Hepatitis B

Hepatitis B
Straight to the point of care
Last updated: Jan 10, 2024

Table of Contents
Overview 3
Summary 3
Definition 3
Theory 4
Epidemiology 4
Aetiology 5
Pathophysiology 5
Classification 7
Case history 7
Diagnosis 9
Approach 9
History and exam 11
Risk factors 13
Investigations 16
Differentials 21
Criteria 23
Screening 25
Management 28
Approach 28
Treatment algorithm overview 34
Treatment algorithm 36
Emerging 45
Primary prevention 45
Secondary prevention 47
Patient discussions 48
Follow up 49
Monitoring 49
Complications 51
Prognosis 52
Guidelines 54
Diagnostic guidelines 54
Treatment guidelines 55
Online resources 59
Evidence tables 60
References 63
Images 81
Disclaimer 82
Hepatitis B Overview
Summary
Hepatitis B infection is the most common liver infection globally, caused by the hepatitis B virus (HBV).
People from endemic areas, or injection drug users and those with high-risk sexual behaviours, are at an
OVERVIEW
increased risk for infection.
Most people are asymptomatic, although some will present with complications such as cirrhosis,
hepatocellular carcinoma, or liver failure.
Serological markers are essential in making the diagnosis and evaluating disease activity, including
differentiating between people with acute and chronic infection and chronic asymptomatic carriers.
Goal of treatment is to improve survival and quality of life by preventing disease progression. Current
treatments do not completely eradicate the virus. The mainstay of management is antiviral therapy, although
some patients also require referral to a liver transplant centre.
Definition
The most common liver infection globally, caused by the hepatitis B virus (HBV). HBV is a DNA virus
transmitted by percutaneous and permucosal routes. HBV infection is also a sexually transmitted infection.
HBV infection may result in a self-limiting disease requiring no treatment, particularly in adult-acquired
infection, but it may also result in a chronically infected state with cirrhosis, hepatocellular carcinoma, or liver
failure, particularly if it is acquired perinatally or in early childhood.
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Hepatitis B Theory
Epidemiology
The World Health Organization estimates that globally there were 296 million people living with Hepatitis
B virus (HBV) infection (defined as being hepatitis B surface antigen-positive) in 2019.[9] Globally, there
THEORY
were 820,000 HBV-related deaths in 2019, mostly from complications such as cirrhosis and hepatocellular
carcinoma.[9] It has been estimated that HBV infection could account for 42% of the global burden of
cirrhosis.[10]
The highest burden of HBV infection is in the Western Pacific and African regions.[9] In endemic regions,
≥8% people have chronic HBV infection.[11] In areas of low endemicity (e.g., western Europe, North
America, Australia), ≤2% people have chronic HBV infection. In addition, the lifetime risk of HBV infection
varies widely around the world, from 80% in highly endemic regions to <20% in low-prevalence regions. The
prevalence of HBV in the general population is <1% in most countries.[12]
The US and UK have historically been regions of low prevalence.
• In the US it has been estimated that 13,300 new acute HBV infections occurred in 2021, with 2045
acute cases 1748 deaths (0.44 deaths per 100,000 population) actually reported. Approximately
73% of acute cases occurred among persons aged 30 to 59 years, and the rate was highest among
non-Hispanic black people. A total of 14,229 new cases of chronic infection were reported in the US
during 2021 (5.9 cases per 100,000 population). Approximately 89% of cases occurred in people aged
30 years and older, and the rate among non-Hispanic Asian/Pacific Islander people was 14 times
higher than the rate among non-Hispanic white people.[13] It has been estimated that the prevalence
of chronic HBV infection in the US may be as high as 2.4 million cases. The weighted average
prevalence of chronic HBV infection for all foreign-born people in the US was 3.07% in 2018.[14]
• In the UK, an average of 350 cases were reported annually in England between 2015 and 2021. The
number of people living with chronic infection in England has been estimated to be approximately
200,000 (0.45% prevalence).[15]
In Europe, there were an estimated 2.1 million incident cases of acute HBV infection in 2019 across all age
groups, with 8.2 million cases of HBV-related cirrhosis and approximately 25,000 deaths due to HBV-related
cirrhosis.[16]
Globally, an estimated 6.4 million children aged ≤5 years are living with chronic HBV infection.[17] There are
almost 2 million new infections in children aged <5 years globally each year, with most cases occurring as
a result of mother-to-child transmission.[18] In the US, a total of 17 cases of perinatal HBV infection were
reported during 2019.[13] In the UK, mother-to-child transmission has been eliminated in England.[19]
The prevalence of occult HBV infection (the presence of replication-competent HBV DNA in liver tissue or
blood in patients who have tested negative for HBsAg) was 0.8% in the general population, globally, with a
higher prevalence in HIV patients (16%), patients with other liver diseases (14%), and haemodialysis patients
(5%). However, the prevalence varies significantly across different populations and geographical locations,
and is much lower in Western countries.[20] The prevalence of occult HBV infection in high-risk groups is
substantial: 5.5% in low-endemicity countries; 5.2% in intermediate-endemicity countries; and 12% in high-
endemicity countries.[21]
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jan 10, 2024.
Hepatitis B Theory
Aetiology
Hepatitis B virus (HBV) is an enveloped, non-cytopathic, hepatotrophic, and highly infectious DNA virus
that belongs in the hepadnaviruses family.[22] [23] The outer envelope of the virus contains three related
THEORY
surface antigens, the most abundant of which is the S protein (hepatitis B surface antigen [HBsAg]). The
development of cellular and humoral immunity to HBsAg is protective. Inside the envelope is the viral
nucleocapsid, or core, which contains partially double-stranded circular DNA (hepatitis B core antigen
[HBcAg]). HBcAg-derived peptides induce a crucial host cellular immune response against (HBV. Hepatitis
B e antigen, a hepatitis B viral protein, serves as a marker for active replication, but its function is unknown.
The X protein may play a role in development of hepatocellular carcinoma. DNA polymerase serves a
reverse-transcriptase function for the synthesis of both negative and positive strands of HBV DNA.[22] [23]
Pathophysiology
The virus does not directly kill hepatocytes.[23] The host's immune response to viral antigens is thought to
be the cause of the liver injury in hepatitis B virus (HBV) infection.[24] The cellular immune response, rather
than the humoral immune response, seems to be primarily involved in disease pathogenesis. Induction of
antigen-specific T-lymphocyte response is thought to occur when host T lymphocytes are presented with
viral epitopes by antigen-presenting cells in lymphoid organs. These antigen-specific T cells mature and
expand and then migrate to the liver. In acute HBV infection, most HBV DNA is cleared from hepatocytes
through non-cytocidal effects of inflammatory byproducts of CD8+ T lymphocytes, stimulated by CD4+ T
lymphocytes, notably interferon-gamma and tumour necrosis factor-alfa. These cause down-regulation of
viral replication, and trigger direct lysis of infected hepatocytes by HBV-specific CD8+ cytotoxic T cells.[25]
In contrast, people with chronic HBV infection display weak, infrequent, and narrowly focused HBV-specific
T-cell responses, and the majority of mononuclear cells in livers of chronic HBV-infected people are non-
antigen-specific.[26]
5
THEORY Hepatitis B Theory
Life cycle of HBV

From Ganem D, Prince AM. Hepatitis B virus infection - natural history and clinical
consequences. N Engl J Med. 2004; 350:1118-1129; used with permission
Due to the presence of HBV in extrahepatic sites, as well as the presence of covalently closed circular DNA
(cccDNA) within hepatocytes, eradication of the virus is an unrealistic goal based on the currently available
drugs. Covalently closed circular DNA serves as a template for transcription of pregenomic messenger RNA,
a vital initial step in HBV replication.[27] [28] [29] [30] The continued presence of cccDNA within hepatocytes
is considered as a marker of viral persistence. Unfortunately, current therapies have not been effective
in eradicating cccDNA and are only able to decrease levels.[31] [32] [33] [34] [35] [36] [37] Persistence
of even low levels of cccDNA in the hepatocyte nucleus has been shown to correlate with viral rebound
after discontinuation of therapy. In addition, the integration of HBV DNA to the hepatocyte nucleus during
replication process could explain increased risk for hepatocellular carcinoma. Furthermore, co-infection with
hepatitis C virus (HCV) can synergistically increase the rate of fibrosis, cirrhosis, and hepatocellular cancer,
because both HBV and HCV can infect the same hepatocyte independently.[38] [39] [40] [41] [42]
Hepatitis B Theory
Classification
HBV genotype
THEORY
Hepatitis B virus (HBV) genotypes are based on 8% intertypic variation of complete nucleotide sequence
of the genome, and are distributed geographically.[1] Data show that HBV genotypes may play a role in
HBV-related liver disease progression and response to interferon therapy.[2] Studies have shown increased
hepatitis B e antigen (HBeAg) seroconversion with both genotype A and genotype B, although one study
demonstrated that the improvement in HBeAg seroconversion was limited to only genotype A.[3] [4] [5] [6]
[7] Given that improvements in treatment response have been observed with interferon treatment and not
nucleotide/nucleoside therapy, further research would be beneficial prior to recommending genotype testing
in clinical practice and correlating with treatment response. Genotyping is not currently recommended for
routine testing or follow-up of patients with chronic HBV infection.[2]
Worldwide distribution of genotypes varies.[8]
• Genotype A is mainly found in the US, north-western Europe, and south-eastern Africa.
• Genotype A is associated with a higher rate of HBeAg seroconversion with interferon therapy
compared with genotypes B, C, and D.
• Genotypes B and C are mainly found in Southeast Asia, China, and Japan.
• Genotype B is associated with earlier age of HBeAg seroconversion, less active hepatic
necro-inflammation, more sustained remission after HBeAg seroconversion, a slower rate of
progression to cirrhosis, and a lower rate of hepatocellular carcinoma (HCC), compared with
genotype C.
• Genotype C is the genotype most associated with cirrhosis and HCC.

• Genotype D is mainly found in the Mediterranean basin and some parts of Asia, but has been found
worldwide.
• Genotype E is mainly found in West and Central Africa.
• Genotype F is mainly found in Central and South America.
• Genotype G is mainly found in Mexico.
• Genotype H is mainly found in Mexico.
• Genotypes I and J have also been identified.
Case history
Case history #1
A 40-year-old asymptomatic man presents for a routine visit with an elevated alanine aminotransferase
level (55 IU/mL). His mother died of hepatocellular carcinoma and he has a middle-aged sister with
hepatitis B infection. He has a normal physical examination and has no stigmata of chronic liver disease.
7
Hepatitis B Theory
Other presentations
It is important to recognise that hepatitis B has different clinical presentations. Patients may be
asymptomatic or may have an enlarged liver or evidence of a liver mass, or stigmata of chronic liver
THEORY
disease. Some patients may present for the first time with symptoms of chronic hepatitis. Patients with
clinical symptoms (e.g., nausea, vomiting, abdominal pain, jaundice, myalgias) may have an acute
presentation of a chronic illness.
Hepatitis B Diagnosis
Approach
The natural history of hepatitis B virus (HBV) infection is variable, complex, and dynamic. The best method
for diagnosis is to have a clinical suspicion in at-risk individuals, and to evaluate the results of specific liver-
related and HBV serological tests. Approximately 70% of patients with acute HBV are asymptomatic, and
diagnosis is often difficult.[70] Patients with chronic HBV may also be asymptomatic, or may have signs and
symptoms of chronic liver disease, including cirrhosis and its complications, hepatocellular carcinoma (HCC),
and liver failure.
History
The main risk factors for HBV infection include perinatal exposure, sexual transmission (multiple sexual
partners, men who have sex with men), injection drug use, living in or travel to a highly endemic region,
incarceration, or a family history of HBV infection, chronic liver disease, and/or HCC.
The key symptoms associated with acute HBV infection, particularly in adults, are those of a serum
sickness-like syndrome: fever, chill, malaise, arthralgias, and a maculopapular or urticarial skin rash.
Other possible symptoms include jaundice, nausea, vomiting, and right upper quadrant pain, which occur
in approximately 30% of patients with acute HBV infection.[71]
The vast majority of patients with chronic HBV infection are asymptomatic, but can present with symptoms
if they develop HCC, cirrhosis and its complications, or liver failure.
Physical examination
The key physical findings in patients with symptomatic acute HBV infection are tender hepatomegaly and
jaundice. However, patients with chronic HBV infection without cirrhosis, liver failure, or HCC may have
a normal physical examination. Some patients with chronic HBV infection and cirrhosis may have palmar
erythema and spider angiomata, with or without signs of portal hypertension, including ascites, jaundice,
and asterixis (suggestive of hepatic encephalopathy).
Laboratory investigations
DIAGNOSIS
Baseline tests
• Order a full blood count, basic metabolic panel, coagulation profile, and hepatic panel (aspartate
aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, alkaline phosphatase, and
albumin) initially in all patients.
• Check the patient's HIV, hepatitis C, and hepatitis D status, as this affects management options.
Serological markers
• Order full HBV serological profiles in all patients to help differentiate between acute and chronic
infection.
• Serological markers include:
• Hepatitis B surface antigen (HBsAg)

• Antibody to hepatitis B surface antigen (anti-HBs)
• Antibody to hepatitis B core antigen (anti-HBc) IgM and IgG
• Hepatitis B e antigen (HBeAg)
9
• Antibody to HBeAg (anti-HBe)
• HBV DNA.
• HBsAg, anti-HBc, and anti-HBs are typically used to differentiate between acute and chronic
infection, while HBeAg and anti-HBe are used to determine the phase of chronic infection.
HBV DNA is essential for diagnosis and to determine the phase of infection, although it may be
undetectable in some patients.[38]
• A positive HBsAg result establishes the diagnosis and indicates active infection. HBsAg will be
detected an average of 4 weeks (range 1-9 weeks) after exposure to the virus. Patients who are
HBsAg-positive and IgM anti-HBc-positive in the presence of HBV DNA are diagnosed with acute
infection or reactivation. Patients who are HBsAg-positive for at least 6 months (with negative anti-
HBs and positive anti-HBc) are diagnosed with chronic infection. The phase of chronic infection is
determined by serum HBV DNA levels, HBeAg and anti-HBe status, and ALT levels (See Criteria
section).[2] [38]
• A few patients may have an acute reactivation of asymptomatic carrier state, or a flare up of chronic
HBV infection, and show IgM anti-HBc-positive status. This is particularly likely in patients with
a known history of being HBsAg-positive, and in those who are receiving chemotherapy or other
immunosuppressive agents.[72] [73] Obtaining HBsAg and total anti-HBc in this population, and
vaccinating those individuals with HBV-seronegative status prior to initiating chemotherapy or
immunosuppressive therapy is recommended. It should be noted that an increased dose may be
needed in immunosuppressed patients to achieve immunity to hepatitis B.[38]
Genotype and resistance testing
• HBV genotype may play a role in HBV-related liver disease progression and response to interferon
therapy, so determination of genotype may have prognostic value, but this needs to be further
validated by additional research. Genotyping is not necessary in the initial evaluation, and is not
currently recommended for routine testing or follow-up of patients with chronic HBV infection.
However, it may be useful for selecting patients to be treated with peginterferon.[2] [38]
• Hepatitis B antiviral drug resistance testing is not recommended in treatment-naive patients, but
can be useful in patients who are treatment experienced, those with persistent viraemia despite
DIAGNOSIS
antiviral therapy, or those who experience virological breakthrough during treatment.[2]

Rapid diagnostic tests
• HBsAg rapid diagnostic tests have excellent specificity and good sensitivity compared with
laboratory immunoassays.[74]
Testing for co-infections
• Check the patient’s HIV, hepatitis C, and hepatitis D status as this affects management options.
• Testing for tuberculosis may be recommended as co-infection can occur. Patients on anti-
tuberculosis multi-drug regimens are at increased risk of drug-induced liver injury, particularly those
with underlying liver disease.[75] [76]
Imaging
Order a baseline abdominal ultrasound in all patients to evaluate the liver for advanced fibrosis, cirrhosis,
and portal hypertension, and for HCC.[38] Triphasic contrast computed tomography or contrast magnetic
resonance imaging of the abdomen can be used to diagnose HCC where this is thought to be likely,
based on history, physical examination, and laboratory investigations that include elevated alpha-
fetoprotein (AFP).
The American Association for the Study of Liver Diseases (AASLD) guidelines recommend ultrasound of
the liver (with or without AFP) every 6 months in patients with cirrhosis, or in adults at high risk for HCC
(e.g., Asian or black men >40 years of age, Asian women >50 years of age, patients with a first-degree
family member with a history of HCC).[2]
Liver disease staging

Staging of liver disease severity using liver biopsy or non-invasive methods (e.g., transient elastography,
fibrosis biomarkers) is recommended to guide surveillance and assist with treatment decisions.[2]
Liver biopsy may be required in some patients with chronic HBV infection to grade and stage liver disease
before initiating therapy, and to rule out other causes of liver disease. Patients with chronic HBV infection
have varying degrees of fibrosis and/or inflammation. AASLD guidelines recommend biopsy in patients
with persistent borderline normal, or slightly elevated, ALT levels, particularly in patients >40 years
of age who have been infected from a young age.[2] European guidelines recommend a liver biopsy
when biochemical and HBV markers reveal inconclusive results.[38] In general, liver biopsy is indicated
if it is likely to influence subsequent treatment decisions. The size of the liver biopsy is of paramount
importance, because small-size biopsies may not be adequate to evaluate the stage of fibrosis and liver
disease. Although there are risks with a percutaneous liver biopsy, the reported risk of complications is
low, with one complication in every 4,000 to 10,000 procedures.[77]
In individuals who are reluctant to undergo the risks of an invasive procedure, non-invasive options to
evaluate liver disease severity include transient elastography and serum liver fibrosis markers (e.g.,
FIB-4®, FibroTest®).[2] [38] [78] [79] [80] [81] [82] [83] [84] [85] Elastography is preferred over liver
fibrosis markers.[2] In Europe, transient elastography is popular in identifying cirrhosis; however, its use
has been limited by false positive results secondary to marked liver inflammation and a lack of uniform
standard to calculate liver stiffness.[38] [86] [87] Magnetic resonance elastography has been shown to be
more accurate than Fibroscan® in diagnosing liver fibrosis in patients with chronic HBV infection.[88]
DIAGNOSIS
History and exam
Key diagnostic factors
presence of risk factors (common)
• Key risk factors include antenatal exposure, multiple sexual partners, men who have sex with men,
injection drug use, family history of hepatitis B virus or hepatocellular carcinoma, incarceration, living
in/travel to a highly endemic region, and household contact with an infected individual.
Other diagnostic factors

asymptomatic (common)
• Approximately 70% of patients with acute hepatitis B virus (HBV) infection are asymptomatic.[70]
The vast majority of patients with chronic HBV are asymptomatic until they develop hepatocellular
carcinoma, cirrhosis and its complications, or liver failure.
11
jaundice (uncommon)
• Present in approximately 30% of patients with acute hepatitis B virus (HBV) infection, and patients >30
years of age are more likely to be symptomatic.[71] Also present in chronic HBV infection with cirrhosis
or liver failure.
hepatomegaly (uncommon)
• More common in acute than in chronic hepatitis B virus infection.[71]
ascites (uncommon)
• More common in patients with chronic hepatitis B virus-related cirrhosis.
fever/chills (uncommon)
• Part of serum sickness-like syndrome and present in some patients with acute hepatitis B virus
infection.
malaise (uncommon)
infection.
maculopapular or urticarial rash (uncommon)

infection.
right upper quadrant pain (uncommon)

• May be present in patients with acute or chronic hepatitis B virus (HBV) infection. Present in
approximately 30% of patients with acute HBV infection.[71]
fatigue (uncommon)
• Present in patients with either acute or chronic hepatitis B virus infection including cirrhosis of liver.
DIAGNOSIS
nausea/vomiting (uncommon)
• Part of serum sickness-like syndrome and present in some patients with acute hepatitis B virus (HBV)
infection. Present in approximately 30% of patients with acute HBV infection.[71]
arthralgia/arthritis (uncommon)
infection.
palmar erythema (uncommon)

spider angiomata (uncommon)

splenomegaly (uncommon)
asterixis (uncommon)
• More common in patients with chronic hepatitis B virus-related cirrhosis including decompensated
cirrhosis.
Risk factors
Strong
perinatal exposure in an infant born to an HBV-infected mother
• Infants born to HBV-infected mothers are at risk of permucosal transmission of hepatitis B virus (HBV)
from infective blood or fluids during childbirth.[43] Transplacental transmission in utero and breast-
feeding are less likely causes of HBV transmission. The majority of infected infants develop chronic
HBV infection if they do not receive post-exposure prophylaxis.
high-risk sexual behaviours

• Sexual contact with infected partners is an important method of transmission. In one study, 27% of
patients with acute hepatitis B virus (HBV) infection had heterosexual contact with an infected partner
or multiple partners, and 13% of patients were men who have sex with men.[44] A meta-analysis found
a 2% global prevalence of HBV among female sex workers.[45] HBV is present in large quantities (10⁸
to 10¹ºcopies/mL) in the serum of infected individuals, and it can also be detected in semen, saliva,
and leukocytes.[22]
injection drug use

• Injection of drugs via shared needles can lead to percutaneous transmission of infection. Injection drug
use has been reported in 18% of patients with a documented acute HBV infection.[44] Globally, 9% of
people who inject drugs are hepatitis B surface antigen-positive.[46]
born in highly endemic region

• Individuals born in regions of high incidence and prevalence (e.g., Asia, Africa) are at increased risk of
DIAGNOSIS
infection.[48] People living in, or travelling to, highly endemic regions are also at risk.
family history of HBV, hepatocellular carcinoma, and/or chronic liver disease

• People with a family history of hepatitis B virus (HBV) infection, hepatocellular carcinoma, and/or
chronic liver disease have an increased risk of infection.
household contact with HBV infection

• In the US during the late 1990s, household contacts of an infected individual accounted for
approximately 4% of cases of acute HBV infection per year.[44] Continuous close, personal,
unapparent or unnoticed contact of infective secretions with skin lesions or mucosal surfaces is
thought to be the mode of transmission, because HBV remains viable outside the body for an indefinite
period of time.[58] Chronically infected children can inadvertently contaminate environmental surfaces
with cuts or open sores. This mode of transmission is felt to account for the majority of the horizontal
transmission of HBV in children in hyper-endemic areas.[59]
13
history of incarceration
• Patients with a history of incarceration have a higher risk for hepatitis B virus (HBV) exposure due to
associated risk factors (e.g., injection drug use, risky sexual behaviours, tattoos). In one systematic
review in Europe, the highest prevalence of hepatitis B surface antigen among three high-risk groups
(people who were incarcerated, men who have sex with men, and people who inject drugs) was found
in those who were incarcerated (0.3% to 25.2%).[60]
Weak
male sex
• Men have 1.6 times the risk of hepatitis B virus infection compared with women.[47]
infected with HIV

• Up to 10% of individuals infected with HIV are co-infected with hepatitis B virus (HBV), and 80% of HIV
patients have serological evidence of HBV exposure.[49]
infected with hepatitis C virus

• Around 10% to 15% of patients with chronic hepatitis B virus (HBV) infection are co-infected with
hepatitis C virus (HCV).[50]
• Treatment of HCV infection with direct-acting antivirals may cause reactivation of HBV in co-infected
patients.[51] [52]
blood or blood product transfusion

• In the US, the rate of transfusion-related hepatitis B virus (HBV) infection is approximately 0.002% per
transfusion recipient.[53] Mandatory screening of blood products began in the US and the UK in the
early 1970s.
healthcare workers
• Historically, healthcare workers and public servants exposed to blood and bodily fluids have had
DIAGNOSIS
higher rates of HBV infection compared with the general public, from percutaneous or permucosal
transmission of hepatitis B virus (HBV). However, the incidence of HBV infection among immunised
healthcare workers is now lower than in the general population.[54] Transmission of HBV to patients
from infected healthcare workers, including large outbreaks, has been reported.[55] [56] Approximately
30% of outbreaks were in situations where infection control policy was not followed. However, this was
based on self-reporting and the true incidence is likely to be higher.[57]
haemodialysis
• Hepatitis B virus (HBV) has been detected on environmental surfaces and in blood leaks during
dialysis sessions.[61] However, few cases of acute HBV infection have been reported in patients
undergoing chronic haemodialysis.[47] The pooled prevalence of HBV infection among haemodialysis
patients was 7.32% globally. However, this varies based on geographical location, ranging from 4.32%
in the US, to 5.52% in Europe, and 9.73% in South America.[62]
solid organ transplantation

• HBV infection in solid organ transplant recipients is due to reactivation of previous HBV infection
or donor-derived transmission. Donors should be screened using HBsAg, HBcAb, and HBV
DNA.[63] Rare cases of unexpected HBV transmission have been reported from donors who are HBV
screen negative. The majority are associated with recent donor intravenous drug use and hepatitis
C infection, and may be due to HBV infection shortly before donor death (eclipse period infection),
or HCV co-infection suppressing HBV replication (occult HBV infection).[64] To expand the donor
pool, organs from HBcAb-positive donors are increasingly transplanted after a detailed risk-benefit
discussion with patients. Transmision is uncommon with the use of intensive antiviral prophylaxis ±
hepatitis B immunoglobulin.[63] All transplant recipients should be tested for HBV at 4-6 weeks post
transplant, with additional testing considered at 1 year or if signs and symptoms of liver injury develop.
All transplant candidates should receive HBV vaccination.[64]
DIAGNOSIS
15
Investigations
1st test to order
Test Result
liver function tests elevated
aminotransferases
• Order in all patients as part of the initial evaluation.
(ALT/AST), alkaline
• Aminotransferases (alanine aminotransferase [ALT]/aspartate
phosphatase, and
aminotransferase [AST]), alkaline phosphatase, or bilirubin levels
may be elevated due to chronic hepatitis B virus (HBV) infection and/ bilirubin; low albumin
or cirrhosis, including decompensated HBV-related cirrhosis. Albumin
level may be low.
• Biochemical response to treatment has been defined as
normalisation of ALT based on usual values. However, the upper
limits of normal for ALT for healthy people are lower than levels based
on the general population, including for people with subclinical liver
disease, and ALT may also fluctuate over time. At least 1 year of
follow-up with levels at 3-month intervals is needed to determine
biochemical responses following therapy.[38]
FBC microcytic anaemia and/
or thrombocytopenia
• Patients with low mean corpuscular volume and low haemoglobin
may have possible gastrointestinal bleeding from portal hypertension
associated with HBV-related cirrhosis. Low platelet count is indicative
of portal hypertension resulting from hepatitis B virus-related
cirrhosis.
urea and electrolytes hyponatraemia; high urea
• Patients may have hyponatraemia due to volume overload or use
of diuretics in patients with hepatitis B virus-related cirrhosis with
ascites. Urea can be elevated secondary to pre-renal azotaemia,
acute renal insufficiency, chronic renal insufficiency, or hepatorenal
DIAGNOSIS
syndrome in cirrhosis of the liver.

coagulation profile normal or elevated
• Helpful in determining the synthetic functional capacity of the liver.
An elevated prothrombin time (PT) and INR indicates that the patient
might have synthetic dysfunction due to cirrhosis of the liver, or liver
failure related to hepatitis B virus infection.
serum hepatitis B surface antigen positive
• A positive hepatitis B surface antigen (HBsAg) result establishes the
diagnosis and indicates active infection. HBsAg will be detected an
average of 4 weeks (range 1-9 weeks) after exposure to the virus. In
self-limiting acute hepatitis B virus (HBV) infection, HBsAg usually
becomes undetectable after 4-6 months of infection. Persistence of
HBsAg for >6 months implies chronic HBV infection.[71]
serum antibody to hepatitis B surface antigen positive
• Appears several weeks after hepatitis B surface antigen has
disappeared, and in most patients provides life-long immunity,
Test Result
suggestive of resolved infection. It is also detectable in those
immunised with hepatitis B vaccine.
serum antibody to hepatitis B core antigen positive
• Order both IgM and IgG antibody to hepatitis B core antigen (anti-
HBc) in all patients as part of the initial evaluation.
• IgM anti-HBc appears within weeks of acute infection and remains
detectable for 4-8 months. During the window period (several weeks
to months) after the disappearance of hepatitis B surface antigen
(HBsAg) and before appearance of antibody to hepatitis B surface
antigen, detection of IgM anti-HBc may be the only way to make the
diagnosis of acute hepatitis B virus (HBV) infection. Some patients
with chronic HBV infection or some inactive HBV carriers become
positive for IgM antibody during acute flares or acute reactivation,
making positive IgM anti-HBc not an absolutely reliable marker for
acute infection.[47]
• IgM and IgG anti-HBc antibodies are detectable in virtually all
patients who have been exposed to HBV (acute or chronic HBV
infection). It does not provide protective immunity. It may be positive
in the following settings: 1) acute infection: during the window period
(mostly IgM anti-HBc); and 2) chronic infection (IgG anti-HBc), when
HBsAg has decreased to undetectable levels. It is common in areas
with high prevalence of HBV infection and in those patients who
are co-infected with HIV or hepatitis C. This is the best single test
for screening household contacts of HBV-infected individuals to
determine need for vaccination.[89]
serum hepatitis B e antigen positive
• This is a soluble viral protein found in serum in the early part of acute
hepatitis B virus (HBV) infection, and it usually disappears at or soon
after the peak in serum alanine aminotransferase (ALT) levels. Its
presence ≥3 months after onset of illness indicates a high likelihood
of development of chronic HBV infection.
• Hepatitis B e antigen (HBeAg) found in the serum of hepatitis B
DIAGNOSIS
surface antigen carriers indicates greater infectivity, with a high level
of viral replication. The vast majority of patients with HBeAg-positive
chronic HBV infection have active liver disease; exceptions include
children and young adults with perinatally acquired infection, with
normal ALT. The spontaneous seroconversion from HBeAg-positive to
HBeAg-negative with positive antibody to hepatitis B surface antigen
is usually associated with reduction in HBV DNA (≥3 log). Some
patients (mostly older individuals) may have active liver disease
with high or detectable HBV DNA without the presence of HBeAg in
serum, resulting in HBeAg-negative chronic HBV infection.
• HBeAg status should be periodically checked in HBeAg-positive
patients during therapy for chronic HBV infection, particularly
if levels of HBV DNA are undetectable in the serum, to monitor
seroconversion.[2]
serum antibody to hepatitis B e antigen positive
• Seroconversion from hepatitis B e antigen (HBeAg)-positive to
antibody to hepatitis B e antigen (anti-HBe)-positive is a useful
indicator of clearance of virus, suggestive of treatment-related
clearance of HBV. Patients with sustained seroconversion typically
have improvement of liver histology. However, some patients will
17
Test Result
become anti-HBe-positive spontaneously without complete clearance
of virus, due to pre-core or core-promoter mutations (HBeAg-negative
chronic HBV) or development of an asymptomatic chronic carrier
state.
• Seroconversion can be a temporary phenomenon and should be
analysed in association with the serum hepatitis B virus DNA level.
serum HBV DNA undetectable or elevated
• Hepatitis B virus (HBV) DNA levels are generally measured by
polymerase chain reaction (PCR) amplification assay. Newer PCR
technology has allowed for improved sensitivity.
• HBV DNA level is commonly used to assess candidacy for antiviral
therapy and to monitor response to therapy.[38] [90]
DIAGNOSIS
Other tests to consider
Test Result
abdominal ultrasound poorly defined margins
and coarse, irregular
• Order in all patients to evaluate the liver for fibrosis, cirrhosis and
internal echoes
portal hypertension, and hepatocellular carcinoma (HCC).
• The sensitivity of ultrasound for HCC detection is 60% and specificity
is 97%.[91]
liver biopsy normal without necro-
inflammation and/or
• May be required in some patients with chronic infection to grade
fibrosis; mild-to-moderate
and stage liver disease before initiating therapy, and to rule out
necro-inflammation
other causes of liver disease. It is also useful for guiding ongoing
with/without fibrosis;
surveillance and assisting with management decisions.
moderate-to-severe
• US guidelines recommend biopsy in patients with persistent
necro-inflammation with
borderline normal or slightly elevated alanine transaminase levels,
particularly in patients aged >40 years who have been infected from advanced fibrosis or
a young age.[2] European guidelines recommend a liver biopsy when cirrhosis
biochemical and HBV markers reveal inconclusive results.[38] In
general, liver biopsy is indicated if it is likely to influence subsequent
treatment decisions.
• Although there are risks with a percutaneous liver biopsy, the
reported risk of complications is low, with one complication in every
4000-10,000 procedures.[77]
transient elastography increased liver stiffness
• Non-invasive alternative to evaluate liver biopsy. Evaluates liver injury
by measuring liver stiffness on ultrasound.[2] [38]
• In Europe, transient elastography is popular in identifying cirrhosis.
However, its use has been limited by false positive results secondary
to marked liver inflammation, as well as the lack of uniform standard
to calculate liver stiffness.[38] [84] [86] [87]
• Magnetic resonance elastography has been shown to be more
accurate than Fibroscan® in diagnosing liver fibrosis in patients with
chronic hepatitis B virus infection.[88]
DIAGNOSIS
serum liver fibrosis biomarkers positive
• Non-invasive alternative to liver biopsy or transient elastography to
assess fibrosis severity.[2] [38]
alpha-fetoprotein normal or elevated
• Used for screening of hepatocellular carcinoma (HCC) in conjunction
with ultrasound every 6 months in patients with cirrhosis, or in adults
at high risk for HCC (e.g., Asian or black men >40 years of age,
Asian women aged >50 years, patients with a first-degree family
member with a history of HCC).[2]
• Alpha-fetoprotein (AFP) level is elevated in 75% of patients with HCC,
but can also be normal. The sensitivity ranges from 41% to 65% and
specificity ranges from 80% to 94%.[92] AFP level >400 nanograms/
mL has a 95% specificity for HCC.[93]
CT/MRI abdomen typical hypervascular
pat tern (CT); high-
• Either a triphasic contrast CT scan or contrast MRI of the abdomen
intensity pat tern on T2-
can be used to diagnose hepatocellular carcinoma where this is
weighted images, and a
thought to be likely, based on history, physical examination, and
low-intensity pat tern on
laboratory investigations, including elevated alpha-fetoprotein.
T1-weighted images (MRI)
19
Test Result
testing for co-infections variable
• Check the patient’s HIV, hepatitis C, and hepatitis D status as this
affects management options.
• Testing for tuberculosis may be recommended as co-infection can
occur. Patients on anti-tuberculosis multi-drug regimens are at
increased risk of drug-induced liver injury, particularly those with
underlying liver disease.[75] [76]
drug resistance testing variable
• Hepatitis B antiviral drug resistance testing is not recommended
in treatment-naive patients, but can be useful in patients who are
treatment experienced, those with persistent viraemia despite
antiviral therapy, or those who experience virological breakthrough
during treatment.[2]
HBV genotype positive for specific
genotype (A to J)
• Genotyping is not necessary in the initial evaluation, and it is not
currently recommended for routine testing, or for follow-up of patients
with chronic HBV infection. However, it may be useful for selecting
patients to be treated with peginterferon alfa.[2] [38]
DIAGNOSIS
Differentials
Condition Differentiating signs / Differentiating tests

symptoms
Acute hepatitis A virus • There may be no differences • Serum laboratory test will be
infection in signs and symptoms. positive for hepatitis A virus-
IgM antibody.
Acute hepatitis C virus • There may be no differences • Serum hepatitis C virus

infection in signs and symptoms. (HCV) antibody and
HCV RNA detected by
polymerase chain reaction
may be positive for hepatitis
C. Typically, symptomatic
acute HCV patients will
show very high alanine
aminotransferase, aspartate
aminotransferase, and
bilirubin.
Chronic hepatitis C virus • There may be no differences • Patients may have normal or
infection in signs and symptoms. elevated liver function tests
with positive serum hepatitis
C virus (HCV) antibody and
HCV RNA polymerase chain
reaction.
Hepatitis D virus co- • There may be no differences • Serum hepatitis D RNA and
infection with HBV in signs and symptoms. hepatitis D IgM antibody
may be positive. Patient may
have sudden rise in hepatic
panel.
Acute hepatitis E virus • Symptoms and signs can • Serum hepatitis E virus
DIAGNOSIS
infection be identical to those of other (HEV) antibody (IgM) and
acute viral hepatitis. It is serum HEV RNA polymerase
most common in pregnant chain reaction may be
women in developing positive.
countries with a hot climate.
Cytomegalovirus • May have history of • Serum cytomegalovirus

hepatitis immunocompromise (CMV)-IgM antibody and
including organ transplant. CMV DNA polymerase chain
reaction may be positive.
Epstein Barr virus • Patients typically can • Positive Monospot test and
hepatitis experience fever, serum heterophile antibody.
fatigue, pharyngitis, Serum Epstein Barr virus
malaise, myalgia, and (EBV)-IgM antibody and
lymphadenopathy EBV DNA polymerase chain
(particularly posterior reaction may be positive.
cervical chain).
Herpes simplex virus • Patient may be • Serum herpes simplex virus

hepatitis immunosuppressed or (HSV) IgM antibody and
pregnant, but can also be
immunocompetent. Patients
21

symptoms
may present as acute viral HSV DNA polymerase chain
hepatitis with or without liver reaction may be positive.
failure.
Acute alcoholic hepatitis • There may be no differences • Negative serological tests

in signs and symptoms. for viral hepatitis. Aspartate
History of moderate or heavy aminotransferase level
alcohol use. is higher than alanine
aminotransferase level,
with elevated gamma
glutamyl transferase. Liver
biopsy may show steatosis,
ballooning hepatocytes,
Mallory hyaline, lobular
neutrophilic infiltration,
with or without pericellular
fibrosis.
Drug- or toxin-induced • There may be no differences • Liver biopsy may show the
hepatitis in signs and symptoms. features of hepatocellular,
There may be a history of cholestatic, or mixed
exposure to hepatotoxic pattern of injury, including
drugs or toxins. cholestasis.
Autoimmune hepatitis • There may be no differences • There may be increased

in signs and symptoms. levels of serum globulin,
antinuclear antibody,
antismooth muscle antibody,
liver/kidney microsomal
antibodies, and/or antibodies
against soluble liver antigen/
liver pancreas antigen. Liver
histology may show interface
hepatitis with plasma cell
DIAGNOSIS
infiltrates.
Biliary obstruction • Symptoms associated • Ultrasound, CT scan, or

with biliary obstruction MRI cholangiography may
may include right upper show dilation of biliary
quadrant pain, fever/chills, tract. In case of malignant
jaundice, pruritus, nausea, obstruction, a mass may be
and vomiting. seen in the liver.
Metastatic liver diseases • Patients may be • CT scan or MRI of abdomen

asymptomatic or have may show one or more
symptoms and signs of metastatic masses in the
malignancy of other primary liver.
sites, including biliary
obstructive features.
Acute ischaemic hepatitis • Typically occurs in patients • ECG may show features
at risk for hypotension or of myocardial ischaemia or
ischaemia, including shock, infarction. Chest x-ray and
heart failure, or vascular echocardiogram may show
insufficiency. Patients may features of congestive heart
have symptoms of ischaemia failure. Doppler ultrasound

symptoms
such as acute heart failure, of liver may show portal
shock, or sepsis. vein thrombosis or acute
occlusion of hepatic artery.
Budd-Chiari syndrome • There may be no differences • Doppler ultrasound

in signs and symptoms. may show hepatic vein
thrombosis or inferior vena
caval thrombosis.
Acute fat ty liver of • Pregnant patient may • Diagnosis of exclusion

pregnancy present with jaundice. of other diseases with
characteristic symptoms and
signs in pregnant patients.
Wilson's disease • There may be no differences • Increased urinary

in signs and symptoms. copper, decreased serum
ceruloplasmin, and Kayser-
Fleischer rings on slit lamp
eye examination.
Haemochromatosis • There may be no differences • High iron saturation (>45%

in signs and symptoms. transferrin saturation) and
haemochromatosis gene
mutations. Liver biopsy
shows iron deposition in
hepatocytes.
Criteria
American Association for the Study of Liver Diseases (AASLD)
phases of chronic HBV infection[2]
DIAGNOSIS
The AASLD classifies chronic hepatitis B virus (HBV) infection into phases, reflecting the relationship
between viral replication and evolution and host immune response. Phases are not always distinct and
patients can move from one phase to another and back again without any clinical change.
• Chronic hepatitis B (CHB):
• Hepatitis B surface antigen (HBsAg): present for ≥6 months

• Serum HBV DNA: varies from undetectable to several billion IU/mL
• Hepatitis B e antigen (HBeAg): positive (HBV DNA levels are typically >20,000 IU/mL) or
negative (HBV DNA levels are typically lower in the range 2000-20,000 IU/mL)
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels: normal or
elevated
• Liver biopsy: chronic hepatitis with variable necro-inflammation and/or fibrosis
• Immune-tolerant CHB:
• HBsAg: present for ≥6 months

• Serum HBV DNA: typically very high (>1 million IU/mL)
23
• HBeAg: positive
• ALT and/or AST levels: normal or minimally elevated
• Liver biopsy or non-invasive tests: no fibrosis and minimal inflammation
• Immune-active CHB:

• Serum HBV DNA: >20,000 IU/mL (HBeAg positive) and >2000 IU/mL (HBeAg negative)
• ALT and/or AST levels: intermittently or persistently elevated
• Liver biopsy or non-invasive tests: chronic hepatitis with moderate or severe necro-inflammation
with or without fibrosis
• Immune-inactive CHB:

• Serum HBV DNA: <2000 IU/mL
• HBeAg: negative (antibody to HBeAg [anti-HBe]-positive)
• ALT and/or AST levels: persistently normal
• Liver biopsy or non-invasive tests: confirms absence of significant necro-inflammation and
shows variable levels of fibrosis
• HBV reactivation is defined as:
• Loss of HBV immune control in HBsAg‐positive/antibody to hepatitis B core antigen (anti‐HBc)-

positive, or HBsAg‐negative/anti‐HBc-positive patients receiving immunosuppressive therapy for
a concomitant medical condition
• A rise in HBV DNA compared to baseline (or an absolute level of HBV DNA when a baseline is
unavailable); and
• Reverse seroconversion (seroreversion) from HBsAg-negative to HBsAg-positive for HBsAg‐
negative/anti‐HBc-positive patients.
European Association for the Study of the Liver (EASL) phases of

DIAGNOSIS
chronic HBV infection[38]

The EASL guidelines classify chronic HBV into five phases, according to serological markers and liver
disease. Phases are not always distinct and patients can move from one phase to another and back again
without any clinical change.
• HBeAg-positive chronic HBV infection: normal ALT levels; elevated HBV DNA; liver biopsy shows
minimal inflammation and fibrosis; previously known as ‘immune tolerant’ phase.
• HBeAg-positive chronic hepatitis B: elevated ALT levels, elevated HBV DNA; moderate-to-severe liver
necro-inflammation and accelerated progression of fibrosis; in most patients, HBeAg seroconversion
and HBV DNA suppression occurs and they enter the HBeAg-negative infection phase, while in other
patients, HBV control does not occur and they progress to the HBeAg-negative chronic hepatitis B
phase, which may remain for many years; previously known as ‘immune-reactive HBeAg-positive’
phase.
• HBeAg-negative chronic HBV infection: anti-HBe-positive; normal ALT levels; low or undetectable HBV
DNA; liver biopsy shows minimal necro-inflammation and low fibrosis; previously known as ‘inactive
carrier’ phase.
• HBeAg-negative chronic hepatitis B: detectable anti-HBe; moderate-to-high HBV DNA; elevated ALT
(persistent or intermittent); moderate-to-severe necro-inflammation and fibrosis.
• HBsAg-negative: patient is HBsAg-negative, anti-HBc-positive, and may have detectable anti-HBe;
normal ALT levels; usually undetectable HBV DNA; immunosuppression in these patients may lead to
reactivation; phase also known as occult HBV infection.
Screening
Screening of high-risk people may reduce incidence and prevalence, and early diagnosis and treatment may
prevent progression to cirrhosis and hepatocellular carcinoma. Universal screening of adults is cost-effective
compared with risk-based screening and reduces the risk of liver disease and death.[94]
Hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs) are recommended for screening.
Antibody to hepatitis B core antigen (anti-HBc) may also be recommended by some organisations.
Recommendations and guidance from different organisations may vary. Consult your local guidelines for
more information.
Centers for Disease Control and Prevention (CDC)

The CDC recommends screening (using a triple panel of HBsAg, anti-HBs, and total anti-HBc) in the
following people:[94]
• All adults ≥18 years of age at least once during their lifetime (universal screening)
• All pregnant women during each pregnancy (preferably in the first trimester), regardless of vaccination
status or history of testing (pregnant women with a history of appropriately timed triple panel screening
and without subsequent risk for exposure only need HBsAg screening).
Risk-based testing is recommend in:[94]
• People with a history of risk for hepatitis B infection if they might have been susceptible during the
period of risk, and susceptible people with ongoing risk while the risk persists (periodic testing),
DIAGNOSIS
regardless of age
• People who have an increased risk of acquiring hepatitis B virus infection:
• Infants born to a HBsAg-positive mother

• People born in regions with a hepatitis B virus infection prevalence of ≥2%
• US-born people not vaccinated as infants whose parents were born in regions with a hepatitis B
virus infection prevalence of ≥8%
• Injecting drug users or people who have a history of injection drug use
• Incarcerated people or people formerly incarcerated in a jail, prison, or other detention setting
• People with HIV infection
• People with a current or past hepatitis C virus infection
• People with a current or past sexually-transmitted infection or multiple sex partners
• Men who have sex with men
• Current or former household contacts of people with known hepatitis B virus infection
• Needle-sharing or sexual contacts of people with known hepatitis B virus infection
• People on maintenance dialysis (including in-center or at-home haemodialysis and peritoneal
dialysis)
25
• People with elevated alanine aminotransferase or aspartate aminotransferase levels of unknown
origin.
• Anyone who requests testing, regardless of disclosure risk.
People who have not completed a hepatitis B vaccine series should be offered vaccination as per current
recommendations, after the collection of blood for serologic testing.
American Association for the Study of Liver Diseases (AASLD)

The AASLD recommend the following people be screened:[2]
• People born in regions of intermediate or high hepatitis B virus infection endemicity (i.e., prevalence of
HBsAg ≥2%)
• US-born people not vaccinated as an infant, and whose parents were born in regions with high
hepatitis B virus infection endemicity (i.e., ≥8%)
• People who have ever injected drugs
• Men who have sex with men
• People with multiple sexual partners
• People on immunosuppressive therapy
• People with elevated liver function tests of unknown etiology
• Blood, plasma, organ, tissue, or semen donors
• People with end-stage renal disease who require dialysis
• Pregnant women
• Infants born to HBsAg-positive mothers
• People with chronic liver disease
• People with HIV infection
• Contacts (e.g., household, sexual, needle-sharing) of HBsAg-positive people
• People seeking treatment for a sexually-transmitted infection
• Healthcare workers or public safety workers at risk for occupational exposure
• Residents and staff of facilities for developmentally disabled persons
• Travellers to countries with an intermediate or high prevalence of hepatitis B virus infection
DIAGNOSIS
• Inmates of correctional facilities

• Unvaccinated people with diabetes aged 19 to 59 years
• People who are the source of blood or body fluid exposures that may require post-exposure
prophylaxis.
Anti-HBs-negative people should be vaccinated.
The AASLD guidance is primarily based on previous recommendations from the CDC that have since been
updated in 2023 (see section above). Current AASLD guidance differs from the new CDC guidance by
recommending screening of: unvaccinated people with diabetes aged 19 to 59 years; travellers to countries
with an intermediate or high prevalence of hepatitis B virus infection; and residents and staff of facilities for
developmentally disabled persons. AASLD only recommends anti-HBc testing for certain groups (i.e., as long
as those who test positive are tested further for HBsAg and anti-HBs to differentiate current infection from
previous hepatitis B virus exposure).
US Preventive Services Task Force (USPSTF)

The USPSTF recommends screening adolescents and adults at increased risk of infection with HBsAg
tests.[95] They also recommend that all pregnant women be screened for hepatitis B virus infection.[95]
American Society of Clinical Oncology (ASCO)

ASCO recommends that all patients receiving systemic anti-cancer therapy should be screened due to the
risk of hepatitis B reactivation. Testing should not delay anti-cancer therapy.[96]
The American College of Obstetricians and Gynecologists

(ACOG)
ACOG recommends early universal antenatal screening for HBsAg in all pregnant women in each pregnancy,
regardless of testing history or vaccination status. ACOG recommends triple panel screening (i.e., HBsAg,
anti-HBs, and total anti-HBc) for all pregnant women who do not have a documented negative triple screen
result after aged 18 years, or who have not completed a hepatitis B vaccine series, or in patients with
ongoing risk factors for HBV infection, regardless of testing history or vaccination status.[67]
DIAGNOSIS
27
Hepatitis B Management
Approach
The main goal of treatment is to improve survival and quality of life by preventing disease progression and
the development of complications. Specific management depends on whether the infection is acute or
chronic. Acute infection is almost always treated with supportive care alone, although antiviral therapy may
be required in select patients. Chronic infection is treated with long-term antiviral therapy. Some patients may
require liver transplantation.
Treatment of acute infection

More than 95% of immunocompetent adults with acute infection will achieve seroconversion with the
appearance of antibodies to hepatitis B surface antigen (anti-HBs) in the absence of treatment. Therefore,
supportive care is usually all that is needed in most patients.[2] [38]
Some patients may require antiviral therapy. Initiate treatment in patients with acute liver failure
or in those who have a severe, protracted course (i.e., total bilirubin level >51.3 micromoles/L (>3
mg/dL), international normalised ratio (INR) >1.5, encephalopathy, or ascites). Entecavir, tenofovir
alafenamide, and tenofovir disoproxil are the drugs of choice in patients with acute infection; peginterferon
is contraindicated. Continue treatment until hepatitis B surface antigen (HBsAg) clearance is confirmed, or
indefinitely in patients who undergo liver transplantation. Simultaneously, assess the patient for the need
for liver transplantation as there is a high risk of mortality in patients with liver failure who do not undergo
a transplant.[2] [38]
There is currently no evidence of benefit of any pharmacological treatment in acute hepatitis B virus
(HBV) infection.[97]
Treatment of chronic infection: general principles

The need for antiviral therapy in patients with chronic HBV infection is based on alanine aminotransferase
(ALT) levels, serum HBV DNA levels, and severity of liver disease, and regular monitoring is important to
determine the phase of infection. Additional factors that should be considered before starting treatment
include the patient’s age, likelihood of response, potential adverse events, family history of hepatocellular
carcinoma (HCC), and extrahepatic manifestations.[2] [38]
The ultimate goal of treatment is amelioration of hepatic dysfunction and the development of a disease-
free state, marked by seroconversion of HBsAg-positive to HBsAg-negative and production of anti-HBs.
Treatment can sometimes lead to hepatitis B e antigen (HBeAg) loss and HBeAg seroconversion to
antibody to HBeAg (anti-HBe) in HBeAg-positive chronic HBV patients. However, overall eradication
of HBV is rare with currently available treatments, so the primary goal of therapy in most patients with
chronic HBV infection is sustained and durable suppression of serum HBV DNA to undetectable levels.
The degree of HBV DNA suppression is inversely related to the emergence of drug-related resistance.
Therefore, greater suppression of serum HBV DNA is better for the long-term outcomes without producing
resistance to the virus. Prolonged suppression may reduce the rate of cirrhosis, hepatic failure, and HCC
in patients with chronic HBV, but does not completely eliminate the risk.[98] [99] [100] [101] However,
there are no randomised controlled trials to support this as such trials would be prohibitively expensive
MANAGEMENT
and take 20 to 30 years.
There are several agents used for the treatment of chronic HBV, including interferon alfa 2b, peginterferon
alfa 2a, nucleoside analogues (e.g., entecavir, lamivudine), and nucleotide analogues (e.g., tenofovir
disoproxil or tenofovir alafenamide, adefovir). Telbivudine may be available in some countries.[102]
Tenofovir alafenamide is more stable in plasma compared to tenofovir disoproxil and therefore delivers
the active metabolite to hepatocytes more efficiently. This allows a lower dose to be used resulting in
less systemic exposure and a decreased risk of renal and bone toxicity. There is some data to suggest
that switching tenofovir disoproxil to tenofovir alafenamide can be done without a loss of efficacy in
patients who are virally suppressed.[103] [104] Five-year data from two randomised controlled trials
found comparable efficacy between tenofovir alafenamide and tenofovir disoproxil (switching to tenofovir
alafenamide after 2 or 3 years), with high rates of viral suppression and no resistance documented.
Improved bone and renal safety with tenofovir alafenamide was maintained over the five years, and
improvements were seen in the comparison group after switching.[105] While interferons are typically
administered for a pre-set duration, the nucleoside/nucleotide analogues are given until specific end
points are achieved, which may mean long-term therapy. For HBeAg-positive patients, viral suppression
can be sustained with currently approved treatments in 50% to 90% of patients if treatment is stopped
after HBeAg seroconversion.[106] However, in HBeAg-negative patients, relapse occurs frequently,
even when HBV DNA is suppressed to undetectable levels for more than 1 year, making end points for
treatment unclear, and lifelong therapy may be required. Dose of nucleoside/nucleotide analogues should
be adjusted based on renal function, and renal function should be monitored during treatment.[2]
Guidelines for the treatment of chronic HBV constantly evolve, particularly with the advent of new
and highly potent antiviral drugs that have a lower risk of resistance. Guidelines may differ in different
countries, and local guidelines should be consulted.[107]
Treatment of chronic infection: without cirrhosis

The need to start treatment depends on the phase of infection.
Immune-active chronic HBV infection
• Initiate antiviral therapy in patients with elevated ALT levels ≥2 the upper limit of normal (ULN) or
evidence of histological disease with elevated HBV DNA levels >2000 IU/mL (if HBeAg negative)
or >20,000 IU/mL (if HBeAg positive). Consider antiviral therapy in patients >30 to 40 years of age
(age cut-off depends on guideline) or with a family history of HCC if ALT levels are <2 ULN and
below the HBV DNA thresholds.[2] [38]
• Entecavir, tenofovir disoproxil or tenofovir alafenamide, or peginterferon alfa 2a are the
recommended first-line drugs. Tenofovir alafenamide or entecavir are preferred in patients who are
at risk of renal dysfunction or bone disease. Combination therapy with peginterferon alfa 2a and a
nucleoside/nucleotide analogue is not recommended due to the lack of safety and efficacy data.[2]
[38]
• No treatment shows superiority over another in terms of risk reduction of hepatic
decompensation.[2] [38] Meta-analyses give conflicting results on risk of HCC due to the patient
populations included and differences in study inclusion criteria. Some have found that tenofovir
disoproxil was associated with a significantly lower risk of HCC compared with entecavir,
particularly in patients who were HBeAg-positive.[108] [109] However, a meta-analysis found no
significant difference between tenofovir disoproxil and entecavir in their association with incident
HCC.[110] [111] [112] Tenofovir disoproxil was associated with a lower risk of recurrence and
MANAGEMENT
mortality after resection or ablation of HCC compared with entecavir.[113] [114]

• Choice of treatment also depends on patient-specific factors including: desire for finite therapy;
anticipated tolerability of potential adverse effects; presence of comorbidities (e.g., peginterferon
is contraindicated in autoimmune disease, severe cardiac disease, uncontrolled seizures,
uncontrolled psychiatric disease, cytopenia); previous history of lamivudine resistance (e.g.,
29
entecavir is not recommended in these patients); HBV genotype; costs; and family planning
factors.[2] [38] Factors that predict a response to interferon include baseline ALT >5 times ULN,
baseline HBV DNA <20,000,000 IU/mL, and HBV genotype A or B.[115]
• Treatment course is variable. Peginterferon alfa 2a has a finite treatment course of 48 weeks. The
duration of nucleotide/nucleoside analogue therapy is variable, and depends on HBeAg status and
HBV DNA suppression. Consider stopping treatment in HBeAg-positive patients who seroconvert
to anti-HBe during therapy after a consolidation period (i.e., 12 months of persistently normal ALT
levels and undetectable serum HBV DNA). Some experts treat until HBsAg loss occurs. Continue
treatment indefinitely in HBeAg-negative patients, unless there is a compelling reason to stop
treatment after carefully weighing the risks and benefits.[2] [38]
• In patients with confirmed viral breakthrough, consider either switching to another antiviral drug with
a high barrier to resistance, or adding a second antiviral with a complementary resistance profile.
There is currently insufficient evidence to recommend one approach over the other.[2]
• Monitor patients who stop treatment every 3 months for at least 1 year for viraemia, ALT flares,
seroconversion, and clinical decompensation.[2]
Immune-tolerant chronic HBV infection
• Antiviral therapy is not recommended in patients with immune-tolerant chronic HBV infection (i.e.,
HBeAg positive, serum HBV DNA >1 million IU/mL, normal or persistently elevated ALT and/or
aspartate aminotransferase levels), except in people >40 years of age with normal ALT levels,
elevated HNV DNA, and a liver biopsy showing significant necro-inflammation or fibrosis. Assess
ALT levels at least every 6 months to monitor for potential transition to immune-active or immune-
inactive chronic HBV infection.[2]
Immune-inactive chronic HBV infection
• Antiviral therapy is not recommended in patients who are HBeAg negative with normal ALT levels
and low-level viraemia (i.e., HBV DNA level <2000 IU/mL).[2]
Treatment of chronic infection: with cirrhosis

All patients with compensated or decompensated cirrhosis require treatment, regardless of ALT levels.
Treatment improves survival and reduces liver-related morbidity and mortality by preventing liver failure or
requirement for liver transplantation.
Compensated cirrhosis
• Initiate antiviral therapy in patients with low-level viraemia (i.e., HBV DNA levels <2000 IU/mL),
regardless of ALT levels, to reduce the risk of decompensation. Treat patients with high-level
viraemia as you would for patients with immune-active chronic HBV infection.[2] [38] Studies have
shown that suppression of HBV DNA levels can halt the natural progression of liver disease to
decompensated cirrhosis, and in some circumstances, show improvements in liver histology.[116]
[117] [118]
• Entecavir, tenofovir disoproxil, and tenofovir alafenamide are the recommended first-line drugs
MANAGEMENT
due to their potency and minimal risk of adverse effects, decompensation, and resistance. While
peginterferon alfa 2a is not contraindicated in these patients, nucleoside/nucleotide analogues are
considered safer. Peginterferon alfa 2a may only be considered in patients who do not have portal
hypertension.[2] [38] [119]
• There is no optimal length of treatment. Monitor patients (at least every 3 months for 1 year)
after stopping therapy to check for viral rebound that could lead to decompensation.[2]
[38]Discontinuation of antiviral therapy in these patients was associated with a high-risk of relapse
(virological relapse 55%, clinical relapse 44%), but the incidence of adverse events was generally
low and controlled. The rate of HCC after discontinuation of antiviral therapy was 9%.[120]
Decompensated cirrhosis
• Initiate antiviral therapy as soon as possible and assess the patient for liver transplantation.
Antiviral therapy has been shown to improve outcomes (e.g., improved liver function, increased
survival, and increased transplant-free survival) in patients with decompensated cirrhosis,
especially with early treatment.[2] [38]
• Entecavir (administered at a higher dose than the dose used for other patients) and tenofovir
disoproxil are the recommended first-line drugs. Tenofovir alafenamide has not been studied in
these patients, but can be considered in patients in whom tenofovir disoproxil or entecavir are not
an option (e.g., patients with renal dysfunction or bone disease).[2] [38]
• Peginterferon alfa 2a is contraindicated in these patients due to safety concerns. High rates of
serious adverse events, including sepsis and the risk of hepatic decompensation, have been
reported.[121]
• Lifelong treatment is recommended, regardless of ALT or HBV DNA levels, or HBeAg status.[2] [38]
• Monitor patients closely for the development of lactic acidosis and renal dysfunction.[2] [38] Lactic
acidosis has been associated with use of entecavir and tenofovir, and the risk is increased in
patients with decompensated cirrhosis.[122]
Treatment of chronic infection: with co-infections

HIV infection
• HBV has no significant effect on the natural history of HIV infection, but HIV infection and its
treatment may profoundly affect the natural history of HBV. Reactivation of HBV may occur in HIV
infection.[123]
• Initiate antiretroviral therapy (ART), regardless of CD4 cell count, according to current local HIV
guidelines and under specialist guidance. The ART regimen should include drugs that are active
against both viruses, with 2 drugs that have activity against HBV. The preferred regimen should
include tenofovir disoproxil or tenofovir alafenamide plus emtricitabine or lamivudine, as the
backbone. In patients already on ART, review the regimen to make sure it includes drugs with HBV
activity.[2] [38] [124] Decisions about the best treatment regimen should be made in conjunction
with an HIV specialist.
• See HIV infection .
Hepatitis C virus infection
• Initiate antiviral therapy in patients with detectable hepatitis C virus (HCV) RNA levels. If HBV DNA
levels are also detectable, treatment is determined by HBV DNA and ALT levels. HBV antiviral
therapy should be started concurrently with direct-acting antiviral therapy (DAA) for HCV, according
MANAGEMENT
to current local hepatitis C guidelines and under specialist guidance.[2] [38]

• Monitor HBV DNA levels every 4 to 8 weeks during treatment (and for 3 months after treatment) as
HBsAg-positive patients are at risk of hepatitis B reactivation with HCV DAA therapy.[2] [38]
31
• The rate of reactivation is higher with patients receiving DAA therapy compared with those
receiving interferon-based therapy for the treatment of hepatitis C.[125]
• See Hepatitis C .
Hepatitis D virus infection
• Fulminant hepatitis is usually seen in patients with HBV and hepatitis D virus (HDV) co-
infection.[126] Refer patient to a specialised centre that offers access to experimental therapies for
HDV infection. Peginterferon alfa 2a (or bulevirtide in locations where it is available) is the treatment
of choice in patients with elevated HDV RNA and ALT levels. If HBV DNA levels are elevated,
entecavir, tenofovir disoproxil, or tenofovir alafenamide can be added.[2] [38]
• See Hepatitis D .
Treatment of chronic infection: special patient groups

Pregnancy
• Consider antiviral therapy in HBsAg-positive pregnant women with an HBV DNA level >200,000 IU/
mL to reduce the risk of perinatal transmission.[2] [38] [67][127]
• Peripartum antiviral prophylaxis has been shown to be highly effective at reducing the
risk of mother-to-child transmission, with no increased risk of infant or maternal safety
outcomes.[128]
• However, one Cochrane review found no evidence to demonstrate or disprove any benefit for
antiviral therapy for the prevention of mother-to-child transmission of hepatitis B virus in HIV-
positive pregnant women with hepatitis B co-infection.[129]
• Tenofovir disoproxil is the preferred drug to minimise the risk of viral resistance during treatment,
and shows high efficacy in preventing perinatal transmission. It is usually started at 28 to 32 weeks'
gestation, and discontinued at birth to 3 months postnatally.[2] [38] [127]
• Reviews have shown that tenofovir disoproxil significantly reduces the rate of mother-to-child
transmission, and is considered safe for the mother and baby.[130] [131] [132] Tenofovir
alafenamide may become an option as evidence emerges.[133]
• Lamivudine can be given during the third trimester of pregnancy and demonstrates safety and
reduction in perinatal and intra-uterine transmission of HBV when given with neonatal hepatitis B
vaccine and hepatitis B immunoglobulin.[134] [135] [136] [137] [138]
• Women who become pregnant while receiving peginterferon alfa 2a or entecavir should be
switched to a safer regimen.
• Pregnant women with immune-active chronic HBV infection should be treated the same as non-
pregnant adults.
• Caesarean section delivery may be considered to reduce the risk of mother-to-child
transmission.[139]
MANAGEMENT
• The American College of Obstetricians and Gynecologists (ACOG) suggest that caesarean
delivery be reserved for obstetric indications for caesarean delivery.[67]
• European guidelines do not recommend caesarean section to reduce the risk of mother-
to-child transmission in HBsAg-positive women. However, caesarean section may be
considered in Asian HBeAg-positive women with a high HBV DNA titer who have not
received antiviral therapy during pregnancy. Recommendations for patients with HDV co-
infection are the same as those with HBV infection.[140]
Breast-feeding
• Breast-feeding is not contraindicated.[2] [38] Breast-feeding of infants born to HBsAg-positive

mothers should be encouraged unless there are contraindications or the mother presents with
cracked nipples and/or the infant has oral ulcers and the mother has detectable HBV DNA.[67]
[140]
• Antivirals are minimally excreted in breast milk and are unlikely to pose a significant risk to the
infant; however, the risks associated with low-level exposure are unknown. Breast-feeding after
proper neonatal immunoprophylaxis does not increase transmission rates compared with non-
breastfeeding, according to one systematic review.[141]
Children
• Chronic hepatitis B runs an asymptomatic course in most children. Generally, a conservative

approach for HBV therapy is acceptable, owing to a paucity of clinical data and therapeutic options.
Treatment should be initiated by a provider experienced in treating children with HBV. Follow-up of
children with chronic HBV to adulthood is important.[2] [38]
• Consider antiviral therapy in HBeAg-positive children aged ≥2 years who have elevated ALT levels
(>1.3 times the ULN for at least 6 months) and measurable HBV DNA levels. HBV DNA levels are
generally very high in children. Therapy may be deferred until other aetiologies of liver disease and
spontaneous HBeAg seroconversion are excluded in patients with HBV DNA levels <10⁴ IU/mL.[2]
• Entecavir, tenofovir disoproxil, and lamivudine are approved for use in children ≥2 years of age.
Tenofovir alafenamide is approved for children ≥12 years of age. Interferon alfa 2b is approved for
use in children aged ≥1 year, while peginterferon alfa 2a is approved for use in children aged ≥3
years.
• The treatment course for interferon alfa 2b is 24 weeks in children. The duration of treatment that
has been studied for oral antivirals is 1-4 years; however, HBeAg seroconversion may be used as
a therapeutic endpoint for oral antivirals, continuing for a further 12 months of consolidation (as in
adults).[2]
• Combination therapy with interferon and nucleoside/nucleotide analogues has been shown to be
more effective than interferon monotherapy in children in terms of serological response and viral
suppression. However, guidelines do not recommend combination therapy, and more studies are
needed.[142]
MANAGEMENT
33
Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute ( summary )
acute HBV infection
1st supportive care
adjunct antiviral therapy + assess for liver

transplantation
MANAGEMENT
Ongoing ( summary )
chronic HBV infection: adult non-
pregnant without co-infection or
cirrhosis
1st antiviral therapy

pregnant with cirrhosis
with compensated 1st antiviral therapy

cirrhosis
with decompensated 1st antiviral therapy

cirrhosis
adjunct assess for liver transplantation

pregnant with HIV co-infection

pregnant with hepatitis C co-
infection

pregnant with hepatitis D co-
infection
chronic HBV infection: adult

pregnant or breast feeding
adjunct delivery via caesarean section
chronic HBV infection: children
1st supportive care
adjunct antiviral therapy

MANAGEMENT
35
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute
acute HBV infection
1st supportive care
» More than 95% of immunocompetent

individuals with acute infection will achieve
seroconversion with appearance of antibody to
hepatitis B surface antigen in the absence of
treatment. Therefore, supportive care is usually
all that is needed in most patients.[2] [38]
adjunct antiviral therapy + assess for liver
transplantation
Treatment recommended for SOME patients in
selected patient group
Primary options
» entecavir: children: consult specialist for

guidance on dose; adults: 0.5 mg orally once
daily
OR
» tenofovir disoproxil: children: consult

specialist for guidance on dose; adults: 300
mg orally once daily
OR
» tenofovir alafenamide: children: consult

specialist for guidance on dose; adults: 25 mg
orally once daily
» Initiate antiviral therapy in patients with acute

liver failure or in those who have a severe,
protracted course (i.e., total bilirubin level
>51.3 micromoles/L (>3 mg/dL), international
normalised ratio >1.5, encephalopathy, or
ascites).[2] [38]
» Simultaneously, assess the patient for the

need for liver transplantation, as there is a high
risk of mortality in patients with liver failure who
do not undergo a transplant.[2] [38]
MANAGEMENT
» Entecavir, tenofovir alafenamide, and tenofovir

disoproxil are the drugs of choice. Continue
treatment until hepatitis B surface antigen
clearance is confirmed, or indefinitely in patients
who undergo liver transplantation.[2] [38]
Ongoing
pregnant without co-infection or
cirrhosis

Primary options
» entecavir: 0.5 mg orally once daily

Dose is 1 mg orally once daily in lamivudine-
experienced patients.
OR
» tenofovir disoproxil: 300 mg orally once

daily
OR
» tenofovir alafenamide: 25 mg orally once

daily
OR
» peginterferon alfa 2a: 180 micrograms

subcutaneously once weekly for 48 weeks
» Initiate antiviral therapy in patients with

immune-active chronic hepatitis B virus (HBV)
infection (i.e., elevated alanine aminotransferase
[ALT] levels ≥2 the upper limit of normal [ULN]
or evidence of histological disease with elevated
HBV DNA levels >2000 IU/mL if hepatitis B e
antigen [HBeAg] negative, or >20,000 IU/mL
if HBeAg positive). Consider antiviral therapy
in patients >30 to 40 years of age (age cut-off
depends on guideline) or with a family history
of hepatocellular carcinoma if ALT levels are <2
ULN and below HBV DNA thresholds.[2] [38]
Antiviral therapy is generally not recommended
in patients with immune-tolerant or immune-
active chronic HBV infection.
» Entecavir, tenofovir disoproxil or tenofovir

alafenamide, or peginterferon alfa 2a are
the recommended first-line drugs. Tenofovir
alafenamide or entecavir are preferred in
patients who are at risk of renal dysfunction
or bone disease. There is some data to
suggest that switching tenofovir disoproxil to
MANAGEMENT
tenofovir alafenamide can be done without

a loss of efficacy in patients who are virally
suppressed.[143] [144] Five-year data from two
randomised controlled trials found comparable
efficacy between tenofovir alafenamide and
tenofovir disoproxil (switching to tenofovir
37
Ongoing
alafenamide after 2 or 3 years), with high
rates of viral suppression and no resistance
documented. Improved bone and renal safety
with tenofovir alafenamide was maintained over
the five years, and improvements were seen in
the comparison group after switching.[145]
» No treatment shows superiority over

another in terms of risk reduction of hepatic
decompensation.[2] [38] Meta-analyses give
conflicting results on the risk of HCC due to the
patient populations included and differences
in study inclusion criteria. Some have found
that tenofovir disoproxil was associated with a
significantly lower risk of HCC compared with
entecavir, particularly in patients who were
HBeAg-positive.[108][109] However, others
have found no significant difference between
tenofovir disoproxil fumarate and entecavir in
their association with incident HCC.[110] [111]
[112] Tenofovir disoproxil was associated with
a lower risk of recurrence and mortality after
resection or ablation of HCC compared with
entecavir.[113][114]
» Treatment course is variable. The treatment

course of peginterferon alfa 2a is 48 weeks.
Consider stopping oral antiviral therapy in
HBeAg-positive patients who seroconvert
to antibody to HBeAg during therapy after
a consolidation period (i.e., 12 months of
persistently normal ALT levels and undetectable
serum HBV DNA). Some experts treat until
hepatitis B surface antigen loss occurs. Continue
treatment indefinitely in HBeAg-negative
patients, unless there is a compelling reason to
stop.[2] [38]
pregnant with cirrhosis
with compensated 1st antiviral therapy

cirrhosis
Primary options
» entecavir: 0.5 mg orally once daily

Dose is 1 mg orally once daily in lamivudine-
experienced patients.
OR
MANAGEMENT

daily
OR
Ongoing
daily
Secondary options
» peginterferon alfa 2a: 180 micrograms

subcutaneously once weekly
» Initiate antiviral therapy in patients with low-

level viraemia (i.e., hepatitis B virus [HBV] DNA
levels <2000 IU/mL), regardless of alanine
aminotransferase levels. Treat patients with high-
level viraemia as you would for patients with
immune-active chronic HBV infection.[2] [38]
» Entecavir, tenofovir disoproxil, and tenofovir

alafenamide are the recommended first-line
drugs. Peginterferon alfa 2a may only be
considered in patients who do not have portal
hypertension.[2] [38] [119] There is no optimal
length of treatment.
» Monitor patients (at least every 3 months for

1 year) after stopping therapy to check for viral
rebound that could lead to decompensation.[38]
[146] Discontinuation of antiviral therapy in
these patients was associated with a high-risk of
relapse (virological relapse 55%, clinical relapse
44%), but the incidence of adverse events was
generally low and controlled. The rate of HCC
after discontinuation of antiviral therapy was
9%.[147]
with decompensated 1st antiviral therapy
cirrhosis
Primary options
» entecavir: 1 mg orally once daily
OR

daily
Secondary options

daily
» Initiate antiviral therapy as soon as possible.

Antiviral therapy has been shown to improve
outcomes (e.g., improved liver function,
increased survival, and increased transplant-
MANAGEMENT
free survival) in patients with decompensated

cirrhosis, especially with early treatment.[2] [38]
» Entecavir (administered at a higher dose than

the dose used for other patients) and tenofovir
disoproxil are the recommended first-line drugs.
39
Ongoing
Tenofovir alafenamide can be considered
in patients in whom tenofovir disoproxil or
entecavir are not an option (e.g., patients
with renal dysfunction or bone disease).[2]
[38]Peginterferon alfa 2a is contraindicated in
these patients due to safety concerns.[121]
» Lifelong treatment is recommended, regardless

of alanine aminotransferase or hepatitis B virus
(HBV) DNA levels, or hepatitis B e antigen
status.[2] [38]
» Monitor patients closely for the development

of lactic acidosis and renal dysfunction.[2] [38]
Lactic acidosis has been associated with use of
entecavir and tenofovir, and the risk is increased
in patients with decompensated cirrhosis.[122]
adjunct assess for liver transplantation
» In patients with chronic HBV and
decompensated cirrhosis, referral to a liver
transplantation centre is necessary.
pregnant with HIV co-infection
» Initiate antiretroviral therapy (ART), regardless

of CD4 cell count, according to current local
HIV guidelines and under specialist guidance.
The ART regimen should include drugs that are
active against both viruses, with two drugs that
have activity against HBV. The preferred regimen
should include tenofovir disoproxil or tenofovir
alafenamide plus emtricitabine or lamivudine as
the backbone. In patients already on ART, review
the regimen to make sure it includes drugs with
HBV activity.[2] [38] [124] See HIV infection .
pregnant with hepatitis C co-
infection
» Initiate antiviral therapy in patients with

detectable hepatitis C virus (HCV) RNA levels.
If hepatitis B virus (HBV) DNA levels are also
detectable, treatment is determined by HBV
MANAGEMENT
DNA and alanine aminotransferase levels. HBV

antiviral therapy should be started concurrently
with direct-acting antiviral therapy (DAA) for
HCV, according to current local hepatitis C
guidelines and under specialist guidance.[2] [38]
See Hepatitis C .
Ongoing
» Monitor HBV DNA levels every 4-8 weeks
during treatment (and for 3 months after
treatment) as hepatitis B surface antigen-positive
patients are at risk of hepatitis B reactivation with
HCV DAA therapy.[2] [38]
pregnant with hepatitis D co-
infection
» Peginterferon alfa 2a (or bulevirtide in

locations where it is available) is the treatment
of choice in patients with elevated hepatitis D
virus (HDV) RNA and alanine aminotransferase
levels. If hepatitis B virus (HBV) DNA levels
are elevated, entecavir, tenofovir disoproxil,
or tenofovir alafenamide can be added.[2]
[38] Refer patient to a specialised centre that
offers access to experimental therapies for HDV
infection. See Hepatitis D .
chronic HBV infection: adult
pregnant or breast feeding

Primary options

daily
Secondary options
» lamivudine: 100 mg orally once daily
» Consider antiviral therapy in hepatitis B

surface antigen-positive pregnant women,
with an hepatitis B virus (HBV) DNA level
>200,000 IU/mL, to reduce the risk of perinatal
transmission. Pregnant women with immune-
active chronic HBV infection should be treated
the same as non-pregnant adults.[2] [38] [67]
[127] Peripartum antiviral prophylaxis has
been shown to be highly effective at reducing
the risk of mother-to-child transmission, with
no increased risk of infant or maternal safety
outcomes.[128] However, one Cochrane review
found no evidence to demonstrate or disprove
any benefit for antiviral therapy for the prevention
of mother-to-child transmission of hepatitis
B virus in HIV-positive pregnant women with
MANAGEMENT
hepatitis B co-infection.[129]
» Tenofovir disoproxil is the preferred drug

to minimise the risk of viral resistance during
treatment, and shows high efficacy in preventing
perinatal transmission. It is usually started
41
Ongoing
at 28-32 weeks' gestation and discontinued
at birth to 3 months postnatally.[2] [38] [127]
Reviews have shown that tenofovir disoproxil
significantly reduces the rate of mother-to-child
transmission, and is considered safe for the
mother and baby.[148] [149] [150] Tenofovir
alafenamide may become an option as evidence
emerges.[151]
» Lamivudine can be given during the third

trimester of pregnancy, and demonstrates
safety and reduction in perinatal and intra-
uterine transmission of HBV when given with
neonatal hepatitis B vaccine and hepatitis B
immunoglobulin.[134] [135] [136] [137] [138]
» Women who become pregnant while receiving

peginterferon alfa 2a or entecavir should be
switched to a safer regimen.
» Breastfeeding is not contraindicated.

Breastfeeding of infants born to HBsAg-positive
mothers should be encouraged unless there are
contraindications or the mother presents with
cracked nipples and/or the infant has oral ulcers
and the mother has detectable HBV DNA.[67]
[140] Antivirals are minimally excreted in breast
milk and are unlikely to pose a significant risk
to the infant; however, the risks associated with
low-level exposure are unknown.[2] [38]
adjunct delivery via caesarean section
» Caesarean section delivery may be
considered to reduce the risk of mother-to-child
transmission.[139]
» The American College of Obstetricians and

Gynecologists (ACOG) suggest that caesarean
delivery be reserved for obstetric indications for
caesarean delivery.[67]
» European guidelines do not recommend

caesarean section to reduce the risk of mother-
to-child transmission in HBsAg-positive women.
However, caesarean section may be considered
in Asian HBeAg-positive women with a high
HBV DNA titre who have not received antiviral
therapy during pregnancy. Recommendations for
patients with HDV co-infection are the same as
MANAGEMENT
those with HBV infection.[140]

chronic HBV infection: children
1st supportive care
Ongoing
» Generally chronic hepatitis B runs an
asymptomatic course in children, and a
conservative approach is acceptable, owing to a
paucity of clinical data and therapeutic options.
adjunct antiviral therapy
Primary options
» entecavir: children ≥2 years of age: consult

specialist for guidance on dose
OR
» tenofovir disoproxil: children ≥2 years of

age: consult specialist for guidance on dose
OR
» tenofovir alafenamide: children ≥12 years of

Approved for use in children aged ≥6 years in
Europe.
OR
» interferon alfa 2b: children ≥1 year of age:

consult specialist for guidance on dose
OR
» peginterferon alfa 2a: children ≥3 years of

Secondary options
» lamivudine: children ≥2 years of age:

consult specialist for guidance on dose
» Consider antiviral therapy in hepatitis B e

antigen (HBeAg)-positive children ≥2 years of
age who have elevated alanine aminotransferase
levels (>1.3 times the upper limit of normal for
at least 6 months) and measurable HBV DNA
levels. HBV DNA levels are generally very high
in children. Therapy may be deferred until other
aetiologies of liver disease and spontaneous
HBeAg seroconversion are excluded in patients
MANAGEMENT
with HBV DNA levels <10⁴ IU/mL.[2] Treatment

should be initiated by a provider experienced in
treating children with hepatitis B virus (HBV).
» The treatment course for interferon alfa 2b is

24 weeks in children. The duration of treatment
43
Ongoing
that has been studied for oral antivirals is 1
to 4 years. However, HBeAg seroconversion
may be used as a therapeutic endpoint for oral
antivirals, continuing for a further 12 months of
consolidation (as in adults).[2]
MANAGEMENT
Emerging
Experimental therapies
Several novel treatments are in development including small molecule drugs, next-generation nucleoside/
nucleotide analogues with reduced toxicity and higher barriers to resistance, direct-acting antivirals
(e.g., core inhibitors, entry inhibitors, nucleic acid polymers, capsid assembly modulators, translation
inhibitors), and therapeutic vaccines.[152] Gene therapy has also shown promise, and different strategies
have been used including gene editing, hepatitis B virus-specific gene silencing, and nucleic acid-based
vaccination.[153] New drug classes such as entry inhibitors (e.g., bulevirtide), prenylation inhibitors
(e.g., lonafarnib), and nucleic acid polymers show promise for the treatment of hepatitis B/hepatitis D
co-infection.[154] Other drugs in development include REP 2139 (hepatitis B surface antigen inhibitor);
selgantolimod, CB06, and GSK 5251738 (toll-like receptor-8 agonists); ruzotolimod and PRTX007 (toll-like
receptor-7 agonists); xalnesiran, imdurisan, BW-20507, ALG-125755, BB-103, JNJ-3989, and VIR-2218
(RNAi gene silencers); cledvudine 3 (HBV polymerase inhibitor); ZM-H1505R, ALG-000184, ABI-H4334,
and EDP-514 (capsid or core inhibitors); bepirovirsen and AHB-137 (antisense molecules); envafolimab,
RG6084, and AB-101 (checkpoint inhibitors); and VIR-3434, burfiralimab, BJT-778, and RG6449VIR-3434,
burfiralimab, BJT-778, and RG6449 (monoclonal antibody).[155]
Statins
Statin use has been associated with a decreased incidence of cirrhosis and hepatocellular carcinoma
(HCC) in patients with viral hepatitis. One systematic review found that use of statins was associated with a
42% reduction in the risk of cirrhosis, with the protective effect more pronounced in Asian countries.[156]A
Swedish cohort study of over 16,000 patients found that patients who used lipophilic statins (e.g.,
atorvastatin, simvastatin, fluvastatin, lovastatin) had a lower 10-year cumulative incidence of hepatocellular
carcinoma (3.3%) compared to patients who do not take statins (8.1%). However, the same effect was
not seen with hydrophilic statins. Ten-year mortality rates were significantly lower with both types of
statins.[157] A large meta-analysis including over 195,000 patients with chronic viral hepatitis found that the
risk of HCC, fibrosis, and cirrhosis decreased by 53%, 45%, and 41% respectively, in statin users compared
with those not using statins. Overall mortality rates did not differ between groups, although there was a
39% reduction in mortality in statin users who were followed up for more than 3 years. The review found no
significant reduction in liver function related to statin therapy.[158] Other meta-analyses also support the
finding that statins reduce the risk of HCC in patients with HBV infection.[159]
Primary prevention
Primary prevention can be via passive immunisation with hepatitis B immunoglobulin (HBIG) or via active
immunisation with hepatitis B vaccine (recombinant inactive hepatitis B surface antigen [HBsAg]).
Infants, children, and adolescents ≤18 years
• The World Health Organization recommends that all infants should receive a hepatitis B vaccine
series, with the first dose given as soon as possible after birth, preferably within 24 hours, followed by
two or three doses administered according to national routine immunisation schedules.[65]
• The monovalent vaccine should be used for the birth dose, while monovalent or combined
vaccines can be used in infants aged >6 weeks.
• In the US, the Advisory Committee on Immunization Practices (ACIP) recommends babies receive a
first dose of hepatitis B vaccine within 24 hours of birth, with a second dose at 1-2 months (minimum
MANAGEMENT
interval after first dose of 4 weeks), and a third dose at 6-18 months (at least 8 weeks after the second
dose and at least 16 weeks after the first dose). If no dose is given at birth, then three doses of a
hepatitis B-containing vaccine should be given on a schedule of 0, 1-2, and 6 months, starting as
soon as possible. A four-dose series is permitted when a combination vaccine containing hepatitis B is
administered after the birth dose. The final (third or fourth) dose should be administered no earlier than
the age of 24 weeks.[66]
45
• Babies born to HBsAg-positive mothers should receive both hepatitis B vaccine and HBIG (in
separate limbs) within 12 hours of birth, regardless of birth weight. Babies <2000 g should
receive three additional doses of vaccine (total of four doses), beginning at age 1 month. Babies
should be tested for HBsAg and antibody to hepatitis B surface antigen at age 9-12 months, or if
vaccination is delayed, at 1-2 months after completion of hepatitis B vaccine series.
• Babies born to mothers with an unknown HBsAg status should receive hepatitis B vaccine within
12 hours of birth regardless of birth weight, and those weighing <2000 g should also receive
HBIG (in separate limbs) and three additional doses of vaccine (total of four doses), beginning
at age 1 month. For babies weighing ≥2000 g, the mother’s HBsAg status should be determined
as soon as possible and, if positive, HBIG given to the baby as soon as possible and within 7
days. If there is evidence to suggest maternal hepatitis B infection, manage infants as if the
mother is HBsAg-positive.
• Babies born to HBsAg-negative mothers should receive one dose of hepatitis B vaccine within
24 hours of birth if medically stable and birth weight is ≥2000 g. Babies <2000 g should receive
one dose at chronological age 1 month or hospital discharge (whichever is earlier, even if weight
is still <2000 g).
• Catch-up vaccination: children and adolescents who have not previously received the hepatitis
B vaccine should receive the standard schedule of three vaccinations at 0, 1-2, and 6 months.
Adolescents ages 11-15 years may receive an alternative two-dose series of adult Recombivax
HB® with at least 4 months between doses. Adolescents ages ≥18 years may receive a two-
dose series of Heplisav-B® at least 4 weeks apart, a three-dose series of PreHevbrio® at 0, 1,
and 6 months, or the combined hepatitis A and hepatitis B vaccine (Twinrix®) as a three- or four-
dose series.
• The American College of Obstetricians and Gynecologists (ACOG) supports the recommendation that
neonates of HBsAg-positive mothers (or whose status is unknown at the time of delivery), receive both
hepatitis B vaccination and HIBIG within 12 hours of birth.[67]
• In the UK, the routine childhood immunisation programme includes hepatitis B in the combination
vaccine for diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type B (DTaP/IPV/Hib/
HepB).[68]
• Vaccination with DTaP/IPV/Hib/HepB is recommended at ages 8, 12, and 16 weeks, but can be
given from age 6 weeks to 10 years.
• Babies born to hepatitis B-infected mothers should receive a monovalent hepatitis B vaccine at
birth (within 24 hours) and at 4 weeks, followed by multivalent vaccine at 8, 12, and 16 weeks;
babies are tested for HBsAg at one year of age and given a further dose of monovalent hepatitis
B vaccine.
• Babies born to hepatitis B-infected mothers should also receive HBIG within 24 hours of birth,
unless the mother is HBsAg-positive and anti-HBe-positive and the baby also weighs >1500 g.
• Children aged 1-10 years of age who have completed their course of immunisations for
diphtheria, tetanus, pertussis and polio, but have not received hepatitis B vaccines do not
require hepatitis B vaccination unless they are in a high-risk group or are exposed to hepatitis B.
• The global coverage with the third dose of hepatitis B vaccine was between 82% and 85% between
2016 to 2020. Coverage was ≥90% for both the birth dose and the 3-dose series in 41% of countries
MANAGEMENT
with data available in 2020.[17]
• Immunisation schedules differ between countries. Consult your local immunisation protocols for more
information.
Adults
• In the US, ACIP recommends universal vaccination in adults ages 19 to 59 years with a two-, three-,
or four-dose series. Adults ≥60 years of age with known risk factors for infection (see below) should
receive a complete vaccine series. Adults ≥60 years of age without known risk factors may receive
a complete vaccine series if they choose to. The dose schedule depends on the vaccine used (e.g.,
Engerix-B®, Recombivax HB®, Heplisav-B®, Twinrix®, PreHevbrio®). Consult the immunisation
schedule for more detailed information.[69]
• At-risk populations include:
• People with chronic liver disease (e.g., hepatitis C, cirrhosis, fatty liver disease, alcoholic liver
disease, autoimmune hepatitis, alanine aminotransferase or aspartate aminotransferase level
greater than twice upper limit of normal)
• People with HIV infection or current or recent injection drug use
• People with a sexual exposure risk (e.g., sex partners of HBsAg-positive people, sexually active
people not in mutually monogamous relationships, men who have sex with men, people seeking
evaluation or treatment of sexually transmitted infection)
• People with percutaneous or mucosal risk for exposure to blood (e.g., patients with diabetes,
dialysis patients, household contacts of HBsAg-positive people, healthcare personnel)
• Incarcerated people
• People traveling to countries with high or intermediate endemic hepatitis B.
• ACOG supports the use of the hepatitis B vaccine with an appropriate vaccine during pregnancy for
recommended patient groups.[67]
• In the UK, an accelerated schedule is given in most risk groups, with the vaccine given at 0, 1, and 2
months, or alternatively, at 0, 1 and 6 months where rapid protection isn’t required and adherence is
likely.[68]
• Immunisation schedules differ between countries. Consult your local immunisation protocols for more
information.
Secondary prevention
The following secondary prevention measures are recommended:[2] [38]
• Screen pregnant women for hepatitis B surface antigen (HBsAg). Pregnant women should also
be encouraged to discuss the need for maternal antiviral therapy, as well as newborn hepatitis B
vaccination and hepatitis B immunoglobulin (HBIG), with their obstetrician to prevent mother-to-child
transmission.
• Advise healthcare workers with HBV infection who perform exposure-prone procedures to seek
counselling and advice from an expert review panel, as antiviral prophylaxis may be recommended.
• Initiate antiviral prophylaxis in patients who are starting on immunosuppressive therapy (including
chemotherapy or immunotherapy) to prevent hepatitis B reactivation.
• Initiate lifelong antiviral prophylaxis with a nucleoside/nucleotide analogue (with or without HBIG) in
all HBsAg-positive patients undergoing liver transplantation, regardless of pre-transplant hepatitis B e
antigen status, or HBV DNA level. An individualised approach to HBIG use is recommended.
MANAGEMENT
• Initiate long-term antiviral therapy in HBsAg-negative patients receiving livers from donors with
evidence of past HBV infection (antibody to hepatitis B core antigen-positive) to prevent HBV
reactivation.
47
Patient discussions
Counsel patients on preventing transmission of hepatitis B virus (HBV) to others and the importance of
lifelong monitoring. Lifestyle modifications to optimise body weight and treat metabolic complications
are recommended in order to prevent the development of metabolic syndrome and fatty liver. No special
precautions are recommended for children in community settings (e.g., daycare, school, contact sports),
unless they are prone to biting. Advise patients who are hepatitis B surface antigen-positive to:[2]
• Have household and sexual contacts vaccinated if they test negative for HBV serological markers
• Use barrier protection during sex if their partner is not vaccinated or is not naturally immune
• Not share toothbrushes, razors, injection equipment, or glucose testing equipment
• Not donate blood, organs, or semen
• Cover open cuts and scratches, and clean blood spills with bleach
• Vaccinate against hepatitis A if necessary
• Abstain from, or limit, alcohol use.
Counselling intervention programmes sometimes include interventions that aim to change risk
behaviours. However, a systematic review found that counselling interventions that are aimed at changing
risk behaviours (e.g., unprotected sex, injection of drugs) among key populations do not change
behaviours or reduce new viral hepatitis infections. Counselling interventions that promote abstinence,
rehabilitation, cessation of sex work, or a ‘cure’ for homosexuality (e.g., conversion therapy) are not
recommended as they create barriers to the key populations accessing services.[181]
MANAGEMENT
Hepatitis B Follow up
Monitoring
Monitoring
FOLLOW UP
In patients who don’t meet the local criteria for treatment with antiviral therapy, the aim of monitoring is
to identify a change in clinical status that indicates progression to disease state that requires treatment.
The aim of monitoring in those who have received antiviral therapy is to evaluate treatment response,
side effects, and disease progression or reactivation.[2] [38] [65][179] [Evidence B] The following
recommendations are based on American Association for the Study of Liver Diseases guidelines and
European Association for the Study of the Liver guidelines.[2] [38] Local guidelines may vary.
Patients not currently on treatment
• Immune-tolerant chronic hepatitis B virus (HBV) infection (hepatitis B e antigen [HBeAg]-positive,

high HBV DNA, and persistently normal alanine aminotransferase [ALT] level): monitor ALT every
3-6 months. Monitor more frequently, along with HBV DNA levels, if ALT level becomes elevated.
Check HBeAg status every 6-12 months. Consider starting antiviral treatment in patients with
compensated liver disease who remain HBeAg-positive with HBV DNA levels >20,000 IU/mL; after
a 3-6 month period of elevated ALT levels greater than 2 times the upper limit of normal. Consider
liver biopsy (or alternative non-invasive tests) in patients with persistent borderline normal, or
slightly elevated, ALT levels, particularly in patients >40 years of age who have been infected from
a young age. Initiate antiviral therapy in patients with moderate to severe inflammation and/or
fibrosis.
• Immune-inactive chronic HBV infection (HBeAg-negative, normal ALT, and HBV DNA <2000 IU/
mL): monitor ALT and HBV DNA levels every 3 months during the first year to confirm patient is
in the inactive phase, then every 6-12 months thereafter. Monitor more frequently (i.e., every 3-6
months) if ALT level becomes elevated. If ALT elevation is persistent or recurrent, evaluate the
patient for other causes of liver disease. If HBV DNA is >2000 IU/mL, assess disease severity with
liver biopsy (or non-invasive methods), and initiate treatment in patients with moderate to severe
inflammation or significant fibrosis. Evaluate for HBsAg loss annually.
• Resolved chronic HBV infection: includes patients who have achieved hepatitis B surface antigen
(HBsAg) loss spontaneously or with therapy (also known as functional cure). Routine monitoring
of ALT and HBV DNA are not required. However, surveillance for hepatocellular carcinoma (HCC)
should continue if the person has cirrhosis, a first-degree family member with HCC, or a long
duration of infection (i.e., >40 years for males and >50 years for females who have been infected
from a young age).
Patients on treatment
• Interferon/peginterferon: monitor full blood count (FBC) every 1-3 months, thyroid-stimulating
hormone every 3 months, and hepatic panel every month. Check HBV DNA levels and HBsAg
status (as well as HBeAg and antibody to HBeAg in HBeAg-positive patients) at 3, 6, and 12
months during treatment, and at 6 and 12 months after treatment. Monitor patients for development
of neuropsychiatric, autoimmune, ischaemic, and infectious complications.
• Nucleoside/nucleotide analogues: perform FBC, hepatic panel, renal function, and HBV DNA
tests at baseline and regularly during treatment. Monitor hepatic panel every 3-4 months during
the first year, and every 6 months thereafter. Monitor HBV DNA every 3-4 months during the first
year, and every 6-12 months thereafter. Check HBsAg status annually. Monitor lactic acid levels if
there is a clinical concern for lactic acidosis (i.e., with use of entecavir or tenofovir in patients with
49
decompensated cirrhosis). Consider bone density study at baseline and during treatment if the
patient has a history of fracture or risks for osteopenia (tenofovir disoproxil).
Screening for HCC
FOLLOW UP
• Treatment with antivirals does not eliminate the risk of HCC and surveillance for HCC should
continue. All HBsAg-positive patients with cirrhosis or at high risk for HCC (e.g., Asian or black
men aged >40 years, Asian women aged >50 years, people with a first-degree family member
with a history of HCC, people with hepatitis D infection) should be screened with an abdominal
ultrasound, with or without alpha-fetoprotein (AFP), every 6 months. In areas where ultrasound is
not readily available, screen with AFP every 6 months.
Patients who come off long-term tenofovir disoproxil treatment can remain in a low replicative state (i.e.,
low HBV DNA and normal ALT), but there is approximately a 30% risk of ALT elevation, so patients should
be closely monitored.[180]
Complications
Complications Timeframe Likelihood
FOLLOW UP
fulminant hepatic failure short term low
• Heightened immune response to hepatitis B virus (HBV) resulting in massive immune-mediated

lysis of infected hepatocytes is thought to be the cause of fulminant hepatitis associated with acute
hepatitis B infection.[22]
• It occurs in <1% (around 0.1% to 0.5%) of cases of acute HBV. Co-infection with hepatitis C or D
virus increases the risk of developing fulminant hepatitis.[174] [175]
• Referral for liver transplantation is essential to prevent morbidity and mortality.
cirrhosis long term medium
• Cirrhosis occurs in about 20% of patients with chronic hepatitis B virus (HBV) and is thought to be
due to ongoing immune attack of infected cells in the liver, resulting in development of fibrosis and
regenerative nodules.[23]
• Risk factors associated with progression to cirrhosis include co-infection (with hepatitis C or D, and/
or HIV), older age, high levels of HBV DNA, and habitual alcohol intake.[162]
• Treatment can be initiated in most patients with chronic HBV and cirrhosis.
hepatocellular carcinoma long term medium
• The incidence of hepatitis B virus (HBV)-related hepatocellular cancer (HCC) has increased and
accounts for 50% of all HCC worldwide.[163] HBV and hepatitis D dual infection may increase the
risk of HCC compared to HBV monoinfection.[164]
• Screening for HCC should be started as suggested by the recommended guidelines.[2]
• HCC associated with hepatitis B is thought to result from chronic inflammation and cellular
regeneration.[22] Cirrhosis seems to be the greatest risk factor for developing HCC, although 30%
to 50% of HBV-related HCC occurs without cirrhosis.[165] Male sex, older age, diabetes mellitus,
co-infection with hepatitis D, co-infection with hepatitis C, core promoter mutation, family history of
HCC, presence of hepatitis B surface antigen, and high levels of HBV DNA are risk factors for the
development of HCC.[166] [167] [168] [169][170]
• Liver transplantation can be considered in the early stages, with small HCC without any evidence of
metastasis. Non-curative therapies, such as transarterial chemo-embolisation (TACE), transarterial
radio-embolisation (TARE), and systemic chemotherapy/immunotherapy, aim to slow tumour
progression and consequently prolong survival.
hepatitis B-associated glomerulonephritis long term low
• Hepatitis B virus (HBV)-related glomerulonephritis is not a common complication of HBV infection,

and the cause of glomerulonephritis in HBV infection is controversial.
• The optimal therapy is also not well defined. One systematic review and meta-analysis evaluating
safety and efficacy of interferon and lamivudine in HBV-infected patients with glomerulonephritis
reported remission of nephritic syndrome with clearance of HBV replication, suggesting a causal
role of HBV in the development of glomerulonephritis.[176]
51
Complications Timeframe Likelihood

extrahepatic malignancy long term low
FOLLOW UP
Chronic HBV infection is a risk factor for various primary extrahepatic malignancies (e.g., cervical,
gastric).[177] Long-term antiviral treatment has been associated with a lower risk of developing
extrahepatic malignancies.[178]
HBV reactivation variable medium
• Reactivation is emerging as an important cause of morbidity and mortality in patients who have
current or prior exposure to hepatitis B virus (HBV) infection, particularly in those who require
immunosuppressive or biological therapies (including chemotherapy or immunotherapies),
people with hepatitis C or D infection who are receiving antiviral treatment, and patients with HIV
infection.[171] [172] HBsAg-positive patients with HCC are at intermediate or high-risk of HBV
reactivation, depending on the type of therapy used to treat HCC.[173]
• Defined as a loss of HBV immune control in hepatitis B surface antigen (HBsAg)‐positive/antibody to
hepatitis B core antigen (anti‐HBc)-positive, or HBsAg‐negative/anti‐HBc-positive patients receiving
immunosuppressive therapy for a concomitant medical condition. Diagnostic criteria include: (a)
a rise in HBV DNA compared to baseline (or an absolute level of HBV DNA when a baseline is
unavailable); and (b) reverse seroconversion (seroreversion) from HBsAg-negative to HBsAg-
positive for HBsAg‐negative/anti‐HBc-positive patients. Following reactivation, a hepatitis flare
(indicated by an increase in alanine aminotransferase [ALT] levels) can occur.[2]
• Onset is variable; it can be up to 2 weeks after starting immunosuppressive therapy, or up to a
year after ceasing immunosuppressive therapy. The risk of reactivation depends on multiple factors
including host factors (e.g., older age, male sex, cirrhosis), virological factors (e.g., hepatitis B e
antigen status, HBV DNA level), and the type and degree of immunosuppressive therapy.[171]
• Screening for HBsAg and anti-HBc (total or IgG) is recommended in patients before starting any
immunosuppressive, cytotoxic, or immunomodulatory therapy.[2]
• Antiviral prophylaxis is required in patients who are at high risk of reactivation (HBsAg-positive/anti-
HBc-positive) before they start immunosuppressive therapy. Lower-risk patients (HBsAg-negative/
anti-HBc-positive) can be monitored (ALT levels, HBV DNA, and HBsAg) for reactivation and started
on prophylaxis if needed. Prophylaxis should be started as soon as possible, continued during
immunosuppressive therapy, and for at least 6 to 12 months after cessation of immunosuppressive
therapy, depending on the type of therapy.[2]
virological failure variable low
• Virological breakthrough, defined as a >1 log10 (10-fold) increase in serum hepatitis B virus DNA
from nadir after initial virological response, can be related to antiviral resistance mutations or
medication non-adherence. Consider drug resistance testing, and either switching to another
antiviral drug with a high barrier to resistance, or adding a second antiviral with a complementary
resistance profile.[2]
Prognosis
Globally, there were 820,000 hepatitis B virus (HBV)-related deaths in 2019, mostly from complications such
as cirrhosis and hepatocellular carcinoma.[9]
Patients with acute HBV infection

More than 95% of immunocompetent individuals with acute infection will achieve seroconversion with
appearance of antibody to hepatitis B surface antigen (anti-HBs) in the absence of treatment.[2] [38]
Patients with hepatitis B e antigen-positive chronic HBV infection

The end point of treatment is well defined in this patient population, based on predictability and durability
of seroconversion to antibody to hepatitis B e antigen (anti-HBe). When treatment is stopped after
FOLLOW UP
seroconversion is achieved, viral suppression is sustained in 50% to 90% of patients. Seroconversion
is associated with maintained long-term improvement in liver histology.[160] However, true cure (loss of
hepatitis B surface antigen and anti-HBs) occurs in a very low percentage of treated patients (1% to 5%).[23]
[161]
Patients with hepatitis B surface antigen-negative chronic HBV

infection
The end point of treatment for this group of patients is poorly defined. Therefore, treatment duration is
prolonged and probably needs to be lifelong unless there is a compelling reason to stop treatment after
carefully weighing the risks and benefits. In addition, relapse with this group of patients is frequent even
when there is complete viral suppression after discontinuation of drugs (undetectable HBV DNA) for >1
year.[2]
53
Hepatitis B Guidelines
Diagnostic guidelines
United Kingdom
Hepatitis B (chronic): diagnosis and management (ht tps://www.nice.org.uk/

guidance/cg165)
Published by: National Institute for Health and Care Excellence Last published: 2017
Europe
European Guideline for the screening, prevention and initial management

of hepatitis B & C infections in sexual health set tings (ht tps://iusti.org/
treatment-guidelines)
Published by: International Union against Sexually Transmitted Last published: 2017
Infections
GUIDELINES
Clinical practice guidelines on the management of hepatitis B virus infection

(ht tp://www.easl.eu/research/our-contributions/clinical-practice-guidelines)
Published by: European Association for the Study of the Liver Last published: 2017
International
Hepatitis B and C testing (ht tps://www.who.int/publications/i)

Published by: World Health Organization Last published: 2017
Prevention, care and treatment of persons with chronic hepatitis B infection

(ht tps://www.who.int/publications/i)
North America
Sexually transmit ted infections treatment guidelines: hepatitis B (ht tps://

www.cdc.gov/std/treatment-guidelines/hbv.htm)
Published by: Centers for Disease Control and Prevention Last published: 2021
Treatment of chronic hepatitis B (ht tps://www.aasld.org/publications/

practice-guidelines)
Published by: American Association for the Study of Liver Disease Last published: 2018
Asia
Asian-Pacific clinical practice guidelines on the management of hepatitis B

(ht tp://apasl.info/guidelines)
Published by: Asian Pacific Association for the Study of the Liver Last published: 2015
Treatment guidelines
United Kingdom
Hepatitis B (chronic): diagnosis and management (ht tps://www.nice.org.uk/

guidance/cg165)
Published by: National Institute for Health and Care Excellence Last published: 2017
Interim update of the 2015national guidelines for the management of the viral
hepatitides (ht tp://www.bashh.org/guidelines)
Published by: British Association for Sexual Health and HIV Last published: 2017
Sexually transmit ted infections in primary care (ht tps://www.rcgp.org.uk/

clinical-and-research/resources/a-to-z-clinical-resources.aspx?l=S)
GUIDELINES
Published by: Royal College of General Practitioners; British Last published: 2013
Association for Sexual Health and HIV
BBVs in healthcare workers: health clearance and management (ht tps://

www.gov.uk/government/publications/bbvs-in-healthcare-workers-health-
clearance-and-management)
Published by: Public Health England Last published: 2020
Hepatitis B: guidance, data and analysis (ht tps://www.gov.uk/government/

collections/hepatitis-b-guidance-data-and-analysis)
Published by: UK Health Security Agency (UKHSA) Last published: 2023
Management of hepatitis B in pregnancy and the exposed infant (ht tps://

www.basl.org.uk/index.cfm/content/page/cid/3)
Published by: British Association for the Study of the Liver Last published: 2022
Europe
Clinical practice guidelines on the management of hepatitis B virus infection

(ht tp://www.easl.eu/research/our-contributions/clinical-practice-guidelines)
Published by: European Association for the Study of the Liver Last published: 2017
European Guideline for the screening, prevention and initial management

of hepatitis B & C infections in sexual health set tings (ht tps://iusti.org/
treatment-guidelines)
Published by: International Union against Sexually Transmitted Infection Last published: 2017
55
International
Prevention of mother-to-child transmission of hepatitis B virus (ht tps://

www.who.int/publications/i)
Prevention, care and treatment of persons with chronic hepatitis B infection

(ht tps://www.who.int/publications/i)
Practice guideline - hepatitis B (ht tp://www.worldgastroenterology.org/

guidelines/global-guidelines)
Published by: World Gastroenterology Organisation Last published: 2015
GUIDELINES
North America
CDC yellow book: health information for international travel - hepatitis B

(ht tps://wwwnc.cdc.gov/travel/page/yellowbook-home)
Viral hepatitis in pregnancy (ht tps://www.acog.org/clinical/clinical-guidance/

clinical-practice-guideline)
Published by: The American College of Obstetricians and Last published: 2023
Gynecologists
Sexually transmit ted infections treatment guidelines: hepatitis B (ht tps://

www.cdc.gov/std/treatment-guidelines/hbv.htm)
Recommended immunization schedule for adults aged 19 years or older -
GUIDELINES
United States (ht tps://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html)
Recommended immunization schedule for children and adolescents aged 18

years or younger - United States (ht tps://www.cdc.gov/vaccines/schedules/hcp/
imz/child-adolescent.html)
Treatment of chronic hepatitis B (ht tps://www.aasld.org/practice-guidelines)

Published by: American Association for the Study of Liver Diseases Last published: 2018
Management of hepatitis B virus infection (ht tps://canlivj.utpjournals.press/

toc/canlivj/1/4)
Published by: Canadian Association for the Study of Liver Disease; Last published: 2018
Association of Medical Microbiology and Infectious Disease Canada
Guidance for evaluating healthcare personnel for hepatitis B virus protection

and for administering postexposure management (ht tp://www.cdc.gov/
hepatitis/HBV/ProfResourcesB.htm#section2)
Serological testing for suspected viral hepatitis (ht tps://

act t.albertadoctors.org/CPGs/Pages/default.aspx)
Published by: Alberta Clinical Practice Guidelines Last published: 2006 (re-
affirmed 2014)
57
Latin America
Bra zilian guidelines for the diagnosis and treatment of hepatitis B (ht tps://
www.sciencedirect.com/science/article/pii/S1413867020301173?via%3Dihub)
Published by: Brazilian Society of Hepatology and Brazilian Society of Last published: 2020
Infectious Diseases
Asia
Taiwan consensus statement on the management of chronic hepatitis B

(ht tps://pubmed.ncbi.nlm.nih.gov/30527436)
Published by: Taiwan Association for the Study of Liver Last published: 2019
Position statements on prevention, diagnosis and management of

hepatitis B virus infection in India: the Andaman statements (ht tps://
www.jcehepatology.com/issue/S0973-6883(18)X0002-4)
GUIDELINES
Published by: The Indian National Association for Study of the Liver Last published: 2018
Prevention and treatment for chronic hepatitis B (ht tps://

www.ncbi.nlm.nih.gov/pmc/articles/PMC5719188)
Published by: Chinese Society of Hepatology; Chinese Medical Last published: 2021
Association (CMA); Society of Infectious Diseases
Asian-Pacific clinical practice guidelines on the management of hepatitis B

(ht tp://apasl.info/guidelines)
Hepatitis B virus in pregnancy (ht tps://link.springer.com/article/10.1007/

s12072-021-10285-5)
Management of hepatitis B in pregnancy (ht tps://www.ranzcog.edu.au/

Statements-Guidelines)
Published by: Royal Australian and New Zealand College of Last published: 2019
Obstetricians and Gynaecologists
Oceania
Australian consensus recommendations for the management of hepatitis B

(ht tps://www.gesa.org.au/education/clinical-information)
Published by: Gastroenterological Society of Australia Last published: 2022
Hepatitis B Online resources
Online resources
1. BMJ Best Practice podcast: hepatitis B - how to approach diagnosis and management of chronic
infection (https://soundcloud.com/bmjpodcasts/hepatitis-b?in=bmjpodcasts/sets/bmj-best-practice-
clinical) (external link)
ONLINE RESOURCES
59
Hepatitis B Evidence tables
Evidence tables
What are the effects of serum alpha-fetoprotein (AFP) and/or ultrasound scan
EVIDENCE TABLES
(USS) to identify hepatocellular carcinoma (HCC) early in people with chronic

hepatitis B?[65]
This table is a summary of the analysis reported in a guideline (underpinned by a systematic review)
that focuses on the above important clinical question.
View the full source guideline (https://www.who.int/publications/i/item/9789241549059)
Evidence B * Confidence in the evidence is moderate or low to moderate where GRADE has been
performed and there may be no difference in effectiveness between the intervention
and comparison for key outcomes.
Population: People with chronic hepatitis B viral infection (hepatitis B surface antigen for more than 6
months)
Intervention: AFP or USS or AFP plus USS
Comparison: Each other or no intervention
† ‡
Outcome Effectiveness (BMJ rating) Confidence in evidence (GRADE)
AFP 6-monthly versus no intervention
New diagnosis of HCC No statistically significant Moderate

difference
Disease-specific mortality No statistically significant Moderate

difference
All-cause mortality No statistically significant Moderate

difference
USS and AFP 6-monthly versus AFP 6-monthly
New diagnosis of HCC No statistically significant Low

difference
USS and AFP 6-monthly versus no intervention
New diagnosis of HCC No statistically significant Moderate

difference
Disease-specific mortality Favours intervention Moderate
Lesion or HCC size <5 cm Favours intervention Low
† ‡
Outcome Effectiveness (BMJ rating) Confidence in evidence (GRADE)
USS and AFP ≤6-monthly versus USS and AFP >6-monthly ᵃ
EVIDENCE TABLES
Disease-specific mortality Favours USS and AFP ≤6-monthly Very Low
Lesion or HCC size <3 cm in Favours USS and AFP ≤6-monthly Low
diameter
Lesion or HCC size ≥3 cm in No statistically significant Very Low

diameter difference
Recommendations as stated in the source guideline

Routine surveillance for HCC with abdominal ultrasound and alpha-fetoprotein testing every 6 months is
recommended for:
• People with cirrhosis, regardless of age or other risk factors (strong recommendation, low quality of
evidence)
• People with a family history of HCC (strong recommendation, low quality of evidence), and
• People aged over 40 years (lower age may apply according to regional incidence of HCC), without
clinical evidence of cirrhosis (or based on aspartate aminotransferase-to-platelet ratio index [APRI]
score ≤2), and with HBV DNA level >2000 IU/mL (where HBV DNA testing is available) (conditional
recommendation, low quality of evidence).
Note
ᵃ Based on one prospective cohort study, while the other comparison groups in this table are underpinned by
RCT evidence.
Overall, the guideline authors felt the evidence suggests that HCC screening with USS and/or AFP every 6
months may be of benefit in people with hepatitis B, although the most clinically effective and cost–effective
screening strategy remains unclear. They recommended further research to inform clinical practice.
* Evidence levels
The Evidence level is an internal rating applied by BMJ Best Practice. See the EBM Toolkit (https://
bestpractice.bmj.com/info/evidence-tables/) for details.
Confidence in evidence
A - High or moderate to high

B - Moderate or low to moderate
C - Very low or low
† Effectiveness (BMJ rating)

Based on statistical significance, which demonstrates that the results are unlikely to be due to chance, but
which does not necessarily translate to a clinical significance.
61
‡ Grade certainty ratings
High The authors are very confident that the true

effect is similar to the estimated effect.
EVIDENCE TABLES
Moderate The authors are moderately confident that

the true effect is likely to be close to the
estimated effect.
Low The authors have limited confidence in the
effect estimate and the true effect may be
substantially different.
Very Low The authors have very little confidence in
the effect estimate and the true effect is
likely to be substantially different.
BMJ Best Practice EBM Toolkit: What is GRADE? (https://bestpractice.bmj.com/info/toolkit/learn-ebm/what-
is-grade/)
Hepatitis B References
Key articles
• Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic
REFERENCES
hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-99. Full text
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975958) Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/29405329?tool=bestpractice.bmj.com)
• European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on
the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-98. Full text
(http://www.journal-of-hepatology.eu/article/S0168-8278(17)30185-X/fulltext) Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/28427875?tool=bestpractice.bmj.com)
• Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic
References
1. Mohanty SR, Kupfer SS, Khiani V. Treatment of chronic hepatitis B. Nat Clin Pract Gastroenterol
Hepatol. 2006 Aug;3(8):446-58. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16883349?
tool=bestpractice.bmj.com)
2. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic
3. Chu CJ, Lok AS. Clinical significance of hepatitis B virus genotypes. Hepatology. 2002
May;35(5):1274-6. Full text (http://onlinelibrary.wiley.com/doi/10.1053/jhep.2002.33161/pdf) Abstract
(http://www.ncbi.nlm.nih.gov/pubmed/11981779?tool=bestpractice.bmj.com)
4. Erhardt A, Blondin D, Hauck K, et al. Response to interferon alfa is hepatitis B virus genotype
dependent: genotype A is more sensitive to interferon than genotype D. Gut. 2005 Jul;54(7):1009-13.
Full text (http://gut.bmj.com/content/54/7/1009.long) Abstract (http://www.ncbi.nlm.nih.gov/
5. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in
combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet.
2005 Jan 8-14;365(9454):123-9. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15639293?
6. Kao JH, Wu NH, Chen PJ, et al. Hepatitis B genotypes and the response to interferon therapy. J
Hepatol. 2000 Dec;33(6):998-1002. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11131465?
63
7. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and the combination for
HBeAg-positive chronic hepatitis B. N Engl J Med. 2005 Jun 30;352(26):2682-95. Abstract (http://
REFERENCES
8. Liu Z, Zhang Y, Xu M, et al. Distribution of hepatitis B virus genotypes and subgenotypes: a meta-
analysis. Medicine (Baltimore). 2021 Dec 17;100(50):e27941. Full text (https://journals.lww.com/
md-journal/fulltext/2021/12170/distribution_of_hepatitis_b_virus_genotypes_and.18.aspx) Abstract
9. World Health Organization. Hepatitis B: fact sheet. Jul 2023 [internet publication]. Full text (https://
www.who.int/news-room/fact-sheets/detail/hepatitis-b)
10. Alberts CJ, Clifford GM, Georges D, et al. Worldwide prevalence of hepatitis B virus and hepatitis C
virus among patients with cirrhosis at country, region, and global levels: a systematic review. Lancet
Gastroenterol Hepatol. 2022 Aug;7(8):724-35. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC9259503) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/35576953?tool=bestpractice.bmj.com)
11. Alter MJ. Epidemiology of hepatitis B in Europe and worldwide. J Hepatol. 2003;39 Suppl 1:S64-9.
Abstract (http://www.ncbi.nlm.nih.gov/pubmed/14708680?tool=bestpractice.bmj.com)
12. Trickey A, Bivegete S, Duffell E, et al. Estimating hepatitis B virus prevalence among key
population groups for European Union and European Economic Area countries and the
United Kingdom: a modelling study. BMC Infect Dis. 2023 Jul 10;23(1):457. Full text (https://
bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-023-08433-3) Abstract (http://
13. Centers for Disease Control and Prevention. Viral hepatitis surveillance - United States: hepatitis
B surveillance 2021. Aug 2023 [internet publication]. Full text (https://www.cdc.gov/hepatitis/
statistics/2021surveillance/hepatitis-b.htm)
14. Wong RJ, Brosgart CL, Welch S, et al. An updated assessment of chronic hepatitis
B prevalence among foreign-born persons living in the United States. Hepatology.
2021 Aug;74(2):607-26. Full text (https://journals.lww.com/hep/fulltext/2021/08000/
an_updated_assessment_of_chronic_hepatitis_b.8.aspx) Abstract (http://www.ncbi.nlm.nih.gov/
15. UK Health Security Agency. Hepatitis B (in England). Feb 2023 [internet publication]. Full text (https://
www.gov.uk/government/publications/hepatitis-b-in-england)
16. GBD 2019 Europe Hepatitis B & C Collaborators. Hepatitis B and C in Europe: an update from the
global burden of disease study 2019. Lancet Public Health. 2023 Sep;8(9):e701-16. Full text (https://
www.thelancet.com/journals/lanpub/article/PIIS2468-2667(23)00149-4/fulltext) Abstract (http://
17. Khetsuriani N, Lesi O, Desai S, et al. Progress toward the elimination of mother-to-child
transmission of hepatitis B virus - worldwide, 2016-2021. MMWR Morb Mortal Wkly Rep. 2022 Jul
29;71(30):958-63. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345178) Abstract (http://
18. Indolfi G, Easterbrook P, Dusheiko G, et al. Hepatitis B virus infection in children and adolescents.
Lancet Gastroenterol Hepatol. 2019 Jun;4(6):466-76. Abstract (http://www.ncbi.nlm.nih.gov/
REFERENCES
19. UK Health Security Agency. Mother-to-child transmission of hepatitis B eliminated in England.
Feb 2023 [internet publication]. Full text (https://www.gov.uk/government/news/mother-to-child-
transmission-of-hepatitis-b-eliminated-in-england)
20. Ji DZ, Pang XY, Shen DT, et al. Global prevalence of occult hepatitis B: a systematic review and
meta-analysis. J Viral Hepat. 2022 May;29(5):317-29. Abstract (http://www.ncbi.nlm.nih.gov/
21. Im YR, Jagdish R, Leith D, et al. Prevalence of occult hepatitis B virus infection in adults: a systematic
review and meta-analysis. Lancet Gastroenterol Hepatol. 2022 Oct;7(10):932-42. Full text (https://
www.thelancet.com/journals/langas/article/PIIS2468-1253(22)00201-1/fulltext) Abstract (http://
22. Lee WM. Hepatitis B virus infection. N Engl J Med. 1997 Dec 11;337(24):1733-45. Abstract (http://
23. Ganem D, Prince AM. Hepatitis B virus infection - natural history and clinical consequences. N Engl
J Med. 2004 Mar 11;350(11):1118-29. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15014185?
24. Guidotti LG, Rochford R, Chung J, et al. Viral clearance without destruction of infected cells during
acute HBV infection. Science. 1999 Apr 30;284(5415):825-9. Abstract (http://www.ncbi.nlm.nih.gov/
25. Guidotti LG, Ishikawa T, Hobbs MV, et al. Intracellular inactivation of the hepatitis B virus by cytotoxic T
lymphocytes. Immunity. 1996 Jan;4(1):25-36. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/8574849?
26. Chisari FV, Ferrari C. Hepatitis B virus immunopathogenesis. Annu Rev Immunol. 1995;13:29-60.
27. Tuttleman JS, Pourcel C, Summers J. Formation of the pool of covalently closed circular viral DNA
in hepadnavirus-infected cells. Cell. 1986 Nov 7;47(3):451-60. Abstract (http://www.ncbi.nlm.nih.gov/
28. Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev. 2000 Mar;64(1):51-68. Full
text (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC98986) Abstract (http://www.ncbi.nlm.nih.gov/
29. Seeger C, Ganem D, Varmus HE. Biochemical and genetic evidence for the hepatitis B virus
replication strategy. Science. 1986 Apr 25;232(4749):477-84. Abstract (http://www.ncbi.nlm.nih.gov/
30. Newbold JE, Xin H, Tencza M, et al. The covalently closed duplex form of the hepadnavirus genome
exists in situ as a heterogeneous population of viral minichromosomes. J Virol. 1995 Jun;69(6):3350-7.
65
Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC189047/pdf/693350.pdf) Abstract (http://
REFERENCES
31. Zoulim F. New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA.
J Hepatol. 2005 Mar;42(3):302-8. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15710212?
32. Yuen MF, Wong DK, Sum SS, et al. Effect of lamivudine therapy on the serum covalently closed-
circular (ccc) DNA of chronic hepatitis B infection. Am J Gastroenterol. 2005 May;100(5):1099-103.
33. Wursthorn K, Lutgehetmann M, Dandri M, et al. Peginterferon alpha-2b plus adefovir

induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B.
Hepatology. 2006 Sep;44(3):675-84. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16941693?
34. Wong DK, Yuen MF, Ngai VW, et al. One-year entecavir or lamivudine therapy results in reduction of
hepatitis B virus intrahepatic covalently closed circular DNA levels. Antivir Ther. 2006;11(7):909-16.
35. Werle-Lapostolle B, Bowden S, Locarnini S, et al. Persistence of cccDNA during the natural
history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology.
2004 Jun;126(7):1750-8. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15188170?
36. Sung JJ, Wong ML, Bowden S, et al. Intrahepatic hepatitis B virus covalently closed circular DNA can
be a predictor of sustained response to therapy. Gastroenterology. 2005 Jun;128(7):1890-7. Abstract
37. Bourne EJ, Dienstag JL, Lopez VA, et al. Quantitative analysis of HBV cccDNA from clinical
specimens: correlation with clinical and virological response during antiviral therapy. J Viral
Hepat. 2007 Jan;14(1):55-63. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17212645?
38. European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on
the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-98. Full text
(http://www.journal-of-hepatology.eu/article/S0168-8278(17)30185-X/fulltext) Abstract (http://
39. Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features,
viral interactions and treatment. J Gastroenterol Hepatol. 2008 Apr;23(4):512-20. Full text
(http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1746.2008.05384.x/full) Abstract (http://
40. Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined

effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer.
1998 Jan 30;75(3):347-54. Full text (http://onlinelibrary.wiley.com/doi/10.1002/%28SICI
%291097-0215%2819980130%2975:3%3C347::AID-IJC4%3E3.0.CO;2-2/pdf) Abstract (http://
REFERENCES
41. Jamma S, Hussain G, Lau DT. Current concepts of HBV/HCV coinfection: coexistence, but not
necessarily in harmony. Curr Hepat Rep. 2010;9(4):260-9. Full text (http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC3023453) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/21258658?
42. Bellecave P, Gouttenoire J, Gajer M, et al. Hepatitis B and C virus coinfection: a novel model
system reveals the absence of direct viral interference. Hepatology. 2009 Jul;50(1):46-55. Full text
(http://onlinelibrary.wiley.com/doi/10.1002/hep.22951/full) Abstract (http://www.ncbi.nlm.nih.gov/
43. Ghendon Y. Perinatal transmission of hepatitis B virus in high-incidence countries. J Virol

Methods. 1987 Aug;17(1-2):69-79. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/3312269?
44. Goldstein ST, Alter MJ, Williams IT, et al. Incidence and risk factors for acute hepatitis B in the United
States, 1982-1998: implications for vaccination programs. J Infect Dis. 2002 Mar 15;185(6):713-9.
45. Rashti R, Alavian SM, Moradi Y, et al. Global prevalence of HCV and/or HBV coinfections among
people who inject drugs and female sex workers who live with HIV/AIDS: a systematic review
and meta-analysis. Arch Virol. 2020 Sep;165(9):1947-58. Full text (https://www.doi.org/10.1007/
s00705-020-04716-1) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/32617764?
46. Degenhardt L, Peacock A, Colledge S, et al. Global prevalence of injecting drug use and
sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject
drugs: a multistage systematic review. Lancet Glob Health. 2017 Dec;5(12):e1192-e1207. Full text
47. Wasley A, Miller JT, Finelli L. Surveillance for acute viral hepatitis: United States, 2005. MMWR
Surveill Summ. 2007 Mar 16;56(3):1-24. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17363893?
48. World Health Organization. Guidelines for the prevention, care and treatment of persons with
chronic hepatitis B infection. March 2015 [internet publication]. Full text (http://apps.who.int/iris/
bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1&ua=1)
49. Thio CL. Hepatitis B in the human immunodeficiency virus-infected patient: epidemiology, natural
history, and treatment. Semin Liver Dis. 2003 May;23(2):125-36. Abstract (http://www.ncbi.nlm.nih.gov/
50. Strader DB. Understudied populations with hepatitis C. Hepatology. 2002 Nov;36(5 Suppl 1):S226-36.
67
51. Chen G, Wang C, Chen J, et al. Hepatitis B reactivation in hepatitis B and C coinfected
patients treated with antiviral agents: A systematic review and meta-analysis. Hepatology. 2017
Jul;66(1):13-26. Full text (https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.29109)
REFERENCES
52. Mücke MM, Backus LI, Mücke VT, et al. Hepatitis B virus reactivation during direct-acting antiviral
therapy for hepatitis C: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2018
Mar;3(3):172-80. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/29371017?tool=bestpractice.bmj.com)
53. Dodd RY, Notari EP, Stramer SL. Current prevalence and incidence of infectious disease markers and
estimated window-period risk in the American Red Cross blood donor population. Transfusion. 2002
Aug;42(8):975-9. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/12385406?tool=bestpractice.bmj.com)
54. Mahoney FJ, Stewart K, Hu H, et al. Progress toward the elimination of hepatitis B virus transmission
among health care workers in the United States. Arch Intern Med. 1997 Dec 8-22;157(22):2601-5.
55. Harpaz R, Von Seidlein L, Averhoff FM, et al. Transmission of hepatitis B virus to multiple patients from
a surgeon without evidence of inadequate infection control. N Engl J Med. 1996 Feb 29;334(9):549-54.
56. Lettau LA, Smith JD, Williams D, et al. Transmission of hepatitis B with resultant restriction of surgical
practice. JAMA. 1986 Feb 21;255(7):934-7. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/3945000?
57. Singh J, Stoitsova S, Zakrzewska K, et al. Healthcare-associated hepatitis B and C transmission to

patients in the EU/EEA and UK: a systematic review of reported outbreaks between 2006 and 2021.
BMC Public Health. 2022 Dec 3;22(1):2260. Full text (https://bmcpublichealth.biomedcentral.com/
articles/10.1186/s12889-022-14726-0) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/36463162?
58. Bond WW, Favero MS, Petersen NJ, et al. Survival of hepatitis B virus after drying and storage for one
week. Lancet. 1981 Mar 7;1(8219):550-1. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/6111645?
59. Davis LG, Weber DJ, Lemon SM. Horizontal transmission of hepatitis B virus. Lancet.
1989 Apr 22;1(8643):889-93. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/2564960?
60. Falla AM, Hofstraat SHI, Duffell E, et al. Hepatitis B/C in the countries of the EU/EEA: a systematic
review of the prevalence among at-risk groups. BMC Infect Dis. 2018 Feb 12;18(1):79. Full text
61. Cendoroglo Neto M, Draibe SA, Silva AE, et al. Incidence of and risk factors for hepatitis B virus
and hepatitis C virus infection among hemodialysis and CAPD patients: evidence for environmental
transmission. Nephrol Dial Transplant. 1995;10(2):240-6. Abstract (http://www.ncbi.nlm.nih.gov/
62. Khalesi Z, Razizadeh MH, Javadi M, et al. Global epidemiology of HBV infection among hemodialysis
patients: A systematic review and meta-analysis. Microb Pathog. 2023 Jun;179:106080. Abstract
REFERENCES
63. Malinis M, Boucher HW, AST Infectious Diseases Community of Practice. Screening of donor and
candidate prior to solid organ transplantation-Guidelines from the American Society of Transplantation
Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13548. Full text
(https://www.doi.org/10.1111/ctr.13548) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/30900327?
64. Bixler D, Annambhotla P, Montgomery MP, et al. Unexpected hepatitis B virus infection after liver
transplantation - United States, 2014-2019. MMWR Morb Mortal Wkly Rep. 2021 Jul 9;70(27):961-6.
Full text (https://www.doi.org/10.15585/mmwr.mm7027a1) Abstract (http://www.ncbi.nlm.nih.gov/
65. World Health Organization. Guidelines for the prevention, care and treatment of persons with
chronic hepatitis B infection. Mar 2015 [internet publication]. Full text (http://apps.who.int/iris/
bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1&ua=1)
66. Centers for Disease Control and Prevention. Immunization schedules: recommended child and
adolescent immunization schedule for ages 18 years or younger - United States, 2023. Feb 2023
[internet publication]. Full text (https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html)
67. American College of Obstetricians and Gynecologists. Clinical practice guideline no. 6: viral hepatitis
in pregnancy. Sep 2023 [internet publication]. Full text (https://www.acog.org/clinical/clinical-guidance/
clinical-practice-guideline/articles/2023/09/viral-hepatitis-in-pregnancy)
68. Public Health England. Hepatitis B: the green book, chapter 18. Feb 2022 [internet publication]. Full
text (https://www.gov.uk/government/publications/hepatitis-b-the-green-book-chapter-18)
69. Centers for Disease Control and Prevention. Immunization schedules: recommended adult
immunization schedule for ages 19 years or older - United States, 2023. Feb 2023 [internet
publication]. Full text (https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html)
70. Liang TJ. Hepatitis B: the virus and disease. Hepatology. 2009 May;49(5 suppl):S13-21. Full text
71. McMahon BJ, Alward WL, Hall DB, et al. Acute hepatitis B virus infection: relation of age to
the clinical expression of disease and subsequent development of the carrier state. J Infect
Dis. 1985 Apr;151(4):599-603. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/3973412?
72. Lok AS, Liang RH, Chiu EK, et al. Reactivation of hepatitis B virus replication in patients receiving
cytotoxic therapy. Report of a prospective study. Gastroenterology. 1991 Jan;100(1):182-8.
Full text (https://www.gastrojournal.org/article/0016-5085(91)90599-G/pdf?referrer=https%3A
%2F%2Fwww.ncbi.nlm.nih.gov%2F) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/1983820?
69
73. Ostuni P, Botsios C, Punzi L, et al. Hepatitis B reactivation in a chronic hepatitis B surface
antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate.
Ann Rheum Dis. 2003 Jul;62(7):686-7. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/
REFERENCES
PMC1754595/pdf/v062p00686.pdf) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/12810441?

74. Amini A, Varsaneux O, Kelly H, et al. Diagnostic accuracy of tests to detect hepatitis B surface
antigen: a systematic review of the literature and meta-analysis. BMC Infect Dis. 2017 Nov 1;17(suppl
1):698. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688498) Abstract (http://
75. Chou C, Veracruz N, Chitnis AS, et al. Risk of drug-induced liver injury in chronic hepatitis
B and tuberculosis co-infection: a systematic review and meta-analysis. J Viral Hepat.
2022 Dec;29(12):1107-14. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/36138556?
76. Wong RJ, Hubbard A, Bagley L, et al. Estimating prevalence of hepatitis B virus coinfection among
adults with tuberculosis: a systematic review with meta-analysis. J Clin Gastroenterol. 2022 Aug
1;56(7):601-17. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/34009841?tool=bestpractice.bmj.com)
77. West J, Card TR. Reduced mortality rates following elective percutaneous liver biopsies.
Gastroenterology. 2010 Oct;139(4):1230-7. Full text (http://www.gastrojournal.org/article/
S0016-5085(10)00874-7/fulltext) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20547160?
78. Cardoso AC, Carvalho-Filho RJ, Marcellin P. Transient elastography in chronic viral hepatitis: a critical
appraisal. Gut. 2011 Jun;60(6):759-64. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/21450696?
79. Cardoso AC, Carvalho-Filho RJ, Stern C, et al. Direct comparison of diagnostic performance
of transient elastography in patients with chronic hepatitis B and chronic hepatitis C. Liver
Int. 2012 Apr;32(4):612-21. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/22103765?
80. Castéra L. Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients
with viral hepatitis. J Viral Hepatol. 2009 May;16(5):300-14. Abstract (http://www.ncbi.nlm.nih.gov/
81. Castéra L, Bernard PH, Le Bail P, et al. Transient elastography and biomarkers for liver fibrosis
assessment and follow-up of inactive hepatitis B carriers. Aliment Pharmacol Ther. 2011
Feb;33(4):455-65. Full text (http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2010.04547.x/full)
82. Fraquelli M, Branchi F. The role of transient elastography in patients with hepatitis B viral disease. Dig
Liver Dis. 2011 Jan;43 Suppl 1:S25-31. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/21195369?
83. Marcellin P, Ziol M, Bedossa P, et al. Non-invasive assessment of liver fibrosis by stiffness
measurement in patients with chronic hepatitis B. Liver Int. 2009 Feb;29(2):242-7. Abstract (http://
REFERENCES
84. Poynard T, Morra R, Halfon P, et al. Meta-analyses of FibroTest diagnostic value in chronic liver
disease. BMC Gastroenterol. 2007;7:40. Full text (http://www.biomedcentral.com/1471-230X/7/40)
85. Yin Z, Zou J, Li Q, et al. Diagnostic value of FIB-4 for liver fibrosis in patients with hepatitis B:
a meta-analysis of diagnostic test. Oncotarget. 2017 Apr 4;8(14):22944-53. Full text (https://
www.ncbi.nlm.nih.gov/pmc/articles/PMC5410276) Abstract (http://www.ncbi.nlm.nih.gov/
86. Arena U, Vizzutti F, Corti G, et al. Acute viral hepatitis increases liver stiffness values measured by
transient elastography. Hepatology. 2008 Feb;47(2):380-4. Full text (http://onlinelibrary.wiley.com/
doi/10.1002/hep.22007/full) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18095306?
87. Tsochatzis EA, Gurusamy KS, Ntaoula S, et al. Elastography for the diagnosis of severity of fibrosis
in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol. 2011 Apr;54(4):650-9.
88. Xiao H, Shi M, Xie Y, et al. Comparison of diagnostic accuracy of magnetic resonance elastography
and Fibroscan for detecting liver fibrosis in chronic hepatitis B patients: A systematic review and
meta-analysis. PLoS One. 2017 Nov 6;12(11):e0186660. Full text (https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC5673175) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/29107943?
89. Centers for Disease Control and Prevention. Public Health Service inter-agency guidelines for
screening donors of blood, plasma, organs, tissues, and semen for evidence of hepatitis B and
hepatitis C. MMWR Recomm Rep. 1991 Apr 19;40(RR-4):1-17. Abstract (http://www.ncbi.nlm.nih.gov/
90. Saldanha J, Gerlich W, Lelie N, et al; WHO Collaborative Study Group. An international collaborative
study to establish a World Health Organization international standard for hepatitis B virus DNA nucleic
acid amplification techniques. Vox Sang. 2001 Jan;80(1):63-71. Abstract (http://www.ncbi.nlm.nih.gov/
91. Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance,
and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J
Gastroenterol. 2006 Mar;101(3):513-23. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16542288?
92. Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular
carcinoma in patients with hepatitis C. A systematic review and critical analysis. Ann Intern
Med. 2003 Jul 1;139(1):46-50. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/12834318?
71
93. Soresi M, Magliarisi C, Campagna P, et al. Usefulness of alpha-fetoprotein in the diagnosis
of hepatocellular carcinoma. Anticancer Res. 2003 Mar-Apr;23(2C):1747-53. Abstract (http://
REFERENCES
94. Conners EE, Panagiotakopoulos L, Hofmeister MG, et al. Screening and testing for hepatitis B
virus infection: CDC recommendations - United States, 2023. MMWR Recomm Rep. 2023 Mar
10;72(1):1-25. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997714) Abstract (http://
95. US Preventive Services Task Force. Final recommendation statement. Hepatitis B virus
infection in adolescents and adults: screening. Dec 2020 [internet publication]. Full text (https://
uspreventiveservicestaskforce.org/uspstf/recommendation/hepatitis-b-virus-infection-screening)
96. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients
with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020 Nov
1;38(31):3698-715. Full text (https://www.doi.org/10.1200/JCO.20.01757) Abstract (http://
97. Mantzoukis K, Rodríguez-Perálvarez M, Buzzetti E, et al. Pharmacological interventions for

acute hepatitis B infection. Cochrane Database Syst Rev. 2017 Mar 21;(3):CD011645. Full text
98. Papatheodoridis GV, Lampertico P, Manolakopoulos S, et al. Incidence of hepatocellular

carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review.
J Hepatol. 2010 Aug;53(2):348-56. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20483498?
99. Wong GL, Yiu KK, Wong VW, et al. Meta-analysis: reduction in hepatic events following interferon-
alfa therapy of chronic hepatitis B. Aliment Pharmacol Ther. 2010 Nov;32(9):1059-68. Full
text (http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2010.04447.x/full) Abstract (http://
100. Sung JJ, Tsoi KK, Wong VW, et al. Meta-analysis: treatment of hepatitis B infection reduces risk
of hepatocellular carcinoma. Aliment Pharmacol Ther. 2008 Nov 1;28(9):1067-77. Abstract (http://
101. Miyake Y, Kobashi H, Yamamoto K. Meta-analysis: the effect of interferon on development

of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J
Gastroenterol. 2009;44(5):470-5. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19308310?
102. Tang LSY, Covert E, Wilson E, et al. Chronic hepatitis B infection: a review. JAMA. 2018
May 1;319(17):1802-13. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/29715359?
103. Lampertico P, Buti M, Fung S, et al. Switching from tenofovir disoproxil fumarate to tenofovir
alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-
blind, phase 3, multicentre non-inferiority study. Lancet Gastroenterol Hepatol. 2020 May;5(5):441-53.
REFERENCES
104. Lim YS, Seto WK, Kurosaki M, et al. Review article: switching patients with chronic hepatitis B to
tenofovir alafenamide-a review of current data. Aliment Pharmacol Ther. 2022 Apr;55(8):921-43. Full
text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304567) Abstract (http://www.ncbi.nlm.nih.gov/
105. Chan HLY, Buti M, Lim YS, et al. Long-term treatment with tenofovir alafenamide for
chronic hepatitis B results in high rates of viral suppression and favorable renal and
bone safety. Am J Gastroenterol. 2023 Aug 10. Full text (https://journals.lww.com/ajg/
fulltext/9900/long_term_treatment_with_tenofovir_alafenamide_for.837.aspx) Abstract (http://
106. Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-
positive chronic hepatitis B. Gastroenterology. 2007 Nov;133(5):1437-44. Abstract (http://
107. Yim HJ, Kim JH, Park JY, et al. Comparison of clinical practice guidelines for the management
of chronic hepatitis B: When to start, when to change, and when to stop. Clin Mol Hepatol.
2020 Oct;26(4):411-29. Full text (https://www.e-cmh.org/journal/view.php) Abstract (http://
108. Choi WM, Yip TC, Wong GL, et al. Hepatocellular carcinoma risk in patients with chronic hepatitis
B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis.
J Hepatol. 2023 Mar;78(3):534-42. Full text (https://www.journal-of-hepatology.eu/article/
S0168-8278(22)03459-6/fulltext) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/36572349?
109. Tang K, Cheng H, Wang H, et al. Meta-analysis of the occurrence of hepatocellular carcinoma
after the treatment of entecavir and tenofovir for chronic hepatitis B. Medicine (Baltimore).
2023 Feb 10;102(6):e32894. Full text (https://journals.lww.com/md-journal/fulltext/2023/02100/
meta_analysis_of_the_occurrence_of_hepatocellular.28.aspx) Abstract (http://www.ncbi.nlm.nih.gov/
110. Tseng CH, Hsu YC, Chen TH, et al. Hepatocellular carcinoma incidence with tenofovir versus entecavir
in chronic hepatitis B: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020
Dec;5(12):1039-52. Full text (https://www.doi.org/10.1016/S2468-1253(20)30249-1) Abstract (http://
111. Huang ZH, Lu GY, Qiu LX, et al. Risk of hepatocellular carcinoma in antiviral treatment-naïve
chronic hepatitis B patients treated with entecavir or tenofovir disoproxil fumarate: a network meta-
analysis. BMC Cancer. 2022 Mar 17;22(1):287. Full text (https://bmccancer.biomedcentral.com/
articles/10.1186/s12885-022-09413-7) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/35300634?
112. Tan DJH, Ng CH, Tay PWL, et al. Risk of hepatocellular carcinoma with tenofovir vs entecavir
treatment for chronic hepatitis B virus: a reconstructed individual patient data meta-analysis.
JAMA Netw Open. 2022 Jun 1;5(6):e2219407. Full text (https://jamanetwork.com/journals/
73
jamanetworkopen/fullarticle/2793772) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/35767258?
REFERENCES
113. Giri S, Agrawal D, Afzalpurkar S, et al. Tenofovir versus entecavir for tertiary prevention of
hepatocellular carcinoma in chronic hepatitis B infection after curative therapy: a systematic review
and meta-analysis. J Viral Hepat. 2023 Feb;30(2):108-15. Abstract (http://www.ncbi.nlm.nih.gov/
114. Liu H, Han CL, Tian BW, et al. Tenofovir versus entecavir on the prognosis of hepatitis B virus-
related hepatocellular carcinoma: a systematic review and meta-analysis. Expert Rev Gastroenterol
Hepatol. 2023 Jan-Jun;17(6):623-33. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/37148261?
115. Carosi G, Rizzetto M, Alberti A, et al. Treatment of chronic hepatitis B: update of the recommendations
from the 2007 Italian Workshop. Dig Liver Dis. 2011 Apr;43(4):259-65. Abstract (http://
116. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced
liver disease. N Engl J Med. 2004 Oct 7;351(15):1521-31. Full text (http://www.nejm.org/doi/
full/10.1056/NEJMoa033364#t=article) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15470215?
117. Papatheodoridis GV, Dimou E, Dimakopoulos K, et al. Outcome of hepatitis B e antigen-negative

chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology.
2005 Jul;42(1):121-9. Full text (http://onlinelibrary.wiley.com/doi/10.1002/hep.20760/full) Abstract
118. Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/
cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010
Sep;52(3):886-93. Full text (http://onlinelibrary.wiley.com/doi/10.1002/hep.23785/full) Abstract (http://
119. Buster EH, Hansen BE, Buti M, et al; HBV 99-01 Study Group. Peginterferon alpha-2b is safe and
effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis. Hepatology. 2007
Aug;46(2):388-94. Full text (http://onlinelibrary.wiley.com/doi/10.1002/hep.21723/full) Abstract (http://
120. Yao Y, Zhang J, Li X, et al. Systematic review: clinical outcomes of discontinuation of oral antivirals
in hepatitis B-related liver cirrhosis. Front Public Health. 2022;10:1037527. Full text (https://
www.frontiersin.org/articles/10.3389/fpubh.2022.1037527/full) Abstract (http://www.ncbi.nlm.nih.gov/
121. Perrillo R, Tamburro C, Regenstein F, et al. Low-dose, titratable interferon alfa in decompensated liver
disease caused by chronic infection with hepatitis B virus. Gastroenterology. 1995 Sep;109(3):908-16.
122. Lange CM, Bojunga J, Hofmann WP, et al. Severe lactic acidosis during treatment of chronic hepatitis
B with entecavir in patients with impaired liver function. Hepatology. 2009 Dec;50(6):2001-6. Full
text (http://onlinelibrary.wiley.com/doi/10.1002/hep.23346/full) Abstract (http://www.ncbi.nlm.nih.gov/
REFERENCES
123. Altfeld M, Rockstroh JK, Addo M, et al. Reactivation of hepatitis B in a long-term anti-HBs-positive
patient with AIDS following lamivudine withdrawal. J Hepatol. 1998 Aug;29(2):306-9. Abstract (http://
124. National Institutes of Health, Centers for Disease Control and Prevention, and HIV Medicine
Association of the Infectious Disease Society of America Panel on Guidelines for the Prevention and
Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the prevention
and treatment of opportunistic infections in adults and adolescents with HIV: hepatitis B virus infection.
2023 [internet publication]. Full text (https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-
adult-and-adolescent-opportunistic-infections/hepatitis-b-0?view=full)
125. Jiang XW, Ye JZ, Li YT, et al. Hepatitis B reactivation in patients receiving direct-acting antiviral
therapy or interferon-based therapy for hepatitis C: A systematic review and meta-analysis. World
J Gastroenterol. 2018 Jul 28;24(28):3181-91. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/
126. Yurdaydın C, Idilman R, Bozkaya H, et al. Natural history and treatment of chronic delta hepatitis.
J Viral Hepat. 2010 Nov;17(11):749-56. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20723036?
127. World Health Organization. Prevention of mother-to-child transmission of hepatitis B virus: guidelines
on antiviral prophylaxis in pregnancy. Jul 2020 [internet publication]. Full text (https://www.who.int/
publications/i/item/978-92-4-000270-8)
128. Funk AL, Lu Y, Yoshida K, et al. Efficacy and safety of antiviral prophylaxis during pregnancy to
prevent mother-to-child transmission of hepatitis B virus: a systematic review and meta-analysis.
Lancet Infect Dis. 2021 Jan;21(1):70-84. Full text (https://hal.science/pasteur-03697722) Abstract
129. Ugwu EO, Eleje GU, Ugwu AO, et al. Antivirals for prevention of hepatitis B virus mother-to-
child transmission in human immunodeficiency virus positive pregnant women co-infected with
hepatitis B virus. Cochrane Database Syst Rev. 2023 Jun 12;6(6):CD013653. Abstract (http://
130. Hyun MH, Lee YS, Kim JH, et al. Systematic review with meta-analysis: the efficacy and safety
of tenofovir to prevent mother-to-child transmission of hepatitis B virus. Aliment Pharmacol
Ther. 2017 Jun;45(12):1493-505. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/28436552?
131. Li W, Jia L, Zhao X, et al. Efficacy and safety of tenofovir in preventing mother-to-infant transmission of
hepatitis B virus: a meta-analysis based on 6 studies from China and 3 studies from other countries.
BMC Gastroenterol. 2018 Aug 2;18(1):121. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/
75
132. Tavakolpour S, Darvishi M, Mirsafaei HS, et al. Nucleoside/nucleotide analogues in the treatment
of chronic hepatitis B infection during pregnancy: a systematic review. Infect Dis (Lond). 2017 Oct
REFERENCES
133. Zhu L, Park J, Deng Y, et al. The use of tenofovir disoproxil fumarate and tenofovir alafenamide for
preventing vertical transmission of hepatitis B. J Clin Gastroenterol. 2023 Feb 1;57(2):127-38. Abstract
134. Han GR, Cao MK, Zhao W, et al. A prospective and open-label study for the efficacy and safety of
telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection.
J Hepatol. 2011 Dec;55(6):1215-21. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/21703206?
135. Shi Z, Yang Y, Ma L, et al. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B
virus: systematic review and meta-analysis. Obstet Gynecol. 2010 Jul;116(1):147-59. Abstract (http://
136. Su GG, Pan KH, Zhao NF, et al. Efficacy and safety of lamivudine treatment for chronic hepatitis B in
pregnancy. World J Gastroenterol. 2004 Mar 15;10(6):910-2. Abstract (http://www.ncbi.nlm.nih.gov/
137. van Zonneveld M, van Nunen AB, Niesters HG, et al. Lamivudine treatment during pregnancy to
prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat. 2003 Jul;10(4):294-7.
138. Xu WM, Cui YT, Wang L, et al. Lamivudine in late pregnancy to prevent perinatal transmission of
hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. J
Viral Hepat. 2009 Feb;16(2):94-103. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19175878?
139. He R, Wen P, Xiong M, et al. Cesarean section in reducing mother-to-child HBV transmission:
a meta-analysis. J Matern Fetal Neonatal Med. 2022 Sep;35(18):3424-32. Abstract (http://
140. European Association for the Study of the Liver. EASL clinical practice guidelines on the management
of liver diseases in pregnancy. J Hepatol. 2023 Sep;79(3):768-828. Full text (https://www.journal-
of-hepatology.eu/article/S0168-8278(23)00181-2/fulltext) Abstract (http://www.ncbi.nlm.nih.gov/
141. Shi Z, Yang Y, Wang H, et al. Breastfeeding of newborns by mothers carrying hepatitis B virus: a meta-
analysis and systematic review. Arch Pediatr Adolesc Med. 2011 Sep;165(9):837-46. Abstract (http://
142. Li M, Li Q, Qu J, et al. The effectiveness of combination therapy with interferon and nucleoside
analogs in pediatric patients with chronic hepatitis B: a systematic review and meta-analysis.
Hepatol Int. 2023 Feb;17(1):52-62. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/36469299?
143. Lampertico P, Buti M, Fung S, et al. Switching from tenofovir disoproxil fumarate to tenofovir
alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-
blind, phase 3, multicentre non-inferiority study. Lancet Gastroenterol Hepatol. 2020 May;5(5):441-53.
REFERENCES
144. Lim YS, Seto WK, Kurosaki M, et al. Review article: switching patients with chronic hepatitis B to
tenofovir alafenamide-a review of current data. Aliment Pharmacol Ther. 2022 Apr;55(8):921-43. Full
text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304567) Abstract (http://www.ncbi.nlm.nih.gov/
145. Chan HLY, Buti M, Lim YS, et al. Long-term treatment with tenofovir alafenamide for
chronic hepatitis B results in high rates of viral suppression and favorable renal and
bone safety. Am J Gastroenterol. 2023 Aug 10. Full text (https://journals.lww.com/ajg/
fulltext/9900/long_term_treatment_with_tenofovir_alafenamide_for.837.aspx) Abstract (http://
146. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic
147. Yao Y, Zhang J, Li X, et al. Systematic review: clinical outcomes of discontinuation of oral antivirals
in hepatitis B-related liver cirrhosis. Front Public Health. 2022;10:1037527. Full text (https://
www.frontiersin.org/articles/10.3389/fpubh.2022.1037527/full) Abstract (http://www.ncbi.nlm.nih.gov/
148. Hyun MH, Lee YS, Kim JH, et al. Systematic review with meta-analysis: the efficacy and safety
of tenofovir to prevent mother-to-child transmission of hepatitis B virus. Aliment Pharmacol
Ther. 2017 Jun;45(12):1493-505. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/28436552?
149. Li W, Jia L, Zhao X, et al. Efficacy and safety of tenofovir in preventing mother-to-infant transmission of
hepatitis B virus: a meta-analysis based on 6 studies from China and 3 studies from other countries.
BMC Gastroenterol. 2018 Aug 2;18(1):121. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/
150. Tavakolpour S, Darvishi M, Mirsafaei HS, et al. Nucleoside/nucleotide analogues in the treatment
of chronic hepatitis B infection during pregnancy: a systematic review. Infect Dis (Lond). 2017 Oct
151. Zhu L, Park J, Deng Y, et al. The use of tenofovir disoproxil fumarate and tenofovir alafenamide for
preventing vertical transmission of hepatitis B. J Clin Gastroenterol. 2023 Feb 1;57(2):127-38. Abstract
152. Papatheodoridi M, Papatheodoridis GV. State-of-the-art and emerging antivirals for chronic
hepatitis B infection. Expert Opin Pharmacother. 2022 Dec;23(18):1999-2012. Abstract (http://
77
153. Bloom K, Maepa MB, Ely A, et al. Gene therapy for chronic HBV-can we eliminate cccDNA? Genes
(Basel). 2018 Apr 12;9(4). Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924549)
REFERENCES
154. Soriano V, Sherman KE, Barreiro P. Hepatitis delta and HIV infection. AIDS. 2017 Apr
155. Hepatitis B Foundation. Treatment options: drug watch. Dec 2023 [internet publication]. Full text
(https://www.hepb.org/treatment-and-management/drug-watch)
156. Wang Y, Xiong J, Niu M, et al. Statins and the risk of cirrhosis in hepatitis B or C patients: a
systematic review and dose-response meta-analysis of observational studies. Oncotarget. 2017 Jul
27;8(35):59666-76. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601766) Abstract
157. Simon TG, Duberg AS, Aleman S, et al. Lipophilic statins and risk for hepatocellular carcinoma and
death in patients with chronic viral hepatitis: results from a nationwide Swedish population. Ann
Intern Med. 2019 Sep 3;171(5):318-27. Full text (www.doi.org/10.7326/M18-2753) Abstract (http://
158. Vahedian-Azimi A, Shojaie S, Banach M, et al. Statin therapy in chronic viral hepatitis: a
systematic review and meta-analysis of nine studies with 195,602 participants. Ann Med. 2021
Dec;53(1):1227-42. Full text (https://www.doi.org/10.1080/07853890.2021.1956686) Abstract (http://
159. Li Z, Li Y, Li X, et al. Statins in Hepatitis B or C patients is associated with reduced hepatocellular

carcinoma risk: a systematic review and meta-analysis. Turk J Gastroenterol. 2022 Feb;33(2):136-44.
Full text (https://turkjgastroenterol.org/en/statins-in-hepatitis-b-or-c-patients-is-associated-with-
reduced-hepatocellular-carcinoma-risk-a-systematic-review-and-meta-analysis-136860) Abstract
160. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with
interferon alfa for chronic hepatitis B. N Engl J Med. 1996 May 30;334(22):1422-7. Abstract (http://
161. Gish RG, Chang TT, Lai CL, et al. Loss of HBsAg antigen during treatment with entecavir or
lamivudine in nucleoside-naive HBeAg-positive patients with chronic hepatitis B. J Viral Hepat. 2010
Jan;17(1):16-22. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19622117?tool=bestpractice.bmj.com)
162. 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 Feb;43(2 Suppl 1):S173-81. Abstract (http://www.ncbi.nlm.nih.gov/
163. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012
May;142(6):1264-73.e1. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338949) Abstract
164. Chang TE, Su CW, Huang YS, et al. Hepatitis D virus dual infection increased the risk of
hepatocellular carcinoma compared with hepatitis B virus mono infection: A meta-analysis. J Chin Med
Assoc. 2022 Jan 1;85(1):30-41. Full text (https://www.doi.org/10.1097/JCMA.0000000000000606)
REFERENCES
165. Bosch FX, Ribes J, Cleries R, et al. Epidemiology of hepatocellular carcinoma. Clin Liver
Dis. 2005 May;9(2):191-211, v. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15831268?
166. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N
Engl J Med. 2002 Jul 18;347(3):168-74. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/12124405?
167. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis
B viral load. Gastroenterology. 2006 Mar;130(3):678-86. Abstract (http://www.ncbi.nlm.nih.gov/
168. Kuang XJ, Jia RR, Huo RR, et al. Systematic review of risk factors of hepatocellular carcinoma after
hepatitis B surface antigen seroclearance. J Viral Hepat. 2018 May 2;25(9):1026-37. Abstract (http://
169. Tsuboi R, Sanada T, Takamori K, et al. Isolation and properties of extracellular proteinases from
Sporothrix schenckii. J Bacteriol. 1987 Sep;169(9):4104-9. Full text (https://www.doi.org/10.1128/
jb.169.9.4104-4109.1987) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/3305479?
170. Kamal H, Fornes R, Simin J, et al. Risk of hepatocellular carcinoma in hepatitis B and D virus co-
infected patients: a systematic review and meta-analysis of longitudinal studies. J Viral Hepat.
2021 Oct;28(10):1431-42. Full text (https://www.doi.org/10.1111/jvh.13577) Abstract (http://
171. Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological
modifier therapies: current concepts, management strategies, and future directions. Gastroenterology.
2017 May;152(6):1297-309. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501983)
172. Shi Y, Zheng M. Hepatitis B virus persistence and reactivation. BMJ. 2020 Sep 1;370:m2200. Full text
(https://www.doi.org/10.1136/bmj.m2200) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/32873599?
173. Papatheodoridi M, Tampaki M, Lok AS, et al. Risk of HBV reactivation during therapies for HCC:
a systematic review. Hepatology. 2022 May;75(5):1257-74. Full text (https://www.doi.org/10.1002/
hep.32241) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/34918361?tool=bestpractice.bmj.com)
174. Smedile A, Farci P, Verme G, et al. Influence of delta infection on severity of hepatitis B.
Lancet. 1982 Oct 30;2(8305):945-7. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/6127458?
79
175. Feray C, Gigou M, Samuel D, et al. Hepatitis C virus RNA and hepatitis B virus DNA in serum and
liver of patients with fulminant hepatitis. Gastroenterology. 1993 Feb;104(2):549-55. Abstract (http://
REFERENCES
176. Fabrizi F, Dixit V, Martin P. Meta-analysis: anti-viral therapy of hepatitis B virus-associated

glomerulonephritis. Aliment Pharmacol Ther. 2006 Sep 1;24(5):781-8. Abstract (http://
177. Kamiza AB, Fatumo S, Singini MG, et al Hepatitis B infection is causally associated with extrahepatic
cancers: a Mendelian randomization study. EBioMedicine. 2022 May;79:104003. Full text
178. Lee DH, Chung SW, Lee JH, et al. Association of chronic hepatitis B infection and antiviral
treatment with the development of the extrahepatic malignancies: a nationwide cohort study. J Clin
Oncol. 2022 Oct 10;40(29):3394-405. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/35561284?
179. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507-39. Full text (http://
onlinelibrary.wiley.com/doi/10.1002/hep.21513/full) Abstract (http://www.ncbi.nlm.nih.gov/
180. Buti M, Wong DK, Gane E, et al. Safety and efficacy of stopping tenofovir disoproxil fumarate in
patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis
of two randomised trials. Lancet Gastroenterol Hepatol. 2019 Apr;4(4):296-304. Abstract (http://
181. World Health Organization. New good practice statement on counselling behavioural interventions
for key populations to prevent HIV, viral hepatitis and STIs. Jun 2023 [internet publication]. Full text
(https://www.who.int/publications/i/item/9789240072275)
Hepatitis B Images
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Figure 1: Life cycle of HBV

IMAGES
From Ganem D, Prince AM. Hepatitis B virus infection - natural history and clinical consequences. N Engl J
Med. 2004; 350:1118-1129; used with permission
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Contributors:
// Authors:
Jawad Ahmad, MD, FRCP, FAASLD

Professor of Medicine
Division of Liver Diseases, Mount Sinai Hospital, New York, NY
DISCLOSURES: JA declares that he has no competing interests.
// Acknowledgements:
Dr Jawad Ahmad would like to gratefully acknowledge Dr Sateesh R. Prakash, Dr Siddarth Verma, Dr
Smruti R. Mohanty, and Dr Jared Hossack, previous contributors to this topic.
DISCLOSURES: SRP, SV, and JH declare that they have no competing interests. SRM serves as a speaker
bureau for Bristol-Myers Squibb regarding the use of entecavir for the treatment of chronic hepatitis B.
// Peer Reviewers:
George Y. Wu, MD, PhD

Chief
Hepatology Section, Department of Medicine, University of Connecticut Health Center, Farmington, CT
DISCLOSURES: GYW is on the medical advisory boards of Gilead Sciences and Bristol-Myers Squibb.
Lucieni Oliveira Conterno, MD, PhD

Director
Clinical Epidemiology Unit, Marilia Medical School, Sao Paulo, Brazil
DISCLOSURES: LOC declares that she has no competing interests.
Mamun-Al-Mahtab, MB BS, MSc, MD

Chairman
Bangladesh Primary Care Research Network, Dhaka, Bangladesh
DISCLOSURES: MAM declares that he has no competing interests.

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Hepatitis B

Straight to the point of care

Last updated: Jan 10, 2024

The US and UK have historically been regions of low prevalence.

Life cycle of HBV

Worldwide distribution of genotypes varies.[8]

• Genotype C is the genotype most associated with cirrhosis and HCC.

• Serological markers include:

• Hepatitis B surface antigen (HBsAg)

antiviral therapy, or those who experience virological breakthrough during treatment.[2]

Liver disease staging

Other diagnostic factors

maculopapular or urticarial rash (uncommon)

right upper quadrant pain (uncommon)

palmar erythema (uncommon)

spider angiomata (uncommon)

high-risk sexual behaviours

injection drug use

born in highly endemic region

family history of HBV, hepatocellular carcinoma, and/or chronic liver disease

household contact with HBV infection

infected with HIV

infected with hepatitis C virus

blood or blood product transfusion

solid organ transplantation

syndrome in cirrhosis of the liver.

Other tests to consider

Condition Differentiating signs / Differentiating tests

Acute hepatitis C virus • There may be no differences • Serum hepatitis C virus

Cytomegalovirus • May have history of • Serum cytomegalovirus

Herpes simplex virus • Patient may be • Serum herpes simplex virus

Condition Differentiating signs / Differentiating tests

Acute alcoholic hepatitis • There may be no differences • Negative serological tests

Autoimmune hepatitis • There may be no differences • There may be increased

Biliary obstruction • Symptoms associated • Ultrasound, CT scan, or

Metastatic liver diseases • Patients may be • CT scan or MRI of abdomen

Condition Differentiating signs / Differentiating tests

Budd-Chiari syndrome • There may be no differences • Doppler ultrasound

Acute fat ty liver of • Pregnant patient may • Diagnosis of exclusion

Wilson's disease • There may be no differences • Increased urinary

Haemochromatosis • There may be no differences • High iron saturation (>45%

• Chronic hepatitis B (CHB):

• Hepatitis B surface antigen (HBsAg): present for ≥6 months

• HBsAg: present for ≥6 months

• HBsAg: present for ≥6 months

• HBsAg: present for ≥6 months

• Loss of HBV immune control in HBsAg‐positive/antibody to hepatitis B core antigen (anti‐HBc)-

European Association for the Study of the Liver (EASL) phases of

chronic HBV infection[38]

Centers for Disease Control and Prevention (CDC)

• Infants born to a HBsAg-positive mother

American Association for the Study of Liver Diseases (AASLD)

• Inmates of correctional facilities

US Preventive Services Task Force (USPSTF)

American Society of Clinical Oncology (ASCO)

The American College of Obstetricians and Gynecologists

Treatment of acute infection

Treatment of chronic infection: general principles

and take 20 to 30 years.

Treatment of chronic infection: without cirrhosis

Immune-active chronic HBV infection

mortality after resection or ablation of HCC compared with entecavir.[113] [114]

Treatment of chronic infection: with cirrhosis

Treatment of chronic infection: with co-infections