Hepatitis D

Hepatitis D
Straight to the point of care
Last updated: Oct 11, 2023

Table of Contents
Overview 3
Summary 3
Definition 3
Theory 4
Epidemiology 4
Aetiology 4
Pathophysiology 4
Classification 5
Case history 5
Diagnosis 7
Approach 7
History and exam 13
Risk factors 15
Investigations 17
Differentials 21
Criteria 23
Management 25
Approach 25
Treatment algorithm overview 28
Treatment algorithm 29
Emerging 34
Primary prevention 34
Secondary prevention 34
Patient discussions 35
Follow up 36
Monitoring 36
Prognosis 37
Guidelines 39
Diagnostic guidelines 39
Treatment guidelines 40
Online resources 41
References 42
Images 49
Disclaimer 52
Hepatitis D Overview
Summary
Hepatitis D virus infection (also known as hepatitis delta infection) affects millions of people globally.
Hepatitis D virus (HDV) is a defective virus that cannot propagate without the presence of hepatitis B
OVERVIEW
virus (HBV) surface antigen. HDV infects susceptible hosts via simultaneous co-infection with HBV or via
superinfection of an individual already infected with HBV. Approximately 5% of individuals living with chronic
HBV infection (around 12 million people) have antibodies indicating infection with HDV. The majority have
chronic HDV infection.
HDV infection is prevalent in western and mid-Africa, Mongolia, eastern Europe, and parts of the
Mediterranean. People at increased risk for HDV infection include those chronically infected with HBV,
injection drug users, and those with increased likelihood of sexual exposure.
Chronic HDV infection is the most severe type of chronic viral hepatitis and commonly leads to cirrhosis, liver
failure, and hepatocellular carcinoma.
Detection of HDV antibody provides evidence of exposure. Detection of HDV RNA indicates a current
infection. The assays are increasingly available, although greater standardisation of HDV RNA assays is
required. The condition should be monitored with regular liver biochemical tests and liver imaging.
The goal of treatment is to prevent disease progression to end-stage liver disease requiring liver transplant.
New treatment options that are in advanced clinical development stages and available for use in some parts
of the world show promise in improving prognosis in patients with chronic infection.
Definition
Hepatitis D virus (HDV) is a defective RNA virus that requires hepatitis B virus (HBV) surface antigen in order
to propagate. It infects susceptible hosts via simultaneous co-infection with HBV or via superinfection of an
individual with chronic HBV infection, and is transmitted by percutaneous, permucosal, and sexual routes.[1]
[2] HDV infection tends to be more aggressive than other types of viral hepatitis; acute infection may cause
acute liver failure, while persistent infection commonly causes a severe chronic hepatitis that can lead to
cirrhosis, hepatocellular carcinoma, or liver failure.[1]
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 11, 2023.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
3
can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (.
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Hepatitis D Theory
Epidemiology
The lack of readily available serological tests means the worldwide prevalence of hepatitis D virus (HDV)
infection is difficult to accurately ascertain. Studies suggest a wide range from 12 to 72 million people,
THEORY
with an estimated 10% to 15% of people with chronic hepatitis B virus (HBV) infection also having chronic
HDV infection.[5] Around 5% of people infected with HBV (at least 12 million people) are estimated to also
have HDV infection.[9] [10] These patients are at high risk of developing liver cirrhosis and hepatocellular
carcinoma within a few years.[10]
A systematic review and meta-analysis of HDV prevalence in the six World Health Organization (WHO)
regions estimated a global prevalence of HDV infection of 4.5% (95% CI 3.6% to 5.7%) among people
positive for hepatitis B surface antigen (HBsAg) and 0.16% (95% CI 0.11% to 0.25%) overall, representing
12 million HDV seropositive individuals globally (95% CI 8.7 to 18.7 million).[11] The geographical distribution
of HDV infection does not mirror that of HBV infection, however, particularly the relatively low prevalence of
HDV infection in many Asian countries. The highest prevalence of HDV infection is seen in parts of western
and mid-Africa, Mongolia, eastern Europe, and parts of the Mediterranean.[11] HDV infection is uncommon
in North America, northern Europe, and Japan, and confined to at-risk groups such as those with increased
likelihood of sexual exposure, injection drug users, and immigrants from endemic areas.[1] [12] Vaccination
against HBV and immigration patterns have affected the prevalence of HDV infection.[11]
There are eight different genotypes of HDV, with genotype 1 being found mainly in North America, Europe,
the Middle East, and north Africa; genotypes 2 and 4 in east Asia; genotype 3 in the Amazon Basin and
South America; and genotypes 5, 6, 7, and 8 in west and central Africa.[3] [12]
Aetiology
Hepatitis D virus (HDV) is a small spherical RNA virus with an inner ribonucleoprotein and an outer envelope.
The ribonucleoprotein contains the HDV RNA that consists of a single, circular, covalently closed strand of
between 1676 and 1683 nucleotides that encodes the HDV antigen.[13] The International Committee on
Taxonomy of Viruses has proposed classifying HDV into the Deltavirus genus of the Kolmioviridae family,
which is part of the Ribozyviria realm.[4]
Although HDV can replicate inside the host cell, it uses the hepatitis B surface antigen to form the outer
envelope, so hepatitis B virus (HBV) infection is required for HDV to propagate.[14]
The virus is transmitted via contaminated blood or blood products through percutaneous, permucosal, and
sexual transmission.[15]
Pathophysiology
Two kinds of human HDV infection have been distinguished:[16]
• Co-infection with HBV, whereby a person is infected simultaneously with both HDV and HBV
• Superinfection, whereby a person who is already chronically infected with HBV acquires HDV.
Co-infection leads to acute HDV and HBV infection, which is usually a self-limited illness but is more likely
than acute HBV infection alone to lead to severe illness and acute liver failure.[17] Since HDV is dependent
on HBV, the progression to chronic infection mirrors that of chronic HBV infection, with younger age at
infection predicting higher risk of chronicity.
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Oct 11, 2023.
Hepatitis D Theory
Superinfection can present as a severe hepatitis, either in someone not known to have chronic HBV infection
or as a flare of disease in someone with chronic HBV infection. Since the patient already has chronic HBV
infection, progression to chronic HDV infection is almost universal.[18]
THEORY
The mechanism of liver damage by HDV is unclear but presumably depends on the interaction of HDV
genotype, host immune response, and activity of HBV.[19] [20] Interestingly, HDV infection suppresses HBV
replication - explaining why liver enzymes can be elevated in patients with chronic HBV infection despite
negative HBV DNA levels.[21]
Classification
HDV genotype[3]
The International Committee on Taxonomy of Viruses has proposed classifying HDV into the Deltavirus
genus of the Kolmioviridae family, which is part of the Ribozyviria realm.[4]
There are eight HDV genotypes (1 through 8) with different geographical distribution and likely different
virulence and pathogenicity.
• Genotype 1 is found mainly in North America, Europe, the Middle East, and north Africa.
• Genotypes 2 and 4 are found in east Asia.
• Genotype 3 is found in the Amazon Basin and South America.
• Genotypes 5, 6, 7, and 8 are found in west and central Africa.
Genotypes 1 and 3 lead to more severe disease and genotype 5 is associated with better response to
therapy.[5] [6] There are also geographical differences in the risk of complications, with studies in Taiwan,
where genotype 2 predominates, suggesting the risk of fulminant liver failure and cirrhosis or hepatocellular
carcinoma is decreased compared with in genotype 1 HDV disease.[7] [8]
Genotype testing of HDV is not routinely available and not part of the management approach.
Case history
Case history #1
A 47-year-old man from eastern Europe presents with fatigue and oedema. He has no other medical
history. Examination shows multiple spider naevi on the anterior and posterior chest, no icterus, a soft
abdomen with a palpable spleen tip, palmar erythema, and mild pitting oedema of both ankles. Laboratory
studies show an alanine aminotransferase of 121 IU/L, total bilirubin 32.49 micromoles/L (1.9 mg/dL),
platelet count 90,000, creatinine 61.89 micromoles/L (0.7 mg/dL), and international normalised ratio (INR)
of 1.4.
Case history #2
A 23-year-old woman presents with several weeks of fatigue and malaise. Her urine is dark and she
has some diffuse abdominal pain. She has a history of active injection drug use. Examination shows
normal vital signs but a low-grade fever of 37.8°C (100.1°F), scleral icterus, and a soft abdomen
5
Hepatitis D Theory
without hepatosplenomegaly. Laboratory studies show an alanine aminotransferase of 237 IU/L, alkaline
phosphatase 102 IU/L, total bilirubin 97.47 micromoles/L (5.7 mg/dL), and international normalised ratio
(INR) of 1.1.
THEORY
Other presentations
Most people with chronic hepatitis D virus (HDV) infection will be asymptomatic. Occasionally, acute
co-infection (simultaneous infection with hepatitis B virus [HBV] and HDV) or superinfection (HDV
infection of a person with chronic HBV infection) can present with acute liver failure. This can present
with non-specific symptoms including fever, fatigue, malaise, nausea, abdominal pain, dark urine, pale
stool, diarrhoea, and jaundice. The development of asterixis or other signs of encephalopathy including
somnolence or coma are indications of cerebral oedema and the need for urgent liver transplantation.
Hepatitis D Diagnosis
Approach
The clinical presentation of hepatitis D virus (HDV) infection ranges from asymptomatic to acute liver failure,
cirrhosis, chronic liver disease, hepatic decompensation, and hepatocellular carcinoma.[1] Cirrhosis of the
liver occurs in up to 70% of patients with chronic infection.[34] Presenting signs and symptoms depend on
numerous factors, including the acuteness of infection and whether there is co-infection (i.e., simultaneous
infection with hepatitis B virus [HBV]) or superinfection (i.e., HDV infection in a person already chronically
infected with HBV).[16]
Co-infection leads to acute HDV and HBV infection, which is usually a self-limited illness but is more likely to
lead to severe illness and acute liver failure (fulminant hepatitis) than is acute HBV infection.[17] Since HDV
is dependent on HBV, the progression to chronic infection mirrors that of chronic hepatitis B, with younger
age at infection predicting higher risk of chronicity.
Superinfection can present as a severe hepatitis, either in someone not known to have chronic HBV infection
or as a flare of disease in someone with chronic HBV infection. Since the patient already has chronic HBV
infection, progression to chronic HDV infection is almost universal.[35]
Evolution to chronic infection occurs in just 2% of patients who have co-infection compared with over 90% of
patients who have superinfection.[34]
As patients with both acute and chronic forms of HDV infection are often asymptomatic, infection should be
suspected in patients at increased risk.[2] Since HDV infection occurs in the setting of HBV infection, patients
with risk factors for HBV infection (e.g., increased likelihood of sexual exposure, injection drug use, being
born in a highly endemic region) are also at risk for HDV infection.
Patients who test positive for hepatitis B surface antigen (HBsAg) should be screened with an HDV antibody
test; if this is found to be positive, testing for HDV RNA should be performed.[1] Diagnosis of exposure is
confirmed by the presence of anti-HDV antibodies, and diagnosis of a current infection by the presence
of HDV RNA.[1] [12] Assays for anti-HDV antibody and HDV RNA level are increasingly available; the first
international external quality control for HDV RNA quantification via the World Health Organization has led to
DIAGNOSIS
improvements in HDV diagnostics.[2]
History
Ask about risk factors for HDV infection, which include:[10] [11] [12] [24]
• HBV infection
• Being born in, living in, or travel to geographical regions where HBV/HDV are endemic (e.g., parts
of western and mid-Africa, Mongolia, eastern Europe, and parts of the Mediterranean)
• Increased likelihood of sexual exposure (e.g., multiple sexual partners, commercial sex workers)
• Having sexual relations with a person infected with HDV
• Men who have sex with men
• Injection drug use
• History of incarceration
• Family history of HBV/HDV infection
• Family history of hepatocellular carcinoma
• Perinatal exposure in an infant born to an HDV-infected mother
• Being a household contact of a person with HDV infection
7
• Haemodialysis
• Multiple blood transfusions
• Being a healthcare worker.
Acute HDV infection
Acute HDV infection occurs after an incubation period of 3-7 weeks.[12] It may present as a self-limited
flu-like illness with non-specific clinical symptoms that may include fatigue, anorexia, nausea, lethargy,
arthritis/arthralgia, fever, and abdominal pain.[12] [34] In some patients this may be followed by jaundice,
ongoing nausea and fatigue, dark urine, and pale stools.[34] [36]
DIAGNOSIS
A patient with jaundice, demonstrating scleral icterus

CDC. Dr Thomas F. Sellers/Emory University; used with permission
Presenting symptoms in acute HDV infection are indistinguishable from those associated with infection
due to other forms of viral hepatitis, although clinical features tend to be more severe.[34] This is
especially true in the case of injection drug users, where a high incidence of acute liver failure has been
noted.[37]
Acute liver failure is a rare sequela of acute viral hepatitis; however, it occurs more frequently in acute
HDV infection than in other forms of viral hepatitis infection.[34] Acute liver failure is defined by the onset
of jaundice, coagulopathy (international normalised ratio [INR] >1.5), and hepatic encephalopathy in
patients with no prior history of liver disease.[38] [39] [40] Abdominal pain, nausea, vomiting, and malaise
are common symptoms, followed by jaundice, coagulopathy, and hepatic encephalopathy (confusion
and changes in personality followed by somnolence and coma).[34] Right upper quadrant tenderness
may also be found on examination.[34] More than half the cases of acute liver failure in HBsAg-positive
patients are due to HDV infection rather than to HBV infection alone.[18] See Acute liver failure .
Chronic HDV infection
Chronic HDV infection is defined as presence of HDV beyond 6 months. Superinfection in the context of
chronic HBV infection can lead to a flare of liver disease and is much more likely to become chronic in the
majority (around 90%) of patients (unlike simultaneous HBV and HDV co-infection, which rarely becomes
chronic).[18]
Although chronic HDV/HBV co-infection is often initially asymptomatic, it is the most severe type of
chronic viral hepatitis and commonly leads to cirrhosis, liver failure, and hepatocellular carcinoma.
Patients may therefore present with symptoms and signs of chronic liver disease and portal hypertension,
such as fatigue, weight loss, spider naevi and palmar erythema. See Cirrhosis and Hepatocellular
carcinoma .
Physical examination
Acute HDV infection
In patients with acute HDV infection, examination may reveal jaundice and, in some patients, right upper
quadrant tenderness. Patients with acute HDV infection that has progressed to acute liver failure may also
have evidence of encephalopathy (often with asterixis).
The physical examination in most patients with chronic HDV infection will be normal; however, patients
with chronic HDV infection who have developed cirrhosis of the liver may have signs of chronic liver
disease, including one or more of the following:
• Palmar erythema
• Spider naevi (in the distribution of the superior vena cava)
DIAGNOSIS
• Scleral icterus
• Ascites
• Peripheral pitting oedema of the ankles/legs
• Splenomegaly
• Loss of secondary sexual characteristics, such as loss of secondary sexual hair and testicular
atrophy in men.
9
Ascites in a female patient with cirrhosis

Science Photo Library; used with permission
Initial investigations
Given the importance of HDV infection to the long-term management of patients who are HBsAg-positive,
all patients with confirmed hepatitis B infection should be tested for antibodies to hepatitis D (anti-HDV).[2]
DIAGNOSIS
Tests to characterise HBV infection
Perform serological tests to characterise HBV infection.[1] Serological markers include:
• Hepatitis B surface antigen (HBsAg)

• Antibody to hepatitis B surface antigen (anti-HBs)
• Antibody to hepatitis B core antigen (anti-HBc) IgM and IgG
• Hepatitis B e antigen (HBeAg)
• Antibody to HBeAg (anti-HBe)
• HBV DNA.
A positive HBsAg establishes the diagnosis of HBV infection. It can be detected an average of 4
weeks (range 1-9 weeks) after virus exposure. Acute HBV infection is characterised by detection of
HBsAg, HBeAg, HBV DNA, and anti-HBc IgM followed by anti-HBc IgG; a resolving acute infection is
characterised by declining HBV DNA levels and disappearance of HBeAg with appearance of anti-HBe,
followed by disappearance of HBsAg with appearance of anti-HBs. Anti-core IgM gradually disappears,
while anti-core IgG (typically measured as 'total' antibody) remains detectable for life.
Chronic HBV infection is characterised by detection of HBsAg for more than 6 months. Anti-HBs are
typically negative, while anti-HBc IgG are positive. Anti-HBc IgM may become transiently positive during
flares. HBeAg and anti-HBe are used to determine the phase of chronic infection and may be positive or
negative.
HBV DNA is essential for diagnosis and to determine the phase of infection; it may be undetectable or low
in some patients with chronic HBV infection.[41] [42]
Hepatitis B e-antigen (HBeAg) indicates high level viral replication and greater infectivity. The vast
majority of patients with HBeAg-positive chronic HBV infection have biochemical and histological evidence
of hepatitis; exceptions include children and young adults with perinatally acquired infection, who may
show normal alanine aminotransferase (ALT) levels and normal liver histology. Absence of HBeAg does
not necessarily indicate lack of virus replication as some patients have high or fluctuating HBV DNA levels
and active hepatitis.
Consider testing for antibody to hepatitis B core antigen (anti-HBc) IgM, which may help distinguish
individuals with HBV/HDV co-infection from HBsAg-positive individuals with HDV superinfection.[1]
Tests to characterise HDV infection
Perform serological tests for HDV.[1] [12]
• Serological markers include:
• Antibody to hepatitis D (anti-HDV) IgM and IgG

• HDV RNA.
• Note that:
• Anti-HDV antibodies may persist after the clearance of HDV infection; therefore, testing for
serum/plasma HDV RNA is required to confirm ongoing HDV infection[1]
• Serological tests are available to detect HDV antigen in serum, but they have variable
DIAGNOSIS
performance and are not routinely recommended
• Anti-HDV IgM testing is not a reliable indicator of acute HDV infection as this test may
become positive during chronic HDV infection
• HDV RNA assays are increasingly available, but require greater standardisation, particularly
with some less common HDV genotypes.
Anti-HDV antibodies appear 3-4 weeks after HDV infection.[43] The result will be positive in people with
chronic HDV infection, but levels can fluctuate based on the degree of replication.
The European Association for the Study of the Liver (EASL) recommends that screening for anti-HDV
antibody should be performed with a validated assay at least once in all HBsAg-positive individuals, and
that re-testing for anti-HDV antibody should be performed in those who initially test negative whenever
clinically indicated (such as in those with aminotransferase flares or acute decompensation of chronic liver
disease) and annually in those remaining at risk of infection.[1]
Guidelines from the American Association for the Study of Liver Diseases (AASLD) recommend risk-
based screening of HBsAg-positive patients for HDV infection in the following situations:[2]
• Elevated ALT or aspartate aminotransferase (AST) with low or undetectable HBV DNA
11
• HIV infection
• Hepatitis C virus (HCV) infection
• History of injection drug use
• Those with multiple sexual partners or any history of sexually transmitted disease
• Immigrants from areas with high HDV endemicity (western and mid-Africa, parts of the
Mediterranean, Pacific Islands, Middle East, Mongolia, eastern Europe, and the Amazonian
basin).[1]
Tests to characterise liver disease status
Request the following in all patients with acute or chronic HDV infection:
• Full blood count

• Renal function tests
• Coagulation profile
• Liver biochemistries
• AST
• ALT
• Total bilirubin (direct and indirect)
• Alkaline phosphatase
• Albumin.
Check the patient's HIV (anti-HIV), hepatitis A (anti-HAV IgG/total), and hepatitis C (anti-HCV antibody ±
HCV RNA) status, as this affects management options.
Perform abdominal imaging; ultrasound is a reasonable first test in all patients to evaluate the liver for
advanced fibrosis, cirrhosis, portal hypertension, and for hepatocellular carcinoma.[41]
• Triphasic contrast computed tomography or contrast magnetic resonance imaging are alternatives,
particularly in patients with advanced fibrosis or cirrhosis.
DIAGNOSIS
Other investigations
Non-invasive methods of assessing liver fibrosis (e.g., transient elastography using magnetic resonance
or FibroScan, fibrosis biomarkers) can be obtained to determine whether surveillance for hepatocellular
carcinoma is required, but are seldom needed to assess therapy decisions.[1] Note that specific cut-off
values for these tests are not well defined.[1]
Consider liver biopsy where results may contribute to the patient’s management, or for grading and
staging liver disease when clinical signs of cirrhosis or evidence of cirrhosis (via imaging techniques)
are not present.[1] Do not obtain liver biopsy routinely unless there is a diagnostic dilemma or if there is
debate regarding whether treatment is required.[1]
History and exam

Key diagnostic factors
presence of risk factors (common)
• Key risk factors include presence of hepatitis B virus (HBV) infection, increased likelihood of sexual
exposure, and injection drug use.[12]
jaundice (uncommon)
• May occur in some patients with acute HDV infection, following the initial incubation period of 3-7
weeks.[12] [34] [36]
ascites (uncommon)
• Patients with chronic HDV infection and cirrhosis may have signs of chronic liver disease including
ascites, palmar erythema, spider naevi (in the distribution of the superior vena cava), scleral icterus,
splenomegaly, and loss of secondary sexual characteristics.
scleral icterus (uncommon)

• Patients with chronic HDV infection and cirrhosis may have stigmata of chronic liver disease including
scleral icterus, palmar erythema, spider naevi (in the distribution of the superior vena cava), ascites,
asterixis (uncommon)
• Patients presenting with acute hepatic failure and hepatic encephalopathy may present with asterixis,
which describes negative myoclonus detected by extending the arms, dorsiflexing the wrist, and
spreading the fingers. This movement will elicit a flapping movement of the hands in patients with
asterixis.
Other diagnostic factors
DIAGNOSIS
asymptomatic (common)
• Patients with both acute and chronic hepatitis D virus (HDV) infection (without cirrhosis or
hepatocellular carcinoma) are often asymptomatic; infection should be suspected in patients at
increased risk.
malaise (common)
• Acute HDV infection refers to the initial infection with HDV and occurs after an incubation period of 3-7
weeks. It may present as a self-limited flu-like illness. This may include symptoms of fever, malaise,
fatigue, nausea, vomiting, and loss of appetite.[34] [36]
fatigue (common)
fatigue, nausea, vomiting, and loss of appetite.[12] [34] [36]
13
hepatomegaly (uncommon)
• Patients with chronic HDV infection may have features of cirrhosis such as hepatomegaly,
splenomegaly, and portal hypertension, along with signs of chronic liver disease.
fever (uncommon)
right upper quadrant tenderness (uncommon)

• May occur in some patients with acute HDV infection.
nausea/vomiting (uncommon)
arthralgia/arthritis (uncommon)
• Acute HDV infection occurs after an incubation period of 3-7 weeks. It may present as a self-limited flu-
like illness. This may include symptoms of fever, malaise, fatigue, arthralgia/arthritis, nausea, vomiting,
and loss of appetite.[12] [34] [36]
palmar erythema (uncommon)

palmar erythema, spider naevi (in the distribution of the superior vena cava), scleral icterus, ascites,
spider naevi (uncommon)

• Spider naevi may occur in the distribution of the superior vena cava in patients with chronic HDV
DIAGNOSIS
infection and cirrhosis.
splenomegaly (uncommon)
splenomegaly, palmar erythema, spider naevi (in the distribution of the superior vena cava), scleral
icterus, ascites, and loss of secondary sexual characteristics.
loss of secondary sexual characteristics (uncommon)

loss of secondary sexual characteristics (such as loss of secondary sexual hair and testicular atrophy
in men), palmar erythema, spider naevi (in the distribution of the superior vena cava), scleral icterus,
ascites, and splenomegaly.
peripheral oedema (uncommon)

• Patients with chronic HDV infection and decompensated cirrhosis may experience peripheral
pitting oedema secondary to salt retention and reduced hepatic synthetic function leading to
hypoalbuminaemia.
Risk factors
Strong
HBV infection
• The hepatitis D virus (HDV) requires hepatitis B virus (HBV) surface antigen to propagate. HDV infects
susceptible hosts via simultaneous co-infection with HBV or via superinfection of an individual already
infected with HBV. Around 5% of people infected with HBV (around 12 million people) have antibodies
indicating infection with HDV. The majority have chronic HDV infection.[10]
increased likelihood of sexual exposure

• Studies have shown sexual transmission of HDV in both heterosexual couples and in men who have
sex with men. People deemed particularly at risk of HDV infection are those with increased likelihood
of sexual exposure, including commercial sex workers, where reported prevalence may be up to 11%,
with a pooled odds ratio of 18.7.[11] [22] [23] Increased likelihood of sexual exposure is also a risk
factor for HBV infection, the presence of which is a requirement for HDV infection.[24] [25]
injection drug use

• Injection of drugs via shared needles can lead to percutaneous transmission of both HBV and HDV.
Injection drug use has been reported in 18% of patients with a documented acute HBV infection.[24]
One study of 652 patients, of which 91 had confirmed HDV, demonstrated that injection drug use
was a significant predictor of HDV infection, with an adjusted odds ratio of 25.2 (95% CI 4.0 to 161.4,
P=0.0007).[26] Injection drug use is also a risk factor for HBV infection, the presence of which is a
requirement for HDV infection.[24] [27]
Weak
born or living in or travel to geographical regions where HDV is endemic
• People born in regions of high incidence and prevalence (e.g., parts of western and mid-Africa,
DIAGNOSIS
Mongolia, eastern Europe, and parts of the Mediterranean) are at increased risk of HDV infection.[11]
People living in, or travelling to, highly endemic regions are also at greater risk.
history of incarceration
• Since HDV infection occurs in the setting of HBV infection, patients with risk factors for HBV infection
(e.g., injection drug use, increased likelihood of sexual exposure, being born in a highly endemic
region) are also at risk for HDV infection.
• Patients with a history of incarceration have a higher risk for HBV exposure due to associated risk
factors (e.g., injection drug use, increased likelihood of sexual exposure, tattoos). In one systematic
review in Europe, the highest prevalence of hepatitis B surface antigen among three high-risk groups
(people who were incarcerated, men who have sex with men, and people who inject drugs) was found
in those who were incarcerated (0.3% to 25.2%).[28]
family history of HBV/HDV infection, hepatocellular carcinoma, and/or

chronic liver disease
• People with a family history of HBV infection, HDV infection, hepatocellular carcinoma, and/or chronic
liver disease have an increased risk of HDV infection.
15
perinatal exposure in an infant born to an HDV-infected mother
• Vertical transmission of HDV is a rare but possible method of transmission. In one study of 36 children
who were born to 22 mothers with HBV and HDV co-infection, only one child was found to be infected
with HBV, and none had serological evidence of HDV.[29]
men who have sex with men

• Many men who have sex with men are at a higher risk of contracting sexually transmitted infections
and bloodborne pathogens, including HDV.[12]
household contact with HDV infection

• Household contacts of people with HDV infection are at risk of becoming infected with HDV.[12] As
with HBV infection, this may be due to continuous close, personal, or unnoticed contact of infective
secretions with skin lesions or mucosal surfaces.[30]
healthcare workers
• Healthcare and public safety workers who are at risk of occupational exposure to blood or blood
contaminated fluids are at an increased risk of acquiring HDV infection.[12]
haemodialysis
• The risk of acquiring HDV infection is increased in patients who receive haemodialysis.[12] [31] One
study that analysed the odds of anti-HDV detection in six selected populations relative to general
populations or asymptomatic hepatitis B surface antigen (HBsAg)-positive people from the same
geographical region found that anti-HDV prevalence was higher in haemodialysis recipients (pooled
odds ratio 3.4).[11]
DIAGNOSIS
Investigations
1st test to order
Test Result
liver biochemistries normal or elevated
aminotransferases (ALT/
• Request in all patients as part of the initial evaluation:
AST), ALP, and bilirubin;
• • Alanine aminotransferase (ALT) low albumin
• Aspartate aminotransferase (AST)
• Alkaline phosphatase (ALP)
• Total bilirubin (direct and indirect)
• Albumin.
• Results may be normal but aminotransferases (ALT and AST),
ALP, and/or bilirubin levels may be elevated in chronic hepatitis
D virus (HDV) infection. Albumin level may be low in patients with
decompensated cirrhosis.
full blood count (FBC) low (particularly platelet
count)
• • Haemoglobin/haematocrit
• White cell count and differential
• Platelet count.
• May be decreased in patients with cirrhosis and portal hypertension
(particularly platelet count).
renal function tests normal or hyponatraemia
and/or high urea
• • Electrolytes
• Urea
• Creatinine.
DIAGNOSIS
• In patients with cirrhosis and ascites, there may be electrolyte
disturbances including hyponatraemia. Renal dysfunction is a risk in
decompensated cirrhosis due to pre-renal azotaemia or hepatorenal
syndrome.
coagulation profile normal or elevated
• • Prothrombin time (PT) and international normalised ratio (INR).
• May be normal. In patients with cirrhosis, however, levels may be
elevated indicative of liver synthetic dysfunction.
serum antibody to HDV variable
• Request antibody to HDV (anti-HDV) (IgG and IgM) in all patients with
confirmed hepatitis B virus (HBV) infection.[44]
• The European Association for the Study of the Liver (EASL)
recommends that screening for anti-HDV antibody should be
performed with a validated assay at least once in all hepatitis B
surface antigen (HBsAg)-positive individuals, and that re-testing
for anti-HDV antibody should be performed in those who initially
test negative whenever clinically indicated (such as in those with
17
Test Result
aminotransferase flares or acute decompensation of chronic liver
disease) and annually in those remaining at risk of infection.[1]
• Guidelines from the American Association for the Study of Liver
Diseases (AASLD) recommend risk-based screening of HBsAg-
positive patients for HDV infection in the following situations:[2]
• • Elevated alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) with low or undetectable HBV DNA
• HIV infection
• Hepatitis C virus (HCV) infection
• History of injection drug use
• Those with multiple sexual partners or any history of sexually
transmitted disease
• Immigrants from areas with high HDV endemicity (western and
mid-Africa, parts of the Mediterranean, Pacific Islands, Middle
East, Mongolia, eastern Europe, and the Amazonian basin).[1]
• Anti-HDV antibodies appear 3-4 weeks after HDV infection.[43] The
result will be positive in people with chronic HDV infection, but levels
can fluctuate based on the degree of replication.
serum HDV RNA positive
• Request HDV RNA (where available) as part of the initial evaluation
in all patients with a positive anti-HDV test result. A standardised
and sensitive reverse transcription polymerase chain reaction assay
should be used.[1]
• Anti-HDV antibodies may persist after the clearance of HDV infection
and therefore testing for HDV RNA is required to confirm ongoing
HDV infection.[1]
• HDV RNA assays are increasingly available, but require greater
standardisation, particularly with some less common HDV genotypes.
• One systematic review and meta-analysis found that the pooled
proportion of detectable HDV RNA in 5073 people with a positive
DIAGNOSIS
anti-HDV test result was 58.5% (95% CI 52.4 to 64.5). The rate of
HDV RNA detection was higher in cohorts with higher prevalence
of anti-HDV and in hepatology clinic populations than in the general
population.[11] Variable performance of HDV RNA with some HDV
genotypes indicates that this figure should be interpreted with
caution.
serum hepatitis B surface antigen positive
• Request hepatitis B surface antigen (HBsAg) in all patients as part of
the initial evaluation.
• A positive HBsAg result indicates a current hepatitis B virus (HBV)
infection. Persistence for more than 6 months indicates chronic HBV
infection.
serum antibody to hepatitis B surface antigen undetectable
• Request antibody to hepatitis B surface antigen (anti-HBs) in all
patients as part of the initial evaluation.
• In resolved acute infections, appears several weeks after hepatitis
B surface antigen has disappeared, and in most patients indicates
lifelong immunity. It is also detectable in those immunised with
hepatitis B vaccine.
Test Result
serum antibody to hepatitis B core antigen positive
• Order both IgM and IgG antibody to hepatitis B core antigen (anti-
HBc) in all patients as part of the initial evaluation.
• IgM anti-HBc appears within weeks of acute infection and remains
detectable for 4-8 months. During the window period (several weeks
to months) after the disappearance of hepatitis B surface antigen
(HBsAg) and before appearance of antibody to HBsAg, detection of
anti-HBc IgM may be the only way to make the diagnosis of acute
hepatitis B virus (HBV) infection. Some patients with chronic HBV
infection become positive for IgM antibody during acute flares or
reactivation, making positive anti-HBc IgM not an absolutely reliable
marker for acute infection.[45]
• Anti-HBc IgM and IgG antibodies are detectable in virtually all
patients who have been exposed to HBV (acute or chronic HBV
infection). They may be positive in the following settings: 1) acute
infection: during the window period (mostly IgM); 2) chronic infection
(IgG and occasionally IgM), when HBsAg has decreased to
undetectable levels; and 3) resolved infections (IgG): detection of
anti-HBc IgG in the absence of HBsAg and with or without anti-HBe
and anti-HBs antibodies characterises HBV infection in the past. The
pattern is common in areas with high prevalence of HBV infection
and in those patients who are co-infected with HIV or hepatitis C.
Patients with HBV infection in the past remain at risk of reactivation if
immunosuppressed.
serum hepatitis B e antigen undetectable or positive
• Request hepatitis B envelope antigen (HBeAg) in all patients as part
of the initial evaluation.
• This is a soluble viral protein found in serum in the early part of acute
hepatitis B virus (HBV) infection, and it usually disappears at or soon
after the peak in serum alanine aminotransferase (ALT) levels. Its
presence ≥3 months after onset of illness indicates a high likelihood
of development of chronic HBV infection. HBeAg can also be present
in chronic HBV infection.
DIAGNOSIS
serum antibody to hepatitis B e antigen undetectable or positive
• Request antibody to hepatitis B envelope antigen (anti-HBe) in all
patients as part of the initial evaluation.
• Seroconversion from hepatitis B e antigen (HBeAg)-positive to
antibody to hepatitis B e antigen (anti-HBe)-positive is a useful
indicator of clearance of virus. Patients with sustained seroconversion
typically have improvement of liver histology. However, some patients
will become anti-HBe-positive without complete clearance of virus,
due to pre-core or core-promoter mutations (HBeAg-negative chronic
HBV).
• Seroconversion can be a temporary phenomenon and should be
analysed in association with the serum hepatitis B virus DNA level.
serum HBV DNA undetectable or positive
• Request hepatitis B virus (HBV) DNA in all patients as part of the
initial evaluation.
• HBV DNA levels are generally measured by polymerase chain
reaction (PCR) amplification assay. Newer PCR technology has
allowed for improved sensitivity. HBV DNA may be positive but is
often suppressed in active HDV infection.
19
Test Result
abdominal ultrasound may reveal coarsened
appearance of the
• Request in all patients as a useful first imaging test to evaluate the
liver with irregular
liver for advanced fibrosis, cirrhosis, and portal hypertension, and for
contours and signs of
hepatocellular carcinoma.
• Ultrasound may be normal. In patients with cirrhosis, the liver may portal hypertension, or
hepatocellular carcinoma
look coarsened with irregular contours and there may be signs of
portal hypertension (which may include increased spleen longitudinal
diameter, oesophageal varices, or mild ascites).
• Continued surveillance imaging every 6 months using ultrasound is
recommended in patients with advanced fibrosis or cirrhosis to look
for hepatocellular carcinoma.[1]
Other tests to consider
Test Result
testing for co-infections variable
• Check the patient’s HIV, hepatitis A, and hepatitis C status as this
affects management options.
liver biopsy may demonstrate
inflammation or fibrosis
• Histology remains the gold standard for the most accurate
characterisation of liver disease, and enables categorical grading
and staging of necro-inflammation and fibrosis. However, liver biopsy
should not be obtained routinely unless there is a diagnostic dilemma
or if there is some debate over whether treatment is required.[1]
transient elastography may demonstrate
increased liver stiffness
• Consider transient elastography as a non-invasive alternative to liver
biopsy.[1] Evaluates liver injury by measuring liver stiffness.
• Transient elastography is used routinely in Europe and may be
considered as a non-invasive alternative to liver biopsy. However,
specific cut-off values are not well established.[1]
DIAGNOSIS
• Magnetic resonance elastography has been shown to be more

accurate than Fibroscan® in diagnosing liver fibrosis in patients with
chronic hepatitis B virus infection.[46]
serum liver fibrosis biomarkers normal or elevated
• Non-invasive alternative to liver biopsy or to transient elastography
which may be used to assess fibrosis severity.[1]
Differentials
Condition Differentiating signs / Differentiating tests

symptoms
Acute viral hepatitis A • There may be no differences • Serum hepatitis A virus-IgM
in signs and symptoms. antibody will be positive.
Acute viral hepatitis B • There may be no differences • Serum hepatitis B surface

in signs and symptoms. antigen and serum antibody
to hepatitis B surface antigen
and/or IgM antibody to
hepatitis B core antigen will
be positive.
• Serum hepatitis B virus
(HBV) DNA detected by
polymerase chain reaction
may be positive for HBV.
Acute viral hepatitis C • There may be no differences • Serum hepatitis C virus

in signs and symptoms. (HCV) antibody and
HCV RNA detected by
polymerase chain reaction
may be positive. Typically,
symptomatic acute HCV
patients will show very high
alanine aminotransferase,
aspartate aminotransferase,
and bilirubin.
Acute viral hepatitis E • Symptoms and signs can • Serum hepatitis E virus
be identical to those of (HEV) antibody (IgM) and
other acute viral hepatitis. serum HEV RNA detected by
Acute hepatitis E is most polymerase chain reaction
commonly found in pregnant may be positive.
DIAGNOSIS
women in developing
countries with a hot climate.
Acute alcoholic hepatitis • History of moderate/heavy • AST:ALT ratio >2:1 in up to

alcohol consumption. 70% of cases.
• Hepatomegaly and jaundice • Full blood count may show
are found in around 95% and anaemia, leukocytosis, and/
55% of people presenting or thrombocytopenia.
with alcoholic hepatitis, • Negative viral hepatitis
respectively. serology.
• Liver biopsy may show
steatosis, ballooning
hepatocytes, Mallory
hyaline, lobular neutrophilic
infiltration, with or without
pericellular fibrosis.
Autoimmune hepatitis • May be more likely to have • There may be increased

constitutional symptoms, levels of serum globulin,
such as fever, myalgias, and antinuclear antibody,
lymphadenopathy. There antismooth muscle antibody,
may be a history of other liver/kidney microsomal
21

symptoms
autoimmune diseases, antibodies, and/or antibodies
such as thyroiditis, type 1 against soluble liver antigen/
diabetes, coeliac disease, liver pancreas antigen. Liver
and ulcerative colitis.[47] [48] histology may show interface
hepatitis with plasma cell
infiltrates.
• Negative viral hepatitis
serology.
Drug- or toxin-induced • May have a history of • Liver biopsy may show the
hepatitis exposure to drugs or toxins. features of hepatocellular,
Evidence of hypotension. cholestatic, or mixed
pattern of injury, including
cholestasis.
Budd-Chiari syndrome • There may be no differences • Doppler ultrasound

in signs and symptoms. may show hepatic vein
thrombosis or inferior vena
caval thrombosis.
Acute ischaemic hepatitis • Typically occurs in patients • ECG may show features
at risk for hypotension or of myocardial ischaemia or
ischaemia, including shock, infarction. Chest x-ray and
heart failure, or vascular echocardiogram may show
insufficiency. Patients may features of congestive heart
have symptoms of ischaemia failure. Doppler ultrasound
such as acute heart failure, of liver may show portal
shock, or sepsis. vein thrombosis or acute
occlusion of hepatic artery.
Acute fat ty liver of • Pregnant patient may • Diagnosis of exclusion

pregnancy present with jaundice. of other diseases with
characteristic symptoms and
signs in pregnant patients.
DIAGNOSIS
Haemochromatosis • May have a family history • Serum transferrin saturation

of haemochromatosis. >45%, raised serum ferritin.
May also have signs • HFE genetic testing
and symptoms such will be positive for
as chronic asthenia, haemochromatosis gene
arthropathy, impotence, mutations.
hyperpigmentation and • Liver biopsy shows iron
skin bronzing, diabetes deposition in hepatocytes.
mellitus, cardiomyopathy,
and porphyria cutanea tarda.
Biliary disease • May have fever, pruritus, • Elevated alkaline

dark urine, pale stool, weight phosphatase and bilirubin
loss. levels.
• Abdominal imaging may
show biliary dilation,
stricture, or obstruction.
• Anti-mitochondrial antibody
will be positive in primary
biliary cholangitis.

symptoms
• Liver biopsy may show
biliary or cholestatic disease.
Alpha-1 antitrypsin • May have chronic lung • Reduced plasma alpha-1

deficiency disease such as emphysema antitrypsin level <20
occurring earlier than micromoles/L confirms the
expected (in the 40- to diagnosis.
50-year-old age group) • Lung function tests may
as well as liver disease. reveal reduced FEV₁, FVC,
Some 50% of patients with and FEV₁/FVC.
severe deficiency of alpha-1 • Chest x-ray may reveal
antitrypsin have a productive emphysema and large lung
cough.[49] Patients with volumes.
respiratory disease may
present with shortness of
breath on exertion.
Wilson's disease • There may be associated • Increased 24-hour urinary

behavioural abnormalities copper, decreased serum
(such as loss of memory, ceruloplasmin, and Kayser-
anxiety, disinhibition), Fleischer rings on slit lamp
dysarthria, and presence eye examination.
of Kayser-Fleischer rings
(gold-brown corneal
pigments representing
copper deposition) on eye
examination.
Criteria
METAVIR[50]
DIAGNOSIS
Meta-analysis of histological data in viral hepatitis (METAVIR) is a histological scoring system used to assess
degree of inflammation and stage of liver disease in chronic hepatitis. The grade indicates the activity or
degree of inflammation and the stage represents the amount of fibrosis or scarring.
Activity grade:
• A0: no activity
• A1: mild activity
• A2: moderate activity
• A3: severe activity
Fibrosis stage:
• F0: no fibrosis
• F1: portal fibrosis without septa
• F2: portal fibrosis with few septa
• F3: numerous septa without cirrhosis
• F4: cirrhosis
23
Ishak score[51]
The Ishak system assesses fibrosis in seven categories, ranging from normal to cirrhosis.
Stage component of the Ishak system

Adapted from Standish RA et al. Gut 2006 Apr;55(4):569-78 and
Ishak K et al. J Hepatol 1995 Jun;22(5):696-9; used with permission
DIAGNOSIS
Hepatitis D Management
Approach
The treatment options for hepatitis D virus (HDV) infection are limited. Currently, no pharmacological
therapies are available for acute infection, while patients with chronic infection may be considered for antiviral
treatment, including peginterferon alfa and bulevirtide (which is specific for HDV infection). Liver transplant is
often required in patients with end-stage liver disease or acute liver failure.[12]
The goal of treatment should be to prevent disease progression and lead to biochemical and virological
resolution. In hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, control of virus replication and
virus eradication, respectively, leads to improvement in liver function tests (LFTs) and a decrease in clinical
endpoints such as cirrhosis, hepatocellular carcinoma, and death.[2] [52] In HDV infection, sustained
suppression of viral replication and seroconversion of HBV surface antigen (HBsAg) - loss of HBsAg and
appearance of antibody to hepatitis B surface antigen (anti-HBs) - would be ideal but is rarely achievable with
currently available therapy.
Given the evolving treatment options and issues with standardisation of virological assays, it is advisable to
refer all patients with confirmed HDV infection to a specialised centre for management.
This topic does not cover the management of special patient groups (e.g., pregnant women, children) as
there are very limited data available on these patients.
Acute HDV infection

Manage patients with acute HDV infection with supportive care, according to their symptoms (e.g.,
encouraging the patient to remain hydrated and maintaining nutrition).
• No antiviral drugs are approved for acute HDV infection.

Note that >95% of immunocompetent adults with simultaneous HDV/HBV co-infection will spontaneously
clear the virus. However, evolution to chronic infection may occur in >90% of patients with superinfection
(HDV infection in a person with chronic HBV infection).[34]
Monitor patients for any change in clinical status that indicates progression to a disease state that
requires treatment.[2]
Evaluate patients with fulminant hepatitis for liver transplantation due to the high risk of mortality in this
group of patients without transplant.[12] See Acute liver failure .
• Transplantation in eligible patients is associated with an excellent outcome.[53]

First-line treatment options for patients with chronic HDV infection include peginterferon alfa-2a
or bulevirtide. The decision about which drug to use usually depends on clinician preference and
experience, and whether or not the patient has any contraindications to either drug. Data on the efficacy
of bulevirtide are limited and the optimal treatment duration is unknown, while the safety and efficacy is
MANAGEMENT
considered to be better with peginterferon alfa-2a.
Peginterferon alfa
25
Consider peginterferon alfa-2a in all eligible patients with chronic HDV infection with detectable HDV RNA
(with or without associated compensated cirrhosis).[1] The preferred duration of treatment is 48 weeks.[1]
[54]
• Note that the National Institute for Health and Care Excellence (NICE) in the UK recommends
giving peginterferon alfa-2a to patients with chronic HDV infection only if there is evidence of
significant fibrosis (METAVIR stage ≥F2 or Ishak stage ≥3) (see Criteria ).[54]
• Consider personalised treatment durations based on HDV RNA and HBsAg kinetics and treatment
tolerability.[1]
• Consider stopping treatment if there is no decrease in HDV RNA following 6 or more months of
treatment.[54]
• Stop treatment after HBsAg seroconversion.[54]
• Treatment success is defined as undetectable HDV RNA 24 weeks after completing treatment
(alongside normalisation of alanine aminotransferase [ALT]).[2] One review of 13 studies including
1078 patients demonstrated that the overall virological response (defined as undetectable HDV
RNA after 24 weeks following the end of treatment) was 31%.[55] However, relapses of HDV RNA
occur commonly in the post-treatment phase and have been reported even 5-10 years after the end
of treatment.[56]
• Peginterferon alfa is contraindicated in patients with decompensated cirrhosis.
Bulevirtide
Consider bulevirtide for patients with chronic hepatitis D infection and compensated liver disease.[1]
• Bulevirtide is an entry inhibitor that blocks HDV from entering hepatocytes by binding and
inactivating the sodium/bile acid cotransporter.
• It is approved in Europe and the UK for the treatment of chronic HDV infection in plasma (or serum)
HDV RNA-positive adults with compensated liver disease.[57]
• NICE recommends bulevirtide as an option for treating chronic HDV infection in adults with
compensated liver disease only if:[57]
• There is evidence of significant fibrosis (METAVIR stage ≥F2 or Ishak stage ≥3), and
• Their hepatitis has not responded to peginterferon alfa‑2a, or for whom peginterferon alfa‑2a is
not tolerated or is contraindicated.
• Clinical trial evidence shows that bulevirtide is effective compared with standard care despite some
uncertainties around how long it works for.[57]
• In a multicentre open-label study, 120 patients with chronic HDV infection were randomised to
various doses of bulevirtide in combination with tenofovir, or to tenofovir alone, for 24 weeks.
The primary endpoint was based on virological response. There was a dose-dependent effect
of bulevirtide on decline in HDV RNA. However, the HDV RNA levels rebounded after the drug
was stopped. Adverse effects were related to the elevation of serum bile acids, but pruritus was
mild.[58]
• Treatment duration is usually more than 48 weeks. However, the optimal treatment duration is yet
to be determined, and treatment should continue until clinical benefit is seen. An ongoing phase
MANAGEMENT
3 randomised trial of bulevirtide in 150 patients with chronic HDV infection over 144 weeks of
treatment found that HDV RNA and ALT levels were reduced after 48 weeks of bulevirtide treatment
compared with a control group receiving no treatment, with increasing response rates at 96 weeks
relative to 24 and 48 weeks.[59]
• Bulevirtide is contraindicated in patients with decompensated cirrhosis.
Combination therapy
Combination therapy may be an option in some patients.
• Peginterferon alfa-2a and bulevirtide may be used together in some circumstances. In practice,
they may be started simultaneously, or one may be added on to the other. However, evidence for
the use of combination therapy is limited and studies are ongoing.
• Based on consensus opinion and weak evidence, guidelines from the European Association for
the Study of the Liver (EASL) state that bulevirtide may be considered for use in combination
with peginterferon alfa‑2a in patients without an intolerance or contraindication to the use of
peginterferon alfa‑2a.[1] In the author’s opinion, combination therapy should only be used with
caution and in consultation with a specialist.
Nucleoside/nucleotide analogue therapy
Give a nucleoside/nucleotide analogue (e.g., entecavir, tenofovir) in all patients with compensated
cirrhosis and detectable HBV DNA, regardless of HBV DNA levels.[1] Also consider a nucleoside/
nucleotide analogue in patients with persistent HBV infection, especially if HBV DNA levels are close to or
higher than 2000 IU/mL.[1] [2] See Hepatitis B .
Give a nucleoside/nucleotide analogue to patients with decompensated cirrhosis irrespective of the

presence of detectable HBV DNA.[1]
Liver transplantation for decompensated cirrhosis
Evaluate patients with decompensated cirrhosis for liver transplantation.[1] [2] This may include patients
with end-stage liver disease as well as those with fulminant hepatitis.[12]
• Transplantation in eligible patients is associated with an excellent outcome.[53]

• If liver transplantation is not possible, a best-supportive-care strategy is recommended.[1] See
Cirrhosis .
Give patients who have undergone liver transplantation for chronic HDV infection hepatitis B
immunoglobulin combined with a high genetic barrier nucleoside/nucleotide analogue after
transplantation.[1]
Patients with hepatocellular carcinoma
Prioritise optimal treatment for hepatocellular carcinoma (including liver transplantation) in patients with
chronic HDV infection and hepatocellular carcinoma.[1] Evaluate patients with hepatocellular carcinoma
for antiviral treatment on an individual basis.[1] See Hepatocellular carcinoma .
MANAGEMENT
27
Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute ( summary )
acute HDV infection
1st supportive care
adjunct liver transplantation
Ongoing ( summary )
chronic HDV infection
1st
compensated cirrhosis or 1st peginterferon alfa and/or bulevirtide

no cirrhosis
1st treatment of hepatitis B co-infection
decompensated cirrhosis 1st treatment of hepatitis B co-infection

MANAGEMENT
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute
acute HDV infection
1st supportive care
» Manage patients with acute hepatitis D virus

(HDV) infection with supportive care, according
to their symptoms (e.g., encouraging the patient
to remain hydrated and maintaining nutrition).
• No antiviral drugs are approved for acute

HDV infection.
» Note that >95% of immunocompetent adults
with simultaneous HDV/hepatitis B virus (HBV)
co-infection will spontaneously clear the virus.
However, evolution to chronic infection may
occur in >90% of patients with superinfection
(HDV infection in a person with chronic HBV
infection).[34]
» Monitor patients for any change in clinical

status that indicates progression to a disease
state that requires treatment.[2]
Treatment recommended for SOME patients in
selected patient group
» Evaluate patients with fulminant hepatitis
for liver transplantation due to the high risk
of mortality in this group of patients without
transplant.[12] See Acute liver failure .
• Transplantation in eligible patients is

associated with an excellent outcome.[53]
MANAGEMENT
29
Ongoing
chronic HDV infection
chronic HDV infection 1st
compensated cirrhosis or 1st peginterferon alfa and/or bulevirtide

no cirrhosis
Primary options
» peginterferon alfa 2a: 180 micrograms

subcutaneously once weekly for 48 weeks
-and/or-
» bulevirtide: 2 mg subcutaneously once daily
» First-line treatment options for patients

with chronic hepatitis D virus (HDV) infection
include peginterferon alfa-2a or bulevirtide.
The decision about which drug to use usually
depends on clinician preference and experience,
and whether or not the patient has any
contraindications to either drug. Data on the
efficacy of bulevirtide are limited and the optimal
treatment duration is unknown, while the safety
and efficacy is considered to be better with
peginterferon alfa-2a.
» Consider peginterferon alfa-2a in all eligible

patients with chronic HDV infection with
detectable HDV RNA (with or without associated
compensated cirrhosis).[1] The preferred
duration of treatment is 48 weeks.[1] [54]
• Note that the National Institute for Health

and Care Excellence (NICE) in the UK
recommends giving peginterferon alfa-2a
to patients with chronic HDV infection only
if there is evidence of significant fibrosis
(METAVIR stage ≥F2 or Ishak stage ≥3)
(see Criteria ).[54]
• Consider personalised treatment durations
based on HDV RNA and hepatitis B
surface antigen (HBsAg) kinetics and
treatment tolerability.[1]
• Consider stopping treatment if there is no
decrease in HDV RNA following 6 or more
months of treatment.[54]
• Stop treatment after HBsAg
seroconversion.[54]
• Treatment success is defined as
undetectable HDV RNA 24 weeks after
completing treatment.[2] One review
of 13 studies including 1078 patients
demonstrated that the overall virological
MANAGEMENT
response (defined as undetectable HDV

RNA after 24 weeks following the end
of treatment), was 31%.[55] However,
relapses of HDV RNA occur commonly in
the post-treatment phase and have been
Ongoing
reported even 5-10 years after the end of
treatment.[56]
• Peginterferon alfa is contraindicated in
patients with decompensated cirrhosis.
» Bulevirtide is an alternative option to consider
for patients with chronic hepatitis D infection and
compensated liver disease.[1]
• Bulevirtide is an entry inhibitor that blocks

HDV from entering hepatocytes by binding
and inactivating the sodium/bile acid
cotransporter.
• It is approved in Europe and the UK for
the treatment of chronic HDV infection
in plasma (or serum) HDV RNA-positive
adults with compensated liver disease.[57]
• Note that NICE recommends bulevirtide
as an option for treating chronic HDV
infection in adults with compensated liver
disease only if:[57]
• There is evidence of significant

fibrosis (METAVIR stage ≥F2 or
Ishak stage ≥3), and
• Their hepatitis has not responded
to peginterferon alfa‑2a, or for whom
peginterferon alfa‑2a is not tolerated
or is contraindicated.
• Clinical trial evidence shows that
bulevirtide is effective compared with
standard care despite some uncertainties
around how long it works for.[57]
• In a multicentre open-label study, 120
patients with chronic HDV infection
were randomised to various doses of
bulevirtide in combination with tenofovir,
or to tenofovir alone, for 24 weeks. The
primary endpoint was based on virological
response. There was a dose-dependent
effect of bulevirtide on decline in HDV
RNA. However, the HDV RNA levels
rebounded after the drug was stopped.
Adverse effects were related to the
elevation of serum bile acids, but pruritus
was mild.[58]
• Treatment duration is usually more than
48 weeks. However, the optimal treatment
MANAGEMENT
duration is yet to be determined, and

treatment should continue until clinical
benefit is seen. An ongoing phase 3
randomised trial of bulevirtide in 150
patients with chronic HDV infection
over 144 weeks of treatment found that
31
Ongoing
HDV RNA and ALT levels were reduced
after 48 weeks of bulevirtide treatment
compared with a control group receiving
no treatment, with increasing response
rates at 96 weeks relative to 24 and 48
weeks.[59]
• Bulevirtide is contraindicated in patients
with decompensated cirrhosis.
» Combination therapy may be an option in
some patients.
• Peginterferon alfa-2a and bulevirtide may

be used together in some circumstances.
In practice, they may be started
simultaneously, or one may be added on
to the other. However, evidence for the
use of combination therapy is limited and
studies are ongoing.
• Based on consensus opinion and weak
evidence, guidelines from the European
Association for the Study of the Liver
(EASL) state that bulevirtide may be
considered for use in combination with
peginterferon alfa‑2a in patients without an
intolerance or contraindication to the use
of peginterferon alfa‑2a.[1]
• In the author’s opinion, combination
therapy should only be used with caution
and in consultation with a specialist.
» Evaluate patients with hepatocellular
carcinoma for antiviral treatment on an individual
basis.[1] See Hepatocellular carcinoma .
1st treatment of hepatitis B co-infection
» Add a nucleoside/nucleotide analogue

(e.g., entecavir, tenofovir) in all patients with
compensated cirrhosis and detectable hepatitis
B virus (HBV) DNA, regardless of HBV DNA
levels.[1] Also consider nucleoside/nucleotide
analogue therapy in patients with persistent
HBV infection, especially if HBV DNA levels
are close to or higher than 2000 IU/mL.[1] [2]
See Hepatitis B .
decompensated cirrhosis 1st treatment of hepatitis B co-infection
» Give a nucleoside/nucleotide analog

(e.g., entecavir, tenofovir) to patients with
MANAGEMENT
decompensated cirrhosis irrespective of the

presence of detectable HBV DNA.[1]
Ongoing
Treatment recommended for SOME patients in
selected patient group
» Evaluate patients with decompensated
cirrhosis for liver transplantation.[1] [2] This may
include patients with end-stage liver disease as
well as those with fulminant hepatitis.[12]
• Transplantation in eligible patients is

associated with an excellent outcome.[53]
• If liver transplantation is not possible,
a best-supportive-care strategy is
recommended.[1] See Cirrhosis .
» Give patients who have undergone liver
transplantation for chronic HDV infection
hepatitis B immunoglobulin combined with a high
genetic barrier nucleoside/nucleotide analogue
after transplantation.[1]
» Prioritise optimal treatment for hepatocellular

carcinoma (including liver transplantation)
in patients with chronic HDV infection and
hepatocellular carcinoma.[1] See Hepatocellular
carcinoma .
MANAGEMENT
33
Emerging
Lonafarnib
Lonafarnib, a prenylation inhibitor, inhibits the farnesyl transferase that is involved in modifying the hepatitis
D virus (HDV) antigen so that it can be incorporated into the hepatitis B virus surface antigen (HBsAg). The
efficacy of lonafarnib was demonstrated in a small pilot study of 14 patients with chronic HDV infection,
followed over 28 days, with a dose-dependent drop in HDV RNA levels that correlated with the lonafarnib
serum concentration.[60] By adding ritonavir (a protease inhibitor) to boost the lonafarnib serum level,
the antiviral response improved and the gastrointestinal adverse effects decreased. Adding peginterferon
alfa improved the antiviral effect further.[61] The D-LIVR study, which is yet to be published, randomised
407 patients with chronic HDV infection to receive lonafarnib boosted with ritonavir alone (all-oral) or in
combination with peginterferon alfa (combination). The composite primary endpoint was a ≥2 log decline
in HDV RNA and normalisation of alanine transaminase at the end of 48 weeks of treatment compared
with placebo. Patients on the all-oral therapy and combination therapy showed a composite response of
10.1% (P=0.0044) and 19.2% (P <0.0001), respectively, compared with those receiving placebo (1.9%).[62]
Similarly, histological response (defined as ≥2-point improvement in histological activity index and no
worsening of Ishak fibrosis scoring) improved with treatment in 35 of 66 patients (53%, P=0.0139) in the
combination group versus 8 of 30 patients (27%) receiving placebo. Lonafarnib has been granted orphan
drug designation in some countries for the treatment of HDV infection, and is approved in some countries for
other indications.
Primary prevention
Since hepatitis D virus (HDV) requires the presence of hepatitis B virus (HBV) surface antigen to propagate,
vaccination against HBV is the main strategy to prevent HDV infection.[12] Worldwide, the number of
HDV infections has decreased since the 1980s, due mainly to a successful global HBV vaccination
programme.[32] HDV vaccines have been developed in animal models with very limited success.[33]
Primary prevention of HBV can be via passive immunisation with hepatitis B immunoglobulin or via active
immunisation with a hepatitis B vaccine. For details of US immunisation schedules, consult the Advisory
Committee on Immunization Practices (ICIP) guidelines. [CDC: hepatitis B vaccination of adults] (https://
www.cdc.gov/hepatitis/hbv/vaccadults.htm)
Secondary prevention
Prevention of HDV infection in the allograft after liver transplantation is an important goal, although
this typically does not occur if HBV re-infection can be prevented. Current regimens using hepatitis B
immunoglobulin and nucleoside/nucleotide analogues are very effective in preventing HBV infection, with
some centres in the US using only hepatitis B immunoglobulin short-term. However, a longer duration of
hepatitis B immunoglobulin was associated with a lower risk of HBV reactivation in HDV-positive patients
in the landmark EUROHEP study, and American Association for the Study of Liver Diseases (AASLD)
guidelines suggest a combination of long-term hepatitis B immunoglobulin and nucleoside/nucleotide
analogues to prevent HBV and HDV infection in the allograft.[2] [58]
Screen pregnant women for hepatitis B surface antigen (HBsAg).[2] Pregnant women should also be
encouraged to discuss the need for maternal antiviral therapy, as well as newborn hepatitis B vaccination and
hepatitis B immunoglobulin, with their obstetrician to prevent mother-to-child transmission.[2]
Healthcare workers with HBV infection who perform exposure-prone procedures should be advised to seek
counselling and advice from an expert review panel, as antiviral prophylaxis may be recommended.[2]
MANAGEMENT
Initiate antiviral prophylaxis in patients with past HBV infection who are starting on immunosuppressive
therapy in order to prevent HBV reactivation.
Initiate lifelong antiviral prophylaxis with a nucleoside/nucleotide analogue (with or without hepatitis
B immunoglobulin) in all HBsAg-positive patients undergoing liver transplantation, regardless of pre-
transplant hepatitis B e antigen status or HBV DNA level. An individualised approach to the use of hepatitis B
immunoglobulin use is recommended.
Initiate long-term antiviral therapy in HBsAg-negative patients receiving livers from donors with evidence of
past HBV infection (antibody to hepatitis B core antigen-positive) to prevent HBV reactivation.
Patient discussions
Counsel patients on preventing transmission of hepatitis D virus (HDV) and hepatitis B virus (HBV) to
others and the importance of lifelong monitoring.
Lifestyle modifications to optimise body weight and treat metabolic complications are recommended in
order to prevent the development of metabolic syndrome and fatty liver.
Advise patients who have chronic HDV to:[2]
• Have household and sexual contacts vaccinated if they test negative for HBV serological markers
• Use barrier protection during sex if their partner is not vaccinated or is not naturally immune to HBV
• Not share toothbrushes, razors, injection equipment, or glucose testing equipment
• Not donate blood, organs, or semen
• Cover open cuts and scratches
• Clean blood spills with bleach
• Vaccinate against hepatitis A virus if not immune
• Abstain from, or limit, alcohol use.
MANAGEMENT
35
Hepatitis D Follow up
Monitoring
Monitoring
FOLLOW UP
Monitoring is required in patients with chronic hepatitis D virus (HDV) infection who are on treatment.
The aim of monitoring in these patients is to evaluate treatment response, adverse effects, and disease
progression or reactivation.
Monitor full blood count and hepatic panel at initiation of treatment, then every 3-6 months and more
frequently if clinically indicated.[1]
Monitor virological response to treatment during and after therapy:[1]
• Hepatitis B virus (HBV) DNA levels every 6 months (patients not on nucleoside/nucleotide analogue
therapy)
• HDV RNA levels should be monitored regularly, with the frequency of testing guided by clinical
circumstances (e.g., every 3-4 months during treatment, whenever there is clinical indication, at the
end of treatment, and at regular intervals following cessation of treatment)
• HBV surface antigen (HBsAg) status every 6 months during therapy and annually after therapy
ends.
Testing should also be performed at the end of treatment, 6 months, and 12 months post treatment (or
more frequently if clinically indicated) and then annually following this.[1]
Additionally for patients on nucleoside/nucleotide analogue therapy:[2]
• Perform renal function tests at baseline and regularly during treatment

• Monitor hepatic panel every 3-4 months during the first year, and every 6 months thereafter
• Monitor HBV DNA at baseline and every 3-4 months during the first year, and every 6-12 months
thereafter
• Check HBsAg status annually
• Monitor lactic acid levels if there is a clinical concern for lactic acidosis (e.g., with use of entecavir
or tenofovir in patients with decompensated cirrhosis)
• Consider bone density study at baseline and during treatment if the patient has a history of fracture
or risks for osteopenia (tenofovir).
In case of bulevirtide discontinuation, test for HDV RNA at the time of treatment discontinuation, after 1, 3,
6, and 12 months, and then annually to monitor relapse of viral replication.[1]
Consider:[1]
• Determination of liver stiffness - can be performed annually during and after antiviral treatment
• Liver biopsy - may be of benefit in patients where histological diagnosis can aid management
• Monitoring for liver-related clinical events, both during and after antiviral treatment.
Also monitor patients for development of neuropsychiatric, autoimmune, ischaemic, and infectious
complications.
Observe patients without detectable HDV RNA, elevated liver function tests (LFTs), or advanced fibrosis
with intermittent monitoring (every few months) and follow guidance for treatment of HBV infection in this
group of patients.[2] See Hepatitis B .
Continue to monitor all patients at least every 6-12 months to identify a change in clinical status that
indicates progression to disease state that requires treatment:[1] [2]
• Monitor alanine aminotransferase (ALT), HBV DNA, HBsAg, and HDV RNA levels
• If ALT level becomes elevated, measure HBV DNA and HDV RNA.
Screening for hepatocellular carcinoma (HCC)
FOLLOW UP
Request alpha-fetoprotein as a part of screening for HCC in conjunction with ultrasound every 6 months in
patients with advanced fibrosis of cirrhosis, regardless of anti-HDV therapy.[1]
• Alpha-fetoprotein is elevated in 75% of patients with HCC, but can also be normal. The sensitivity
ranges from 41% to 65% and specificity ranges from 80% to 94%.[67] Alpha-fetoprotein level >400
nanograms/mL has a 95% specificity for HCC.[68]
Additionally, all HBsAg-positive patients with cirrhosis at high risk for HCC (e.g., Asian or black men aged
>40 years, Asian women aged >50 years, people with a first-degree family member with a history of HCC)
should be screened with an abdominal ultrasound, with or without alpha-fetoprotein, every 6 months.
In areas where ultrasound is not readily available, screen with alpha-fetoprotein every 6 months.
Prognosis
As with other types of viral hepatitis, (decompensated) cirrhosis, hepatocellular carcinoma (HCC), and liver-
related mortality are potential complications of hepatitis D virus (HDV) infection.[63]
Patients with chronic HDV infection who have a higher risk of progression of liver disease include those with
any of:[1]
• Elevated aminotransferases
• Elevated gamma-glutamyl transpeptidase (GGT) levels
• Advanced stage of liver disease
• Persistent HDV viraemia
• High serum hepatitis B virus (HBV) DNA levels
• Viral co-infection
• A history of other conditions associated with chronic liver disease (e.g., obesity, alcohol abuse,
diabetes).
HDV infects susceptible hosts via simultaneous co-infection with HBV or via superinfection of an individual
already infected with HBV. Very early studies suggest that both superinfection and co-infection with HDV
increase the risk of fulminant hepatitis twofold compared with acute HBV infection alone.[64]
The natural history of HDV infection is likely more severe than that of HBV infection alone and appears to be
related to the degree of HDV replication.[18] [65] [66]
An Italian study followed 299 patients with chronic HDV infections for almost 30 years and noted that 46
patients (15.4%) developed HCC, 43 (14.4%) developed ascites, 63 (21.1%) died, and 29 (9.7%) received
liver transplantation. HDV replication was the only independent predictor of mortality.[18] Similar findings
were noted in a Greek study of almost 5000 patients with chronic HBV infection. Patients with a positive
anti-HDV (4.2%) had more active and advanced disease at baseline, were more likely to have cirrhosis at a
younger age, and were more likely to develop a liver related event (20.0% vs. 8.5%) over a median follow-
up of 4.2 years, compared with patients negative for anti-HDV.[66] After adjusting for clinical and serological
differences, the increased risk of complications in patients with compensated cirrhosis with HDV/HBV co-
infection compared with HBV infection alone were 3.2-fold for HCC, 2.2-fold for any decompensation, and
2.0-fold for mortality.[65]
37
There are some geographical differences in the risk of complications, with studies in Taiwan, where genotype
2 HDV predominates, suggesting that the risk of fulminant liver failure and cirrhosis or HCC is decreased
compared with genotype 1 disease (found mainly in North America, Europe, the Middle East, and north
Africa).[7] [8] Conversely, genotypes 1 and 3 (which predominate in South America) lead to more severe
FOLLOW UP
disease and genotype 5 is associated with better response to therapy.[5] [6]
Hepatitis D Guidelines
Diagnostic guidelines
United Kingdom
Hepatitis B (chronic): diagnosis and management (ht tps://www.nice.org.uk/

guidance/cg165)
Published by: National Institute for Health and Care Excellence Last published: 2017
Europe
EASL clinical practice guidelines on hepatitis delta virus (ht tps://

www.journal-of-hepatology.eu/article/S0168-8278(23)00317-3/fulltext)
Published by: European Association for the Study of the Liver Last published: 2023
GUIDELINES
North America
Viral hepatitis: hepatitis D (ht tps://www.cdc.gov/hepatitis/hdv/index.htm)

Published by: Centers for Disease Control and Prevention Last published: 2020
A guide to utilization of the microbiology laboratory for diagnosis of

infectious disease (ht tps://www.idsociety.org/practice-guideline/laboratory-
diagnosis-of-infectious-diseases)
Published by: Infectious Diseases Society of America; American Society Last published: 2018
for Microbiology
AASLD guidelines for the treatment of chronic hepatitis B (ht tps://

www.aasld.org/practice-guidelines/chronic-hepatitis-b)
Published by: American Association for the Study of Liver Diseases Last published: 2018
Asia
Diagnosis, management and treatment of hepatitis delta virus infection

(ht tps://www.turkjgastroenterol.org/en/diagnosis-management-and-
treatment-of-hepatitis-delta-virus-infection-turkey-2017-clinical-practice-
guidelines-135198)
Published by: Turkish Association for the Study of the Liver Last published: 2017
39
Hepatitis D Guidelines
Treatment guidelines
United Kingdom
Hepatitis B (chronic): diagnosis and management (ht tps://www.nice.org.uk/

guidance/cg165)
Published by: National Institute for Health and Care Excellence Last published: 2017
Europe
EASL clinical practice guidelines on hepatitis delta virus (ht tps://

www.journal-of-hepatology.eu/article/S0168-8278(23)00317-3/fulltext)
Published by: European Association for the Study of the Liver Last published: 2023
GUIDELINES
North America
Adult immunization schedule by age (ht tps://www.cdc.gov/vaccines/

schedules/hcp/imz/adult.html)
Viral hepatitis: hepatitis D (ht tps://www.cdc.gov/hepatitis/hdv/index.htm)

AASLD guidelines for the treatment of chronic hepatitis B (ht tps://

www.aasld.org/practice-guidelines/chronic-hepatitis-b)
Published by: American Association for the Study of Liver Diseases Last published: 2018
Asia
Diagnosis, management and treatment of hepatitis delta virus infection

(ht tps://www.turkjgastroenterol.org/en/diagnosis-management-and-
treatment-of-hepatitis-delta-virus-infection-turkey-2017-clinical-practice-
guidelines-135198)
Published by: Turkish Association for the Study of the Liver Last published: 2017
Hepatitis D Online resources
Online resources
1. CDC: hepatitis B vaccination of adults (https://www.cdc.gov/hepatitis/hbv/vaccadults.htm) (external
link)
ONLINE RESOURCES
41
Hepatitis D References
Key articles
• European Association for the Study of the Liver. EASL clinical practice guidelines on hepatitis delta
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53. Martini S, Tandoi F, Romagnoli R, et al. Liver transplantation in hepatitis B/hepatitis D (delta)
virus coinfected recipients. Transplantation. 2022 Oct 1;106(10):1935-9. Abstract (http://
54. National Institute for Health and Care Excellence. Hepatitis B (chronic): diagnosis and management.
October 2017 [internet publication]. Full text (https://www.nice.org.uk/guidance/cg165)
55. Brancaccio G, Gaeta GB. Treatment of chronic hepatitis due to hepatitis B and hepatitis delta virus
coinfection. Int J Antimicrob Agents. 2019 Dec;54(6):697-701. Abstract (http://www.ncbi.nlm.nih.gov/
56. Sandmann L, Wedemeyer H. Interferon-based treatment of chronic hepatitis D. Liver Int. 2023 Aug;43
Suppl 1:69-79. Full text (https://onlinelibrary.wiley.com/doi/10.1111/liv.15410) Abstract (http://
57. National Institute for Health and Care Excellence. Bulevirtide for treating chronic hepatitis D. June
2023 [internet publication]. Full text (https://www.nice.org.uk/guidance/TA896)
58. Wedemeyer H, Schöneweis K, Bogomolov P, et al. Safety and efficacy of bulevirtide in combination
with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection
(MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect
Dis. 2023 Jan;23(1):117-29. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/36113537?
59. Wedemeyer H, Aleman S, Brunetto MR, et al. A phase 3, randomized trial of bulevirtide in chronic
hepatitis D. N Engl J Med. 2023 Jul 6;389(1):22-32. Abstract (http://www.ncbi.nlm.nih.gov/
60. Koh C, Canini L, Dahari H, et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D
infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet
Infect Dis. 2015 Oct;15(10):1167-74. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/26189433?
61. Yurdaydin C, Keskin O, Kalkan Ç, et al. Optimizing lonafarnib treatment for the management of
chronic delta hepatitis: The LOWR HDV-1 study. Hepatology. 2018 Apr;67(4):1224-36. Abstract (http://
62. ClinicalTrials.gov. Study of the efficacy and safety of lonafarnib/ritonavir with and without pegylated
interferon-alfa-2a (D-LIVR). NCT03719313. April 2023 [internet publication]. Full text (https://
classic.clinicaltrials.gov/ct2/show/NCT03719313)
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63. Kamal H, Westman G, Falconer K, et al. Long-term study of hepatitis delta virus infection at secondary
care centers: the impact of viremia on liver-related outcomes. Hepatology. 2020 Oct;72(4):1177-90.
Full text (https://www.doi.org/10.1002/hep.31214) Abstract (http://www.ncbi.nlm.nih.gov/
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64. Romeo R, Del Ninno E, Rumi M, et al. A 28-year study of the course of hepatitis delta infection: a
risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology. 2009 May;136(5):1629-38.
Full text (https://www.doi.org/10.1053/j.gastro.2009.01.052) Abstract (http://www.ncbi.nlm.nih.gov/
65. Fattovich G, Giustina G, Christensen E, et al. Influence of hepatitis delta virus infection on morbidity
and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis
(Eurohep). Gut. 2000 Mar;46(3):420-6. Full text (https://www.doi.org/10.1136/gut.46.3.420) Abstract
66. Manesis EK, Vourli G, Dalekos G, et al. Prevalence and clinical course of hepatitis delta infection
in Greece: a 13-year prospective study. J Hepatol. 2013 Nov;59(5):949-56. Abstract (http://
67. Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular
carcinoma in patients with hepatitis C. A systematic review and critical analysis. Ann Intern Med. 2003
Jul 1;139(1):46-50. Full text (https://www.doi.org/10.7326/0003-4819-139-1-200307010-00012)
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of hepatocellular carcinoma. Anticancer Res. 2003 Mar-Apr;23(2c):1747-53. Abstract (http://
Hepatitis D Images
Images
IMAGES
Figure 1: A patient with jaundice, demonstrating scleral icterus
CDC. Dr Thomas F. Sellers/Emory University; used with permission
49
IMAGES Hepatitis D Images
Figure 2: Ascites in a female patient with cirrhosis

Science Photo Library; used with permission
Hepatitis D Images
IMAGES
Figure 3: Stage component of the Ishak system
Adapted from Standish RA et al. Gut 2006 Apr;55(4):569-78 and Ishak K et al. J Hepatol 1995
Jun;22(5):696-9; used with permission
51
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53
Contributors:
// Authors:
Jawad Ahmad, MD, FRCP, FAASLD

Professor of Medicine
Division of Liver Diseases, Mount Sinai Hospital, New York, NY
DISCLOSURES: JA declares that he has no competing interests.
Anna Maria Geret ti, MD, PhD, FRCPath

Professor and Consultant in Virology & Infectious Diseases
Fondazione PTV, University of Rome Tor Vergata, Rome, Italy, North Middlesex University Hospital,
London, UK, King’s College London, London, UK
DISCLOSURES: AMG has received personal payments from Abbott, Gilead, GSK, Roche, and ViiV;
research funding (to the institution) from Roche and ViiV.
// Peer Reviewers:
Scot t Cotler, MD
Professor of Medicine
Loyola University Chicago, Chicago, IL
DISCLOSURES: SC declares that he has no competing interests.

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Hepatitis D

Straight to the point of care

Last updated: Oct 11, 2023

A patient with jaundice, demonstrating scleral icterus

Chronic HDV infection

Chronic HDV infection

Ascites in a female patient with cirrhosis

Tests to characterise HBV infection

Perform serological tests to characterise HBV infection.[1] Serological markers include:

• Hepatitis B surface antigen (HBsAg)

Tests to characterise HDV infection

Perform serological tests for HDV.[1] [12]

• Serological markers include:

• Antibody to hepatitis D (anti-HDV) IgM and IgG

• Full blood count

History and exam

scleral icterus (uncommon)

Other diagnostic factors

right upper quadrant tenderness (uncommon)

palmar erythema (uncommon)

spider naevi (uncommon)

infection and cirrhosis.

loss of secondary sexual characteristics (uncommon)

peripheral oedema (uncommon)

increased likelihood of sexual exposure

injection drug use

family history of HBV/HDV infection, hepatocellular carcinoma, and/or

men who have sex with men

household contact with HDV infection

Other tests to consider

• Magnetic resonance elastography has been shown to be more

Condition Differentiating signs / Differentiating tests

Acute viral hepatitis B • There may be no differences • Serum hepatitis B surface

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

Acute alcoholic hepatitis • History of moderate/heavy • AST:ALT ratio >2:1 in up to

Autoimmune hepatitis • May be more likely to have • There may be increased

Condition Differentiating signs / Differentiating tests

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

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

Haemochromatosis • May have a family history • Serum transferrin saturation

Biliary disease • May have fever, pruritus, • Elevated alkaline

Condition Differentiating signs / Differentiating tests

Alpha-1 antitrypsin • May have chronic lung • Reduced plasma alpha-1

Wilson's disease • There may be associated • Increased 24-hour urinary

Stage component of the Ishak system

Acute HDV infection

• No antiviral drugs are approved for acute HDV infection.

• Transplantation in eligible patients is associated with an excellent outcome.[53]

Chronic HDV infection

considered to be better with peginterferon alfa-2a.

Combination therapy may be an option in some patients.

Give a nucleoside/nucleotide analogue to patients with decompensated cirrhosis irrespective of the

Liver transplantation for decompensated cirrhosis

• Transplantation in eligible patients is associated with an excellent outcome.[53]

Patients with hepatocellular carcinoma

Treatment algorithm overview

1st supportive care

adjunct liver transplantation

compensated cirrhosis or 1st peginterferon alfa and/or bulevirtide

1st treatment of hepatitis B co-infection

decompensated cirrhosis 1st treatment of hepatitis B co-infection

adjunct liver transplantation

1st supportive care

» Manage patients with acute hepatitis D virus