas in most neonates and infants they
become chronic. Those with chronic HBV may present in 1 of 4
phases of infection: (1) in a state of immune tolerance, (2) with
hepatitis B e antigen (HBeAg)positive chronic hepatitis, (3) as
an inactive hepatitis B surface antigen carrier, or (4) with HBeAgnegative chronic hepatitis. Of these, HBeAg-positive and HBeAgnegative chronic hepatitis may progress to cirrhosis and its longterm sequelae including hepatic decompensation and hepatocellular carcinoma. Several prognostic factors, such as serum HBV
DNA concentrations, HBeAg status, serum aminotransferases,
and certain HBV genotypes, have been identified to predict longterm outcome. These data emphasize the importance of monitoring all patients with chronic HBV infection to identify candidates
for and select optimal timing of antiviral treatment, to recognize
those at risk of complications, and to implement surveillance for
early detection of hepatocellular carcinoma.

Mayo Clin Proc. 2007;82(8):967-975

ALT = alanine aminotransferase; CI = confidence interval; HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface
antigen; HCC = hepatocellular carcinoma; HCV = hepatitis C virus;
HDV = hepatitis D virus; HR = hazard ratio

epatitis B virus (HBV) infection is a challenging global health problem, affecting an estimated 2 billion
persons worldwide. Of those infected with HBV, 400 million remain chronically infected, and an estimated 1 million die of HBV-related liver diseases annually.1 According to the Centers for Disease Control and Prevention, the
incidence of newly acquired HBV infection in the United
States has declined steadily since the mid-1980s,2-4 a decrease attributed to several public health interventions such
as screening of pregnant women, vaccination of infants and
adolescents, and safe injection practices in general.5 If the
incidence of new infections continues to decrease in the
United States, depleting the pool of infected persons, it is
hoped that endogenous transmission will eventually be
From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
This work was supported by grant DK 61617 from the National Institute of
Diabetes and Digestive and Kidney Diseases.
Individual reprints of this article are not available. Address correspondence to
W. Ray Kim, MD, Division of Gastroenterology and Hepatology, Mayo Clinic,
200 First St SW, Rochester, MN 55905 (kim.ray@mayo.edu).
2007 Mayo Foundation for Medical Education and Research

Mayo Clin Proc.

eliminated. However, the prevalence of chronic HBV infection has yet to show a decrease.6 Moreover, the rate of
HBV-related hospitalizations, cancers, and deaths has
more than doubled during the past decade, largely because
of an influx of immigrants to the United States from endemic areas.7
Understanding the natural history of HBV infection has
become increasingly relevant for clinicians for several reasons. First, in the past 10 years, antiviral agents specific for
the treatment of HBV have proliferated, providing opportunities to fundamentally alter the natural history of HBV
infection. However, limitations of the currently available
therapies, including their inability to eradicate the infection
completely or to prevent emergence of resistant mutations,
necessitate optimal timing of the therapies in selected patients. Second, epidemiologic studies have yielded important information about the effects of the genetic diversity of
HBV on its natural history. For example, hepatitis B e
antigen (HBeAg)-negative chronic hepatitis B, which is
associated with the so-called precore mutant, was once
thought rare but now is seen commonly in practice. As
more information about the HBV genotype becomes available, it may play a greater role in clinical decision making.
Third, the availability of highly sensitive HBV DNA assays, combined with a better understanding of HBV virology and of the host immune response to HBV infection, has
led to new insights into the natural history of HBV infection. Thus, understanding the dynamic nature of chronic
HBV infection is essential for management of HBV carriers, not only in selecting optimal treatment candidates but
also in instituting appropriate monitoring for the prevention and early detection of complications from chronic
HBV infection.
PATHOGENESIS OF HBV INFECTION
The observation that many HBV carriers are asymptomatic
with minimal liver injury, despite extensive and continuing
intrahepatic replication of the virus, supports the concept
that HBV is not directly cytotoxic to hepatocytes.8,9 The
severity of hepatocellular injury is modulated by the
strength of host immune responses.10-12 In patients with
fulminant HBV infection, rapid viral clearance is achieved
after severe liver injury as a result of a vigorous host
immune response.10-12 However, in neonates with an imma-

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NATURAL HISTORY OF HEPATITIS B VIRUS INFECTION

ture immune system, exposure to HBV often results in

minimal acute liver injury but high rates of chronic infection (up to 90%). Conversely, HBV carriers with mild or no
liver disease may have a severe flare of hepatitis when they
undergo cancer chemotherapy or immunosuppressive
therapy for organ transplantation.13-15 Limited data suggest
that in this setting an overwhelming degree of viral replication usurps the cellular functions necessary for viability
and makes HBV essentially cytopathic.16
Hepatitis B virus was thought to be cleared completely
in those who recover from acute HBV infection. However,
with the development of sensitive assays for HBV DNA
detection, traces of the HBV genome have been frequently
identified in the liver or serum up to 10 years after clinical
recovery from acute HBV infection, despite the disappearance of viral antigens and the appearance of antiviral antibodies and specific cytotoxic T lymphocytes.17-20 These
observations suggest that HBV is rarely completely eradicated after recovery from acute infection, which may account for several reports of reactivation of HBV replication
in persons with serologic markers of recovery from HBV
who receive chemotherapy or immunosuppression after
organ transplantation.21,22
ACUTE HBV INFECTION
In acute HBV infection, hepatitis B surface antigen (HBsAg)
becomes detectable in the serum after an incubation period
of 4 to 10 weeks, followed shortly by the appearance of
antibody against the hepatitis B core antigen, which is
predominantly of the IgM isotope in the early phase.23
Levels of HBV DNA are generally very high, frequently in
the range of 200 million IU/mL to 200 billion IU/mL (1091012 copies/mL).24 Circulating HBeAg can be detected in
most patients with acute HBV infection, and these patients
can readily transmit the infection.25,26 Aminotransferase
levels do not increase until after viral infection is well
established because time is required for specific cytotoxic
T lymphocyte responses to develop against virally infected
hepatocytes. Approximately 30% to 50% of infected adults
present with an icteric illness after an incubation period of
6 weeks to 6 months.27 The outcome of acute HBV infection depends on age and immune competence at the time of
infection.27-30 For example, chronic HBV infection will
develop in as many as 90% of infected neonates and infants
but only in 1% to 5% of immunocompetent adults (excluding those with acute exacerbations of chronic HBV infection). Children aged 1 to 5 years have an intermediate risk
(approximately 30%).27-30
In the United States, most persons with acute HBV
infection are adults. As a rule, acute HBV infection resolves without the need for intervention or antiviral treat968

Mayo Clin Proc.

ment. Fulminant hepatitis occurs in 0.1% to 0.5% of those

with acute HBV infection and often demonstrates no evidence of HBV replication because of the massive immunemediated lysis of infected hepatocytes.31 In endemic areas,
exposure to HBV at birth or in early childhood results in
higher rates of chronic HBV infection. Persons infected as
children may present in adulthood with clinical manifestations similar to those of acute hepatitis if they have acute
exacerbation of chronic HBV infection. These exacerbations frequently may be associated with elevated levels of
IgM antibody to hepatitis B core antigen, which may lead
to misdiagnosis of acute HBV infection,32-34 and an increase
in the serum -fetoprotein concentration, which may raise
concerns for the presence of hepatocellular carcinoma
(HCC).35 Thus, it is important to define and understand the
phases of acute and chronic HBV infection.
PHASES OF CHRONIC HBV INFECTION
Those with chronic HBV infection may present: (1) in a
state of immune tolerance, (2) with HBeAg-positive
chronic hepatitis, (3) as an inactive HBsAg carrier, or (4)
with HBeAg-negative chronic hepatitis (Figure 1).
PHASE 1: IMMUNE TOLERANCE
Persistent HBV infection has an initial immune tolerance
phase that can be characterized by the presence of HBeAg
and high levels of serum HBV DNA due to a high rate of
viral replication. This phase is mostly seen in patients who
acquire the infection at birth or during early childhood;
rarely, it also can be seen briefly in those who acquire the
infection in late childhood or adulthood and have subsequent development of chronic HBV infection.36,37
The absence of liver disease despite high levels of HBV
replication is thought to be a consequence of immune tolerance to HBeAg.38 However, the mechanisms underlying
this tolerance are incompletely understood. Experiments
in mice suggest that transplacental transfer of maternal
HBeAg may induce specific unresponsiveness of T
cells to HBeAg and to hepatitis B core antigen, resulting
in ineffective cytotoxic T cell lysis of infected hepatocytes.39,40 This tolerization leads to minimal host immune
activity, characterized by normal serum aminotransferase
levels and liver histological findings of minimal or no
inflammation.41,42
PHASE 2: HBEAG-POSITIVE CHRONIC HEPATITIS
As the host immune system matures and begins to recognize HBV-related epitopes on hepatocytes, immune-mediated hepatocellular injury ensues.43,44 Although HBV replication continues in the liver and viremia is continual, the
viral level in the serum becomes lower than during the

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NATURAL HISTORY OF HEPATITIS B VIRUS INFECTION

Immune
tolerance
Positive HBeAg
DNA
Normal ALT
HBeAg-negative
chronic
hepatitis
Negative HBeAg
DNA
Abnormal ALT

Progression to
cirrhosis

Inactive
carrier
Negative HBeAg
DNA
Normal ALT

Precore
mutation

HBeAg-positive
chronic
hepatitis
Positive HBeAg
DNA
Abnormal ALT

HBeAg
seroconversion

FIGURE. 1. Phases of chronic hepatitis B virus infection. White arrows represent changes of histopathology,
whereas gray arrows represent the changes in serologic markers between phases. Up- and down-facing
arrows represent an increase or decrease of DNA level ( = low increase; = moderate increase; =
moderate decrease; = high increase). ALT = alanine aminotransferase; HBeAg = hepatitis B e antigen.

immune tolerance phase when viral replication is completely unopposed.45 In patients with perinatally acquired
HBV infection, transition from the immune tolerance to the
HBeAg-positive chronic hepatitis phase occurs during the
second or third decade of life.46 This phase is characterized
by the presence of HBeAg, high levels of serum HBV
DNA, elevation of serum aminotransferase levels, and histological findings of active inflammation and often fibrosis
in the liver.32,47
Most patients with HBeAg-positive chronic hepatitis
remain asymptomatic, making it difficult to detect the transition from the immune tolerance phase based on clinical
grounds alone. However, some patients present with a
symptomatic flare of hepatitis that mimics acute hepatitis
or even with fulminant hepatic failure.48,49 These flares may
precede the disappearance of HBeAg and the development
of antibody against it, culminating in remission of hepatitis
activity.32 However, some flares result in only transient
decreases in serum HBV DNA levels without the clearance
of HBeAg.32 Occasionally, hepatic decompensation may
occur after these flares.50
Spontaneous HBeAg seroconversion, which occurs annually in as many as 10% to 20% of those with HBeAgpositive hepatitis, is an important landmark in the natural
history of chronic HBV infection.37,51-55 In a populationbased study of 1536 Alaskan natives who acquired HBV
infection in adulthood, spontaneous seroconversion was
Mayo Clin Proc.

observed in 70% during the 10-year follow-up period.55

Factors associated with a higher rate of spontaneous
HBeAg seroconversion include older age,55 higher aminotransferase levels,56,57 and certain HBV genotypes.58,59
High aminotransferase levels are considered surrogate
markers for a vigorous host immune response that results in
higher spontaneous and treatment-induced HBeAg seroconversion.37 In contrast, spontaneous HBeAg clearance or
seroconversion occurs in fewer than 5% of patients with
normal or mildly elevated levels of alanine aminotransferase (ALT).24,37,51,52 Recent reports from Asian countries
have shown that HBV genotype B, compared with genotype C, is associated with HBeAg seroconversion at an
earlier age and with more sustained viral and biochemical
remission after HBeAg seroconversion, resulting in a lower
prevalence of HBeAg.58,59
Many HBeAg-positive persons undergo seroconversion
over time. However, those who remain HBeAg positive
continue to be at risk for progressive liver disease. Approximately 12% to 20% of them will develop serious liver
injury that results in cirrhosis and complications within 5
years,60-63 depending on the duration of the chronic hepatitis
and the frequency and severity of flares.55,62 For example, in
a prospective study of 509 patients with HBeAg-positive
chronic hepatitis B who were followed up for a mean of 35
months, cirrhosis eventually developed in 35 (7%).62 These
35 patients included those who seroconverted during fol-

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NATURAL HISTORY OF HEPATITIS B VIRUS INFECTION

low-up; therefore, the risk of cirrhosis among patients who

remained persistently HBeAg positive is most likely
higher. A randomized trial by Lin et al64 evaluated the
efficacy of interferon treatment. Of 57 patients in the study
who did not have cirrhosis at the beginning of the study and
remained HBeAg positive at the end of follow-up, cirrhosis
developed in 12 (21%) after a mean of 6.5 years of followup. Although the retrospective nature of these data may
limit their clinical applicability, they do point to the increased risk of disease progression in these patients and the
need for antiviral therapy and/or close monitoring.
In a small proportion of patients with HBeAg-positive
chronic hepatitis B, HCC may develop without cirrhosis.
Although this phenomenon is widely recognized among
clinicians, the rate at which it occurs is low. In a study of
432 patients with clinicopathologically proven chronic
hepatitis B who were screened regularly, only 8 developed
HCC within 27 months, corresponding to an annual rate of
0.8%.65
PHASE 3: INACTIVE HBSAG CARRIERS
After seroconversion, most patients remain negative for
HBeAg and positive for anti-HBe antibody. Seroconversion is usually accompanied by stabilization of hepatitis,
characterized by normalization of ALT levels and decreases in HBV DNA to low (<1000 copies/mL) or undetectable levels, depending on the assays used. This condition is commonly referred to as the inactive carrier
state.66 Histologically, minimal to mild hepatitis may be
observed, although the degree of fibrosis may be variable.37
For example, inactive cirrhosis may be identified in patients who had severe liver injury before seroconversion.37
Most patients remain in this phase for many years, if not
indefinitely.8 Their prognosis is generally favorable, particularly if this phase is reached early in the disease course.
No difference in survival was observed between 296
healthy blood donors with positive HBsAg and 157
uninfected controls who were followed up over 30 years in
a study from northern Italy.67 Similarly, in a study by Hsu et
al68 of 283 inactive HBsAg carriers who seroconverted and
remained HBeAg negative, 189 (67%) had persistently
normal ALT levels over a 9-year follow-up period, and
only 1 developed cirrhosis. Thus, unlike patients with continued active viral replication, most inactive carriers do not
have progressive liver disease. The other 94 (33%) patients
in the Hsu et al68 study had ALT levels that were more than
twice the upper limit of normal; these elevated levels were
attributed to HBeAg reversion (4%), HBeAg-negative
chronic hepatitis (24%), and undetermined causes (5%).
Hepatitis B e antigen reversion occurs in a minority of
patients who have seroconversion. In a study by McMahon,69
432 of 541 seroconverters (80%) remained HBeAg nega970

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tive and anti-HBe positive throughout the study, whereas

the other 109 (20%) seroreverted after the initial seroconversion. Seroreverting patients tended to fluctuate between
seroconversion and seroreversion, commonly having 2 to
3 reversions over the 6 to 7 years of this study. Seroreversion episodes are frequently accompanied by a flare of
hepatitis activity.70 In the study by Hsu et al,68 12 patients
reverted to HBeAg positivity, 5 of whom developed cirrhosis during follow-up. In addition to these spontaneous
seroreversion episodes, HBV replication can reactivate in
inactive HBV carriers as a result of immunosuppression or
chemotherapy.46,48,52,71
Spontaneous clearance of HBsAg was delayed in a
small number of inactive HBV carriers, at the estimated
annual rate of 0.5% to 2% in Western countries and at a
much lower rate of 0.1% to 0.8% in Asian countries.72,73
Patients with delayed spontaneous clearance of HBsAg are
thought to have a favorable prognosis (ie, lack of progression to cirrhosis). However, patients with cirrhosis and
HBsAg clearance should continue to be monitored because
clearance of HBsAg may not necessarily preclude the development of complications of cirrhosis or HCC in these
patients.74-76
PHASE 4: HBEAG-NEGATIVE CHRONIC HEPATITIS
Chronic hepatitis may recur in up to one third of inactive
HBV carriers without reversion of HBeAg in their serum.77-79
Some of these carriers are likely infected with 1 of the HBV
variants that cannot express HBeAg because of mutations
in the precore or core-promoter regions of the HBV genome.80-84 Most patients progress to this phase after a variable length of time in the inactive HBV carrier state,
whereas some progress to HBeAg-negative chronic hepatitis directly from HBeAg-positive chronic hepatitis.68
This phase is characterized by the absence of HBeAg,
the presence of anti-HBe antibody, detectable levels of
HBV DNA, elevated levels of serum ALT, and histological
findings of continued necroinflammation of the liver.85
Compared to those with HBeAg-positive chronic hepatitis,
patients with HBeAg-negative chronic hepatitis are generally older, have more advanced disease as evidenced by
liver histology, and have lower serum HBV DNA levels.37
The course of disease can fluctuate, as demonstrated in a
study of 164 patients with detectable anti-HBe antibody
who were followed up for a median of 21 months.86 Of the
105 (64%) patients who developed at least 1 flare of recurrent disease, 70% had a fluctuating disease course characterized by periods of apparent inactivity during which serum
ALT levels normalized. Because of such fluctuation, serial
testing of serum ALT levels (with or without HBV DNA
levels) is necessary to distinguish patients with HBeAgnegative chronic infection from inactive HBV carriers.87

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NATURAL HISTORY OF HEPATITIS B VIRUS INFECTION

The natural course of HBeAg-negative chronic hepatitis

B is incompletely understood. In some patients, disease
may progress silently for years, escaping clinical recognition.85 In such patients, serum HBV DNA levels may increase only transiently before serum ALT levels increase.85
In general, HBeAg-negative chronic hepatitis represents a
potentially severe and progressive form of chronic liver
disease.88,89 Because most, if not all, of these patients
have gone through the HBeAg-positive chronic hepatitis
phase, varying degrees of hepatic fibrosis are already
present. Liver histological studies performed at the time
of diagnosis of chronic HBV infection reveal that 50% of
patients have moderate or severe necroinflammation and
fibrosis and 25% to 40% have cirrhosis.86,90-93 Moreover,
continued hepatitis activity (persistent or intermittent) in
the absence of spontaneous, sustained remission further
increases the risk of progressive fibrosis. Spontaneous
clearance of HBsAg is rare, with an annual incidence of
0.5% to 1.0%.93
SEQUELAE OF CHRONIC HBV INFECTION AND
PATIENT PROGNOSIS
CHRONIC HBV INFECTION AND CIRRHOSIS
Sequelae of chronic HBV infection may include mild to
moderate fibrosis, compensated cirrhosis, hepatic decompensation, and HCC. The annual incidence of cirrhosis in
patients with HBeAg-negative chronic hepatitis may be as
high as 8% to 10%, compared with 2% to 5% in those with
HBeAg-positive chronic hepatitis.62,94-96 The higher rate of
cirrhosis in patients presenting with HBeAg-negative
chronic hepatitis, a late phase in the natural history of
chronic HBV infection, is not surprising because these patients tend to be older and have more advanced liver disease.94,96 In addition, long-term remission of hepatitis activity
is much less likely in HBeAg-negative patients than in those
with HBeAg-positive chronic hepatitis, whose liver disease
may be halted or even reversed after HBeAg seroconversion.
For example, among patients with HBeAg-positive chronic
hepatitis, the rate of cirrhosis development is higher in
those who remain HBeAg positive during follow-up than in
those who seroconvert.62 As discussed previously, HBeAgnegative patients who have HBeAg reversion are at increased risk of cirrhosis compared with those with sustained HBeAg seroconversion.52,55,62,68
In addition to HBeAg status, HBV genotype and high
levels of HBV replication have been found to affect the
natural history of HBV infection.52,55,58,59,68,97-100 In a recent
population-based prospective cohort study, 3582 Taiwanese patients with chronic HBV infection were followed up
without treatment for 11 years.97 The cumulative incidence
of cirrhosis increased with increasing HBV DNA levels
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(4.5% for <300 copies/mL; 36.2% for 106 copies/mL).

Hepatitis B virus DNA levels were the strongest predictor
of progression to cirrhosis in a multivariable regression
model (hazard ratio [HR], 2.5; 95% confidence interval
[CI], 1.6-3.8 for 104 to <105 HBV DNA copies/mL; HR,
5.6; 95% CI, 3.7-8.5 for 105 to <106 HBV DNA copies/
mL; HR, 6.5; 95% CI, 4.1-10.2 for 106 HBV DNA copies/
mL).97 In addition, HBeAg positivity (HR, 1.7; 95% CI,
1.2-2.3), abnormal ALT levels (ALT >45; HR, 1.5; 95%
CI, 1.1-2.1), male sex, and increasing age were associated
with increased risk of cirrhosis.
Patients included in the study were mostly middle-aged
(mean, 45 years), were HBeAg negative (85%), and had
normal ALT levels (94%).97 In this group, high levels of
HBV DNA at baseline are likely to be an indicator of the
presence of or propensity to progress to HBeAg-negative
chronic hepatitis. Presumably, if disease status had been
followed up serially in these patients, significant hepatitis activity would have been detected before cirrhosis
developed.
Thus, in our opinion, the main lesson to be gleaned from
these data is that asymptomatic patients must be followed
up carefully, especially if their HBV DNA levels are high.
Currently, candidacy for antiviral therapy is determined by
serum ALT levels, HBV DNA levels, and, in some cases,
liver histology. More emphasis may be placed on HBV
DNA as we learn more about its impact on the long-term
outcome of HBV infection. However, currently available
data are insufficient to support administering antiviral
agents indiscriminately to every patient who has high HBV
DNA levels. Rather, careful follow-up of these patients is
recommended, so that treatment may be instituted at an
opportune time.
Worldwide, 8 HBV genotypes have been identified, and
our understanding of their clinical importance is increasing. Although genotype A is classically attributed to populations in North America and Western Europe, the most
commonly encountered genotypes in practice today are
genotypes B and C because more patients with chronic
HBV infection are of Asian descent. In studies comparing
genotypes B and C, patients with genotype B are more
likely to undergo spontaneous HBeAg seroconversion at a
younger age, have less-active liver disease, and have a
slower rate of progression to cirrhosis.101 Moreover, genotype B may be associated with fewer hepatitis flares, a
higher likelihood of sustained remission after HBeAg
seroconversion, and a lower incidence and later onset of
HCC. In our opinion, however, these data are not strong
enough to justify a role for genotype information in the
monitoring of these patients.58,59,98-100
Additional risk factors associated with progression to
cirrhosis include habitual alcohol intake102 and concurrent

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NATURAL HISTORY OF HEPATITIS B VIRUS INFECTION

infection with hepatitis C or D virus (HCV, HDV) or

human immunodeficiency virus.103,104 In a study from Taiwan, the 10-year cumulative probability of cirrhosis among
persons with chronic HBV infection was 48% in those with
HCV coinfection, 21% in those with HDV superinfection,
and 9% in those without coinfection or superinfection103
Coinfection with human immunodeficiency virus and HBV
has also been shown to increase the risk of cirrhosis and
liver-related mortality more than HBV infection alone.104
CHRONIC HBV INFECTION AND HEPATIC DECOMPENSATION
Once cirrhosis is established, the incidence of hepatic decompensation is approximately 3% per year.61,105 The risk is
much higher, however, in patients with active viral replication than in inactive carriers.105-107 Fattovich et al107 showed
that persistently high levels of HBV replication are associated with an increased risk of hepatic decompensation
(relative risk, 4.1; 95% CI,1.1-15.1) and mortality (relative
risk, 5.9; 95% CI, 1.6-21.3). In a randomized controlled
trial, antiviral treatment delayed progression of advanced
fibrosis or cirrhosis to hepatic decompensation: the rate of
hepatic decompensation after 3 years was 8% in the group
receiving lamivudine compared with 20% in the placebo
group.108 Uncontrolled trials have suggested that inhibition of viral replication with antiviral therapy improves
survival.109,110
CHRONIC HBV INFECTION AND HCC
Hepatis B virus has been well established as a substantial
carcinogen. The risk of HCC in patients with chronic HBV
infection is 100 times higher than in persons without infection,111 and their risk differs depending on their disease
characteristics.112 The single most important risk factor for
HCC is cirrhosis. The annual incidence of HCC has been
estimated to be less than 1% for HBV carriers without
cirrhosis and 2% to 3% for those with cirrhosis.55,68,107,113 In
a study from Taiwan, the presence of cirrhosis at study
entry was associated with a high risk of HCC (HR, 9.1;
95% CI, 5.9-13.9).112
Other factors found to be important predictors of HCC
development are HBeAg positivity (HR, 2.6; 95% CI, 1.64.2) and high levels of HBV DNA (HR, 6.1; 95% CI, 2.912.7 for 106 copies/mL; HR, 6.6; 95% CI, 3.3-13.1 for
105 to <106 copies/mL; HR, 2.3; 95% CI, 1.1-4.9 for 104
to <105 copies/mL).112 These results confirm those of a
previous study, also from Taiwan, in which 11,893 men
aged 30 to 65 years were followed up for 8.5 years.114 The
risk of HCC was highest in men who were positive for both
HBsAg and HBeAg (HR, 60.2; 95% CI, 35.5-102.1) followed by those who were positive for HBsAg and negative
for HBeAg (HR, 9.6; 95% CI, 6.0-15.2), compared with
those who were negative for both HBsAg and HBeAg.114
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High levels of HBV DNA are also an important risk factor

for HCC in patients positive for HBsAg and negative for
HBeAg.114-116 For HBV DNA levels greater than 13.0 pg/mL
(or 3,679,000 copies/mL), the risk of HCC is 6 times higher
than for undetectable HBV DNA levels.114
Several relevant points must be considered when interpreting these data. First, as discussed previously, patients
included in these prospective studies were largely middleaged (minimum, 30 years). Thus, the data should not be
extrapolated to young HBV carriers who are HBeAg positive and have very high levels of HBV DNA. It is possible
that a subgroup of patients aged 30 to 50 years who fail to
seroconvert and remain HBeAg positive are at a particularly high risk of HCC. Second, the risk factors for cirrhosis
and those for HCC are markedly similar, namely high HBV
DNA levels, HBeAg positivity, older age, and male sex.
Although the study did not report the prevalence of cirrhosis among patients with HCC, it is likely very high because
cirrhosis is a highly significant risk factor for HCC. As a
result, it is difficult to determine whether increased viral
replication (HBeAg and HBV DNA), known to encourage
the development of cirrhosis, has any additional direct
impact on the development of HCC. Finally, the observations made here should not be construed as advocating the
use of antiviral agents for the purpose of cancer prevention in
patients who otherwise do not meet the treatment criteria.
Various studies have found additional risk factors for
HCC, including abnormal ALT levels, long duration of
infection, coinfection with HCV117 or HDV, a family history of HCC,118 excessive alcohol intake,102,119 cigarette
smoking,120 HBV genotype C (vs genotype B),113,116 and
core promoter mutations.121,122 Probably because of infection in early childhood, Asian and African people are at
much higher risk for HCC than white people.
Given the significant differences in risk for HCC among
various populations, practice guidelines were developed
and published by the American Association for the Study
of Liver Diseases.123 Surveillance is recommended for atrisk patients, including all HBV carriers with cirrhosis and
the following groups regardless of cirrhosis: Asian men
aged 40 years and older, Asian women aged 50 years and
older, those with a family history of HCC, African people
aged 20 years and older, and possibly those with high HBV
DNA levels and ongoing inflammatory activity. Surveillance strategies may vary depending on local expertise in
cross-sectional imaging. The guidelines recommend ultrasonography because it offers acceptable sensitivity and
specificity at a lower cost than other imaging modalities. If
performed in conjunction with imaging, -fetoprotein measurement is acceptable, but it should not be used alone for
screening unless other modalities are unavailable. Surveillance should be performed at 6- to 12-month intervals.

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NATURAL HISTORY OF HEPATITIS B VIRUS INFECTION

SUMMARY AND CONCLUSIONS

The dynamic balance between viral replication and host
immune response plays a key role in the pathogenesis of
liver disease from HBV infection. Most infections in immunocompetent adults are resolved, whereas most neonates and infants develop chronic HBV infection. Those
with chronic HBV infection may present in 1 of 4 phases:
(1) in a state of immune tolerance, (2) with HBeAg-positive chronic hepatitis, (3) as an inactive HBsAg carrier, or
(4) with HBeAg-negative chronic hepatitis. Of these, the
HBeAg-positive and -negative chronic hepatitis phases are
associated with a significant risk of progression to cirrhosis. Several risk factors such as HBV DNA levels, HBeAg
status, and ALT levels have been identified to predict longterm outcome such as cirrhosis and HCC. These data highlight the importance of monitoring all patients with chronic
HBV infection to identify treatment candidates and select
optimal timing for treatment, to recognize those at risk for
complications, and to implement surveillance for HCC.
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