Infectious Diseases

ISSN: 2374-4235 (Print) 2374-4243 (Online) Journal homepage: https://www.tandfonline.com/loi/infd20

Management of hepatitis B virus

infection, updated Swedish guidelines

Johan Westin, Soo Aleman, Maria Castedal, Ann-Sofi Duberg, Anders

Eilard, Björn Fischler, Christian Kampmann, Karin Lindahl, Magnus
Lindh, Gunnar Norkrans, Stephan Stenmark, Ola Weiland & Rune Wejstål

To cite this article: Johan Westin, Soo Aleman, Maria Castedal, Ann-Sofi Duberg, Anders Eilard,
Björn Fischler, Christian Kampmann, Karin Lindahl, Magnus Lindh, Gunnar Norkrans, Stephan Stenmark, Ola
Weiland & Rune Wejstål (2020) Management of hepatitis B virus infection, updated Swedish guidelines,
Infectious Diseases, 52:1, 1-22, DOI: 10.1080/23744235.2019.1675903
To link to this article: https://doi.org/10.1080/23744235.2019.1675903

© 2019 The Author(s). Published Published online: 15 Oct 2019.

by Informa UK Limited, trading as
Taylor & Francis Group.

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INFECTIOUS DISEASES, https://doi.org/10.1080/23744235.2019.1675903 2020; VOL. 52,

NO. 1, 1–22

REVIEW ARTICLE

Management of hepatitis B virus infection, updated

Swedish guidelines

a b c d a
Johan Westin , Soo Aleman , Maria Castedal , Ann-Sofi Duberg , Anders Eilard , Bjorn€
e f b a a
Fischler , Christian Kampmann , Karin Lindahl , Magnus Lindh , Gunnar Norkrans , Stephan
g b a
Stenmark , Ola Weiland and Rune Wejstål
a
Deparment of Infectious Diseases, Institute of Biomedicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg,
b
Sweden; Deparment of Medicine, Division of Infectious Diseases, Karolinska Institutet and Karolinska University Hospital Huddinge,
c
Stockholm, Sweden; Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg,
d
Gothenburg, Sweden; Deparment of Infectious Diseases, School of Medical Sciences, Faculty of Medicine and
€ € e
Health, Orebro University, Orebro, Sweden; Deparment of Pediatrics, CLINTEC, Karolinska Institutet and Karolinska University
f
Hospital, Stockholm, Sweden; Deparment of Infectious Diseases, Skåne University Hospital Lund, Lund, Sweden;
g
Deparment of Clinical Microbiology and Infectious Diseases, Umeå University, Umeå, Sweden

ABSTRACT
Despite access to effective antiviral drugs and vaccines, hepatitis B virus (HBV) infection remains a major health issue
worldwide. HBV is highly infectious and may cause chronic infection, progressive liver damage, hepatocellular cancer
(HCC) and death. Early diagnosis, proper management and timing of treatment are crucial. The Swedish Reference
group for Antiviral Treatment (RAV) here provides updated evidence-based guidelines for treatment and management
of HBV infec-tion which may be applicable also in other countries. Tenofovir alafenamide (TAF) has been introduced
as a novel treat-ment option and new principles regarding indication and duration of treatment and characterization of
hepatitis B have been gradually introduced which justifies an update of the previous guidelines from 2007. Updated
guidelines on HCC sur-veillance in HBV-infected patients, treatment and prophylaxis for patients undergoing liver
transplantation as well as man-agement of pregnant women and children with HBV infection are also provided.

KEYWORDS ARTICLE HISTORY CONTACT

Hepatitis B virus Received 24 September 2019 Johan Westin
chronic hepatitis Accepted 27 September 2019 johan.westin@gu.se
antiviral treatment Deparment of Infectious Diseases, University
hepatocellular cancer of Gothenburg, Diagnosv€agen 21, Gothenburg
surveillance
se-41650, Sweden
prophylaxis

2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
 Rating of evidence

Throughout this paper, the strength of recommenda-
tions and the underlying evidence have been rated
according to the scale from the European Association
for the Study of the Liver (EASL), which is based on the
GRADE system [1], according to the table below and
indicated in bold as A1, B2, etc. If such a designation is
lacking, the recommendation is the expert group’s own
opinion (corresponding to C2).
This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivatives License
(http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial
re-use, distribution, and reproduction in any medium, provided the original work is
properly cited, and is not altered, transformed, or built upon in any way.
It is very likely that further research will have an impact on the
confidence in the estimate of effect. The estimate should be
considered uncertain.

Level of J. WESTIN ET AL.

evidence
High Definition
Moderate It is unlikely that further
research will change
the confidence in the
estimate of effect.
L It is likely that further
ow
research will have
an impact on the
confidence in the
Recommendati
on Strong
W
eak

Prevalence and natural course

Approximately, one-third of the world’s population has

been or is infected with hepatitis B virus (HBV) and around
290 million are chronic carriers [2]. Effective vac-cines are
available in most countries and a decline in global
prevalence of HBV is expected, but vertical trans-mission
still occurs in some countries, where availability of early
vaccination (birth dose) and prophylactic treat-ment to
mothers with a high viral load is lacking. Regarding acute
HBV infection, the predominant trans-mission routes in
Sweden are sexual contacts or injec-tion drug use. Acute
HBV infection is usually cleared in immunocompetent
adults. Approximately, 95% of chil-dren infected perinatally
develop chronic infection, while less than 5% of infected
adults do [3,4]. However, peo-ple with an impaired immune
system, and probably also elderly over 70 years old, have
an increased risk of devel-oping chronic infection [5].

Most people with chronic HBV infection in Sweden are

born outside of Europe and have been infected early in
life. Around 17,000 cases of HBV infection, mostly chronic
infections [6], were reported to the Public Health Authority
2008–2017. Without treatment, around 20% of individuals
with chronic HBV infection in Sweden would probably
develop severe liver disease during their lifetime, and
around 10% would develop hepatocellular cancer (HCC)
[7]. In other parts of the world, such as Southeast Asia,
this number is higher [8].
estimate of effect.
Phases of HBV infection
Chronic HBV infection is characterized by
different stages or phases, which reflect the
interaction between HBV replication and the
immune system. These phases are
particularly evident in patients infected during
the perinatal period. The phases are based
on the degree of liver inflammation, HBe
antigen and viral load (HBV DNA) in serum
[3,9] (Table 1).
Approximately, 1% of the chronic
infections each year proceed into a
resolution phase with HBsAg-negativity,
with or without development of antibodies
against
A HBsAg (anti-HBs) and without liver
inflammation [3].
B Patients who reach the HBsAg-negative
resolution phase, may still have covalently
closed circular HBV DNA
C (cccDNA) in the liver, which means that
the infection and the inflammation can be
reactivated in case of
immunosuppression, e.g. after
transplantation or during
treatment of malignant or inflammatory diseases [10].
1
2

HBV genotypes and mutations

The course of chronic hepatitis B may be affected
by the HBV genotype and mutations in the viral gen-
ome. Hence, these markers can be of value for clinical
assessment [11].

Prognosis
In the case of acute hepatitis B, or severe acute reactiva-
tion of chronic infection, the inflammation can develop
into life-threatening fulminant hepatitis (<1%). Patients
who do not achieve a durable immune control,
but who develop a chronic infection with ongoing mod-
erate to high HBV replication and a continuous or inter-
mittent immune activation with elevated alanine
aminotransferase (ALT) [3,12] have the highest risk of
developing liver cirrhosis and HCC. Virus replication at a
relatively low level is now also considered a risk factor
during long-term infection, particularly after perinatal
transmission [8].
In HBeAg-negative patients, the risk of progressive
liver damage is low when the HBV DNA level is
<2000 IU/mL and relatively high when HBV DNA is
>20,000 IU/mL. Among HBeAg-positive patients in the
tolerance phase, the differences in viral load have no
definite significance for the prognosis of inflammation
and fibrosis, but potentially for the cancer risk [13].
Among patients with an untreated chronic HBV infec-
tion with inflammation (hepatitis), 8-38% develop liver
cirrhosis within 5 years, where patients with HBeAg-
 INFECTIOUS DISEASES

Table 1. Immunological phases of chronic hepatitis B.

Immunological phase
Immune surveillance Immune reactivation
Immune tolerance Immune activation (HBeAg-negative (HBeAg-negative
Factors (HBeAg-positive chronic infection) (HBeAg-positive chronic hepatitis) chronic infection) chronic hepatitis)
7
Decreasing, fluctuating (from Low (<2 x 103) 3
Viral load (HBV DNA IU/ High (>10 ) Moderately high (>2 x 10 )
7 4
mL plasma) >10 and 10 )
Liver-inflammation None or minimal Mild to severe None or minimal Mild to severe
S-ALT Normal Continuously or Normal Intermittently elevated
intermittently elevated
HBeAg Positive Positive Negative Negative
Prognosis Uncertain (favourable for Prolonged inflammation Generally good, possibly Prolonged inflammation
most patients) increases the risk of cirrhosis increased risk of HCC after a increases the risk of cirrhosis
and HCC previous prolonged and HCC
inflammation
Risk of transmission High High, decreasing Low Moderate
ALT: alanine aminotransferase; HCC: hepatocellular cancer
Text given in italics indicate the classification according to EASL 2017 [9].

negative chronic hepatitis are at the highest risk [8,14]. treatment with nucleoside analogue (NA) can be given
Liver cirrhosis may also occur in patients who previously [19,20].
had a prolonged immune activation but who later entered
the surveillance phase. The 5-year survival rate for
Box 1. . Factors increasing the risk of developing cirrhosis and/or
untreated compensated cirrhosis is around 85% but only HCC [3,8]
15-30% for decompensated cirrhosis [8].
Prolonged immune activation phase (>2 years) or intermittent
The most important risk factor for the development reactivation
of HCC is liver cirrhosis, which accounts for a 2–4% High HBV DNA levels, particularly in combination with long-
annual risk of HCC [8,14]. The highest risk is seen in last-ing infection
High age (unusual before 40 years of age)
Southeast Asia. Approximately 90% of patients with
HBV-associated HCC have underlying cirrhosis [15]. Concomitant infection with hepatitis C virus, hepatitis D virus
or HIV
However, also patients without cirrhosis and even
Immunosuppression
patients with anti-HBs antibodies may develop HCC
High alcohol consumption
[16]. Factors increasing the risk of liver cirrhosis and/or
Male gender
HCC are summarized in Box 1. There are several
Smoking
scoring sys-tems that can be used for assessment of
HBV genotype C (vs. B)
HCC risk in patients of both Asian and Caucasian
(HCC) Dietary aflatoxin (HCC)
origin, with or without antiviral therapy [17,18].
African or Asian origin (HCC)
Diabetes mellitus and metabolic syndrome
Transmission risks of HBV infection (HCC) HCC in close relative (HCC)

HBeAg-positive carriers usually have a high plasma

viral load and are highly infectious. HBeAg-negative
patients are often less infectious, but some may have
high viral load in plasma and high infectivity. This
occurs mainly in infection with HBV with precure
mutations that prevent the production of HBeAg.
Extrahepatic manifestations of HBV
As for hepatitis C, immune mediated manifestations may
occur in HBV infection, e.g. vasculitis, skin rash (purpura),
polyarteritis nodosa, joint pain, peripheral neuropathy and
glomerulonephritis. Sometimes mixed cryoglobuli-nemia
is also observed in these patients. In such cases,
treatment with interferon should be avoided, while
Assessment and management of patients with
chronic HBV infection
Patients with a recently discovered chronic HBV infec-
tion, i.e. HBsAg-positive patients without any signs of
acute infection, should be assessed as outlined in Box
2. The infection is considered to be chronic when the
patient is still HBsAg-positive after 6 months.
The HBV infection should be characterized and
assessed regarding severity and transmission risk. The
need for monitoring and treatment should be estab-lished.
Family members and sexual partner(s) should be tested
and, when necessary, vaccinated. All patients
4 J. WESTIN ET AL.

with chronic hepatitis B should be followed at a clinic
with experience of HBV infections.
Box 2. Initial assessment for diagnosis and staging of the HBV infection
At the first visit:
Medical history (incl. alcohol) and physical examination
Laboratory tests: haemoglobin, leukocytes, platelets and S-albumin,
(possibly S-IgG, B-PEth), S-AST, S-ALT, S-ALP, S-bilirubin, PT(INR).
Virological/serological tests: HBsAg, HBsAg quantification, HBeAg,
anti-HBe, anti-HBc and HBV DNA quantification.
HDV virology: screening with antibodies (anti-delta). HDV RNA
quantifi-cation if anti-delta is positive.
Other virological tests: Serology for hepatitis A, C and HIV.
Assessment of fibrosis stage, primarily by liver elastography.
After 3 months:
S-AST, S-ALT, PT(INR)
Other tests depending on findings at the first visit.
After 6 months:
S-AST, S-ALT, PT(INR), platelets, HBsAg, HBeAg, anti-HBe and HBV DNA
quantification.
Management and monitoring
A. Patients with normal ALT and no fibrosis/cirrhosis
Immune tolerance phase (HBeAg-positive chronic
infec-tion). Antiviral treatment is usually not
recommended. The patient should be monitored one to
two times per year, to detect the transition to chronic
hepatitis (immune activation phase) or to the
surveillance phase. Patients in the immune tolerance
phase are often young, with a high viral load and the
risk of sexual transmission must be considered.
Surveillance phase (HBeAg-negative chronic infection).
HBeAg-negative patients with repeatedly normal ALT are
likely in the surveillance phase, and have a good prog-
nosis. These patients typically have low HBV DNA levels,
usually below 2,000 IU/mL and HBsAg below 1,000 IU/
mL. Antiviral treatment is not recommended in this group.
Further monitoring should be performed accord-ing to the
recommendations below. At an early stage it can be
difficult to distinguish such “inactive” HBV car-riers from
those with ongoing intermittent inflammation
or compensated inactive cirrhosis, caused by a
previous more active stage. Therefore, repeated
testing, and assessment of fibrosis (with liver elasticity
measurement and/or liver biopsy) may be necessary.
In unclear cases, a liver biopsy should be performed.
B. Patients with elevated ALT
Patients with elevated ALT should be monitored two to
three times per year, since treatment may be indicated.
Other causes of elevated ALT should be excluded, includ-
ing history of alcohol use, combined with analysis of blood
levels of phosphatidylethanol (B-PEth) or other bio-
markers of alcohol use. Liver elastography has been vali-
dated for chronic hepatitis B in a meta-analysis, and 7.2
kPa was suggested as cut-off for fibrosis stage 2 (F2) and
12.2 kPa for cirrhosis (F4) [21]. This is a good method to
exclude significant fibrosis (<7.2 kPa) and to confirm
cirrhosis (>12.2 kPa), but the accuracy within the range
7.2–12.2 kPa is low. It must also be taken into consider-
ation that elevation of ALT more than FIVE times the
upper limit of normal (>5 x ULN) may significantly affect
liver elasticity. In cases where significant inflammation
and/or fibrosis is suspected, a liver biopsy should be per-
formed to better assess treatment indication and progno-
sis. Patients with liver cirrhosis should be monitored
according to Table 2, and endoscopy should be per-
formed to identify potential oesophageal varices and then
be repeated according to local guidelines. However, gas-
troscopy is not necessary in cases with liver elastography
6
levels <20 kPa and platelet count >150 10 /mL [22].
New biomarkers for hepatitis B
Quantification of HBsAg has become established to assess
activity and treatment efficacy at the various stages of HBV
infection [23]. An HBsAg level below 1,000 IU/mL in
combination with HBV DNA below 2,000 IU/mL in HBeAg-

Table 2. Monitoring and laboratory testing of patients with chronic HBV infection.
Immunological phase
Immune activation/HBeAg-positive
Immune tolerance/HBeAg-positive chronic chronic hepatitis or reactivation / HBeAg-
Immune surveillance/HBeAg-negative
infection (normal ALT) negative chronic hepatitis (elevated ALT) chronic infection (normal ALT)
Monitoring 1 to 2 times/year 2-3 times/year 1 time/year
Laboratory testing S-ALT, HBeAg/anti-HBe, S-ALT, S-albumin, PT(INR),platelet count
S-ALT, PT(INR),
HBV DNA quantification should be HBeAg/anti-HBe, platelet count, quantitative HBsAg,
performed once per year HBV DNA quantification (possibly anti-HBs) or
1-2 times/year HBV DNA quantification should be
performed yearly or every two years
Patients with (and even some patients without) cirrhosis should also be monitored for HCC development every sixth month; see the chapter about
HCC surveillance.
Patients who are in a stable surveillance phase, without any signs of liver damage (documented with a stable low HBV DNA level and repeatedly
normal ALT), so-called inactive HBV carriers, can after a few years of annual monitoring be monitored less often, e.g. every 2 or 3 years.
Monitoring can stop when seroconversion from HBsAg to anti-HBs is achieved.
negative patients (genotype D) indicate that the patient is
in the
D) [24].immune
This cansurveillance phase, inactive
be used to identify with a carriers,
positive who
pre-
dictive
do not value of undergo
need to 90% (for repeated
patients infected with
testing to genotypethe
determine
stage of HBV infection. HBsAg quantification can also be
used to monitor peg-IFN treatment (see below). During
treatment with NA, the level of HBsAg in serum is
generally not greatly affected, since it likely reflects the
number of hepatocytes with HBV DNA integration, rather
than the viral replication rate. Nevertheless, HBsAg quan-
tification may be of value to assess the probability of
HBsAg clearance to be reached during treatment. In
untreated patients, HBsAg levels below 100 IU/mL predict
spontaneous HBsAg clearance [25].
Quantification of HBeAg is a potentially useful
marker for treatment efficacy but it is affected by the
presence of certain mutations in the core promoter or
precore region which limits its value.
Quantification of core-related antigen (HBcrAg) is a
method that detects and measures the sum of different
antigens that are built up by amino acids from the core
protein. It correlates well with HBV DNA levels and can
become a supplement, particularly for monitoring
during antiviral therapy. However, it is not yet available
for clin-ical use in all laboratories.
Quantification of HBV RNA in serum has also been pro-
posed as a method to monitor the virological response to NA
treatment, as a marker for the effect on cccDNA. As
opposed to HBV DNA, HBV RNA is not directly affected by
NA, as these agents block reverse transcription of HBV RNA
into HBV DNA. During NA treatment, the initial decrease of
HBV RNA is therefore smaller than the decrease of HBV
DNA. Subsequently, they follow each other and it is
uncertain whether measurement of HBV RNA adds enough
information to justify its clinical use.
Chronic hepatitis B and vaccination against
hepatitis a
The risk of more severe outcomes for patients with
chronic hepatitis B who acquire acute hepatitis A, justi-
fies vaccination against hepatitis A in these patients.
HCC surveillance (tumour monitoring) in patients
with chronic hepatitis B virus infection
European guidelines for management of HCC were pub-
lished in 2018 [26] and Swedish guidelines including
6 J. WESTIN ET AL.
INFECTIOUS DISEASES 5
recommendations for HCC surveillance will soon be
available in an updated version.
HCC in patients with a chronic HBV infection mainly
occurs in patients with cirrhosis (80-90%), but also in some
patients without cirrhosis [8,15,27], see risk factors in Box 1.
The prognosis of HCC depends on the tumour bur-den,
liver function (Child-Pugh score) and general health
condition. These factors also determine whether curative
treatment can be given. The 5-year survival rate follow-
ing treatment aiming to cure, given at an early stage (liver
transplantation, resection or local ablative treat-ment), is
40-75%, while the median survival rate for untreated
patients at an advanced stage is 8 months, and for
palliative treatment 10-20 months.
The purpose of HCC surveillance is to enable early
detection of HCC as well as treatment that may
prolong survival. Surveillance should be stopped if
active treat-ment can no longer be offered due to
changed condi-tions such as, poor general health or
severe comorbidity. The need of surveillance should
therefore be regularly assessed by a physician.
The recommended method for surveillance is ultrason-
ography of the liver, without administration of contrast
medium, every 6 months. However, early detection of HCC
using ultrasound requires a skilled and experienced
examiner [28]. Additional serum alpha-fetoprotein (AFP)
analysis should be considered [29]. Particularly an increas-
ing value over time warrants further investigation [30].
Previous studies suggest that surveillance is cost-effect-
ive when the HCC incidence exceeds 1.5% per year for cir-
rhosis patients, or 0.2% per year for HBV-infected patients
without cirrhosis [26,31]. Patients from Asia and Africa (sub-
Saharan Africa), infected with HBV early in life, have an
enhanced risk of HCC, also without cirrhosis. However, the
incidence of HCC in these groups, after migrating to a
western country, has rarely been studied [32]. One study
showed that the incidence increased with age, to exceed
0.2% at the age of 40–50 years for men and 60 years for
women of African or Asian origin living in Sweden, which
correlates well with results from an American study [27,33].
NA treatment can prevent further inflammation and the
progression of fibrosis and thereby reduce the HCC
incidence in patients with liver cirrhosis, but it is not clear
whether treatment would prevent development of HCC in
patients without inflammation and fibrosis. A long-term
study of patients from Europe (Caucasians), who were
treated with NA, showed a decreasing but still high HCC
incidence in patients with cirrhosis, and an unchanged
low risk in patients without cirrhosis [34]. Continued
surveillance during NA treatment is therefore recom-
mended for patients with cirrhosis or other risk factors.
Recommendation: Indication for HCC surveillance
in patients with chronic HBV infection
Patients with cirrhosis, Child-Pugh A and B (B1)
Patients with cirrhosis, Child-Pugh C (liver failure)
waiting for a liver transplantation (C1)
Patients without cirrhosis, over 40 years old (men) or
50 years old (women), after individual risk assess-
ment, considering the following risk factors for HCC
(C2):
High age
Male
Fibrosis stage F3
Originating from area with high HCC incidence
(East or Southeast Asia and Sub-Saharan Africa)
Close relative with HCC
Prolonged active liver inflammation
HBV DNA above 20,000 IU/mL
HBV genotype C
Diabetes mellitus
Concomitant infection with HDV, HCV or HIV
Evidence suggests that age, gender and development of
fibrosis may be particularly important. For individual HCC
risk assessment, different scoring systems are available.
PAGE-B, based on age, gender and platelet count is simple
and well documented, especially in Caucasians with ongoing
NA treatment. A total score of <10 means low or no risk, 10-
17 means intermediate risk, especially during long follow-up
and >17 means high risk [35,36] (see also Table 3).
Recommendation: Prerequisites and HCC
surveillance method in patients with chronic HBV
The patient should have a generally good health
and be compliant, to enable active treatment
The patient must be well-informed and willing to
undergo repeated check-ups
Table 3. Template for calculation of PAGE-B score for HCC
predic-tion, modified from [35].
9
Age (years) Gender Platelet count ( 10 /L)
16–29 0 Female 0 >200
30–39 2 Male 6 100–199
40–49 4 <100
50–59 6
60–69 8 However, the effect of the treatment is usually not per-
>70 10
The recommended method for surveillance is ultra-
sound, without contrast enhancement þ/- alpha-
fetoprotein
The time between examinations should be around 6
months
An “automated routine” for management of surveil-
lance is recommended
Treatment of hepatitis B virus infection
There are currently two main options for treating
chronic HBV infection:
Nucleos(t)ide analogues (NA)
or Alpha-interferon (IFN)
See Table 4 for the antiviral effects of these treat-
ment options.
Nucleos(t)ide analogues (NA)
NA has a direct antiviral effect against HBV by inhibiting
DNA polymerase and is administered orally. Six different
NAs are approved for the treatment of HBV: lamivudine
(LAM), adefovir (ADV), telbivudine (TBV), entecavir
(ETV), tenofovir disoproxil fumarate (TDF) and tenofovir
alafe-namide (TAF). Emtricitabine has antiviral activity
against HBV, but is only approved for the treatment of
HIV infection. A combination tablet with emtricitabine and
TDF is also approved for HIV and has been studied in the
treatment of patients co-infected with HBV and HIV.
ETV, TDF or TAF, which all have a high barrier to
drug resistance, are recommended as preferred
treatments of HBV infection, while LAM, ADV, TBV
(which have a low barrier to drug resistance) are no
longer recommended. Furthermore, ETV, TDF and
TAF have a high safety pro-file, even for patients with
advanced liver disease. Hence, patients with
decompensated cirrhosis, liver transplanted patients,
patients who have a severe acute HBV infection and/or
HBV reactivation can be safely treated.
NAs are used as antiviral treatment against HBV infec-
tions in more than 90% of the cases in Sweden and
internationally. During ongoing therapy, most patients
0
6 achieve non-detectable HBV-DNA levels, histological
9 improvement, and normalization of ALT values (Table 4).
sistent when treatment is discontinued, which may entail
lifelong treatment. Non-detectable HBsAg (func-tional
cure) is only achieved in 4–8% of HBeAg-positive
 INFECTIOUS DISEASES 7

Table 4. Outcomes from treatment of HBeAg-positive and negative patients with chronic hepatitis B, 6 months after 48–52 weeks of treat-
ment with peg-IFN and after 48-52 weeks of ongoing treatment with NA (adapted after [9], where references for the table are shown).
PEG IFN alpha 2a LAM TBV ETV ADV TDF TAF
Dose 180 mg 100 mg 600 mg 0.5 mg 10 mg 245 mg 25 mg
HBeAg-positive
Anti-HBe seroconversion 32% 16–18% 22% 21% 12–18% 21% 10%
HBV DNA <60–80 IU/mL 14% 36–44% 60% 67% 13–21% 76% 64%
ALT < ULN 41% 41–72% 77% 68% 48–54% 68% 72%
Loss of HBsAg 3% 0–1% 0.5% 2% 0% 3% 1%
HBeAg-negative
HBV DNA <60–80 IU/mL 19% 72–73% 88% 90% 51–63% 93% 94%
ALT < normal upper limit 59% 71–79% 74% 78% 72–77% 76% 83%
Loss of HBsAg 4% 0% 0% 0% 0% 0% 0%
LAM, TBV, and ETV are nucleoside analogues.
ADV, TDF, and TAF are nucleotide analogues.

patients and <1% of HBeAg-negative patients after 5–
10 years of treatment. To the best of our knowledge,
there are no follow-up studies exceeding 10–15 years;
hence, data on the safety of lifelong treatment are
lacking.
Entecavir (ETV)
creatinine clearance <50 mL/min, the dose should be
modified according to the SPC. TDF also has an impact
on bone density; hence, patients with increased risk of
fractures (high age, post-menopausal women, steroid
treatment, impaired renal function) should be monitored
regarding bone density. For these patient groups, TAF
(see below) or ETV are better treatment options.

For treatment-naïve non-cirrhotic HBeAg-positive

patients, ETV at a recommended dose of 0.5 mg once
daily will decrease more than 6 log 10 units after 48
weeks of treatment [37]. In 90% of the patients, HBV
DNA is not detectable after 3 years of treatment [38].
For HBeAg-negative patients, a reduction of HBV DNA
by more than 5 log10 units is achieved at week 48 [39].
In less than 1% of previously untreated patients, resist-
ance to ETV has developed after 3 years of treatment.
ETV is not recommended in patients treated with LAM
who developed resistance, since cross-resistance
exists. However, cross-resistance to tenofovir has not
been observed and TDF is therefore recommended in
cases of LAM or ETV resistance. The ETV dose
should be reduced in patients with renal impairment
(creatinine clearance <50 mL/min).
Tenofovir disoproxil fumarate (TDF)
TDF monotherapy is approved for the treatment of HBV. It
is also (in combination with other antiretrovirals) approved
for the treatment of HIV (± HBV infection) and is available
as a combination tablet (tenofovir plus emtri-citabine).
Studies have confirmed this drug’s high anti-viral effect on
hepatitis B with a 4-6 log10 reduction of HBV DNA after 48
weeks of treatment [40]. Drug resist-ance to TDF is rare.
The risk of renal side effects should be particularly
considered in patients who already have renal impairment
or who are on drugs that are poten-tially toxic to the
kidneys. Renal function should be monitored every 6
months during therapy. At a
8 J. WESTIN ET AL.
Tenofovir alafenamide (TAF)
TAF is the most recently approved drug for the treat-ment
of patients with chronic HBV infection. TAF has the same
mode of action as TDF, but is associated with a lower
level of active metabolites in plasma. In two randomized
phase-3 studies with HBeAg-positive and negative
patients, TAF 25 mg was equivalent to TDF 300 mg
regarding primary endpoints [41]. TAF treatment resulted
in a significantly smaller decrease of eGFR and had less
impact on bone density in hips/spine compared with TDF.
The TAF dose does not need to be adjusted for patients
with renal insufficiency, but is not recom-mended in
patients with creatinine clearance below 15 mL/min, who
are not on haemodialysis. TAF is mainly recommended in
patients who are at risk of developing or who have an
underlying kidney disease or osteope-nia/osteoporosis.
ETV may also be an option for patients that did not
previously develop resistance to LAM.
Alpha-interferon (IFN)
Pegylated IFN (peg-IFN) has a weaker antiviral effect
than NA treatment, but an important advantage is that a
persistent effect can be achieved with a finite treat-ment.
In general, 48 weeks of treatment is given by sub-
cutaneous injections once per week, giving a sustained
treatment response in approximately 30% of the patients
with HBeAg-positive or HBeAg-negative infec-tion.
Approximately 11% of HBeAg-positive patients and
6% of HBeAg-negative patients achieve HBsAg clear-
ance [9].
 Disadvantages of peg-IFN treatment are primarily the
limited treatment response, that it requires subcutane-ous
injection, and is poorly tolerated. Only patients with a high
probability of a favourable treatment response should
therefore be treated, and contraindications should be
considered (see SPC). For HBeAg-positive patients,
factors indicating good probability of response are
genotype A or B (vs. C and D), high ALT levels, low viral
load, apparent necroinflammatory activity, and low HBsAg
levels. Predictive baseline factors have not been clearly
identified in HBeAg-negative chronic hepatitis B patients
[9]. When peg-IFN treatment is given, stopping rules
based on levels of HBsAg and HBV DNA after 12–24
weeks of treatment can be used to discontinue treatment
in cases less likely to respond, see below.
Combination therapy
NA þ NA
Monotherapy with ETV or TDF is very effective and leads
to reduced viral load already during the first week. The
subsequent decline is probably due to eradication of
infected hepatocytes, and is much slower. This explains
why some patients with a high viral load before treat-ment
do not achieve non-detectable HBV DNA levels within the
first year of treatment. However, the antiviral effect is not
better when two NAs are combined; hence, combination
of two or more NAs from the start of treat-ment is not
indicated. When the decrease in HBV DNA during
treatment with TDF or ETV decline and reach a plateau in
spite of good adherence, switching to another drug, or in
carefully selected cases – particularly in patients with
cirrhosis – a combination of both may be considered.
(C2).
Peg-IFN þ NA
Combination therapy with peg-IFN and NA, combining
potent antiviral and immunomodulatory effects, has
been investigated in various studies [42]. The
reduction of the HBV DNA level during combination
therapy is more pronounced when peg-IFN is given in
combination with an NA, but the effect does not persist
after discon-tinuation of treatment. No convincing
benefits have yet been demonstrated with this
strategy, which is therefore not recommended.
New treatment regimens
New drugs are being assessed in different stages of
development and some of them will undergo phase III
trials during 2018–2019. Most of them aim to achieve a
functional cure, with clearance of HBsAg. Several specific
steps of the HBV life cycle are being studied to obtain
antiviral effect, for example, receptor blockers, blocking
the entry of HBV into hepatocytes, RNA interference
(RNAi), inducing gene silencing at post-transcriptional
level, capsid inhibitors, interfering with the formation of
viral capsids, surface antigen inhibitors (sAGs), interfering
with the production of HBsAg, which is needed for the
virus to enter or exit the cell, and nucleic acid polymers
(NAP), inhibiting secretion of HBsAg. Even new NAs
might become available. Moreover, receptor blockers
(bulevirtide, Myrcludex B), antigen blockers and prenyla-
tion inhibitors (lonafarnib) have been tested, also in com-
bination with peg-IFN/NA against hepatitis D infection.
Other future treatment methods might be gene therapy or
immunomodulators, e.g. therapeutic vaccination in
combination with other drugs, to stimulate the immune
system to recognize and interact with HBV infection fol-
lowing antiviral treatment.
Treatment of hepatitis B virus infection
Acute hepatitis B virus infection
Most acute HBV infections (over 95%) lead to
clearance of HBsAg within a few months. However, in
a small number of cases, fulminant hepatitis may
develop result-ing in need of a liver transplant or even
with a fatal outcome.
The scientific evidence for antiviral therapy of acute
hepatitis B is limited, and treatment is only recom-
mended when a severe infection, with a risk of devel-
oping fulminant hepatitis, is suspected. The definition
of severe acute HBV infection varies between studies.
Most commonly, biomarkers of liver damage with a
PT(INR) 1.6, bilirubin 170 lM (10 mg/dL) or clinical
signs of impaired liver function, such as ascites or
encephalopathy are used. A meta-analysis from
Cochrane 2017, found that studies of treatment of
acute hepatitis B are of low quality and that evidence
to recommend such treatment is lacking [43]. However,
with regards to the potentially serious consequences
and the lack of severe side-effects, it is reasonable to
recommend treatment as described below in cases
where a severe disease progression is suspected, as
outlined in the recently published guideline from the
British Transplantation Society [44]. If treatment is initi-
ated at a late stage, in patients with signs of liver fail-
ure and low or undetectable HBV DNA levels, the
benefit of treatment is probably limited but treatment is
still recommended.
Recommendation
Consider treatment for patients with severe acute
hepatitis B virus infection (C1)
Fulminant hepatitis
Severe hepatitis – defined as 2 of the following 3
criteria
bilirubin >100 lmol/L
PT(INR) 1.6
liver encephalopathy
Long-lasting symptoms or increased bilirubin for
over 4 weeks
Immunocompromized patients
Treatment with ETV, TDF or TAF is primarily recom-
mended. Treatment should continue until HBsAg is
undetectable. If HBsAg is still detectable, treatment
should be discontinued after 6-12 months. The future
need of treatment should then be assessed according
to the same guidelines as for chronic hepatitis B. After
treatment is discontinued, patients must be monitored
for potential reactivation of the infection. Interferon is
contraindicated in acute hepatitis B, due to the risk of
liver decompenzation.
Chronic hepatitis B virus infection
The overall treatment goal in chronic hepatitis B is to
prevent further disease progression and liver cirrhosis
and to reduce the risk of HCC. The risk of
transmission, reactivation and extrahepatic
manifestations is also decreased by treatment and the
quality of life may be improved [45–47].
Specific Treatment Goals, Easily Measurable
Undetectable HBV DNA in serum (inhibited HBV
replication)
Normal ALT (absence of inflammation)
Undetectable HBeAg (if HBeAg was detected
before treatment)
Undetectable HBsAg
10 J. WESTIN ET AL.
INFECTIOUS DISEASES 9
Treatment response and cure
There are different definitions of treatment response
and cure in chronic hepatitis B:
Suppression of viral replication: undetectable/low
lev-els of HBV DNA in serum and normalization of
ALT. However, in cases with only suppression,
residual HBsAg is present in serum.
Functional cure: undetectable HBV DNA and HBsAg in
serum, with or without anti-HBs seroconversion. This
can also be achieved spontaneously following acute
infection and significantly reduces the risk of
progression of liver damage and HCC. Already pre-
sent liver damage may partly regress. However, even
in cases where functional cure is achieved, intrahe-
patic cccDNA and integrated HBV DNA will remain.
Virological cure: functional cure and eradication of
intrahepatic cccDNA. It is expected to eliminate the
risk of reactivation of hepatitis B.
Complete cure: virological cure and eradication of
intrahepatic integrated DNA. This can probably fur-
ther reduce the risk of HCC.
Currently available treatment options usually allow
suppression of viral replication, while functional cure
(HBsAg-negativity) is rarely achieved. Complete cure
can-not be achieved with current treatment regimens
or with those that are currently being developed.
Indications for treatment in adults
When assessing the indication for treatment of chronic
hepatitis B, in addition to the severity of liver damage
and the expected natural course, one should also con-
sider the probability of treatment response, the risk of
adverse events and development of resistance as well
as expected adherence.
Recommendation: Indications for treatment of
chronic hepatitis B
Treatment should be given to
Patients with cirrhosis, independent of viral load (A1)
Patients with HBV DNA >20,000 IU/mL (4.3 log10) and
repeatedly elevated ALT, > 2 x ULN (if other causes
can be excluded) with a duration of more than a
year (B1)
Patients with HBV DNA >2000 IU/mL (3.3 log10) and
repeatedly elevated ALT with a duration of more
than a year and fibrosis stage 2, primarily verified
by liver biopsy (A1)
Patients with extrahepatic manifestations of HBV (C2)
Treatment can be considered for
Patients over 40 years old, with positive HBeAg and
high levels of HBV DNA, regardless of other crite-ria
(C2)
Patients with a close relative (children, siblings,
parents, grandparents) with HBV-related HCC,
regard-less of other criteria (C2)
Choice of treatment
Interferon
Peg-IFN is a preferred treatment in selected patients
without liver cirrhosis. It is given subcutaneously once
weekly, usually for 48 weeks. Peg-IFN is given during
a defined treatment period, without the risk of
developing drug resistance, but since the side-effects
are substantial, patients with a high probability of
treatment response should be primarily selected and
contraindications should be considered (see SPC).
Nucleos(t)ide analogues (NA)
Due to a higher threshold for developing drug resist-
ance (see above), only ETV, TDF or TAF is currently
rec-ommended. They are all given orally once daily.
The advantages of NA include their good antiviral
efficacy and tolerability. The disadvantage is the need
for long-term monitoring and that the optimal duration
of treat-ment is not clearly defined.
Recommendation: Choice of medication
HBeAg-positive chronic hepatitis B (without cirrhosis)
with indication for treatment
For NA treatment, ETV 0.5 mg or TDF 245 mg daily
(normal renal function) is primarily recommended,
until HBeAg seroconversion is achieved and
consoli-dated for 12 months (A1). ETV or TAF is
recom-mended in patients with renal impairment
(GFR <50 mL/min).
Peg-IFN alpha 2a, 180 mg subcutaneously, once
weekly, for 48 weeks, is recommended particularly
for younger patients infected with genotype A or B
(A2). Consider stopping rules, see below.
HBeAg-negative chronic hepatitis B (without cirrhosis)
with indication for treatment
ETV or TDF (A1) is primarily recommended for NA treat-
ment. Patients with renal impairment (GFR <50 mL/ min)
should receive ETV or TAF. Treatment can be dis-
continued when seroconversion from HBsAg to anti-HBs
is achieved. Earlier treatment discontinuation may be
followed by relapse. In such cases, the indication of
treatment should be re-evaluated, and treatment may be
reinitiated. If drug resistance develops, see below.
Peg-IFN alpha 2a is recommended at a dose of 180
mg per week, for 48 weeks (A1). Consider stopping
rules, see below.
Recommendation: Monitoring during
NA treatment
During treatment, the following markers should be
checked after 3 and 6 months, and then every 6 months:
HBV DNA level, (A1) and HBsAg quantification
HBeAg if the patient was HBeAg-positive pre-
treatment. ALT, PT(INR), platelet count
S-creatinine (calculation of eGFR) in patients with renal
impairment and for all patients treated with TDF. (B1)
HCC surveillance is recommended every 6 months when the
patient has an increased risk of HCC (see above). (B1)
The HBV DNA level in serum is the most important
marker for treatment response. The level will typically
decrease already after 1 week of treatment with TDF or
ETV by 2-3 log10 units, followed by a further reduction of
another 2 log10 after 6 months. Except for HBeAg-positive
patients with high pre-treatment HBV DNA lev-els, HBV
DNA should no longer be detectable after 12 months, or
at least be below 100 IU/mL. To document efficacy and
adherence, analysis of HBV DNA is recom-mended every
6 months (this interval can in some cases be extended to
9-12 months). If the HBV DNA level increases more than
1 log10 unit despite good adher-ence, the presence of a
resistance mutation should be considered, even though
such mutations are unusual in patients treated with TDF
or ETV. Resistance mutations are detected by
sequencing the polymerase gene. Even though HBV DNA
decreases to undetectable levels rela-tively early during
NA treatment, the decrease of the HBsAg level is slow.
However, HBsAg quantification can be of value to assess
the probability of achieving clear-ance of HBsAg during
treatment.
Recommendation: Discontinuation of
NA treatment

NA should be discontinued when HBsAg is no longer
detectable, with or without anti-HBs seroconversion. (B1)
NA may be discontinued when HBeAg is no longer
detectable (in initially HBeAg-positive patients), but only
after at least 12 months of consolidating treatment. (B2)
Discontinuation of NA may be considered in non-cir-rhotic
HBeAg-negative patients, who have achieved long-
standing treatment response (HBV DNA undetect-able or
detectable at levels below the quantifiable limit) but
require close monitoring after termination. (B2)
As it is currently unclear which patients (except those
mentioned above) benefit from discontinued NA treat-
ment, this should be evaluated within clinical studies.
NA treatment should not be discontinued in patients
with liver cirrhosis.
Remaining cccDNA in a small proportion of the hepato-
cytes is probably the reason why viral replication almost
always returns when NA treatment is discontinued, before
HBsAg becomes negative. It has been shown that such
relapses induce an immune response that can be more
effective than before the treatment, which may cause a
transient increase of ALT (flare). HBV DNA is often
stabilized at a lower level than before the NA treatment
was initiated. Discontinuation trials have mainly been
performed in patients with HBeAg-negative chronic
hepatitis B, after NA treatment with a favourable response
(normal ALT and undetectable HBV DNA) for at least 3
years [48]. Clearance of HBsAg seems to occur mainly
after reactivation with a flare and is more fre-quent in
patients who, before discontinuation of NA treatment,
have low HBsAg levels (less than 100 IU/mL) [49,50].
Because discontinuation of NA may be danger-ous for
patients with advanced disease, it is currently not
recommended.
Monitoring of patients with Peg-IFN treatment
Recommendation: Monitoring of Patients with Peg-IFN Treatment (B1)
Haemoglobin, platelet count, leucocyte count (incl.
neutrophils), ALT every 4 weeks
Thyroid-stimulating hormone (TSH), HBV DNA and HBsAg
quantifica-tion in serum after 12, 24 and 48 weeks.
HBeAg and anti-HBe after 24 and 48 weeks for initially
HBeAg-posi-tive patients.
12 J. WESTIN ET AL.
INFECTIOUS DISEASES 11
Due to the side-effect profile, stopping rules should be
applied for treatment with peg-IFN (see recommenda-
tions below [9]). Patients who achieve a virological
response and discontinue peg-IFN should be
monitored for a long time – in the beginning every 3
months – to detect any recurrence. TSH should also
be checked 6 months after the end of treatment.
Recommendation: Stopping rules for
IFN treatment
HBeAg-positive patients
Peg-IFN should be discontinued when the HBsAg level
is >20,000 IU/mL (for genotype B and C), or has not
decreased at all (for genotype A and D) after 12 weeks
of treatment, due to the very low probability of
subsequent HBeAg seroconversion. (B2)
Peg-IFN should be discontinued when the HBsAg
level is >20,000 IU/mL after 24 weeks of treatment,
due to the very low probability of subsequent
HBeAg seroconversion. (B2)
HBeAg-negative patients (with genotype D)
PegIFN should be discontinued in case of a combin-
ation of no decrease in HBsAg level, and a less than
2 log10 IU/mL decrease in HBV DNA level at 12
weeks of treatment, due to the very low probability
of subsequent HBeAg seroconversion. (B1)
Treatment of special patient categories
Chronic hepatitis B with cirrhosis
Compensated cirrhosis
NA treatment is the primary recommendation in patients
with compensated cirrhosis and persistent viral replica-
tion. Treatment in these cases should not be discontin-
ued due to the risk of recurrent HBV replication with
severe flare reactions and decompenzation. (A1)
Decompensated cirrhosis
Patients with decompensated cirrhosis, who are candi-
dates for transplantation, should at an early stage be
managed and treated in joint consultation with the
transplantation unit. Treatment should be given immedi-
ately to quickly achieve undetectable HBV DNA. Peg-IFN
is contraindicated in patients with decompensated liver
disease.
ETV or TDF is recommended, since both drugs are
effective and safe, also in the case of decompensated
disease [51–54]. A higher dose of ETV (1 mg) is
recom-mended for decompensated cirrhosis and side-
effects should be carefully monitored [51,55].
The NA dose must be adjusted according to kidney
function. Studies of safety and efficacy of TAF in
patients with decompensated cirrhosis are lacking, but
this may be an alternative, particularly in patients with
renal impairment.
The main goal of NA treatment in patients with
decompensated cirrhosis is to achieve compenzation
and to avoid liver transplantation [9]. The treatment
sig-nificantly modifies the natural course, with
improved liver function and prolonged survival [56,57].
Meta-analy-ses show a transplantation free survival
and total sur-vival rate of over 80% in patients treated
with NA [56]. Approximately 35% can be removed from
the trans-plantation waiting list and the Child-Pugh
score is improved by 2 points in 40-50% of the patients
treated with NA [57].
The NA treatment above leads to undetectable HBV
DNA levels in >80% of the patients after 1 year of
treat-ment. Treatment should be lifelong, and HCC
monitor-ing should continue in patients who might be
considered for liver transplantation [9]. When antiviral
efficacy is considered insufficient or when drug resist-
ance develops, the NA treatment must be adjusted.
Recommendation: Treatment of patients with
decompensated cirrhosis
1. Patients with decompensated cirrhosis should
receive NA treatment immediately. (A1)
2. Interferon is contraindicated in patients with
decom-pensated cirrhosis. (B1)
3. Close monitoring of tolerability of NA treatment is
required, particularly regarding renal function and
potential development of lactic acidosis. (B1)
Coinfection with hepatitis D virus (HDV)
The Hepatitis D virus needs HBsAg for its replication. All
patients who are HBsAg-positive should be tested for
antibodies against hepatitis D (anti-HDV). When anti-HDV
is positive, HDV RNA is checked to detect a current
infection. Repeated analysis of anti-HDV may be needed
for HBsAg carriers who are at risk of being exposed to
HDV.
Antiviral NA treatment has no documented efficacy
against HDV infection, as it does not prevent production
of HBsAg. Interferon is the only registered drug with effi-
cacy against HDV, but treatment efficacy is limited. A
scoring system (BEA score ¼ baseline-event-anticipation
score), assessing the risk of developing progressive HDV-
related liver disease has been suggested [58]. The BEA
score includes age, gender, origin, bilirubin, platelets and
prothrombin time – international normalized ratio PT(INR)
and can be of use in assessing the need for treatment.
The goal is to achieve negative HDV RNA and
normalization of transaminases. Currently, 48 weeks of
treatment with peg-IFN (A1) is recommended, where 17-
47% of the patients achieve the treatment goal [59].
Approximately 50% of the patients with undetectable HDV
RNA after 48 weeks of treatment will relapse after
treatment discontinuation [60]. Prolonging the treatment
to 96 weeks does not improve treatment outcome [61]. If
HDV RNA has decreased less than 2 log10 units from the
initial level after 24 weeks of treatment, the chance of
treatment success is less than 5%. When the treat-ment
is well tolerated, it is still recommended to con-tinue, as
there are currently no other treatment options available.
(B1) NA treatment is recommended when the HBV
infection is assumed to contribute to liver damage, which
might be the case when the HBV DNA level is relatively
high. NA should always be given to patients with liver
cirrhosis and detectable HBV DNA (B1). Since a chronic
HDV infection results in a high risk of progres-sive and
severe liver damage, new drugs against HDV are needed.
Coinfection with hepatitis C virus (HCV)
Patients with chronic HBV infection should be screened
for HCV infection, since coinfection with HCV increases
the risk of severe liver damage. Treatment with direct-
acting antivirals (DAAs) cures the HCV infection in >95%
of the treated patients, also in patients coinfected with
HBV. Hence, HCV treatment is recommended for these
patients. DAA treatment can in rare cases lead to reacti-
vation of a chronic HBV infection. Therefore, HBV treat-
ment with NA before the initiation of HCV treatment
should be considered. Patients who meet the criteria for
treatment of the HBV infection should start HBV treat-
ment before HCV treatment. This is particularly import-ant
for patients with advanced liver fibrosis ( F3), since
reactivation of HBV increases the risk of liver failure in
these patients. Occasional cases of reactivation of a
pre-vious HBV infection (HBsAg-negative, anti-HBc-
positive) during DAA treatment have been reported
[62]. Therefore, elevated ALT levels during or within 12
weeks after DAA treatment should result in HBsAg and
HBV DNA testing.
Recommendation: Treatment of patients
coinfected with HBV/HCV
In patients coinfected with HBV/HCV, the HCV
infec-tion should be treated.
Patients with indication for HBV treatment should
start NA treatment for HBV before DAA treatment is
given for the HCV infection. (B1)
HBsAg positive patients, without indication for HBV
treatment, should be considered for NA treatment
against HBV, to prevent harmful reactivation of
HBV. In such cases, NA should be initiated prior to
DAA treatment of hepatitis C and continued until 12
weeks after the DAA treatment has ended. When
no HBV treatment is given, monitoring of HBV DNA
and ALT is recommended every four weeks, until 12
weeks after DAA discontinuation. When these
analy-ses suggest HBV reactivation, NA treatment
should be initiated. (B2)
Patients with resolved previous HBV infection (anti-
HBc-positive, HBsAg-negative) should be monitored
for ALT every 4 weeks during DAA treatment for
hepatitis C, in order to detect potential reactivation
of HBV. (B1)
Prophylaxis and treatment of hepatitis B for
patients undergoing liver transplantation
Before NA treatment was available, HBV recurrence after
liver transplantation was almost universal and was con-
sidered a major complication. The current combination
therapy of NA and hepatitis B immunoglobulin (HBIG) has
reduced this risk to less than 5% [9,63].
Assessment before liver transplantation
Before decision regarding liver transplantation, it is
important to assess and characterize the patient’s HBV
infection, in order to evaluate the individual prognosis and
risk of hepatitis B recurrence. The assessment should
include serological markers for hepatitis B, C and D as
well as quantification of HBsAg and HBV DNA. HDV RNA
should be analysed when anti-HDV is positive. The
INFECTIOUS DISEASES 13
risk of hepatitis B recurrence after liver transplantation
is mainly depending on the patient’s HBV DNA level in
serum at the time of the liver transplantation.
Preventive antiviral hepatitis B treatment
All patients on the transplantation waiting list with HBV-
related liver disease should receive preoperative hepa-
titis B treatment with NA, aiming at reduction of serum
HBV DNA to undetectable levels at the time of trans-
plantation. As for other patients, TDF or ETV is recom-
mended. In cases with renal impairment (GFR <50mL/
min), TAF or ETV (dose depending on renal function)
is the primary option. TDF could also be used, given at
a reduced dose according to kidney function.
Treatment efficacy should be monitored by HBV DNA
quantifica-tion, at least every other month during
ongoing treat-ment, before liver transplantation.
Perioperative treatment
HBIG should be administered perioperatively, during
the anhepatic phase, at a dose of 4,000–5,000 IU
intravenously.
Postoperative treatment
It is unlikely that treatment with HBIG and
ETV/TDF/TAF during and after liver transplantation will
cause perman-ent eradication of the virus, even
though the HBV DNA level at the time of
transplantation is undetectable. In general, complete
suppression of virus replication, i.e. undetectable HBV
DNA, is achieved. Previously, HBIG and NA were
given as lifelong treatments. Currently, the common
praxis is to discontinue HBIG after 6–12 months, and
continue with lifelong NA treatment, if HBV DNA was
undetectable at the time of transplant-ation [63].
However, in patients with HDV infection, lifelong
combination therapy with HBIG þ NA should be given
(possibly with the exception of patients with undetect-able
or low levels of HDV-RNA), since treatment options for
recurrence of HDV infection are lacking. Longer/life-long
combination therapy should also be considered for
patients with HCC, HIV coinfection or adherence issues.
Hepatitis B vaccination might be considered to
reduce the risk of recurrence of HBV infection after
transplantation, but the benefit of vaccination has not
yet been demonstrated.
14 J. WESTIN ET AL.

When the immunosuppressive regimen includes corti- haemodialysis. TAF is not recommended in patients with
costeroids, the dosage should be as low as the condition CrCl <15 mL/min, who are not on haemodialysis.
of the graft allows, in order to minimize stimulation of
HBV replication. Summary of treatment schedule for liver
transplantation
Recommendation: Treatment in connection to
HBIG and NA should be given according to Table 5,
transplantation (see also Table 5)
depending on the levels of HBV DNA/HDV RNA and
serological status of HBV/HDV at the time of liver
All patients with HBV-related liver disease, on the liver transplantation.
transplantation waiting list should be treated with
NA. (A1)
Monitoring after liver transplantation
Postoperative combination prophylaxis with
Anti-HBs titre and HBV DNA should be monitored every
HBIG þ NA is recommended after liver transplantation 3 months if HBIG is given during the first year.
in patients with highly replicative HBV infection or
Thereafter, HBsAg should be checked every 3 months
high-risk patients coinfected with HDV. (B1)
and HBV DNA once per year. When the indication for
Low-risk patients should get HBIG during the anhe- transplantation is hepatitis D, HDV RNA should also be
patic phase of the transplantation and should there-
checked every 6 months.
after continue with only NA prophylaxis. (B2)
HBsAg-negative recipients, who receive a liver from a
donor who had a previous HBV infection (anti-HBc Patients with acute fulminant hepatitis B
positive) are at risk of a de novo HBV infection and
Antiviral treatment is recommended in patients with
should get NA prophylaxis. (B1)
acute fulminant hepatitis B (see above). When liver fail-
HBsAg-negative recipients who receive any organ
ure results in liver transplantation, peri- and postopera-
other than the liver from a donor with a resolved
tive treatment should be given according to the
HBV infection (HBsAg-negative, but anti-HBc-positive),
guidelines above.
who are anti-HBs negative, should receive HBIG
before reperfusion of the transplanted organ.
Patients with recurring hepatitis B after liver
NA treatment should be started immediately after trans- transplantation
plantation (B1). In NA treatment-experienced patients, the If the patient has a relapse of hepatitis B after trans-
same treatment should be continued postoperatively. plantation with detectable HBsAg and/or HBV DNA,
Patients without NA treatment before transplantation (e.g. HBIG treatment should be discontinued, since it has no
because HBV DNA was not detected) are recommended effect in such cases. On the other hand, lifelong treat-
to get NA postoperatively. In patients with impaired renal ment with NA should be given [64]. The cause of the
function and TDF/ETV treatment, the dose should be HBV relapse should be investigated and, if the patient
adjusted. No dose adjustment of TAF is needed when the discontinued the medication, NA treatment should be
calculated creatinine clearance (CrCl) is 15 mL/min, or immediately reinitiated. It is important to support the
when CrCl <15 mL/min in patients who are on patient to be adherent.

Table 5. Treatment schedule for liver transplantation.

Donor with negative HBsAg/anti-HBc Periop HBIG Postop HBIG NA
Patient HBV status
Previous HBV infection (HBsAg neg, anti-HBc pos) 2,000–2,500 IU No No
Low replicative HBV infection (HBV–DNA <10,000 IU/mL) 4,000–5,000 IU No Lifelong
 High replicative HBV infection (HBV–DNA >10,000 IU/mL) 4,000–5,000 IU 6 months Lifelong
Low-risk HBV/HDV coinfection (HBV–DNA <100 IU/mL and HDV–RNA <10,000 IU/mL) 4,000–5,000 IU 6 months Lifelong
High-risk HBV/HDV coinfection (HBV–DNA >100 IU/mL or HDV–RNA >10,000 IU/mL) 4,000–5,000 IU Lifelong Lifelong
Donor with previous HBV infection
HBV-negative recipient (HBsAg-neg, anti-HBc-neg), but donor with previous No No Lifelong
HBV infection (HBsAg-neg, anti-HBc-pos)
Note: Liver from a donor with previous resolved HBV infection cannot be used in recipients with HDV infection.
Postoperative HBIG is given either as a subcutaneous or intramuscular injection, or as an intravenous infusion. The choice should be made with
regards to the patient’s preferences, treatment adherence and to which drugs are available..
 INFECTIOUS DISEASES 15

Hepatitis B virus in donated organs
Organs from HBsAg-positive donors are usually not used
for transplantation. When the donor is HBsAg-negative,
but anti-HBc-positive, the liver can be used for a recipi-ent
with active hepatitis B, but when the need is urgent, also
in a recipient without HBV markers. The liver recipi-ent
should then receive lifelong treatment with NA. (B1)
The risk for a recipient to acquire hepatitis B from
transplanted organs other than liver, from a donor who
is HBsAg-negative, anti-HBc-positive, is low. When
donor is HBsAg-negative, anti-HBc-positive and anti-HBs-
positive, the risk of transmission is very low, and no anti-
viral prophylaxis is needed. In cases where the donor is
HBsAg-negative and anti-HBc-positive, but anti-HBs-
negative, HBIG is given before reperfusion of the trans-
planted organ [64]. However, no treatment is needed
after the transplantation.
Hepatitis B and immunosuppressive therapy
An important indication for antiviral therapy is to
vent hepatitis B reactivation during immunosuppressive
treatment. Symptoms of reactivation may vary within a
wide range from asymptomatic ALT elevation to severe
fulminant hepatitis and liver failure. The risk of reactiva-
tion depends on host factors, the degree of immunosup-
pression and the type of drugs used (Table 6). The risk
of reactivation can be classified as high (>10%), moder-
ate (1-10%) or low (<1%) [65,66]. Examples
treatments with a high risk are monoclonal antibodies
that target B cells/CD20 (e.g. rituximab) or TNF-a
(inflixi-mab), high dose steroids, doxorubicin, and
transarterial chemoembolization (TACE) treatment in
patients with HCC. Methotrexate, low dose steroids
and azathioprine are associated with a low risk.
Screening and prevention
All patients who are scheduled for immunosuppressive
the
treatment should be screened for current or previous HBV
infection (anti-HBc-positive with or without anti-HBs). Also
patients who receive immunosuppressive treatment for
non-malignant disease, e.g. rheumatoid disease or inflam-
matory bowel disease, should be screened for HBV
markers [10,65]. This is particularly important for patients
from geographic regions with a moderate or high HBV
prevalence. Screening is required in order to assess the
risk of reactivation of hepatitis B and to determine
whether prophylactic treatment is indicated. When screen-
ing reveals that the patient is seronegative, vaccination
pre-
against hepatitis B may be useful. Monitoring of anti-HBs
response is recommended when vaccination is given.
HBsAg-positive patients
Patients who will undergo haematopoietic stem cell
transplantation, lymphoma treatment, curative chemo-
therapy for tumour diseases or organ transplantation
of and who are HBsAg-positive should in general receive

Table 6. Risk of hepatitis B reactivation associated with immunosuppressive treatment.

Risk of reactivation
HBsAg-positive patients
High risk (>10%)
Moderate risk (1-10%)
Low risk (<1%)
HBsAg-neg/anti-HBc-pos
High risk ( 10%)
Immunosuppressive therapy
Drugs targeting B cells: rituximab, ofatumumab, natalizumab, alemtuzumab, ibritumomab
High dose steroids (>10 mg prednisolone for 4 weeks or longer)
Anthracyclines: doxorubicin, epirubicin
Potent TNF inhibitors: infliximab, adalimumab, certolizumab, golimumab
Local therapy for HCC such as TACE
Systemic chemotherapy
Cytokine-based therapy e.g. abatacept etc.
Immunophilin inhibitors e.g. ciclosporin, tacrolimus
Tyrosine kinase inhibitors: imatinib, nilotinib
Moderate dose of steroids
Less potent TNF inhibitors: etanercept
Antimetabolites: azathioprine, methotrexate, 6-mercaptopurine
Low dose steroids during a shorter time
Intra-articular steroids
Drugs targeting B cells: rituximab, ofatumumab, natalizumab, alemtuzumab, ibritumomab
 Moderate risk (1–10%) High dose steroids (>10 mg prednisolone for 4 weeks or longer)
Anthracyclines: doxorubicin, epirubicin
Potent TNF inhibitors: infliximab, adalimumab, certolizumab, golimumab
Systemic cancer chemotherapy
Cytokine-based therapy e.g. abatacept, etc.
Immunophilin inhibitors e.g. ciclosporin, tacrolimus
Tyrosine kinase inhibitors: imatinib, nilotinib
Low risk (<1%) Moderate and low dose steroids
Antimetabolites: azathioprine, methotrexate, 6-mercaptopurine
Table modified from Loomba et al. [10].

16 J. WESTIN ET AL. (see Figure 1 and Table 6) [9]. However, in most cases it
is easier and preferred to give prophylactic NA treatment.
Check HBsAg, anti-HBc and anti-

HBs

HBsAg-positive HBsAg-negative and anti-HBc-

positive

HBV-DNA ≥2000 IU/mL and HBV-DNA <2000 IU/mL and

High Moderate Low

elevated ALAT normal ALAT

risk risk risk

High Moderate Low

risk risk risk Alternatives

can be

considered

Treat chronic Start prophylactic Monitor without

hepatitis B treatment treatment

Figure 1. Recommendation: prophylactic treatment in patients

who are on immunosuppressive therapy, modified from [10].

prophylactic treatment with NA (ETV, TDF, TAF) (A1).

Antiviral therapy should be initiated one week before the
immunosuppressive treatment is initiated and should
continue as long as the immune inhibition persists and 12
months after it has ended. When rituximab or equiva-lent
treatment is given, particularly in combination with
steroids, HBV treatment should continue for 18 months
after the discontinuation of immune suppression [67,68].
For patients who are in a stable surveillance phase
(normal ALT and HBV DNA <2,000 IU/mL), the risk of
reactivation is lower, and when this group receives
immunosuppressive treatment with a low risk of reactiva-
tion, they can be monitored for HBV DNA and ALT, with-
out antiviral therapy unless signs of reactivation appear

Recommendation: Prophylactic Treatment of
Hepatitis B during Immunosuppressive Treatment (see
Table 1 for the immunological phases of chronic
hepatitis)
All patients who are on chemotherapy or immuno-
suppressive treatment should be tested for HBV
markers. (A1)
All HBsAg-positive patients with indication for HBV
treatment should receive treatment with ETV, TDF
or TAF before immunosuppression is initiated. (B1)
Before initiating immunosuppressive treatment in
patients with chronic HBsAg-positive infection (also in the
immune surveillance phase), prophylactic treat-ment
with ETV, TDF or TAF should be considered. (B1)
HBsAg-negative, anti-HBc-positive patients
For this category, the risk of reactivation varies greatly
depending on virological profile, underlying disease and the
type and duration of immunosuppressive regimen. These
patients should be tested for HBV DNA before
immunosuppressive treatment is initiated. Patients with
detectable HBV DNA can be treated in the same manner as
HBsAg-positive patients (B1). One option for patients with a
lower risk of reactivation (see Table 6 and Figure 1) and
negative HBV DNA, is to monitor ALT every month and HBV
DNA every 3 months and give antiviral treatment
(preemptive treatment) in case of increasing ALT and/or
HBV DNA levels, before clinical reactivation has occurred.
Recommended regimen
Currently, as for other patients ETV, TDF or TAF are
rec-ommended [9, 63] (A1).
more severe than in HIV negative patients, a liver
biopsy should be performed in all unclear cases.
Recommendation: Hepatitis B treatment in
patients with HBV/HIV coinfection
Patients with concomitant HIV treatment
Tenofovir/emtricitabine should be included in the HIV
treatment, regardless of HBeAg/HBV status. This rec-
ommendation applies even in patients with a con-
firmed/suspected lamivudine-resistant HBV. (B1)
For anti-HBe-positive patients with negative HBV DNA
and ongoing HIV treatment, including only lamivu-dine,
no treatment change is recommended. (B1)
HBsAg-negative, anti-HBc-positive patients should
receive prophylactic treatment when the risk of HBV
reactivation is high. (A1)
Monitoring
HBsAg-positive and HBV DNA-positive patients who are
on prophylactic NA treatment should be monitored for
HBV DNA levels and ALT/AST every 3– 6 months. When
HBV DNA increases with 1 log10 unit during ongoing
antiviral therapy, resistance or poor adherence to
prophylaxis should be excluded. After discontinuation of
NA treatment, patients should be closely monitored for 12
months due to the risk of reactivation with flare [9].
Treatment of chronic hepatitis B in patients with
concomitant HIV infection
Concomitant untreated HIV infection will increase the risk
of rapid progression of HBV-induced liver damage [69].
Currently however, all patients with HIV are recom-
mended antiretroviral treatment. When patients with
HIV/HBV coinfection are treated, possible effect of the
HBV regimen on HIV, potential drug-drug interactions as
well as the effect of HIV status on the treatment out-come
should be considered. TDF, LAM and emtricitabine have
clinically relevant activity against both HBV and HIV.
Entecavir (ETV) has a weak effect on HIV, which may
promote resistance to the HIV drugs when HBV treatment
is given in coinfected patients, without any effective HIV
treatment. NA should therefore not be given without
concomitant HIV treatment.
The treatment indication for hepatitis B is the same
as for HIV negative patients. Since ALT levels in these
patients are usually lower, and the stage of fibrosis
Patients without HIV treatment, but with treatment
indication for hepatitis B
For most patients, initiation of antiretroviral treat-
ment and treatment as above is recommended.
(B1)
When HIV treatment is not initiated, peg-interferon
alpha-2a 180 lg subcutaneously is recommended
once weekly for (6–)12 months. (B1)
In patients where tenofovir for specific reasons is not
preferred as part of the HIV treatment (side effects,
etc.), it is recommended to replace TDF/TAF in
lamivudine-sensitive HBV with ETV (i.e. complete
sensitivity to ETV) (C1). However, the experience of
ETV in patients with concomitant antiretroviral
treatment as well as inter-action studies, are limited.
TAF is recommended instead of TDF when the HIV regi-
men includes a so-called booster (ritonavir or cobicistat),
which increases the exposure for tenofovir and hence
increases the risk of renal and bone toxicity. However, a
non-boosted antiretroviral regimen (NNRTI and most inte-
grase inhibitors) may be administered along with TDF.
For patients who seroconvert to anti-HBs, TDF/TAF
treatment may be discontinued for other reasons.
Recommendation: Monitoring of patients with
HBV/HIV coinfection
Patients without concomitant HBV treatment (in
connection with HIV monitoring)
Same as for HIV-negative patients, according to
immunological phase (see Table 2)
18 J. WESTIN ET AL.
INFECTIOUS DISEASES 17
Patients with HBV treatment
Same as for HIV-negative patients (see Monitoring
during NA/IFN treatment). In addition, CD4 counts
are recommended before and every 3 months
during interferon treatment.
Hepatitis B virus infection in children/adolescents
Prevalence and natural course
Hepatitis B in children/adolescents occurs in Sweden
mainly when born in or having a parent originating from a
high or intermediate endemic HBV area, such as Asia, the
Middle East, sub-Saharan Africa and parts of Eastern
Europe. During the past 10 years, over 2,000 per-sons
between 0 and 19 years old have been reported to the
Public Health Authority with chronic hepatitis B. As for
adults, there are probably many unrecorded cases.
Children have most commonly been infected by their
mother (vertical transmission) or at a young age (hori-
zontal transmission). In patients infected by their mother
at an early age, the risk of developing chronic hepatitis B
is around 95%. The risk of chronic infection then
decreases, and is from early school age less than 5%, i.e.
the same as for adults. Previous studies of children from
southern Europe, mostly horizontally infected, reported
spontaneous seroconversion to anti-HBe before adult-
hood in more than 80% of the cases [70]. The propor-tion
of patients with spontaneous HBeAg seroconversion is
significantly lower in children from Southeast Asia, who
are more often pre- or perinatally infected. During the
immune activation phase, i.e. HBeAg-positivity and
elevated transaminases, a liver biopsy may show signs of
inflammation, while clinical symptoms are mild or absent.
Cirrhosis and HCC occur occasionally during childhood,
but usually not until much later.
Assessment and monitoring of children with chronic
HBV infection
Assessment, laboratory testing, and monitoring are
per-formed as for adults (see Box 2 and Table 2). All
patients and legal guardians should be repeatedly
informed about the transmission risks and codes of
conduct, and also receive information about the
specific measures, such as that vaccination of family
members, sexual part-ners and future children may
become relevant. Information regarding sexual
transmission should be adapted according to age.
 Children who have developed cirrhosis should be
managed at a specialist unit and monitored in the
same way as adults. Ultrasound of the liver should be
per-formed every 6 months and if applicable, also
gastroscopy.
Assessment to determine treatment regimen
In patients with repeated ALT elevations over a period
of at least 1 year, treatment should be considered. This
applies mainly to children and adolescents with
remain-ing HBeAg, but may also be relevant to a few
patients who have seroconverted to anti-HBe. Before
determining the treatment regimen, a liver biopsy
should be consid-ered to assess necroinflammation
and fibrosis stage, as this is important for the treatment
decision. Treatment may be considered when the
histological classification shows at least moderate or
mild inflammation, with at least moderate fibrosis
(>F2). Predictive factors for a beneficial treatment
response are the same as for adults. Elastography for
fibrosis assessment is generally much less evaluated
in children than in adults, and clear cut-offs are lacking.
Treatment regimen (B1)
Treatment can be given either in the form of peg-IFN or
NA and is currently indicated only for patients with
transaminase elevation or histological signs of inflamma-
tion. Results from ongoing controlled studies of combin-
ation therapy with peg-IFN and NA in patients with normal
transaminase levels should be awaited before such
treatment can be used routinely [71].
Peg-IFN alpha-2a was given at the dose 100 mg/m
2 Patients with a positive HBeAg almost always have a
per week during 1 year in a recently published random-
ized controlled study, resulting in a HBeAg serocnversion
rate of 25 vs 6% for placebo treated patients [72]. Among
the NAs, ETV is approved for children from
2 years of age, at a dose of 0.015 mg/kg daily, max.
0.5 mg/day [73]. Both TDF (245 mg/day) and TAF (25
mg/ day) are approved for children from 12 years of
age. LAM, at a dose of 10 mg/kg daily, max. 300
mg/day is approved from infancy.
In practice, the choice is to either give a time-limited
peg-IFN treatment with expected side-effects, or to give
NA for several years, where the main rule is to treat at
least 1 year after HBeAg seroconversion. Even though
treatment with interferon is demanding, due to side-
effects, treatment interruptions are rare. Except for the
side-effects described in adults, Peg-IFN treatment
often leads to anorexia and weight loss and risk of
affecting growth, and should therefore be avoided
before the age of three and during puberty. It should
also be noted that hypothyroidism is a more common
side effect in children than in adults (around 10%) [74].
Monitoring after treatment
Monitoring of children after treatment is discontinued
should be performed as for adults (see the section
about adults).
Treatment effects
Seroconversion of HBeAg to anti-HBe, as well as normal-
ization of liver function can be expected in approxi-mately
30% of the patients treated with interferon. The results
are comparable to those observed for NA treat-ment. It
has also been shown that HBsAg disappears more often
in patients treated with interferon than in untreated
patients [72]. Long-term benefits regarding development
of cirrhosis and HCC cannot yet be eval-uated due to
limited follow-up times.
Pregnancy and childbirth
Screening for HBsAg is recommended in all pregnant
women. When HBsAg is detected, the patient should
be referred to a specialist unit to prevent transmission
to the baby. Mainly two factors affect the risk of HBV
transmission: the viral load in blood (HBV DNA level)
and the presence of hepatitis B e antigen (HBeAg).
high virus load. In cases of acute hepatitis B during
pregnancy, there is a significant risk of transmission to
the baby, especially when the mother was infected dur-
ing the third trimester. For chronic hepatitis, the risk of
HBeAg-positive women giving birth to babies who get
a chronic HBV infection is 70-90% when no preventive
measures are taken. When the mother is HBeAg-nega-
tive, only a few percent of the newborn infants become
chronically infected without prophylaxis, and around 10%
may have a transient infection. By giving passive and
active prophylaxis, i.e. both specific hepatitis B globulin
(HBIG) and HBV vaccine to the newborn infant, the risk of
maternal transmission from HBeAg-positive highly
infectious mothers is reduced to <5–10%. For optimal risk
reduction, prophylaxis should be given as
soon as possible after delivery [4]. Internationally, both
immunoglobulin and vaccination are recommended for
all children who are born by HBsAg-positive women,
irrespective of HBeAg status. In Sweden, there is
exten-sive experience of giving only vaccine without
immunoglobulin to children born by HBeAg-negative
women. This strategy is supported in a systematic
review and a meta-analysis from 2015, as well as in
fur-ther recent studies [75].
The introduction of antiviral treatment with NA in
pregnant highly infectious women has reduced the
transmission rate to babies. Internationally, initiation of
antiviral therapy during the last trimester of the preg-
nancy is recommended when HBV DNA exceeds
200,000 IU/mL (5.3 log10 IU/mL) [9,76]. There is limited
scientific evidence supporting antiviral treatment at this
relatively low level. Reducing the transmission risk by
rd
adding antiviral therapy during the 3 trimester has
been demonstrated for lamivudine, telbivudine and
tenofovir (TDF).
Currently, TDF is the recommended antiviral treat-
ment, due to extensive experience during pregnancy of
using this medication with no known risk of drug
resistance [77]. Teratogenic effects of antiviral therapy
during pregnancy have not been demonstrated. One
study showed that exposure to TDF during pregnancy
led to a 12% decrease in bone mineralization in
exposed children after birth [78], but this difference had
completely disappeared at the age of 2 [79]. No
transmission was demonstrated in studies where
highly viremic women received antiviral therapy during
the last trimester, and where the children were
vaccinated and received HBIG soon after childbirth
[80,81]. Sufficient protection can possibly be achieved
using only HBIG þ vaccine, when given very soon after
child-birth [81], and this should be considered in cases
where antiviral therapy for some reason is not given,
even though it is indicated. Antiviral therapy is initiated
during weeks 28–32 of pregnancy, and no difference in
protective efficacy has been demonstrated within this
period. Some individuals respond slowly to antiviral
therapy, and at the same time premature births are
common. It is therefore suggested that women with
HBV DNA HBeAg Treatment HBIG
>200,000 IU/mL status to the mother to the child
Yes Positive Yes Yes
Yes Negative Yes Yes
No Positive No Yes
No Negative No No
20 J. WESTIN ET AL.
INFECTIOUS DISEASES 19
high virus load initiate treatment in the earlier part of
this period. Treatment with TDF, initiated during weeks
28-32 of pregnancy should end 0–3 months after child-
birth, provided the mother is not supposed to undergo
continued treatment for chronic HBV infection [82].
There are no reasons to advise against breastfeeding,
even for women who continue antiviral therapy after
childbirth [83]. Treatment indication is kept unchanged
when a woman becomes pregnant during ongoing
treatment of hepatitis B, although the regimen should
be changed to TDF when another medication is given
[9]. The risk of reactivation of the hepatitis B infection
increases during the first 6 months after childbirth;
hence, women should be monitored during this period
[9].
Recommendation: Management during pregnancy
and childbirth in patients with HBV. (B1)
Treatment to the woman: Tenofovir disoproxil
fumar-ate, 245 mg, once daily, initiated during
weeks 28–32 of pregnancy.
HBIG to the child: Umanbig, 180 IE/mL. 1 ml is given
intramuscularly, as soon as possible after childbirth.
Vaccination of the child: Engerix B, 10 lg, 1 dose or
HBVAXPRO, 5 mg, 1 dose. Given intramuscularly,
as soon as possible after childbirth.
Further vaccination
Combination vaccines within the paediatric vaccination
programme contain a component against hepatitis B;
therefore, all children born in Sweden are currently vac-
cinated against hepatitis B (despite the lack of a general
national recommendation). Vaccine dose number 2, with
Engerix-B or HBVAXPRO is recommended at the age of
1 month and then further vaccinations against hepatitis B
within the vaccination programme is given at the age of 3,
5 and 12 months [84].
It is recommended that children are tested for HBsAg,
Vaccination anti-HBs and anti-HBc IgG at the age of 15–18 months.
of the child
Yes
Yes
Yes
Recommendations in special cases (C1)
Yes
Children should receive both immunoglobulin and
vaccination, regardless of the mother’s HBeAg sta-tus
when:
Premature birth before week 34 of pregnancy or
weighs less than 2,000 g at birth.
 At very early premature delivery (week 24 or
earlier), a second dose of HBIG is recommended at
the age of 1 month.
The mother has previously been giving birth to a
baby who was infected with hepatitis B dur-ing
childbirth.
The mother is coinfected with hepatitis D.
The mother has a congenital or acquired immune
deficiency.
Other circumstances that would increase the risk of
transmission.
Disclosure statement
JW has received honoraria for teaching from AbbVie, BMS, Gilead,
Janssen and MSD/Merck. SA has received honoraria for teaching or
advisory boards from AbbVie, BMS, Gilead and MSD, and received
research grants from AbbVie and Gilead. ASD has received
honoraria for teaching and/or consultancy from AbbVie, BMS,
Gilead, Janssen, and MSD/Merck. AE has received honoraria for
teaching from Roche, MSD/Merck, AbbVie and Gilead. BF has
participated in a phase 2 study on treatment for pediatric hepa-titis
C virus infection sponsored by MSD/Merck. OW has received
honoraria for teaching and/or consultancy from AbbVie, BMS,
Gilead, Janssen, and MSD/Merck. MC, CK, KL, GN, SS and RW
declared no potential conflict of interest.
ORCID
Maria Castedal http://orcid.org/0000-0002-4782-2752
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