4. natural history of hepatitis b virus infection

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Mayo Clin Proc. August 2007;82(8):967-975 www.mayoclinicproceedings.com 967

NATURAL HISTORY OF HEPATITIS B VIRUS INFECTION

For personal use. Mass reproduce only with permission fromM ayo Clinic Proceedings.For personal use. Mass reproduce only with permission fromM ayo Clinic Proceedings.

REVIEW

From the Division of Gastroenterology and Hepatology, Mayo Clinic, Roches-ter, MN.

This work was supported by grant DK 61617 from the National Institute ofDiabetes and Digestive and Kidney Diseases.

Individual reprints of this article are not available. Address correspondence toW. Ray Kim, MD, Division of Gastroenterology and Hepatology, Mayo Clinic,200 First St SW, Rochester, MN 55905 ([email protected]).

2007 Mayo Foundation for Medical Education and Research

SURAKITPUNGPAPONG, MD; W. RAYKIM, MD; ANDJOHNJ. POTERUCHA, MD

Natural History of Hepatitis B Virus Infection:

An Update for Clinicians

Hepatit is B virus (HBV) is a c ommon viral pathogen that causes asubstantial health burden worldwide. Significant progress hasbeen made in the past few decades in understanding the naturalhistory of HBV infection. A dynamic balance between viral replica-tion and host immune response is pivotal t o t he pathogenesis ofliver disease. In immunocompetent adults, most HBV infectionsspontaneously resolve, whereas in most neonat es and infants t heybecome chronic. Those with chronic HBV may present in 1 of 4phases of infection: (1) in a st ate of immune tolerance, (2) wit hhepatit is B e antigen (HBeAg)posit ive chronic hepatit is, (3) asan inactive hepatit is B surface antigen carrier, or (4) with HBeAg-negative chronic hepatitis. Of these, HBeAg-positive and HBeAg-negative chronic hepatit is may progress to cirrhosis and it s long-term sequelae including hepatic decompensation and hepatocellu-

lar carcinoma. Several prognostic factors, such as serum HBVDNA concentrations, HBeAg status, serum aminotransferases,and certain HBV genotypes, have been identified to predict long-term outcome. These data emphasize the importance of monitor-ing all patients w ith c hronic HBV infection to identify candidatesfor and select optimal t iming of antiviral treatment, to recognizethose at r isk of complicat ions, and to implement surveil lance forearly detection of hepatocellular carcinoma.

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

ALT = alanine aminotransferase; CI = c onfidence int erval; HBV = hepati-tis B virus; HBeAg = hepatit is B e antigen; HBsAg = hepatitis B surfaceantigen; HCC = hepatocellular carcinoma; HCV = hepatitis C virus;HDV = hepatitis D virus; HR = hazard ratio

Hepatitis B virus (HBV) infection is a challenging glo-bal health problem, affecting an estimated 2 billionpersons worldwide. Of those infected with HBV, 400 mil-lion remain chronically infected, and an estimated 1 mil-

lion die of HBV-related liver diseases annually.1Accord-

ing 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,2-4a de-

crease attributed to several public health interventions such

as screening of pregnant women, vaccination of infants and

adolescents, and safe injection practices in general.5If 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

eliminated. However, the prevalence of chronic HBV in-

fection has yet to show a decrease.6Moreover, 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 en-

demic areas.7

Understanding the natural history of HBV infection has

become increasingly relevant for clinicians for several rea-

sons. First, in the past 10 years, antiviral agents specific for

the treatment of HBV have proliferated, providing opportu-

nities 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 pa-

tients. Second, epidemiologic studies have yielded impor-

tant 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 avail-

able, it may play a greater role in clinical decision making.

Third, the availability of highly sensitive HBV DNA as-says, combined with a better understanding of HBV virol-

ogy and of the host immune response to HBV infection, has

led to new insights into the natural history of HBV infec-

tion. Thus, understanding the dynamic nature of chronic

HBV infection is essential for management of HBV carri-

ers, not only in selecting optimal treatment candidates but

also in instituting appropriate monitoring for the preven-

tion and early detection of complications from chronic

HBV infection.

PATHOGENESIS OF HBV INFECTION

The observation that many HBV carriers are asymptomaticwith 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.10-12However, in neonates with an imma-


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Mayo Clin Proc. August 2007;82(8):967-975 www.mayoclinicproceedings.com968



ture immune system, exposure to HBV often results in

minimal acute liver injury but high rates of chronic infec-

tion (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.13-15Limited data suggestthat in this setting an overwhelming degree of viral replica-

tion 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 disappear-

ance of viral antigens and the appearance of antiviral anti-

bodies and specific cytotoxic T lymphocytes.17-20 These

observations suggest that HBV is rarely completely eradi-

cated after recovery from acute infection, which may ac-

count 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 (109-

1012copies/mL).24Circulating 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.27The outcome of acute HBV infec-

tion depends on age and immune competence at the time of

infection.27-30 For example, chronic HBV infection willdevelop in as many as 90% of infected neonates and infants

but only in 1% to 5% of immunocompetent adults (exclud-

ing those with acute exacerbations of chronic HBV infec-

tion). 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 re-

solves without the need for intervention or antiviral treat-

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

with acute HBV infection and often demonstrates no evi-

dence of HBV replication because of the massive immune-

mediated lysis of infected hepatocytes.31In endemic areas,

exposure to HBV at birth or in early childhood results in

higher rates of chronic HBV infection. Persons infected aschildren may present in adulthood with clinical manifesta-

tions similar to those of acute hepatitis if they have acute

exacerbation of chronic HBV infection. These exacerba-

tions frequently may be associated with elevated levels of

IgM antibody to hepatitis B core antigen, which may lead

to misdiagnosis of acute HBV infection,32-34and an increase

in the serum -fetoprotein concentration, which may raiseconcerns for the presence of hepatocellular carcinoma

(HCC).35Thus, 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).

PHASE1 : IMMUNETOLERANCEPersistent 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 theinfection in late childhood or adulthood and have subse-

quent 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 toler-

ance 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 hepato-

cytes.39,40This tolerization leads to minimal host immune

activity, characterized by normal serum aminotransferase

levels and liver histological findings of minimal or noinflammation.41,42

PHASE2: HBEAG-POSITIVECHRONICHEPATITISAs the host immune system matures and begins to recog-

nize HBV-related epitopes on hepatocytes, immune-medi-

ated hepatocellular injury ensues.43,44Although HBV repli-

cation continues in the liver and viremia is continual, the

viral level in the serum becomes lower than during the


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immune tolerance phase when viral replication is com-

pletely unopposed.45In 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.46This phase is characterized

by the presence of HBeAg, high levels of serum HBVDNA, elevation of serum aminotransferase levels, and his-

tological 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 tran-

sition 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.48,49These 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 clearanceof HBeAg.32 Occasionally, hepatic decompensation may

occur after these flares.50

Spontaneous HBeAg seroconversion, which occurs an-

nually in as many as 10% to 20% of those with HBeAg-

positive hepatitis, is an important landmark in the natural

history of chronic HBV infection.37,51-55 In a population-

based study of 1536 Alaskan natives who acquired HBV

infection in adulthood, spontaneous seroconversion was

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 ami-

notransferase levels,56,57 and certain HBV genotypes.58,59

High aminotransferase levels are considered surrogate

markers for a vigorous host immune response that results inhigher spontaneous and treatment-induced HBeAg sero-

conversion.37In contrast, spontaneous HBeAg clearance or

seroconversion occurs in fewer than 5% of patients with

normal or mildly elevated levels of alanine aminotrans-

ferase (ALT).24,37,51,52Recent reports from Asian countries

have shown that HBV genotype B, compared with geno-

type 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. Ap-proximately 12% to 20% of them will develop serious liver

injury that results in cirrhosis and complications within 5

years,60-63depending on the duration of the chronic hepatitis

and the frequency and severity of flares.55,62For 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%).62These

35 patients included those who seroconverted during fol-

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-facingarrows represent an increase or decrease of DNA level (=low increase; =moderate increase; =moderate decrease; =high increase). ALT =alanine aminotransferase; HBeAg =hepatitis B e antigen.

HBeAgseroconversion

Positive HBeAgDNA

Normal ALT

Immunetolerance

Positive HBeAgDNA

Abnormal ALT

HBeAg-positivechronic

hepatitis

Negative HBeAgDNA

Normal ALT

Inactivecarrier

Negative HBeAgDNA

Abnormal ALT

HBeAg-negativechronichepatitis

Precoremutation

Progression tocirrhosis


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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, cirrhosisdeveloped in 12 (21%) after a mean of 6.5 years of follow-

up. Although the retrospective nature of these data may

limit their clinical applicability, they do point to the in-

creased 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

PHASE3 : INACTIVEHBSAGCARRIERSAfter seroconversion, most patients remain negative for

HBeAg and positive for anti-HBe antibody. Seroconver-

sion is usually accompanied by stabilization of hepatitis,

characterized by normalization of ALT levels and de-

creases in HBV DNA to low (


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The natural course of HBeAg-negative chronic hepatitis

B is incompletely understood. In some patients, disease

may progress silently for years, escaping clinical recogni-

tion.85In such patients, serum HBV DNA levels may in-

crease only transiently before serum ALT levels increase.85

In general, HBeAg-negative chronic hepatitis represents apotentially 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.86,90-93Moreover,

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 ANDPATIENT PROGNOSIS

CHRONICHBV INFECTIONANDC IRRHOSISSequelae of chronic HBV infection may include mild to

moderate fibrosis, compensated cirrhosis, hepatic decom-

pensation, 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.62,94-96The higher rate of

cirrhosis in patients presenting with HBeAg-negativechronic hepatitis, a late phase in the natural history of

chronic HBV infection, is not surprising because these pa-

tients tend to be older and have more advanced liver dis-

ease.94,96In 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.62As discussed previously, HBeAg-

negative patients who have HBeAg reversion are at in-

creased risk of cirrhosis compared with those with sus-tained 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.52,55,58,59,68,97-100In a recent

population-based prospective cohort study, 3582 Taiwan-

ese patients with chronic HBV infection were followed up

without treatment for 11 years.97The cumulative incidence

of cirrhosis increased with increasing HBV DNA levels

(4.5% for


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

human immunodeficiency virus.103,104In a study from Tai-

wan, 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

CHRONICHBV INFECTIONANDHEPATICDECOMPENSATIONOnce cirrhosis is established, the incidence of hepatic de-

compensation is approximately 3% per year.61,105The risk is

much higher, however, in patients with active viral replica-

tion than in inactive carriers.105-107Fattovich et al107showed

that persistently high levels of HBV replication are associ-

ated 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 inhibi-

tion of viral replication with antiviral therapy improves

survival.109,110

CHRONICHBV INFECTIONANDHCCHepatis 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 infec-tion,111 and their risk differs depending on their disease

characteristics.112The 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, 1.6-

4.2) and high levels of HBV DNA (HR, 6.1; 95% CI, 2.9-

12.7 for !106 copies/mL; HR, 6.6; 95% CI, 3.3-13.1 for

!105to


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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 im-

munocompetent adults are resolved, whereas most neo-nates 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-posi-

tive 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 cirrho-

sis. Several risk factors such as HBV DNA levels, HBeAg

status, and ALT levels have been identified to predict long-

term outcome such as cirrhosis and HCC. These data high-

light 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 forcomplications, and to implement surveillance for HCC.

REFERENCES1. Ocama P, Opio CK, Lee WM. Hepatitis B virus infection: current status.

Am J Med. 2005;118:1413.e15-1413.e22.2. Mast EE, Mahoney FJ, Alter MJ, Margolis HS. Progress toward elimi-

nation of hepatitis B virus transmission in the United States. Vaccine.

1998;16(suppl):S48-S51.3. Alter MJ. Community acquired viral hepatitis B and C in the United

States. Gut. 1993;34(2 suppl):S17-S19.4. Goldstein ST, Alter MJ, Williams IT, et al. Incidence and risk factors

for acute hepatitis B in the United States, 1982-1998: implications for vaccina-tion programs.J Infect Dis. 2002 Mar 15;185:713-719. Epub 2002 Feb 28.

5. Mast EE, Williams IT, Alter MJ, Margolis HS. Hepatitis B vaccinationof adolescent and adult high-risk groups in the United States. Vaccine.

1998;16(suppl):S27-S29.6. Kim WR, Benson JT, Therneau TM, Torgerson HA, Yawn BP, Melton

LJ III. Changing epidemiology of hepatitis B in a US community. Hepatology.

2004;39:811-816.7. Kim WR, Ishitani MB, Dickson ER. Rising burden of hepatitis B in the

United States: should the other virus be forgotten? [abstract]. Hepatology.

2002;36:222A.8. de Franchis R, Meucci G, Vecchi M, et al. The natural history of

asymptomatic hepatitis B surface antigen carriers.Ann Intern Med. 1993;118:191-194.

9. Ganem D, Prince AM. Hepatitis B virus infectionnatural history andclinical consequences [published correction appears in N Engl J Med. 2004;351:351].N Engl J Med. 2004;350:1118-1129.

10. Villeneuve JP. The natural history of chronic hepatitis B virus infection.J Clin Virol. 2005;34(suppl 1):S139-S142.

11. Eddleston AL, Mondelli M. Immunopathological mechanisms of livercell injury in chronic hepatitis B virus infection. J Hepatol. 1986;3(suppl2):S17-S23.

12.Rapicetta M, Ferrari C, Levrero M. Viral determinants and host immuneresponses in the pathogenesis of HBV infection. J Med Virol. 2002;67:454-

457.13. Vassiliadis T, Garipidou V, Tziomalos K, Perifanis V, Giouleme O,

Vakalopoulou S. Prevention of hepatitis B reactivation with lamivudine inhepatitis B virus carriers with hematologic malignancies treated with chemo-therapya prospective case series.Am J Hematol. 2005;80:197-203.

14. Idilman R. Lamivudine prophylaxis in HBV carriers with haemato-oncological malignancies who receive chemotherapy. J Ant imicro bChemother. 2005 Jun;55:828-831. Epub 2005 Apr 22.

15. Lin PC, Poh SB, Lee MY, Hsiao LT, Chen PM, Chiou TJ. Fatalfulminant hepatitis B after withdrawal of prophylactic lamivudine in hemato-poietic stem cell transplantation patients.Int J Hematol. 2005;81:349-351.

16. Meuleman P, Libbrecht L, Wieland S, et al. Immune suppression un-covers endogenous cytopathic effects of the hepatitis B virus. J Virol.

2006;80:2797-2807.17. Yuki N, Nagaoka T, Yamashiro M, et al. Long-term histologic and

virologic outcomes of acute self-limited hepatitis B. Hepatology. 2003;37:1172-1179.

18. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B

virus persists for decades after patients recovery from acute viral hepatitisdespite active maintenance of a cytotoxic T-lymphocyte response.Nat Med.

1996;2:1104-1108.19. Yotsuyanagi H, Yasuda K, Iino S, et al. Persistent viremia after recov-

ery from self-limited acute hepatitis B.Hepatology. 1998;27:1377-1382.20. Marusawa H, Uemoto S, Hijikata M, et al. Latent hepatitis B virus

infection in healthy individuals with antibodies to hepatitis B core antigen.Hepatology. 2000;31:488-495.

21. Blanpain C, Knoop C, Delforge ML, et al. Reactivation of hepatitis Bafter transplantation in patients with pre-existing anti-hepatitis B surface anti-gen antibodies: report on three cases and review of the literature. Transplanta-tion. 1998;66:883-886.

22. Coiffier B. Hepatitis B virus reactivation in patients receiving chemo-

therapy for cancer treatment: role of Lamivudine prophylaxis. Cancer Invest.

2006;24:548-552.23. Hoofnagle JH. Serologic markers of hepatitis B virus infection. Annu

Rev Med. 1981;32:1-11.24. Ribeiro RM, Lo A, Perelson AS. Dynamics of hepatitis B virus infec-

tion.Microbes Infect. 2002;4:829-835.25. Koff RS, Slavin MM, Connelly JD, Rosen DR. Contagiousness of acute

hepatitis B: secondary attack rates in household contacts. Gastroenterology.

1977;72:297-300.26. Kajino K, Jilbert AR, Saputelli J, Aldrich CE, Cullen J, Mason WS.

Woodchuck hepatitis virus infections: very rapid recovery after a prolonged

viremia and infection of virtually every hepatocyte. J Virol. 1994;68:5792-5803.

27. McMahon BJ, Alward WL, Hall DB, et al. Acute hepatitis B virusinfection: relation of age to the clinical expression of disease and subsequentdevelopment of the carrier state.J Infect Dis. 1985;151:599-603.

28. Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen andvertical transmission of hepatitis B surface antigen.Am J Epidemiol. 1977;105:94-98.

29. Tassopoulos NC, Papaevangelou GJ, Sjogren MH, Roumeliotou-Karayannis A, Gerin JL, Purcell RH. Natural history of acute hepatitis Bsurface antigen-positive hepatitis in Greek adults. Gastroenterology. 1987;92:1844-1850.

30. Beasley RP, Hwang LY, Lin CC, et al. Incidence of hepatitis B virusinfections in preschool children in Taiwan.J Infect Dis. 1982;146:198-204.

31. Wright TL, Mamish D, Combs C, et al. Hepatitis B virus and apparentfulminant non-A, non-B hepatitis.Lancet. 1992;339:952-955.

32. Liaw YF, Chu CM, Su IJ, Huang MJ, Lin DY, Chang-Chien CS.Clinical and histological events preceding hepatitis B e antigen seroconversionin chronic type B hepatitis. Gastroenterology.1983;84:216-219.

33. Liaw YF, Yang SS, Chen TJ, Chu CM. Acute exacerbation in hepatitisB e antigen positive chronic type B hepatitis: a clinicopathological study. J

Hepatol. 1985;1:227-233.34. Liaw YF, Chu CM, Huang MJ, Sheen IS, Yang CY, Lin DY. Determi-

nants for hepatitis B e antigen clearance in chronic type B hepatitis. Liver.1984;4:301-306.

35. Lok AS, Lai CL. alpha-Fetoprotein monitoring in Chinese patients withchronic hepatitis B virus infection: role in the early detection of hepatocellularcarcinoma.Hepatology. 1989;9:110-115.

36. Chu CM, Karayiannis P, Fowler MJ, Monjardino J, Liaw YF, ThomasHC. Natural history of chronic hepatitis B virus infection in Taiwan: studies ofhepatitis B virus DNA in serum.Hepatology. 1985;5:431-434.

37. Yim HJ, Lok AS. Natural history of chronic hepatitis B virus infection:what we knew in 1981 and what we know in 2005. Hepatology. 2006;43(2suppl 1):S173-S181.

38. Hsu HY, Chang MH, Hsieh KH, et al. Cellular immune response toHBcAg in mother-to-infant transmission of hepatitis B virus. Hepatology.

1992;15:770-776.39. Milich DR, Jones JE, Hughes JL, Price J, Raney AK, McLachlan A. Is a

function of the secreted hepatitis B e antigen to induce immunologic tolerancein utero? Proc Natl Acad Sci U S A. 1990;87:6599-6603.

40. Chen M, Sallberg M, Hughes J, et al. Immune tolerance split betweenhepatitis B virus precore and core proteins.J Virol. 2005;79:3016-3027.


8/9




41. Chang MH, Hwang LY, Hsu HC, Lee CY, Beasley RP. Prospectivestudy of asymptomatic HBsAg carrier children infected in the perinatal period:clinical and liver histologic studies.Hepatology. 1988;8:374-377.

42. Lok AS, Lai CL. A longitudinal follow-up of asymptomatic hepatitis Bsurface antigen-positive Chinese children.Hepatology. 1988;8:1130-1133.

43. Tsai SL, Chen PJ, Lai MY, et al. Acute exacerbations of chronic type Bhepatitis are accompanied by increased T cell responses to hepatitis B core and

e antigens: implications for hepatitis B e antigen seroconversion.J Clin Invest.1992;89:87-96.

44. Chu CM, Liaw YF. Intrahepatic distribution of hepatitis B surface andcore antigens in chronic hepatitis B virus infection: hepatocyte with cytoplas-mic/membranous hepatitis B core antigen as a possible target for immunehepatocytolysis.Gastroenterology.1987;92:220-225.

45. Tedder RS, Ijaz S, Gilbert N, et al. Evidence for a dynamic host-para-site relationship in e-negative hepatitis B carriers.J Med Virol. 2002;68:505-512.

46. Liaw YF, Tai DI, Chu CM, Pao CC, Chen TJ. Acute exacerbation inchronic type B hepatitis: comparison between HBeAg and antibody-positivepatients.Hepatology. 1987;7:20-23.

47. Liaw YF, Pao CC, Chu CM, Sheen IS, Huang MJ. Changes of serumhepatitis B virus DNA in two types of clinical events preceding spontaneoushepatitis B e antigen seroconversion in chronic type B hepatitis. Hepatology.1987;7:1-3.

48. Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactiva-tion of hepatitis B virus replication in patients receiving cytotoxic therapy:

report of a prospective study. Gastroenterology. 1991;100:182-188.49. Davis GL, Hoofnagle JH, Waggoner JG. Spontaneous reactivation of

chronic hepatitis B virus infection. Gastroenterology. 1984;86:230-235.50. Sheen IS, Liaw YF, Tai DI, Chu CM. Hepatic decompensation associ-

ated with hepatitis B e antigen clearance in chronic type B hepatitis. Gastroen-terology. 1985;89:732-735.

51. Liaw YF, Chu CM, Lin DY, Sheen IS, Yang CY, Huang MJ. Age-specific prevalence and significance of hepatitis B e antigen and antibody inchronic hepatitis B virus infection in Taiwan: a comparison among asymptom-atic carriers, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma.J

Med Virol. 1984;13:385-391.52. Lok AS, Lai CL, Wu PC, Leung EK, Lam TS. Spontaneous hepatitis

B e antigen to antibody seroconversion and reversion in Chinese patientswith chronic hepatitis B virus infection. Gastroenterology. 1987;92:1839-1843.

53. Hoofnagle JH, Dusheiko GM, Seeff LB, Jones EA, Waggoner JG, BalesZB. Seroconversion from hepatitis B e antigen to antibody in chronic type Bhepatitis.Ann Intern Med. 1981;94:744-748.

54. Realdi G, Alberti A, Rugge M, et al. Seroconversion from hepatitis B eantigen to anti-HBe in chronic hepatitis B virus infection. Gastroenterology.1980;79:195-199.

55. McMahon BJ, Holck P, Bulkow L, Snowball M. Serologic and clinicaloutcomes of 1536 Alaska Natives chronically infected with hepatitis B virus.

Ann Intern Med. 2001;135:759-768.56. Yuen MF, Yuan HJ, Hui CK, et al. A large population study of sponta-

neous HBeAg seroconversion and acute exacerbation of chronic hepatitis Binfection: implications for antiviral therapy. Gut. 2003;52:416-419.

57. Liaw YF. Hepatitis flares and hepatitis B e antigen seroconversion:implication in anti-hepatitis B virus therapy.J Gastroenterol Hepatol. 2003;18:246-252.

58. Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B virus genotypes andspontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis Bcarriers.J Med Virol. 2004;72:363-369.

59. Chu CJ, Hussain M, Lok AS. Hepatitis B virus genotype B is associatedwith earlier HBeAg seroconversion compared with hepatitis B virus genotypeC. Gastroenterology.2002;122:1756-1762.

60. Fattovich G, Brollo L, Giustina G, et al. Natural history and prognosticfactors for chronic hepatitis type B. Gut. 1991;32:294-298.

61. Fattovich G, Giustina G, Schalm SW, et al. Occurrence of hepatocellu-lar carcinoma and decompensation in western European patients with cirrhosistype B: the EUROHEP Study Group on Hepatitis B Virus and Cirrhosis.

Hepatology. 1995;21:77-82.62. Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in

patients with chronic type B hepatitis: a prospective study.Hepatology. 1988;8:493-496.

63. Liaw YF, Lin DY, Chen TJ, Chu CM. Natural course after the develop-ment of cirrhosis in patients with chronic type B hepatitis: a prospective study.

Liver. 1989;9:235-241.

64. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficialeffect of interferon therapy in patients with chronic hepatitis B virus infection.

Hepatology. 1999;29:971-975.65. Liaw YF, Tai DI, Chu CM, et al. Early detection of hepatocellular

carcinoma in patients with chronic type B hepatitis: a prospective study.Gastroenterology.1986;90:263-267.

66. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B:

2000summary of a workshop. Gastroenterology.2001;120:1828-1853.67. Manno M, Camma C, Schepis F, et al. Natural history of chronic HBV

carriers in northern Italy: morbidity and mortality after 30 years. Gastroenter-ology. 2004;127:756-763.

68. Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontane-ous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology.

2002;35:1522-1527.69. McMahon BJ. The natural history of chronic hepatitis B virus infection.

Semin Liver Dis. 2004;24(suppl 1):17-21.70. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatu-

ral history of an immunologically mediated liver disease. Gastroenterology.

2001;120:1009-1022.71. Lok AS, Lai CL. Acute exacerbations in Chinese patients with chronic

hepatitis B virus (HBV) infection: incidence, predisposing factors and etiol-ogy.J Hepatol. 1990;10:29-34.

72. Alward WL, McMahon BJ, Hall DB, Heyward WL, Francis DP, BenderTR. The long-term serological course of asymptomatic hepatitis B virus carri-ers and the development of primary hepatocellular carcinoma. J Infect Dis.

1985;151:604-609.73. Liaw YF, Sheen IS, Chen TJ, Chu CM, Pao CC. Incidence, determi-

nants and significance of delayed clearance of serum HBsAg in chronic hepati-tis B virus infection: a prospective study.Hepatology. 1991;13:627-631.

74. Chen YC, Sheen IS, Chu CM, Liaw YF. Prognosis following spontane-ous HBsAg seroclearance in chronic hepatitis B patients with or withoutconcurrent infection. Gastroenterology.2002;123:1084-1089.

75. Yuen MF, Wong DK, Sablon E, et al. HBsAg seroclearance in chronichepatitis B in the Chinese: virological, histological, and clinical aspects [pub-lished correction appears inHepatology 2004;40:767].Hepatology. 2004;39:1694-1701.

76. Huo TI, Wu JC, Lee PC, et al. Sero-clearance of hepatitis B surfaceantigen in chronic carriers does not necessarily imply a good prognosis.

Hepatology. 1998;28:231-236.77. Chung HT, Lai CL, Lok AS. Pathogenic role of hepatitis B virus in

hepatitis B surface antigen-negative decompensated cirrhosis. Hepatology.

1995;22:25-29.78. Sung JJ, Chan HL, Wong ML, et al. Relationship of clinical and

virological factors with hepatitis activity in hepatitis B e antigen-nega-tive chronic hepatitis B virus-infected patients. J Viral Hepat. 2002;9:229-234.

79. Funk ML, Rosenberg DM, Lok AS. World-wide epidemiology ofHBeAg-negative chronic hepatitis B and associated precore and core promotervariants.J Viral Hepat. 2002;9:52-61.

80. Brunetto MR, Giarin MM, Oliveri F, et al. Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad SciU S A. 1991;88:4186-4190.

81. Chu CJ, Keeffe EB, Han SH, et al, US HBV Epidemiology StudyGroup. Prevalence of HBV precore/core promoter variants in the United States.

Hepatology. 2003;38:619-628.82. Carman WF, Jacyna MR, Hadziyannis S, et al. Mutation preventing

formation of hepatitis B e antigen in patients with chronic hepatitis B infection.Lancet. 1989;2:588-591.

83. Lok AS, Akarca U, Greene S. Mutations in the pre-core region ofhepatitis B virus serve to enhance the stability of the secondary structure of thepre-genome encapsidation signal. Proc Natl Acad Sci U S A. 1994;91:4077-

4081.84. Okamoto H, Tsuda F, Akahane Y, et al. Hepatitis B virus with muta-

tions in the core promoter for an e antigen-negative phenotype in carriers withantibody to e antigen.J Virol. 1994;68:8102-8110.

85. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negativechronic hepatitis B.Hepatology. 2001;34(4 pt 1):617-624.

86. Brunetto MR, Oliveri F, Coco B, et al. Outcome of anti-HBe positivechronic hepatitis B in alpha-interferon treated and untreated patients: a longterm cohort study.J Hepatol. 2002;36:263-270.

87. Chu CJ, Hussain M, Lok AS. Quantitative serum HBV DNA levelsduring different stages of chronic hepatitis B infection.Hepatology. 2002;36:1408-1415.


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88. Lai ME, Solinas A, Mazzoleni AP, et al. The role of pre-core hepatitis Bvirus mutants on the long-term outcome of chronic hepatitis B virus hepatitis: alongitudinal study.J Hepatol. 1994;20:773-781.

89. Naoumov NV, Schneider R, Grotzinger T, et al. Precore mutant hepati-tis B virus infection and liver disease. Gastroenterology.1992;102:538-543.

90. Di Marco V, Lo Iacono O, Camma C, et al. The long-term course ofchronic hepatitis B.Hepatology. 1999;30:257-264.

91. Zarski JP, Marcellin P, Cohard M, Lutz JM, Bouche C, Rais A, FrenchMulticentre Group. Comparison of anti-HBe-positive and HBe-antigen-posi-tive chronic hepatitis B in France.J Hepatol. 1994;20:636-640.

92. Papatheodoridis GV, Dimou E, Dimakopoulos K, et al. Outcome ofhepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ideanalog therapy starting with lamivudine.Hepatology. 2005;42:121-129.

93. Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term out-come of interferon-alpha treated and untreated patients with HBeAg-negativechronic hepatitis B.J Hepatol. 2001;34:306-313.

94. Fattovich G. Natural history of hepatitis B.J Hepatol. 2003;39(suppl 1):S50-S58.

95. Fattovich G, Brollo L, Alberti A, Pontisso P, Giustina G, Realdi G.Long-term follow-up of anti-HBe-positive chronic active hepatitis B.

Hepatology. 1988;8:1651-1654.96. Brunetto MR, Oliveri F, Rocca G, et al. Natural course and response to

interferon of chronic hepatitis B accompanied by antibody to hepatitis B eantigen.Hepatology. 1989;10:198-202.

97. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, The Risk

Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-InHBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based onthe level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678-686.

98. Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlatewith clinical outcomes in patients with chronic hepatitis B. Gastroenterology.2000;118:554-559.

99. Sumi H, Yokosuka O, Seki N, et al. Influence of hepatitis B virusgenotypes on the progression of chronic type B liver disease. Hepatology.

2003;37:19-26.100. Orito E, Mizokami M, Sakugawa H, et al, Japan HBV Genotype Re-

search Group. A case-control study for clinical and molecular biological differ-ences between hepatitis B viruses of genotypes B and C. Hepatology. 2001;33:218-223.101. Fung SK, Lok AS. Hepatitis B virus genotypes: do they play a role in the

outcome of HBV infection? [editorial].Hepatology. 2004;40:790-792.102. Ohnishi K, Iida S, Iwama S, et al. The effect of chronic habitual

alcohol intake on the development of liver cirrhosis and hepatocellular carci-

noma: relation to hepatitis B surface antigen carriage. Cancer. 1982;49:672-677.103. Liaw YF, Chen YC, Sheen IS, Chien RN, Yeh CT, Chu CM. Impact of

acute hepatitis C virus superinfection in patients with chronic hepatitis B virusinfection. Gastroenterology.2004;126:1024-1029.104. Thio CL, Seaberg EC, Skolasky R Jr, et al, Multicenter AIDS Cohort

Study. HIV-1, hepatitis B virus, and risk of liver-related mortality in theMulticenter Cohort Study (MACS).Lancet. 2002;360:1921-1926.105. Realdi G, Fattovich G, Hadziyannis S, et al, Investigators of the Euro-

pean Concerted Action on Viral Hepatitis (EUROHEP). Survival and prognos-tic factors in 366 patients with compensated cirrhosis type B: a multicenterstudy.J Hepatol. 1994;21:656-666.

106. de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW, vanBlankenstein M. Survival and prognostic indicators in hepatitis B surfaceantigen-positive cirrhosis of the liver. Gastroenterology.1992;103:1630-1635.

107. Fattovich G, Pantalena M, Zagni I, Realdi G, Schalm SW, ChristensenE, European Concerted Action on Viral Hepatitis (EUROHEP). Effect of hepati-tis B and C virus infections on the natural history of compensated cirrhosis: acohort study of 297 patients.Am J Gastroenterol. 2002;97:2886-2895.

108. Liaw YF, Sung JJ, Chow WC, et al, Cirrhosis Asian Lamivudine Multi-centre Study Group. Lamivudine for patients with chronic hepatitis B andadvanced liver disease.N Engl J Med. 2004;351:1521-1531.

109. Villeneuve JP, Condreay LD, Willems B, et al. Lamivudine treatmentfor decompensated cirrhosis resulting from chronic hepatitis B. Hepatology.

2000;31:207-210.110. Schiff ER, Lai CL, Hadziyannis S, et al, Adefovir Dipivoxil Study 435

International Investigators Group. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients.Hepatology.

2003;38:1419-1427.111. Beasley RP. Hepatitis B virus: the major etiology of hepatocellular

carcinoma. Cancer. 1988;61:1942-1956.112. Chen CJ, Yang HI, Su J, et al, REVEAL-HBV Study Group. Risk of

hepatocellular carcinoma across a biological gradient of serum hepatitis Bvirus DNA level.JAMA. 2006;295:65-73.

113. Tsubota A, Arase Y, Ren F, Tanaka H, Ikeda K, Kumada H. Genotype maycorrelate with liver carcinogenesis and tumor characteristics in cirrhotic patientsinfected with hepatitis B virus subtype adw.J Med Virol. 2001;65:257-265.

114. Yang HI, Lu SN, Liaw YF, et al, Taiwan Community-Based CancerScreening Project Group. Hepatitis B e antigen and the risk of hepatocellularcarcinoma.N Engl J Med. 2002;347:168-174.

115. Tang B, Kruger WD, Chen G, et al. Hepatitis B viremia is associatedwith increased risk of hepatocellular carcinoma in chronic carriers. J MedVirol. 2004;72:35-40.

116. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNAlevel and hepatocellular carcinoma: a prospective study in men.J Natl Cancer

Inst. 2005;97:265-272.117. Benvegnu L, Gios M, Boccato S, Alberti A. Natural history of compen-

sated viral cirrhosis: a prospective study on the incidence and hierarchy ofmajor complications. Gut. 2004;53:744-749.

118. Yu MW, Chang HC, Liaw YF, et al. Familial risk of hepatocellular car-cinoma among chronic hepatitis B carriers and their relatives.J Natl Cancer

Inst. 2000;92:1159-1164.119. Donato F, Tagger A, Gelatti U, et al. Alcohol and hepatocellular carci-

noma: the effect of lifetime intake and hepatitis virus infections in men andwomen.Am J Epidemiol. 2002;155:323-331.

120. Yuan JM, Govindarajan S, Arakawa K, Yu MC. Synergism of alcohol,diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacksand whites in the US. Cancer. 2004;101:1009-1017.

121. Baptista M, Kramvis A, Kew MC. High prevalence of 1762(T) 1764(A)mutations in the basic core promoter of hepatitis B virus isolated from blackAfricans with hepatocellular carcinoma compared with asymptomatic carriers.

Hepatology. 1999;29:946-953.122. Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of

hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis Bcarriers. Gastroenterology. 2003;124:327-334.

123. Bruix J, Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005;42:1208-1236.

4. natural history of hepatitis b virus infection

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