2015 Hepatitis B PDF

World Gastroenterology Organisation Global Guideline
Hepatitis B
Version 2.0, February 2015
Chairs
J. Feld (Canada) and H.L.A. Janssen (Canada/Netherlands)
Review team
Z. Abbas (Pakistan)
A. Elewaut (Belgium)
P. Ferenci (Austria)
V. Isakov (Russia)
A.G. Khan (Pakistan)
S.G. Lim (Singapore)
S. Locarnini (Australia)
S.K. Ono (Brazil)
J. Sollano (Phillippines)
C.W. Spearman (South Africa)
C.T. Yeh (Taiwan)
M.F. Yuen (Hong Kong)
A.W. LeMair (Netherlands)
WGO Global Guideline Hepatitis B 2
Contents
1 Introduction 4
1.1 WGO Cascades 4
1.2 Epidemiology and transmission of hepatitis B 4
2 Clinical course of HBV infection 7
2.1 Natural history 7
2.2 Chronic HBV infection 7
2.3 CHB disease phases 8
2.4 Progression of CHB 9
3 Diagnosis and monitoring of hepatitis B 10
3.1 Cascade—acute hepatitis B 10
3.2 Resolved HBV infection 11
3.3 Chronic HBV infection 12
3.4 Initial evaluation of patients with chronic HBV infection 13
3.5 Occult HBV 14
3.6 HBV reactivation 15
3.7 HCC screening 16
4 Treatment for CHB 17
4.1 Cascades for CHB management—a resource-sensitive approach 19
4.2 Treatment for CHB 22
4.3 Coinfection 26
4.4 Pregnancy 28
5 Hepatitis B vaccination 28
5.1 Active vaccination with hepatitis B vaccine 29
5.2 Passive vaccination with hepatitis B immunoglobulin 29
5.3 Preexposure prophylaxis 29
5.4 Vaccination schedules 29
5.5 Postexposure prophylaxis 30
5.6 Pregnancy and hepatitis B vaccination 31
6 Appendix 31
6.1 Abbreviations 31
6.2 References 32
Cascades—resource-sensitive options
Cascade 1 Diagnostic tests for acute hepatitis B 11
Cascade 2 Immunotolerant phase monitoring (no therapy) 19
Cascade 3 Immunoactive phase monitoring (off therapy) 19
Cascade 4 Immune-control phase monitoring, HBeAg-negative (off therapy) 20
Cascade 5 Reactivation phase monitoring, HBeAg-negative (off therapy) 20
Cascade 6 Immunoactive phase monitoring, HBeAg-positive (IFN-based therapy) 20
Cascade 7 Immunoactive phase monitoring, HBeAg-positive (on NA therapy) 21
Cascade 8 Reactivation phase monitoring, HBeAg-negative (on NA therapy) 21
Tables
Table 1 Geographical distribution of genotypes and subgenotypes of HBV infection 6
Table 2 Risk of chronicity and age at primary infection 7
Table 3 Factors in the disease outcome with chronic hepatitis B 10
Table 4 Differentiation of phases of CHB infection 12
Table 5 Host and viral risk factors associated with progression of chronic hepatitis B 14
Table 6 Approved drugs for chronic hepatitis B 22
Table 7 Treatment of HBeAg-negative and HBeAg-positive chronic hepatitis B 22
© World Gastroenterology Organisation, 2015

Figures
Fig. 1 Geographic distribution of hepatitis B virus genotypes worldwide 5
Fig. 2 Sequence of serologic markers in acute hepatitis B infection 8
Fig. 3 Markers and natural history of chronic hepatitis B infection 9
Fig. 4 Risk of progression in patients with HBV-related cirrhosis 10
Fig. 5 APASL algorithm for all candidates for chemotherapy 16
Fig. 6 Management of chronic HBeAg-positive infection 18
Fig. 7 Management of chronic HBeAg-negative infection 18

1 Introduction
The hepatitis B virus (HBV) causes acute and chronic liver disease and is endemic in
many areas of the world. The virus is transmitted through contact with blood or other
body fluids from an infected person.
• When transmission occurs vertically (from mother to child) or horizontally to
small children (during play, from household contacts etc), the infection usually
becomes chronic.
• By contrast, when transmission occurs in adolescents/adults—usually via sexual
contact, contaminated needles (“sharps”), and less often from transfusion of
blood products—the infection usually resolves unless the individual is
immunocompromised (e.g., infected with human immunodeficiency virus).
• Education about how to avoid risky behavior plays an important role in HBV
prevention.
• HBV is an important occupational hazard for health-care workers.
• A safe and effective vaccine for HBV has been available since 1982 and is 95%
effective at preventing new infections.
Every individual with chronic HBV infection (CHB) represents an opportunity for
further cases to be prevented. It is important to take the time needed to educate
patients and to explain the risks that the infection poses to the patients themselves and
to others.
• HBV vaccination is highly effective, and universal vaccination at a young age—
preferably at birth in high-endemicity countries—is desirable.
• At the very least, vaccination should be offered to all individuals who are at risk.
• Pregnant women must be screened for HBV before delivery, as this offers an
opportunity to prevent another generation of chronically infected persons.
Although most patients with CHB do not develop hepatic complications, all
infected individuals are at increased risk of progressive liver fibrosis, leading to
cirrhosis and ultimately to hepatic decompensation and/or hepatocellular carcinoma
(HCC). Fortunately, effective treatment can reduce the risk of HBV-related
complications.
1.1 WGO Cascades

This Global WGO Guideline includes a set of cascades to provide resource-sensitive
options for the diagnosis and management of hepatitis B. These WGO Cascades
are intended to serve as a “global” complement to, rather than a replacement for, the
“gold standard” guidelines from the European Association for the Study of the Liver
(EASL), the American Association for the Study of Liver Diseases (AASLD), the
Asian–Pacific Association for the Study of the Liver (APASL), and the National
Institute for Care and Health Excellence (NICE) [1–4].
1.2 Epidemiology and transmission of hepatitis B

Of the many viral causes of human disease, few are of greater global importance than
hepatitis B virus [5]:

• More than 2 billion people alive today have serologic evidence of past or present
HBV infection.
• 250 million are chronically infected and are at risk of developing HBV-related
liver disease [6].
• Some 15–40% of chronically infected patients will develop cirrhosis, progressing
to liver failure and/or HCC during their lifetime.
• Every year, there are over 4 million acute clinical cases of HBV.
• An estimated 1 million people die each year from chronic HBV infection and its
complications: cirrhosis or primary liver cancer [7].
• HBV-related liver deaths (2010) are estimated at 786,000 annually [8].
The prevalence of HBV varies markedly between different regions of the world
(Fig. 1). In the literature, a distinction is usually made between areas of high, medium,
low, and very low endemicity.
• In high-endemicity areas [5], approximately 70–90% of the population become
infected with HBV before the age of 40, and 8–20% of people develop chronic
infection with persistent carriage of the virus [9].
• The prevalence of CHB ranges from over 10% of the population in South-East
Asia, China, the Amazon area, and sub-Saharan Africa to less than 1% in
Western Europe and North America.
• Overall, approximately 45% of the global population live in areas of high
endemicity. With globalization, many individuals with HBV are immigrating to
areas in which the CHB rate has traditionally been low and the condition may
easily go unnoticed.
Fig. 1 Geographic distribution of hepatitis B virus genotypes worldwide (reproduced with
permission from [10,11]). With immigration patterns, the HBV genotype distribution for chronic
hepatitis B may change rapidly, particularly in the Western world.
Notes: Recently published data [12,13] demonstrated the following genotype distribution for
Russia: genotype D, 85%; genotype A, 10.7%; genotype C, 3.2%; all other genotypes, 1.1%.
In Venezuela, HBV genotype F is the most frequent one in the general population (as in
Colombia and Peru) [14]; the prevalence in urban populations is approximately 80% [15],
while in “Amerindians” it is almost 100% [16].

The wide range of prevalence figures for CHB infection is largely related to
differences in age at infection.
• The chance that acute infection will become chronic is 70–90% for perinatally
acquired (vertical) infection and 20–50% for (horizontal) infections acquired
during early childhood (under the age of 5 years).
• The chance of developing CHB is in the range of 1–3% in immunocompetent
adult-acquired HBV infections, with higher rates in immunosuppressed
individuals.
• Eight [17] (and possibly up to 10) genotypes of hepatitis B virus have been
identified (A–H), which differ in their geographic distribution and in their
potential to affect the clinical course of disease (Table 1). The current prevalence
of HBV genotypes in different regions is highly dependent on immigration
patterns.
Table 1 Geographical distribution of genotypes and subgenotypes of hepatitis B infection

[10]
Country Genotypes Subgenotypes
Central African Republic A, D, E A1, D4
Egypt D D1
Gambia, Nigeria, Haiti, Congo, A A4, A5, A6, A7
Rwanda, Cameroon
Morocco D, A D1, D7, A2
South Africa A [18–20], D A1, A2
Sudan D, E [21] –
Tunisia D, F –
Italy D –
Mongolia D –
Russia D, A, C D1, D2, D3, A2, C1
Spain A, D, F –
Turkey D D2, D1, D3
Canada C, B, A, D –
Mexico H, G –
Argentina F F1, F2, F4
Brazil A, F A1, F2a, A2, F4
Venezuela F F3, F2 [14,16,22]
Australia C, D C4, D4
China B, C B2, C1, C2
Hong Kong C,B –
India A, C, D –
Indonesia C, B C1, B3, B7, C10, B9, C8
Borneo J –
Iran D D1
Japan A, C C1, C2, C3

Country Genotypes Subgenotypes

Pakistan D D1 [23]
Philippines A, B, C A1, B5, C5
Saudi Arabia D, E D1
South Korea C –
Taiwan B B2,B5
Thailand C, B C1-5
Vietnam B, C, I B2–5, C5–16
Increasing numbers of patients with chronic infection are developing HBV variants
that express little or no hepatitis B e antigen (HBeAg); this HBeAg-negative form of
hepatitis B may require long-term therapy to reduce the likelihood that liver disease
will progress, with relapse occurring when the patient is off treatment. A distinction is
made between a precore mutation, in which a stop mutation in the precore gene
completely eliminates HBeAg production, and the basal core promoter (BCP)
mutation, which affects the promoter and thus reduces, but does not eliminate, HBeAg
production. The prevalence of precore mutations is highest in the Mediterranean
countries and they are most prevalent in genotype D, while the core promoter
mutations are mostly found in genotype C (in East Asia and South-East Asia).
2 Clinical course of HBV infection

The outcome of HBV infection largely depends on the host–virus interaction,
mediated by the adaptive immune response. The virus-specific T cell response is one
of the key factors in the pathogenesis of HBV infection. Viral variants may influence
the course and outcome of the disease. The effect of host factors on the progression of
disease is poorly understood. Only very rarely (when there is profound immune
suppression) does the hepatitis B virus probably become directly cytopathic.
2.1 Natural history

The clinical course of HBV infection is variable and includes acute (self-limiting)
infection, fulminant hepatic failure, inactive carrier state, and chronic hepatitis with
chances of progression to cirrhosis and HCC [24,25].
2.2 Chronic HBV infection

The risk of chronicity in acute HBV infection is related to age at primary infection.
Adults who become chronically infected during childhood have a 15–25% lifetime
risk of dying from HBV-related cirrhosis or liver cancer, with a significantly
increased risk in men in comparison with women [26].
Table 2 Risk of chronicity and age at primary infection

Outcome Neonates Children Adults
Chronic infection 90% 30% 1–5%
Recovery 10% 70% 95–99%

Fig. 2 Sequence of serologic markers in acute hepatitis B infection (reproduced with

permission from [27]). A, resolution of active infection; B, progression to chronic infection.
2.3 CHB disease phases

CHB is a dynamic disease that fluctuates over time, likely relating to interactions
between the virus and the host immune system. The following five—not necessarily
sequential—phases can be identified in chronic HBV infection.
• Immune-tolerant phase:
— Characterized by high levels of serum HBV DNA, HBeAg positivity, normal
alanine aminotransferase (ALT) levels, and absent liver necroinflammation.
— Disease progression is minimal in patients who remain in this phase [28].
— Patients are highly contagious in this phase.
• Immune-reactive phase (HBeAg-positive CHB):
— Patients enter this phase after a variable time, linked to the age when HBV
infection occurred.
— The immune system becomes more active and the infected hepatocytes are
attacked.
— Characterized by highly ﬂuctuating, but progressively decreasing, HBV-DNA
levels, elevated ALT, and hepatic necroinﬂammation (HBeAg-positive CHB).
— A prolonged immune-active phase with multiple ALT flares may result in
progressive liver fibrosis, leading to cirrhosis.
• Immune-control phase (and inactive carrier state):
— Transition into this phase as an outcome of the immune-active phase is
marked by seroconversion from HBeAg to anti-HBe positivity.
— Characterized by low (< 2000 IU/mL) or undetectable serum HBV DNA,
normal ALT levels, and disappearance of liver necroinflammation (inactive
carrier state).
• Reactivation phase (HBeAg-negative CHB):
— Despite HBe seroconversion, reactivation of HBV replication may occur due
to the selection of HBeAg-defective HBV mutants.
— Characterized by positive anti-HBe antibody levels, fluctuating HBV DNA
and ALT levels, and a high risk of progression to severe hepatic fibrosis (HBeAg-
negative CHB).

— Periodic ALT flares with intervening normalization may make it difficult to

distinguish between HBeAg-negative CHB and inactive disease, and thus
continued follow-up is required before patients with normal ALT and low HBV
DNA levels are designated as inactive carriers.
— Emerging evidence suggests that a low HBV DNA titer (< 2000 IU/mL)
combined with a low hepatitis B surface antigen (HBsAg) titer (< 1000 IU/mL)
may help identify inactive carriers, particularly those with genotype D infection
[29].
• HBsAg-negative phase:
— After HBsAg loss, low-level HBV replication may persist, with detectable
HBV DNA in the liver and rarely in the serum [30].
— In patients with “occult” HBV infection, persistence of effective HBV
immunological control has been demonstrated [31].
— Significant immunosuppression may lead to HBV reactivation, with
reappearance of HBsAg, known as “reverse seroconversion.”
Fig. 3 Markers and natural history of chronic hepatitis B infection (reproduced with
permission from [27]).
2.4 Progression of CHB

CHB has a very variable course, ranging from silent subclinical infection to persistent
hepatitis with progressive fibrosis leading to cirrhosis, liver failure and/or liver
cancer. The determinants of disease outcome are incompletely understood, but include
viral, host, and environmental factors (Table 3), all of which interact. Viral
determinants of the prognosis have different significance depending on the stage of
the disease. For example, serum HBV DNA titers are highest in the immune-tolerant
phase of disease, despite the lack of hepatic inflammation or progressive fibrosis
during this period. In contrast, in HBeAg-negative CHB, the higher the HBV DNA
level, the greater the risk of disease progression and HCC. The rates of progression to
cirrhosis and HCC and associated mortality rates are shown in Fig. 4.

Table 3 Factors in the disease outcome with chronic hepatitis B

Viral factors Host factors Environmental factors
HBV genotype Age Aflatoxin
HBV DNA titer (varies with phase) Age at infection Alcohol use
HBeAg status Sex Viral coinfections (HIV, HCV,
HDV)
Presence of pre-core or BCP Ethnicity Obesity
mutation
Presence of pre-S1 mutations Family history of Iron overload
HCC
BCP, basal core promoter; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human
immunodeficiency virus.
Fig. 4 Risk of progression in patients with HBV-related cirrhosis. Reproduced with

permission from Peng et al. (2012) [32], to which reference may be made for a detailed
discussion of the natural course of HBV-related cirrhosis and HCC.
3 Diagnosis and monitoring of hepatitis B
3.1 Cascade—acute hepatitis B

The diagnosis of acute hepatitis B is based on the detection of HBsAg and anti-HBc
(immunoglobulin M).
• During the initial phase of infection, markers of HBV replication—HBeAg and
HBV DNA—are also present.
• Recovery is accompanied by the disappearance of detectable HBV DNA, HBeAg
seroconversion to anti-HBe, and subsequent clearance of HBsAg with
seroconversion to anti-HBs and appearance of anti-HBc (IgG).

• The course of acute HBV should take place within 3 months of the diagnosis—
chronic HBV infection is characterized by persistence of plasma HBsAg for more
than 6 months.
Rarely, patients present during the window period when HBsAg has already become
negative but anti-HBs is not yet positive. In this setting, which is more common in
patients with fulminant hepatitis B, in whom viral clearance tends to be more rapid,
immunoglobulin M (IgM) anti-HBc is the sole marker of acute HBV infection.
Cascade 1 Diagnostic tests for acute hepatitis B

Resource level Testing
High HBsAg
Anti-HBc (IgM) and anti-HBs
HBV DNA
ALT
Bilirubin
INR
Medium Anti-HBc (IgM)
HBsAg
ALT
Bilirubin
INR
Low Anti-HBc (IgM)
HBsAg
ALT
Bilirubin
INR
The differential diagnosis of HBsAg-positive acute hepatitis includes exacerbations of

CHB, which may occur at any time in any individual who is chronically infected (at
these times, reversion back to anti-HBc IgM may occur). Acute hepatitis may occur
following withdrawal from immunosuppressive therapy or through superinfection of a
person chronically infected with hepatitis B with hepatitis C and/or D virus, or
hepatitis A virus. Superimposed acute hepatitis due to drugs and other toxins
administered to someone who has “silent” CHB infection may also present as acute
hepatitis. A precipitating factor is sometimes not identified.
3.2 Resolved HBV infection

Previous HBV infection is characterized by the presence of anti-HBs and IgG anti-
HBc. Anti-HBs sometimes becomes undetectable after many years. (Anti-HBs is
frequently undetectable if HBV infection occurred during childhood, as is seen in sub-
Saharan Africa). Notably, although these individuals are referred to as having
“resolved HBV” infection, trace amounts of HBV DNA remain in their livers for
years and possibly even lifelong. Immune control prevents viral expansion, but means
that with severe immunosuppression (e.g., with advanced human immunodeficiency
virus (HIV) coinfection, bone marrow transplantation, rituximab use, etc.), HBsAg
may reappear (reverse seroconversion) or viral replication may be detectable in the

liver even without the reappearance of serum HBV DNA. Immunity to HBV infection
after vaccination is characterized by the presence of only anti-HBs.
3.3 Chronic HBV infection

Diagnosis of chronic HBV infection is defined as the persistence of HBsAg for more
than 6 months.
• It must first be established whether the individual is in the HBeAg-positive or
HBeAg-negative phase of the infection (Table 4).
• Additional tests for markers of HBV replication—namely, HBeAg and serial
measurements of serum HBV DNA, in addition to ALT—should be carried out.
• This will in part determine whether the patient should be considered for HBV
therapy.
• Both HBeAg-positive and HBeAg-negative patients, even if they have normal
serum ALT (women < 20 IU/L and men < 30 IU/L) and/or undetectable HBV
DNA, still need to be monitored lifelong, as the condition may change over time
even if they remain asymptomatic.
• Among individuals with chronic persistence of HBsAg, those with elevated serum
ALT concentrations should be followed more closely, preferably with serial HBV
DNA measurements.
• It is important to know the lower limit of detection of the method used to measure
HBV DNA, as values that are persistently ≥ 2000 IU/mL will prompt
consideration of antiviral therapy.
• The decision on whether to initiate therapy depends on multiple factors (i.e., not
just the level of HBV DNA and/or ALT). If the liver disease appears to be
progressing (as judged by liver biopsy and noninvasive markers of inflammation
and fibrosis such as transient elastography), treatment should be considered.
• Additional tests for hepatitis C and hepatitis D should also be conducted in order
to rule out superinfection with other hepatitis virus(es), particularly in patients
with elevated ALT but low or undetectable HBV DNA.
• Other things to consider include drug-induced liver injury (due to supplements),
nonalcoholic steatohepatitis (NASH), and iron overload.
Table 4 Differentiation of phases of CHB infection

HBsAg ALT* HBeAg Anti- HBV DNA LLD
(≥ 6 months) HBe < 6–12 IU/mL
9–12
HBeAg-positive, Normal Positive Negative > 1 × 10 IU/mL
immune-tolerant
phase
HBeAg-positive CHB Increased Positive Negative > 2000 IU/mL
CHB, immune- Normal Negative Positive < 2000 IU/mL
control phase
HBeAg-negative Increased (sustained or Negative Positive > 2000 IU/mL
CHB intermittent)
Hepatitis D Increased +/– +/– Negative/low

HBsAg ALT* HBeAg Anti- HBV DNA LLD

(≥ 6 months) HBe < 6–12 IU/mL
Coinfection with Increased/normal +/– +/– Negative/low
hepatitis C (HCV RNA-positive)
Coinfection with HIV Increased/normal +/– +/– High**

CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen;
HBV, hepatitis B virus; HIV, human immunodeficiency virus; LLD, lower limit of detection.
*Normal range < 20 IU/L in women, < 30 IU/L in men.
** May be variable, depending on the mode and age of acquisition of HBV, HIV/HBV
coinfection, and on the CD4 count.
Different levels of HBV DNA are used for initiating treatment for HBeAg-positive
and HBeAg-negative disease, depending on the genotype prevalent in different
regions. As a general rule (and because genotyping all patients is not feasible), the
EASL level can be used for Caucasian patients: 2 × 103 IU/mL level (and age > 30 y);
and the APASL/AASLD level can be used for Asian patients: 2 × 104 IU/mL (and age
> 40 y).
3.4 Initial evaluation of patients with chronic HBV infection

Individuals with newly detected CHB need to understand that long-term monitoring
for the development of chronic hepatitis, cirrhosis, and HCC via a series of clinical
examinations and laboratory tests is required even if they are asymptomatic. It is
important to verify the stage of CHB and decide the frequency of follow-up
examinations needed.
• Chronic HBV infection is not necessarily accompanied by progressive liver
disease requiring antiviral therapy.
• Accurate evaluation of all HBsAg-positive carriers is required in order to identify
[33]:
— Phase of infection
— Grade of liver inflammation
— Stage of liver fibrosis
— Concurrent causes of liver disease
— Need for treatment
— Presence of cofactors increasing the risk of progression to cirrhosis or HCC:
coinfections with hepatitis D virus (HDV), hepatitis C virus (HCV), and HIV;
comorbidities including alcoholism, autoimmune disease, or metabolic liver
disease
The initial examination should include:

• History and physical examination, including skin and abdominal examination.
• Markers of HBV infection, including: HBeAg/anti-HBe and HBV DNA to
classify the phase of CHB, as well as the HBV genotype if antiviral therapy with
interferon is contemplated.
• Markers of other viral infections, including HCV and HDV, particularly if ALT
is elevated but HBV DNA is low or undetectable.

• Before oral antiviral therapy is introduced, all patients should be screened for
human immunodeficiency virus (HIV).
• Complete liver panel (ALT/AST to identify active inflammation, and bilirubin,
prothrombin time, and albumin to check liver synthetic function).
• Complete blood count, particularly platelets, which serve as a surrogate marker
for portal hypertension.
• Abdominal ultrasonography for baseline screening for HCC—alpha fetoprotein
may be used in areas with high HBV endemicity and poorly differentiated HCC,
as well as in areas without easy access to high-quality ultrasound.
• Measurement of liver fibrosis by serological testing, FibroScan (transient
elastography), or liver biopsy.
Table 5 Host and viral risk factors associated with progression of chronic hepatitis B
Factors Host Viral

Nonmodifiable Male gender Unrelenting HBeAg-seropositive
Older age hepatitis
Family history of HCC Sustained elevation in serum HBV
DNA
Host genetic polymorphisms [34]
Sustained elevation in serum ALT
HBV genotypes C and D
Modifiable Excess alcohol intake Coinfection with HIV

Obesity/NAFLD Coinfection with HCV and HDV
Drugs (immunosuppressive /
hepatotoxic)
Aflatoxin exposure
ALT, alanine aminotransferase; HBeAg hepatitis B e antigen; HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HDV, hepatitis D virus; HIV, human immunodeficiency virus;
NAFLD, nonalcoholic fatty liver disease.
3.5 Occult HBV

Occult HBV infection refers to the persistence of HBV DNA in liver tissue (and in
some cases in serum) in individuals in whom hepatitis B surface antigen (HBsAg) is
not detectable in the blood, usually with positive anti-HBc.
Occult HBV infection is prevalent worldwide, but its frequency is related to the
prevalence of overt HBV infection in a specific geographic area. Occult HBV is
transmissible through blood transfusions and organ transplantation.
• Blood products should be screened for HBsAg, anti-HBc, and ideally HBV DNA.
• Organs from donors with anti-HBc and/or anti-HBs should preferably be used
only for recipients who test positive for anti-HBs or HBsAg.
Although the true relevance of occult HBV infection is unknown, it may be an
additional risk factor for HCC in anti-HCV–positive patients and in HIV-infected
individuals. It may also be associated with progression of chronic liver disease due to
causes other than HBV.

3.6 HBV reactivation

HBV replication is controlled by the host immune system. Immune suppression of
any kind can lead to a loss of immune control and subsequent HBV reactivation,
which can result in a range of consequences, from a subclinical increase in HBV
DNA to icteric and even fulminant and/or fatal liver failure. Reactivation occurs most
frequently with cancer chemotherapy, but may occur with other immunosuppressive
or immunomodulator therapy (e.g., targeted immunotherapy). The addition of
systemic corticosteroids (SCS) to inhaled corticosteroids increases the risk of HBV
reactivation, especially when SCS are administered chronically or at high doses [35].
Preemptive treatment with a nucleoside/nucleotide analogue is recommended in
HBsAg-positive patients who are going to receive anticancer or immunosuppressive
drugs. Treatment should continue throughout the course of immunosuppression and
for 6–12 months afterwards, with follow-up monitoring to ensure that flares do not
occur upon withdrawal of antiviral therapy.
Reactivation may also occur in patients who are HBsAg-negative but anti-HBc-
positive (with or without occult HBV DNA), but more significant immune
suppression is required. Reappearance of HBsAg is referred to as reverse
seroconversion. The risk appears to be increased with rituximab or other anti-CD20–
based chemotherapy, probably due to the long-lasting depletion of B cells. HBV DNA
may increase even before HBsAg reappears in the serum. Preemptive treatment with a
nucleoside/nucleotide analogue reduces the risk of HBV reactivation, but may not be
required in all patients [36]. Those who are not preemptively treated should be
monitored with serial HBsAg, ALT, and possibly HBV DNA with antiviral therapy
being started if HBsAg reappears or HBV DNA increases.
In summary:
• Screening for HBsAg and anti-HBc is necessary before chemotherapy or
immunosuppressive/immunomodulator therapy is started.
• Patients who are HBsAg-positive should receive preemptive antiviral therapy
during and for 6–12 months after chemotherapy.
• The benefits of preemptive treatment for occult HBV reactivation remain unclear
at present.
• For patients with evidence of previous HBV infection, as confirmed by positive
anti-HBc with or without anti-HBs, serial monitoring of HBV-related markers is
recommended during and after immunosuppressive therapy.
• Patients receiving chemotherapy or immunosuppression should follow the
American Association for the Study of Liver Diseases (AASLD) and Asian-
Pacific Association for the Study of the Liver (APASL) guidelines (Fig. 5).

Fig. 5 APASL algorithm for all candidates for chemotherapy. NA, nucleoside analogue.
Source: Asian–Pacific Association for the Study of the Liver.
All chemotherapy candidates

Screening for HBsAg and anti-HBc
 
HBsAg-negative/
HBsAg-positive
Anti-HBc-positive
   
DNA ≤ 2000 IU/mL DNA > 2000 IU/mL Rituximab No rituximab
   
Prophylactic NAs until 6–
12 months after
Prophylactic NAs during and
chemotherapy or serial
for 6–12 months after Long-term NAs No prophylaxis
monitoring with start of NA
chemotherapy
therapy if HBsAg becomes
positive
3.7 HCC screening

The aim is to detect tumors smaller than 3 cm in diameter, and preferably less than
2 cm, in order to offer a potential for curative treatment. Screening for HCC is
advocated in all cirrhotic patients, as they are at the highest risk of developing HCC.
However, in Africa and South-East Asia, where HBV infection is acquired early in
life, HCC may develop in a noncirrhotic liver.
The AASLD recommends HCC surveillance in the following types of patients with
CHB:
• Asian men over the age of 40 and Asian women over the age of 50
• All patients with cirrhosis, regardless of age
• Patients with a family history of HCC; any age
• Africans over the age of 20
• Any individuals with HBV/HIV coinfection
Singal et al. showed that in a “real-world” clinical setting, a combination of
ultrasound and alpha fetoprotein (AFP) is the most effective strategy for detecting
HCC at an early stage. The sensitivity significantly improved to 90%, with a minimal
loss of specificity (83%). AFP alone may be better than ultrasound alone, as the
reliability of ultrasound is very dependent on the skill and experience of the
ultrasonographer [37].
For hepatitis B carriers not included in this list, the risk of HCC varies depending
on the severity of the underlying liver disease and current and past hepatic
inflammatory activity. Those with high HBV DNA concentrations and ongoing
hepatic inflammatory activity (evidenced by elevated ALT values) are at increased
risk for HCC, and surveillance should be considered. Genotype C infection and the
presence of BCP and pre-S1 mutations are also associated with an increased risk of
HCC.

4 Treatment for CHB

Before any form of HBV therapy is started, and optimally at the time of first
presentation, the patient needs to be provided with information about CHB and its
treatment. Important information includes:
• The dynamic clinical course of CHB.
• Most infections remain initially entirely asymptomatic, even in the case of severe
disease.
• The need for regular lifelong monitoring.
• Possible transmission to contacts—family and contacts need HBV screening and
vaccination of those who are not immune to HBV, and referral for clinical
evaluation of those who are HBsAg-positive.
• Timing of the start of treatment.
• The need for absolute compliance with potentially long-term therapy.
• The need for absolute compliance with follow-up examinations both when the
patient is on treatment and when he/she is off treatment.
• The importance of alcohol abstinence and attention to the use of medications that
may be hepatotoxic or dangerous in patients with advanced liver disease (e.g.,
NSAIDs) should be emphasized.
• Those who are not immune to hepatitis A should receive two doses of hepatitis A
vaccine 6–18 months apart.
This information should be explained and discussed with the patient. In women of
childbearing potential, drugs that are considered safe in pregnancy are preferred,
because once a nucleoside or nucleotide has been prescribed it cannot be stopped in
those who remain HBeAg-positive. The patient needs to understand that cessation of
treatment may precipitate severe hepatitis, which can, rarely, lead to fulminant acute
liver failure, even in the absence of cirrhosis.
The phase of CHB can be determined on the basis of the serological and virological
profile—each type is characterized by a distinct natural course, prognosis, and
treatment indications [1,2,38]
1 Immune-tolerant carrier:
• Treatment not indicated.
• Appropriate longitudinal follow-up is crucial.
• Measure ALT every 3–6 months.
2 Inactive carrier:
• Treatment not indicated.
• Appropriate longitudinal follow-up is crucial.
• Assess ALT and HBV DNA levels every 3 months during the first year, then
every 6 months.
• If the serum HBV DNA is < 2000 IU/mL and the HBsAg level is < 1000 IU/mL,
the probability of disease reactivation is low and patients may require less
frequent monitoring.
3 Active CHB:
• HBeAg-positive CHB.
• HBeAg-negative CHB..

The prognosis and management of CHB greatly depend on the phase of the disease
and the stage of liver fibrosis, and thus the risk of cirrhosis developing. Follow-up in
CHB HBsAg carriers includes:
• Continuation of diagnostic work-up.
• Assessment of the severity of the liver disease.
— Laboratory tests for inflammation (ALT), hepatic function (bilirubin, albumin,
coagulation factors) and viral load (HBV DNA), if available.
— Hepatic ultrasound examination.
— Noninvasive measures to assess fibrosis (serum panels, transient
elastography).
— Liver biopsy, useful for determining the grade of necroinflammation and the
stage of fibrosis.
— Liver biopsy. This can help exclude other coexistent causes of liver disease
and clarify the diagnosis when ALT and HBV DNA levels are discordant.
The current standards for deciding on treatment for CHB are shown in Figures 6 and
7. Cascades are included to reflect resource-sensitive options.
Fig. 6 Management of chronic HBeAg-positive infection. Surveillance for hepatocellular
carcinoma should be carried out if indicated (depending on age, sex, severity of liver disease,
and family history). Adapted from Lok and McMahon 2007 [39].
HBsAg+

HBeAg-positive
  
ALT < ULN ALT 1–2 × ULN ALT > 2x ULN
HBV DNA* > 2000 IU/mL HBV DNA > 2000 IU/mL HBV DNA >2000 IU/mL
  
Q 3–6 mo ALT Consider biopsy if age > 40, Liver biopsy optional
Q 6–12 mo HBV DNA and elevated ALT, Q 1–3 mo ALT & HBV DNA
HBeAg family history of HCC Q 3 mo HBeAg
  
Active inflammation? Active inflammation? Active inflammation?
  No  No
No Yes Yes
  
Antiviral therapy
No treatment** Antiviral treatment as needed indicated if HBeAg remains positive
> 3–6 mo
* In patients of Asian origin, very high HBV DNA levels are frequently observed—mostly in
patients with perinatal transmission. It is unclear whether they should receive antiviral
treatment with NAs. The level of HBV DNA correlates with the risk of HCC during follow-up,
but whether viral suppression reduces the risk is unclear.
** Patients with cirrhosis and detectable HBV DNA should be treated regardless of their ALT
value and level of HBV DNA.
Fig. 7 Management of chronic HBeAg-negative infection.
HBsAg+

HBeAg-negative
(serial ALT and HBV DNA)
  
ALT < ULN ALT 1–2 × ULN ALT ≥ 2 × ULN
HBV DNA < 2000 IU/mL HBV DNA > 2000 IU/mL HBV DNA > 2000 IU/mL
  

Q 3 mo ALT & HBV DNA × 3, then if

ALT still < 1 × ULN and HBV DNA Q 3 mo ALT & HBV DNA Q 3–6 mo ALT & HBV DNA
remains < 2000 IU/mL, Consider biopsy if persistent
monitor Q 6–12 mo
  
Consider antiviral therapy if
No treatment needed ALT remains elevated Antiviral treatment indicated
Liver biopsy optional
NB: Surveillance for HCC should be carried out if indicated (depending on age, sex, severity
of liver disease, and family history).
The upper limit of normal for ALT is 20 IU/L in women and 30 IU/L in men.
Monitoring HBV DNA every 3 months in patients with ALT one to two times the upper limit of
normal is expensive and may not be practical when economic resources are limited—see the
cascades below for alternative approaches.
4.1 Cascades for CHB management—a resource-sensitive approach

A standard approach is only feasible if the full scale of diagnostic tests and medical
treatment options are available. Such resources may not be sufficiently available
throughout the world. With their diagnostic and treatment cascades, the World
Gastroenterology Organisation guidelines provide a resource-sensitive approach.
• Assessment of the baseline HBV DNA level, HDV and HIV are recommended
for all resource levels prior to any therapy.
• Initial HCC assessment using ultrasonography should be done in all cases, where
possible. Alpha fetoprotein still has a role in monitoring in resource-poor areas
with high HBV endemicity, poorly differentiated HCC, and limited access to
high-quality ultrasound.
Cascade 2 Immunotolerant phase monitoring (no therapy)

Access level Testing
High Annual HBeAg and HBV DNA
6-monthly ALT
Medium Annual HBeAg

6-monthly ALT
Low 6-monthly ALT
Cascade 3 Immunoactive phase monitoring (off therapy)

High 3-monthly ALT and HBV DNA
6-monthly HBeAg and CBC
Prior to any treatment, do HIV test
Medium 3-monthly ALT
6-monthly HBeAg, HBV DNA, and CBC
Low 3-monthly ALT
6-monthly HBeAg and CBC

Cascade 4 Immune-control phase monitoring, HBeAg-negative (off therapy)

High Annual HBsAg and anti-HBeAg
6-monthly ALT, HBV DNA, and CBC
(consider less frequent monitoring if stable over 2–3 years)
Medium Annual HBsAg

6-monthly ALT, HBV DNA, and CBC
Low 6-monthly ALT and CBC

Cascade 5 Reactivation phase monitoring, HBeAg-negative (off therapy)

High 3-monthly ALT and HBV DNA
6-monthly CBC
Medium 6-monthly ALT and HBV DNA

6-monthly CBC
Low 6-monthly ALT

6-monthly CBC
Cascade 6 Immunoactive phase monitoring, HBeAg-positive (interferon-based therapy)

High Monthly ALT, CBC, creatinine, bilirubin
3-monthly HBeAg, HBV DNA and HBsAg titer*
Pretreatment and post-treatment: HBV DNA and HBsAg
Medium Monthly ALT, CBC, creatinine, bilirubin

3-monthly HBsAg titer*
6-monthly HBeAg, HBV DNA
Low Monthly ALT, CBC, creatinine, bilirubin

3-monthly HBsAg* titer, HBeAg
titer
* HBsAg titer at week 12—“week 12 interferon stopping rule.”

Cascade 7 Immunoactive phase monitoring, HBeAg-positive (on NA therapy)

High ALT CBC, creatinine, HBV DNA at 3 and 6 months
Thereafter, 6-monthly ALT, HBV DNA, CBC, creatinine*, phosphate**
If cirrhotic: then HBV DNA 3-monthly and 6-monthly once undetectable
HBeAg 6-monthly
Medium ALT, CBC, creatinine, HBV DNA at 3 and 6 months

Then 6-monthly ALT, CBC, creatinine
HBV DNA, HBeAg annually
Low ALT, CBC, creatinine at 3 and 6 months

Then 6-monthly ALT and creatinine
HBeAg annually
* At all levels: if the patient is receiving tenofovir, the frequency of creatinine testing is guided
by renal function.
** Phosphate testing required only for patients receiving tenofovir.
Cascade 8 Reactivation phase monitoring, HBeAg-negative (on NA therapy)

High ALT and HBV DNA at 3 months
Thereafter every 6 months with CBC, creatinine*, phosphate**
annually (unless cirrhotic; then 3-monthly)
HBsAg titers annually
Medium ALT and HBV DNA at 3 months

Then ALT, CBC, creatinine* 6-monthly
HBV DNA annually
Low ALT, CBC 3-monthly

Creatinine* 6-monthly
* If the patient is receiving tenofovir, the frequency of creatinine testing is guided by renal
function.
** Phosphate testing is required only for patients receiving tenofovir.

4.2 Treatment for CHB
Approved drugs
Table 6 Approved drugs for chronic hepatitis B

Family/drug name Status [40] Global access: percentage on
national essential medicines lists *
Interferons (IFNs)—immunomodulators
Activate a host of genes with antiviral, antiproliferative, and immunostimulatory activities
Interferon alfa-2b FDA approval 1991 54.0%
Peginterferon alfa-2a FDA approval 2005 50.8%
Peginterferon alfa-2b FDA approval 2011 –
Nucleoside/nucleotide analogues (NAs)

Inhibit the DNA polymerase of HBV and thus HBV replication
Lamivudine FDA approval 1998 66.7%
Adefovir dipivoxil FDA approval 2002 34.1%
Entecavir FDA approval 2005 34.9%
Telbivudine FDA approval 2006 23.8%
Tenofovir FDA approval 2008 48.4%
* Reported percentages of WHO member states with drugs for hepatitis B on their national
essential medicines lists or subsidized by their governments [41].
Table 7 shows the results of the major studies on the treatment of HBeAg-negative
and HBeAg-positive chronic hepatitis B 6 months after completion of 12 months
(48 weeks) of pegylated interferon alpha (PEG-IFN) and after 12 months (48 or
52 weeks) of nucleoside/nucleotide analogue therapy.
Table 7 Research results on the treatment of HBeAg-negative and HBeAg-positive chronic

hepatitis B
Nucleotide
PEG-IFN Nucleoside analogues analogues
PEG-IFN- PEG-IFN-
2a 2b Lamivudine Telbivudine Entecavir Adefovir Tenofovir
Treatment of HBeAg-negative chronic hepatitis B

Dose * 180 μg – 100 mg 600 mg 0.5 mg 10 mg 300 mg
HBV DNA < 60– 19 – 72–73 88 90 51–63 93
80 IU/mL (%)
ALT normaliz- 59 – 71–79 74 78 72–77 76
ation (%) **
HBsAg loss (%) 4 – 0 0 0 0 0
Treatment of HBeAg-positive chronic hepatitis B

Dose * 180 μg 100 μg 100 mg 600 mg 0.5 mg 10 mg 245 mg
Anti-HBe 32 29 16–18 22 21 12–18 21
seroconversion
(%)

Nucleotide
PEG-IFN Nucleoside analogues analogues
HBV DNA < 60– 14 7 36–44 60 67 13–21 76
80 IU/mL (%)
ALT normaliz- 41 32 41–72 77 68 48–54 68
ation (%) **
HBsAg loss (%) 3 7 0–1 0.5 2 0 3
ALT, alanine aminotransferase; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen;
PEG-IFN, peginterferon. Adapted from the 2012 EASL guideline [2]; for further references,
the source should be consulted.
* Administration of PEG-IFN: percutaneous injections once weekly; nucleoside/nucleotide
analogues: oral tablets once daily.
** The definition of ALT normalization varied among different trials (e.g., with a decrease of
ALT up to 1.25 times the upper limit of normal (ULN) in the entecavir trial or up to 1.3 times
the ULN in the telbivudine trial).
For a detailed discussion of the “gold standard” treatment for CHB, reference should
be to the latest 2012 EASL guideline [2] (www.easl.eu).
Drug resistance
If there is no response or virological breakthrough, as defined by an increase in the
HBV DNA level of more than 1 log10 IU/mL in comparison with the nadir (lowest
value) HBV DNA level during treatment with confirmed compliance, then another
agent with the optimal resistance profile—i.e., tenofovir or entecavir—should be
substituted or added.
The following strategies can be used to prevent resistance:
• For the first-line therapy, choose a potent antiviral drug and/or one with a low
incidence of resistance (high genetic barrier) over time (entecavir/tenofovir).
• Emphasize to the patient once again the importance of absolute compliance with
therapy.
• The HBV DNA level should be monitored frequently when using drugs with a
low barrier to resistance (every 3–6 months) during treatment, and resistance
testing (genotyping) should be carried out in case of viral breakthrough or
suboptimal viral suppression, to allow genotypic resistance to be detected before
clinical consequences develop.
• No drug resistance to interferon has been described, although some individuals
do not respond to therapy, in which case it should be stopped. If available, the
HBsAg titer can be used to guide interferon therapy (see below).
HBeAg-positive hepatitis
Recommendations. HBeAg-positive patients with persistent ALT ≥ 2 × the upper
limit of normal, and with HBV DNA ≥ 2000 IU/mL, should be considered for
treatment.
• It is imperative to check for HIV coinfection before treatment, because all
approved nucleoside/nucleotide analogues have activity against HIV and will
rapidly lead to drug-resistant HIV if used as monotherapy.

• HDV testing should be mandatory in countries with a high prevalence of hepatitis

D infection (Romania, Moldavia, former Soviet central Asian republics, Russia).
• In patients who have had a liver biopsy, treatment should be started for those with
moderate to severe inflammation or significant fibrosis (≥ F2).
• Treatment should be initiated in those who have cirrhosis with detectable HBV
DNA, even those with a low HBV DNA level, irrespective of the ALT level.
• Any of the approved therapies can be chosen, and the decision regarding the
selection of therapy should include an assessment of efficacy, safety, and genetic
barriers to resistance. To avoid resistance, entecavir and tenofovir are the
preferred choices for NA therapy. It is important to ensure that patients have a
secure source of support to pay for medications over the longer term before
starting therapy, to avoid abrupt cessations of treatment, which can be dangerous.
• Patients should be monitored regularly during therapy at 3–6-monthly intervals,
or more frequently if they are receiving interferon-based therapy, to monitor for
efficacy, safety, and early evidence of resistance (for nucleoside/nucleotide
analogues).
• Ideally, patients should be monitored with ALT, HBeAg, anti-HBe, and HBV
DNA, but this may not be possible in countries in which these tests are not
available or are prohibitively expensive, in which case ALT will have to suffice.
• Virologic breakthrough: an increase in HBV DNA > 1 log above the nadir after a
virologic response has been achieved during continued treatment (for
nucleoside/nucleotide analogues). Before assuming this is resistance, adherence
should be discussed with the patient. A continued increase in the HBV DNA titer
over time is suggestive of resistance in a patient who is complying with the
treatment.
• Patients with resistance should be considered for rescue therapy with
nucleosides/nucleotides that do not have a cross-resistant profile (lamivudine,
telbivudine, and entecavir have an overlapping resistance profile, so that
tenofovir substitution would be preferable—or if unavailable, adefovir add-on
therapy).
• Oral agents should be continued until at least 12 months after the end point of
HBeAg seroconversion occurs in HBeAg-positive hepatitis, and it may be
preferable to continue until HBsAg loss occurs because of the high risk of
reactivation after cessation of therapy. Close monitoring is recommended after
oral therapy has been stopped or withdrawn, because of the risk of a treatment
withdrawal flare.
• Peginterferon-based therapies have the advantage of a fixed duration of therapy.
HBeAg seroconversion may take place up to 6 months after discontinuation of
interferon. HBeAg loss and seroconversion appear to be much more durable when
induced with interferon in comparison with a nucleoside/nucleotide analogue.
Interferon is most effective in patients with genotype A infection and least
effective in those with genotypes D and C.
• If HBsAg titers are available, they can be used to guide interferon-based therapy.
Discontinuation of interferon therapy is indicated in all patients with HBsAg
> 20,000 IU/mL at week 24, irrespective of the HBV genotype [42].
Alternatively, those with no decline in the HBsAg titer at 12 weeks should also
stop therapy. Stopping rules improve the cost-effectiveness of peginterferon
therapy [43].

HBeAg-negative hepatitis
HBeAg-negative CHB represents a late phase in the course of chronic HBV infection.
• The patient should be considered for treatment if:
— HBV DNA ≥ 20,000 IU/mL and serum ALT > 2 × ULN
• Liver biopsy or other forms of fibrosis assessment should be considered in
patients with:
— HBV DNA ≥ 20,000 IU/mL and serum ALT < 2 × ULN
— HBV DNA ≥ 2000 IU/mL and/or serum ALT > ULN
— Treatment should be administered if the liver biopsy shows moderate/severe
necroinflammation or significant fibrosis (≥ F2)
• Treat any patient with cirrhosis who has detectable HBV DNA.
Recommendations for treatment:

• It is imperative to check for HIV coinfection before treatment, since all approved
nucleoside/nucleotide analogues have activity against HIV and will rapidly lead
to drug-resistant HIV if used as monotherapy.
• The treatment regimen can be conventional interferon, peginterferon alfa, or
nucleoside/nucleotide analogues. Interferon-based therapy must not be used in
the presence of liver failure.
• In patients with contraindications to interferon, such as decompensated cirrhosis
or autoimmune disease, oral nucleoside/nucleotide analogues are recommended.
• The duration of interferon or peginterferon therapy is 1 year. If by week 12
HBsAg has not dropped, combined with a less than 2 log decline in HBV DNA,
interferon therapy should be stopped, as a response is unlikely [42,44].
• For oral antiviral therapy, agents with a low resistance rate such as entecavir or
tenofovir are preferred, particularly in patients with cirrhosis. However, where
economic constraints are a consideration, therapy can be started with lamivudine
(or telbivudine), with early adefovir add-on therapy or a switch to tenofovir when
drug resistance is detected or when HBV DNA remains at ≥ 2000 IU/mL at
week 24 of therapy.
• The optimal duration of antiviral therapy for HBeAg-negative CHB is not known,
but long-term therapy is required—possibly lifelong, or until loss of HBsAg.
• Monitoring both biochemistry and HBV DNA every 3–6 months is recommended
for assessing the treatment response and for early detection of drug resistance.
• A drug with a nonoverlapping resistance profile should be added (adefovir for
lamivudine resistance) when drug resistance is detected.
• If ALT is elevated and HBV DNA levels are low (< 2000 IU/mL), other causes
of inflammation (fatty liver, medication, coinfection with HDV and HCV) should
be excluded. HDV inhibits HBV replication, and HDV-coinfected patients are
therefore typically HBeAg-negative, with low or even undetectable levels of HBV
DNA but persistently high ALT levels, often with evidence of advanced
fibrosis/cirrhosis.

4.3 Coinfection
HBV–HDV
Hepatitis D virus (HDV) is a defective virus with a circular RNA genome and a single
structured protein, the hepatitis delta antigen. The virus requires HBV surface antigen
to serve as an envelope for its delta antigen. This helper function of HBV is required
for HDV assembly and propagation.
• Up to 5% of the world’s population is infected with HBV, and probably 5% of
those chronically infected with HBV have HDV infection.
• However, some endemic areas in the developing world may have much higher
rates (Horn of Africa, Eastern Europe, Amazon Basin). The virus simultaneously
coinfects with HBV, or superinfects in someone already chronically infected with
HBV.
• Coinfection evolves to chronicity in only 2% of cases, but is associated with a
higher chance of fulminant acute infection, while superinfection leads to
progressive disease and cirrhosis in more than 80% of cases.
• Cirrhosis develops at a younger age than in patients with chronic HBV
monoinfection.
Recommendations:
• Universal HBV vaccination should be implemented to prevent HDV infection in
the community and thereby decrease its prevalence.
• HBsAg-positive patients should be evaluated to rule out HDV infection,
particularly if hepatitis is present in the face of little or no HBV viral replication
(i.e., a low HBV DNA), or if they come from an HDV-endemic region or have
acquired HBV through injection drug use.
• HDV infection can be diagnosed by detection of HDV RNA in serum by
polymerase chain reaction, or indirectly by detection of antibodies against
hepatitis D antigen (anti-HDV) of the IgG and IgM classes.
• Chronic hepatitis D should be treated with interferon (preferably pegylated
interferon) for at least 12 months, but the treatment results are suboptimal.
Patients with active HBV replication despite HDV coinfection may benefit from
treatment with nucleoside/nucleotide analogues (NAs) in combination with
peginterferon.
HBV–HCV
Infection with HBV and hepatitis C (HCV) viruses may occur, as the two share
similar risk factors and some common modes of transmission. Coinfection is most
common in regions highly endemic for both viruses and in individuals who have
contracted the infection through injection drug use—since unlike HBV, HCV is
poorly transmitted via the sexual or vertical route. For the same reasons, HBV and
HCV coinfection—and even triple infection with HBV, HCV and HIV and potentially
quadruple infection (with HDV in addition)—may be observed in high-risk
populations.
• The interferons (and pegylated interferons) are well-established therapeutic
agents for both HBV and HCV and represent the treatment of choice for
coinfected patients (in the absence of HIV).

• When HCV predominates (with detectable HCV RNA and low or undetectable
HBV DNA), HCV therapy, which is rapidly evolving, should be prioritized. IFN-
based therapy for HCV may be preferable in order to control HBV as well, but
there are no robust data on this approach to date. New interferon-free therapies
for HCV are highly effective and should be considered in HBV/HCV-coinfected
patients. Optimal approaches for this population are being evaluated.
• When HBV predominates (with high HBV DNA levels), hepatitis C has often
been cleared (i.e., undetectable HCV-RNA). In such cases, treatment decisions
regarding HBV should be made irrespective of the presence of past HCV
infection.
• Regular monitoring of ALT and of HCV RNA and HBV DNA during and after
therapy is required, as suppression of the dominant virus by antiviral therapy may
result in reactivation of the previously suppressed virus.
HBV–HIV
An estimated 36 million persons throughout the world are infected with HIV. Chronic
coinfection with HBV may be present, due to the common modes of transmission of
the viruses—parenteral, vertical, and sexual.
• The prevalence of CHB among HIV-infected persons may be ten times or more
higher than that of the background population.
• Chronic HBV infection occurs in 5–10% of HIV-infected persons in Western
Europe and the United States [45]
• Progression of CHB to cirrhosis, end-stage liver disease, and/or HCC is more
rapid in HIV-infected persons than in persons with CHB alone [46].
The absence of controlled trials and the dual activity of some agents complicate the
management of CHB infection in patients with HIV coinfection. Treatment regimens
depend on the clinical status of both HIV and HBV.
• Many approved nucleoside/nucleotide analogues with activity against HBV also
suppress HIV, and it is therefore critical that monotherapy with any approved oral
HBV agents should be avoided, as resistance to HIV and possibly to HBV will
rapidly occur. When treatment is indicated, a tenofovir-based regimen is
preferred, in combination with other highly active agents for HIV.
• All patients with CHB should therefore always be checked for HIV coinfection
before antiviral treatment is initiated.
The principal objectives of anti-HBV treatment are to stop or decrease the
progression of liver disease, and to prevent cirrhosis and HCC.
• Prolonged suppression of HBV replication leads to histologic improvement, a
significant decrease in or normalization of aminotransferases, and prevention of
progression to cirrhosis and end-stage liver disease.
• Sustained viral control requires long-term maintenance therapy.
• Treatment discontinuation in particular may be associated with HBV reactivation
and ALT flares.
• The drawback of long-term therapy is the risk of HBV resistance. To reduce drug
resistance, most coinfected patients require HBV combination therapy.

4.4 Pregnancy
The following recommendations are also based on the 2012 EASL guideline [2]:
• All pregnant women should be screened for HBsAg.
• Before HBV treatment is started, the risk to the fetus in case of pregnancy and the
patient’s family planning should be discussed.
• (PEG-)IFN is contraindicated during pregnancy.
• Tenofovir has a better resistance profile and more extensive safety data in
pregnant, HBV-positive women than telbivudine (both are pregnancy category B
drugs: no risk in animal studies, but unknown in humans) [47]. The data in HIV-
positive pregnant women suggest that the use of lamivudine, emtricitabine, and
tenofovir is safe [48,49].
• Perinatal HBV transmission mainly occurs at delivery, and prevention focuses on
passive and active immunization with hepatitis B immunoglobulin (HBIg) and
HBV vaccination, both of which must be given within 12 hours of birth.
• In a meta-analysis of the utility of HBIg given to newborns to prevent mother-to-
child transmission (MTCT) of HBV, HBIg and HBV plasma–derived vaccine
reduced transmission from 20% to 10% in comparison with plasma vaccine alone
(RR 0.49; 95% CI, 0.32 to 0.74); with HBIg and recombinant HBV vaccine,
transmission was reduced from 30.8% to 18.9% (RR 0.61; 95% CI, 0.41 to 0.92)
[50].
• Women with high concentrations of HBV DNA (serum HBV DNA > 106–
7
IU/mL, and mostly HBeAg-positive) may still have a high risk of MTCT despite
appropriate vaccination and should be considered for treatment with lamivudine,
telbivudine, or tenofovir during the last trimester of pregnancy, in addition to
passive and active vaccination with HBIg and HBV vaccination.
• In a meta-analysis of RCTs, lamivudine reduced the transmission of HBV from
25.4% to 12% in comparison with a placebo when it was administered in late
pregnancy. In comparison with patients who received HBIg, lamivudine reduced
transmission from 20.4% to 6.3% [51]. In a meta-analysis of telbivudine
treatment in pregnancy, the pooled results were similar to those with lamivudine,
but the analysis only included two RCTs and three non-RCTs [52].
• NA therapy given only for the prevention of perinatal transmission may be
discontinued within the first 3 months after delivery.
• HBV-infected women should be monitored closely after delivery, as flares may
occur [53].
5 Hepatitis B vaccination
A program for universal vaccination of all newborns is a key step toward effective
control of HBV infection throughout the world. HBV vaccination has been shown to
be highly cost-effective. Vaccination prevents infection with HBV and thus reduces
the incidence of chronic hepatitis, cirrhosis, and HCC in the vaccinated population, as
well as reducing transmission by limiting the number of susceptible individuals.

5.1 Active vaccination with hepatitis B vaccine

HBsAg is the antigen used in the formulation of the hepatitis B vaccine. It is produced
from yeast through recombinant DNA technology. It is available as a single-agent
preparation or as a fixed combination with other vaccines.
5.2 Passive vaccination with hepatitis B immunoglobulin

Hepatitis B immunoglobulin (HBIg) is prepared from the plasma of individuals who
have a high concentration of anti-HBs. The standard dose of HBIg is 0.06 mL/kg for
all applications in adults or 200 IU in infants. In standard doses, it provides temporary
protection (i.e., for approximately 3–6 months) against HBV infection. HBIg is
administered by intramuscular injection, preferably into the deltoid or gluteal muscle.
If it is given with hepatitis B vaccine, the HBIg vaccine should be administered at a
different injection site.
5.3 Preexposure prophylaxis

A comprehensive strategy for eliminating HBV transmission should start with a
preexposure vaccination program. This should include:
• Universal vaccination of all infants at birth; mandatory for infants born to
pregnant women who test positive when screened for hepatitis B surface antigen.
• Postexposure immunoprophylaxis for children born to mothers whose HBsAg
status is unknown.
• Catch-up vaccination of all children and adolescents who have not previously
been vaccinated.
• Vaccination of unvaccinated adults exposed to risks of HBV infection (however,
typically “high-risk” individuals frequently do not access health care or inform
health-care facilities; hence the need for universal infant vaccination).
• Vaccination of those at risk of more severe infection—e.g., patients with chronic
liver disease.
5.4 Vaccination schedules

The combination of prevalence, route of transmission, and viral factors has
implications for the vaccination strategy—vaccination of at-risk groups, infant
vaccination, or adolescent vaccination.
The vaccine is administered by intramuscular injection into the deltoid muscle (not
the gluteal muscle) in adults, or into the anterolateral aspect of the thigh in neonates.
• Studies suggest that universal vaccination at birth is cost-effective in countries
with high and moderate prevalence.
• Europe and North America, with very low incidence rates, have implemented
either routine infant vaccination or vaccination for newborns of mothers who test
positive for hepatitis B surface antigen (HBsAg).
• Routine adolescent vaccination at the age of 10 and catch-up vaccination for at-
risk adults (it is difficult to identify and/or access those who are “at risk”) are
recommended in some countries, but this will have little effect on the rate of
chronic infection.
Vaccination recommendations:

• Primary vaccination, consisting of three or more intramuscular doses of hepatitis

B vaccine administered at 0, 1, and 6 months, results in a positive antibody
response in 30–55% of adults aged ≤ 40 years after the first dose, 75% after the
second dose, and > 90% after the third dose. These response rates decline when
the vaccine is given to older individuals (e.g., < 90% in persons > 40 years old,
75% in those over 60 years old).
• Other innovative vaccination schedules (e.g. 0, 1, and 4 months or 0, 2, and
4 months or 0, 1, and 2 months) are able to produce dose-specific and final rates
of protection similar to those obtained with the 0, 1, 6-month schedule, and may
be more practical for newborns.
• Accelerated vaccination schedules for postexposure prophylaxis in adults often
ensure compliance with completion of the vaccination schedule.
• Babies born to HBsAg-positive mothers should receive the first dose of vaccine
within 12 hours of birth.
• Host factors (e.g., smoking, obesity, cirrhosis, genetic factors, immune
suppression, renal failure, etc.) are known to result in a decreased vaccine
response.
• Individuals who do not mount an anti-HBs response (≥ 10 mIU/mL) to the
primary vaccination schedule should receive a repeat three-dose vaccination (at 0,
1 and 2 months). This gives rise to protective antibody levels in 44–100% of
individuals. Individuals who do not develop protective anti-HBs levels after
revaccination can be considered for repeat vaccination (0, 1, and 2 months, with a
6-month booster) with double the standard dosage of vaccine.
• For persons ≥ 18 years old who do not live in an area endemic for hepatitis A, a
combined hepatitis A–hepatitis B vaccine (Twinrix) is available.
5.5 Postexposure prophylaxis

Postexposure prophylaxis should be considered for individuals who have had recent
exposure (either parenteral or sexual) to blood or other body fluids, if it can be carried
out in a timely fashion.
• Evaluation of the HBsAg status of the infective source and the anti-HBs status of
the exposed person should be carried out before the vaccine is administered.
• In countries with a high level of HBV endemicity, HBsAg in the exposed
individual should also be checked.
• Individuals without prior vaccination should receive both HBIg and hepatitis B
vaccine soon after exposure (preferably within 24 h). Hepatitis B vaccine
administered simultaneously with HBIg must be at a different injection site.
• Completion of the hepatitis B vaccine series is again at 0, 1, and 6 months or 0, 1,
and 2 months.
Exposed individuals who are in the process of being vaccinated (but who have not
completed the vaccine series) should receive the appropriate dose of HBIg and should
be advised to complete the hepatitis B vaccination series.
Vaccine responders may maintain protective anti-HBs levels for various lengths of
time. Individuals who respond to hepatitis B vaccination are protected for at least
20 years (perhaps lifelong), even if vaccinees lack detectable anti-HBs at the time of a
recent exposure. Asymptomatic acute hepatitis B infection can occur in vaccine
responders following a decrease in anti-HBs levels, but it is usually self-limited.

Occult hepatitis B infection has been recognized in some vaccinated patients, but the
clinical significance of this is unclear [54].
Thus, immunocompetent persons who are known to have responded to hepatitis B
vaccination with anti-HBs concentrations of ≥ 10 mIU/mL do not require additional
passive or active immunization after an HBV exposure. In addition, they do not need
further periodic testing to assess anti-HBs concentrations. However, if the previous
anti-HBs concentration is not known (not routinely tested) or is < 10 mIU/mL, then
HBIg and hepatitis B vaccine should be given. If the exposed individual is a known
nonresponder, then two doses of HBIg, 1 month apart, can be given.
Booster doses are not recommended routinely for immunocompetent individuals,
whether they have received the vaccination as infants, adolescents, or adults.
Likewise, serologic testing to assess antibody concentrations in any age group is not
recommended, except perhaps for individuals at high risk of infection such as
household contacts of infected persons or health-care workers—e.g., a booster dose
should be administered when the anti-HBs level is < 10 mIU/mL. It is prudent to
recommend booster doses to individuals with a clear, ongoing risk of HBV infection
(e.g., when the sexual partner is HBsAg-positive, or in health-care personnel).
5.6 Pregnancy and hepatitis B vaccination

There are no teratogenic or other risks to the fetus if hepatitis B vaccine is
administered to pregnant women. There are no contraindications for hepatitis B
vaccination or HBIg administration in pregnant or lactating mothers.
6 Appendix
6.1 Abbreviations
AASLD American Association for the Study of Liver Diseases
AFP Alpha fetoprotein
ALT Alanine aminotransferase
AST Aspartate aminotransferase
APASL Asian–Pacific Association for the Study of the Liver
BCP Basal core promoter
CBC Complete blood count
CHB Chronic hepatitis B
CI Confidence interval(s)
EASL European Association for the Study of the Liver
FDA Food and Drug Administration (United States)
HBc Hepatitis B core (antigen)
HBeAg Hepatitis B extracellular antigen
HBIg Hepatitis B immunoglobulin
HBsAg Hepatitis B surface antigen
HBV Hepatitis B virus

HCC Hepatocellular carcinoma

HCV Hepatitis C virus
HDV Hepatitis D virus
HIV Human immunodeficiency virus
IFN Interferon
IgG Immunoglobulin G
IgM Immunoglobulin M
INR International normalized ratio
IU/mL International units per milliliter
(the WHO standard for HBV DNA concentrations)
LLD Lower limit of detection
MTCT Mother-to-child transmission
NA Nucleoside analogue
NAFLD Nonalcoholic fatty liver disease
NASH Nonalcoholic steatohepatitis
NICE National Institute for Care and Health Excellence
NSAID Nonsteroidal anti-inflammatory drug
PCR Polymerase chain reaction
PEG-IFN Peginterferon
RCT Randomized controlled trial
RR Relative risk
SCS Systemic corticosteroids
ULN Upper limit of normal
WGO World Gastroenterology Organisation
WHO World Health Organization
For a definition of frequently used terms, reference may be made to page 533 of the 2012
APASL guideline [4].
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World Gastroenterology Organisation Global Guideline

© World Gastroenterology Organisation, 2015

© World Gastroenterology Organisation, 2015

1.1 WGO Cascades

1.2 Epidemiology and transmission of hepatitis B

© World Gastroenterology Organisation, 2015

© World Gastroenterology Organisation, 2015

Table 1 Geographical distribution of genotypes and subgenotypes of hepatitis B infection

© World Gastroenterology Organisation, 2015

Country Genotypes Subgenotypes

2 Clinical course of HBV infection

2.1 Natural history

2.2 Chronic HBV infection

Table 2 Risk of chronicity and age at primary infection

© World Gastroenterology Organisation, 2015

Fig. 2 Sequence of serologic markers in acute hepatitis B infection (reproduced with

2.3 CHB disease phases

© World Gastroenterology Organisation, 2015

— Periodic ALT flares with intervening normalization may make it difficult to

2.4 Progression of CHB

© World Gastroenterology Organisation, 2015

Table 3 Factors in the disease outcome with chronic hepatitis B

Fig. 4 Risk of progression in patients with HBV-related cirrhosis. Reproduced with

3 Diagnosis and monitoring of hepatitis B

3.1 Cascade—acute hepatitis B

© World Gastroenterology Organisation, 2015

Cascade 1 Diagnostic tests for acute hepatitis B

The differential diagnosis of HBsAg-positive acute hepatitis includes exacerbations of

3.2 Resolved HBV infection

© World Gastroenterology Organisation, 2015

3.3 Chronic HBV infection

Table 4 Differentiation of phases of CHB infection

© World Gastroenterology Organisation, 2015

HBsAg ALT* HBeAg Anti- HBV DNA LLD

Coinfection with HIV Increased/normal +/– +/– High**

3.4 Initial evaluation of patients with chronic HBV infection

The initial examination should include:

© World Gastroenterology Organisation, 2015

Factors Host Viral

Modifiable Excess alcohol intake Coinfection with HIV

3.5 Occult HBV

© World Gastroenterology Organisation, 2015

3.6 HBV reactivation

© World Gastroenterology Organisation, 2015

3.7 HCC screening

© World Gastroenterology Organisation, 2015

4 Treatment for CHB

© World Gastroenterology Organisation, 2015

© World Gastroenterology Organisation, 2015

Q 3 mo ALT & HBV DNA × 3, then if

4.1 Cascades for CHB management—a resource-sensitive approach

Cascade 2 Immunotolerant phase monitoring (no therapy)

Medium Annual HBeAg

Low 6-monthly ALT

Cascade 3 Immunoactive phase monitoring (off therapy)

© World Gastroenterology Organisation, 2015

Cascade 4 Immune-control phase monitoring, HBeAg-negative (off therapy)

Medium Annual HBsAg

Low 6-monthly ALT and CBC