Seminar

www.thelancet.com Vol 378 July 2, 2011 73

Hepatitis delta virus
Sarah A Hughes, Heiner Wedemeyer, Phillip M Harrison
Hepatitis delta virus (HDV) is a small, defective RNA virus that can infect only individuals who have hepatitis B virus
(HBV); worldwide more than 15 million people are co-infected. There are eight reported genotypes of HDV with
unexplained variations in their geographical distribution and pathogenicity. The hepatitis D virion is composed of a
coat of HBV envelope proteins surrounding the nucleocapsid, which consists of a single-stranded, circular RNA
genome complexed with delta antigen, the viral protein. HDV is clinically important because although it suppresses
HBV replication, it causes severe liver disease with rapid progression to cirrhosis and hepatic decompensation. The
range of clinical presentation is wide, varying from mild disease to fulminant liver failure. The prevalence of HDV is
declining in some endemic areas but increasing in northern and central Europe because of immigration. Treatment
of HDV is with pegylated interferon alfa; however, response rates are poor. Increased understanding of the molecular
virology of HDV will identify novel therapeutic targets for this most severe form of chronic viral hepatitis.
Introduction
Hepatitis delta virus (HDV) is a small, defective RNA
virus that is related more to plant viroids than to other
human pathogens. It can propagate only in an individual
who has coexistent hepatitis B virus (HBV), either after
simultaneous transmission of the two viruses, or via
superinfection of an established HBV carrier.
1
Clinical
expression of HDV is wide, and although it sometimes
follows a benign course, the disease is clinically
important. Studies have consistently shown that most
patients with HBV and HDV co-infection have more
severe liver disease,
2,3
more rapid progression to
cirrhosis,
4,5
and increased hepatic decompensation and
death
6,7
than do those with HBV infection alone. Advances
have improved our understanding of the transmission,
replication, and pathogenesis of the virus; however, we
do not yet fully understand the mechanisms by which it
causes such severe liver disease. In this Seminar, we will
review the biology, pathogenesis, epidemiology, natural
history, clinical presentation, and management of this
disease. We discuss how the most recent evidence might
help in the design of novel therapeutic agents for HDV,
the most severe of all the chronic viral hepatitides.
Historical perspective
Rizzetto and colleagues
8
discovered HDV in the mid-
1970s while investigating a group of patients with HBV
who had severe hepatitis. They showed a novel antigen-
antibody system, which they called delta-antigen and
delta-antibody, and noted that this system occurred only
in patients with HBV and was associated with severe
liver disease. The disease was later associated with a
particle consisting of an RNA genome of low molecular
weight that was encapsidated by HBV envelope proteins.
9

This particle was termed the delta agent, or HDV, and
was classied under the Deltavirus genus.
Viral structure
The HDV virion is a small, spherical particle of about
36 nm in diameter. It is composed of an outer coat
containing the three HBV envelope proteins termed
large, medium, and small hepatitis B surface antigen
(HBsAg),
10
and host lipids surrounding an inner
nucleocapsid, consisting of a single-stranded, circular
RNA of 1679 nucleotides and about 200 molecules of
hepatitis D antigen (HDAg) per genome.
11,12
Because of
the high GC content of the nucleotide sequence,
12
the
circular genome, which is unique to animal viruses and
more closely related to plant viroids than to human
pathogens,
13
can fold into an unbranched, rod-like
structure with 74% intra molecular base-pairing.
Virus life cycle
The HDV receptor on the human hepatocyte remains
unidentied, but is thought to be the same as that of
HBV because of the shared identity of their outer coat.
HDV infectivity is dependent upon a receptor-binding
domain in the N-terminal region of the pre-S1 moiety of
large HBsAg.
14,15
For HDV infectivity, this domain
requires modication by myristoylation.
16
Fine mapping
has identied aminoacid residues 915 as the receptor
binding site.
17
A second infectivity region in the antigenic
loop of all three envelope proteins is also required for
infectivity,
18,19
but whether the antigenic loop and the
pre-S1 determinants act synergistically or independently
in viral entry is unclear.
The virus is uncoated after entering the hepatocyte,
and a signal in HDAg translocates the nucleocapsid to
the nucleus.
20
The antigen has no RNA polymerase
Lancet 2011; 378: 7385
Published Online
April 20, 2011
DOI:10.1016/S0140-
6736(10)61931-9
Institute of Liver Studies, Kings
College Hospital, London, UK
(S A Hughes MBBCh);
Transplantation Immunology
and Mucosal Biology, Kings
College London, London,
UK (P M Harrison MD);
and Department of
Gastroenterology, Hepatology
and Endocrinology, Hannover
Medical School, Hannover,
Germany (H Wedemeyer MD)
Correspondence to:
Dr Phillip M Harrison,
Transplantation Immunology
and Mucosal Biology, Kings
College London, Denmark Hill
Campus, London SE5 9PJ, UK
phillip.harrison@kcl.ac.uk
Search strategy and selection criteria
We searched PubMed, Embase, and the Cochrane Library, with
no date or language restrictions. We used the search terms
hepatitis delta virus, hepatitis D virus, and Delta hepatitis,
in combination with the following terms: replication,
epidemiology, genotype, transmission, clinical
presentation, pathogenesis, diagnosis, and treatment. We
largely selected publications in the past 5 years. We searched the
reference lists of articles identied by this strategy, and selected
references that were most relevant. Abstracts from international
congressional proceedings in the past 3 years that were thought
to add key information were also included.
Seminar
74 www.thelancet.com Vol 378 July 2, 2011
activity; to replicate its genome, the virus hijacks the
cellular RNA polymerases of the host, which might then
treat the genome as double-stranded DNA because of its
folded, rod-like structure.
21
Three forms of RNA are made
in the host during replication: circular genomic RNA,
circular complementary antigenomic RNA, and a linear
polyadenylated antigenomic RNA of 08 kb, which is the
messenger RNA (mRNA) containing the open reading
frame of the HDAg.
Initial studies implicated RNA polymerase II in HDV
replication; however, one study has shown that RNA
polymerases I and III also interact with HDV RNA,
suggesting a more complex reliance on several host
polymerases.
22
Evidence suggests that synthesis of the
dierent RNA species occurs in dierent subcellular
locations, mediated by distinct cellular polymerases:
synthesis of antigenomic RNA occurs in the nucleolus
mediated by RNA polymerase I, whereas synthesis of
genomic RNA takes place more diusely in the
nucleoplasm by RNA polymerase II.
23
Replication of the
circular HDV RNA template occurs via a rolling
mechanism that is unique to animal viruses but analogous
to that of plant viroids. HDV RNA is rst synthesised as a
linear molecule, potentially containing many copies of
the genome, but in the genomic and antigenomic RNA, a
sequence of 85 nucleotides acts as a ribozyme, which self-
cleaves the linear HDV RNA into monomers.
24,25
These
monomers are then ligated to form circular RNA (the
involvement of a host RNA ligase remains controversial).
Ribozymes are regarded as a feature of plant viroids,
26
but
a self-cleaving RNA sequence in an intron of the CPEB3
gene is structurally and biochemically related to the HDV
ribozymes; therefore, HDV might have arisen from the
human transcriptome.
27
HDAg is the only protein that is known to be encoded
by the HDV genome. It consists of two isoforms: the
27 kDa large-HDAg with 214 aminoacids; and a 24 kDa
small-HDAg with 195 aminoacids.
28
The N-terminal
sequence of the two isoforms is the same; they dier by
only 19 aminoacids at the C-terminus of the large-HDAg.
The open reading frame of the antigenomic RNA
generates both isoforms because of heterogeneity in the
RNA at codon 196.
28
A UAG stop codon at this position
leads to translation of small-HDAg; however, RNA
editing by the cellular enzyme adenosine deaminase-1
changes the sequence to UGG and, consequently, the
longer large-HDAg is produced.
12,28,29
Small-HDAg
returns to the nucleus and supports viral replication,
30,31

whereas large-HDAg is a negative regulator of HDV
replication and is essential for virion assembly.
32

Therefore, RNA editing is central to the replication cycle
of HDV because it controls the levels of each isoform,
and consequently, the balance between viral synthesis
and particle assembly.
Post-translational modication of large-HDAg, espe-
cially prenylation of the cysteine residue at the C-terminus,
is integral to its ability to bind HBsAg and assemble the
viral particle.
33
Phosphorylation of a serine residue at
position 177 of small-HDAg increases replication of
antigenomic RNA by interacting with RNA poly-
merase II,
34,35
whereas the sumoylation of small-HDAg
enhances the synthesis of genomic RNA and mRNA, but
not of antigenomic RNAproperties that are also
ascribed to acetylation.
36
Methylation of small-HDAg by
arginine methyltransferase at arginine-13 (an RNA-
binding domain), is essential for translocation of small-
HDAg to the nucleus, and for replication of the
antigenomic RNA strand to form the genomic RNA
strand.
37
Hence, post-translational modications deter-
mine the balance of the viral life cycle, and present
attractive novel therapeutic targets for drug development.
In the nucleus, molecules of large-HDAg form complexes
with small-HDAg and new constructs of genomic RNA,
and these complexes are exported to the Golgi membranes
by a signal in the C-terminus of large-HDAg. Once there,
these complexes associate with HBV envelope proteins to
create an infectious virion.
14,38
Interaction of the C-terminus
of large-HDAg with the clathrin heavy-chain in the trans-
Golgi network is essential for viral assembly.
39
Figure 1 is
a schematic representation of the delta particle and its
life cycle.
Viral heterogeneity
The sequence of the HDV RNA genome is highly
variable, and there is divergence of up to 16% within the
same genotype, compared with 2040% between dierent
genotypes. Even in one individual the virus is a pool of
closely related quasispecies.
40
This divergence is partly
due to the scarcity of proofreading ability of RNA
polymerases. The average mutation rate for the non-
coding region of HDV is about 35210

base sub-
stitutions per genome site per year, whereas for the HDV
coding region, it is about 14910

for non-synonymous
substitutions, and 06710

for synonymous sub-

stitutions.
41
However, heterogeneity is not uniform for
the entire coding region of the genome; the self-cleaving
ribozyme sequence and the RNA-binding domain of
HDAg are highly conserved, whereas the C-terminal
region of large-HDAg is very divergent. Historically,
HDV genotyping was achieved by either immuno-
histochemical analysis of liver tissue
42
or by restriction
fragment length polymorphism of PCR products,
43
and
the virus was thought to have evolved into three major
genotypes that diered in their global distribution.
44

Genotyping by direct sequencing and analysis of
molecular phylogenetic trees has shown that HDV exists
as at least eight dierent clades, four of which seem to be
of exclusively African origin.
45,46
Epidemiology
Of the 350 million chronic carriers of HBV worldwide,
more than 15 million have serological evidence of
exposure to HDV.
47
Traditionally, the regions with high
rates of HDV carriage where the virus is endemic are
Seminar
www.thelancet.com Vol 378 July 2, 2011 75
central Africa, the Horn of Africa, the Amazon Basin,
eastern and Mediterranean Europe, the Middle East, and
parts of Asia.
48
Rates of HDV infection are generally
highest in regions where HBV is endemic, but there are
exceptionseg, HDV co-infection is uncommon in
Vietnam and Indonesia.
49,50
In Chinaa large reservoir of
HBV infectionHDV prevalence varies widely between
provinces despite a high prevalence of HBV. In one study
from Hong Kong, carriage of HDV was almost universal
in intravenous drug users who were HBsAg positive,
contrasting with low rates in non-drug users.
51
HDV genotype 1 is prevalent worldwide,
52
whereas
genotype 2 (previously termed genotype-2a) is found in
Japan, Taiwan, and the Yakutia region of Russia.
5355

Genotype 3the most divergent genotypeis common
in the Amazon Basin,
56
whereas genotype 4 (previously
2b) is found in Taiwan and Japan.
54,57
HDV genotypes 58
are found in individuals of African origin, including in
those who have migrated to northern Europe.
45,46
Figure 2
shows the worldwide prevalence of HDV and distribution
of its genotypes.
Longitudinal studies have shown a decrease in HDV
prevalence in some endemic areas, such as in Italy, where
infection in HBsAg carriers has fallen from 246% in
1983, to 14% in 1992, and 83% in 1997.
5860
Infection rates
are especially reduced in younger patients, and evidence
suggests that in Italy HDV infection is restricted to
ageing cohorts who were infected in the 1980s. In the
past three decades, reductions in HDV prevalence have
also been reported in Spain, Taiwan, and Turkey.
6163

Vaccination programmes for HBV have probably
contributed substantially to the decline in HDV in these
regions, but additional factors, including increased
awareness of the virus and its mode of transmission,
have led to better implementation of preventive measures,
such as the change to disposable needles, syringes, and
other medical equipment, and a general improvement in
socioeconomic conditions.
There are caveats to the assertion that HDV prevalence
is declining. First, developing countries have not always
had the same measures of HBV control, and have not
shown the same improvements in socioeconomic
conditions as have developed countries. Data for
prevalence in these regions are sparse, but cross-sectional
studies have shown that rates of HDV co-infection in
carriers of HBsAg remain greater than 10%, and
sometimes as high as 70% in Nigeria, Gabon, India,
Pakistan, Iran, the western Brazilian Amazon, Tajikistan,
and Mongolia.
6471
Second, HDV prevalence has not
decreased in northern Europe. Prevalence in northern
Europe and the USA was thought to be low and conned
to high-risk groups, such as intravenous drug-users;
however, in London, UK, HDV prevalence in people with
HBV increased from 26% in the 1980s to 85% in
2005.
72,73
In Germany, although the prevalence of anti-
HDV antibody in those with HBV reduced from 186% in
1992 to 68% in 1997, from 1999 onwards the rates have
increased again to between 8% and 14%.
74
HDV remains
prevalent in France.
75
The common factor in these three
countries is HDV infection in young individuals who
L-HDAg
Delta virion
Ribonucleoprotein
Hepatocyte
membrane
receptor
L-HBsAg
S-HBsAg
M-HBsAg
S-HDAg
1
2 3
9
Nucleus
Genomic RNA
Endoplasmic
reticulum
Golgi complex
Antigenomic RNA
mRNA 6
7
6
8
4 4
5
Figure 1: Schematic representation of the delta virion and its replication cycle
(1) The virion attaches to the hepatocyte via an interaction between large-HBsAg and an uncharacterised membrane receptor in the host cell; (2) the virion enters the
cell and is uncoated; (3) the RNP is targeted to the nucleus; (4) genomic RNA is transcribed in the nucleus to form antigenomic RNA, which forms the template for
replication of new transcripts of the circular genome, and mRNA, which contains the open reading frame; (5) the mRNA is exported to the cytoplasm where it is
translated at the endoplasmic reticulum to form new molecules of hepatitis D antigen; (6) the new antigen molecules return to the nucleus where the small-HDAg
isoform supports further genome replication, and where both forms of hepatitis D antigen associate with new transcripts of genomic RNA to form new RNPs;
(7) RNPs are exported to the cytoplasm where large-HDAg facilitates association with HBV envelope proteins in the ER to form new virus particles; (8) these particles
bud through an intermediate compartment; (9) they are then exported from the hepatocyte via the trans-Golgi network to re-infect further cells.
RNP=ribonucleoprotein. mRNA=messenger RNA. HBV=hepatitis B virus. HBsAg=hepatitis B surface antigen. HDAg=hepatitis D antigen. ER=endoplasmic reticulum.
Seminar
76 www.thelancet.com Vol 378 July 2, 2011
have migrated from regions of high prevalence. Even in
Italy the decline in HDV has now reached a plateau,
76
and
a report has shown a high prevalence of HDV of 17% in
non-EU citizens (mainly those from eastern Europe) who
are infected with HBV.
77
Third, clustered outbreaks of
HDV superinfection continue to be reported, notably in
Venezuela, Ecuador, Mongolia, and Greenland,
7881
which
are similar to those recorded in Samara (Russia), Okinawa
(Japan), Central Africa, and the Amazon Basin in the
1980s and 1990s.
8285
Thus, while outbreaks still occur and
population migration from endemic countries increases,
the threat of HDV infection remains.
Modes of transmission
Like HBV, HDV is transmitted via the parenteral route
through exposure to infected blood or body uids, and
tests in chimpanzees have shown that only a very small
inoculum is su cient to transmit infection.
86
Thus,
transmission rates remain high in intravenous drug
users. There is evidence for sexual transmission,
87
and
people with high-risk sexual activity are at increased risk
for infection.
88
Intrafamilial spread occurs and seems to
be common in regions of high prevalence, which is
known as inapparent parenteral transmission. Perinatal
transmission of HDV is uncommon. Because of screening
of blood products, new infections in haemophiliacs, blood
transfusion recipients, and patients receiving haemo-
dialysis are no longer seen in developed countries.
Clinical expression and natural history
With HBV and HDV co-infection, the fate of HDV is
determined by the host response to HBV, which in more
than 95% of adults results in viral clearance. Acute
co-infection can be more severe than acute mono-
infection with HBV, thereby resulting in acute liver
failure; however, disease expression is wide-ranging. By
contrast, HDV superinfection of an individual with
chronic HBV results in chronic HDV infection in most
people. In the remainder, replication of HDV stops, and
the natural history of the disease is that of the underlying
HBV; however, the residual liver disease might be
advanced. Important evidence from an Italian cohort
showed that 10% of patients with anti-HDV antibodies
cleared HBsAg after a mean follow-up of 4 years,
compared with 28% of those with HBV mono-infection.
89

The mechanism for increased rate of HBsAg loss after
clearance of HDV RNA is unknown, but an enhanced
immune response against HBV and HDV seems
plausible. Figure 3 shows the typical evolution of
serological and virological markers in co-infected patients
versus super infected patients.
Superinfection can present as acute hepatitis in a
previously undiagnosed carrier of HBsAg, and is often
misdiagnosed as acute HBV or as worsening liver
disease due to chronic HBV.
90
At initial histological
assessment, patients with HDV superinfection are
often shown to have severe hepatitis with advanced
brosis.
9193
These patients undergo more rapid
progression to cirrhosis
4,5
and increased hepatic
decompensation leading to death
6,7
than do those with
HBV infection alone. Despite the high rate of
progression to cirrhosis, not all studies show an
increased rate of hepatocellular carcinoma, perhaps
because of suppression of HBV replication by HDV.
73

High
Intermediate
Low
Very low
Insucient data
Genotype 58
Genotype 1
Genotype 1
Genotype 1/3
Genotype 1/2/4
Genotype 1
Figure 2: Worldwide prevalence of HDV and the geographic distribution of its genotypes
Two subtypes1A and 1Bhave been identied in HDV genotype 1. 1A is predominant in Asia and 1B in the USA. Both are common in the Mediterranean. HDV genotype 2 occurs in the Far East.
HDV genotype 3 occurs exclusively in the northern part of South America and is linked to HBV genotype F. Genotypes 58 have been identied primarily in patients from Africa. HDV=hepatitis D virus.
Seminar
www.thelancet.com Vol 378 July 2, 2011 77
In liver transplantation for HDV, hepatitis B
hyperimmune globulin (HBIg) leads to rapid reduction
in HBsAg concentrations, and serum HDV RNA
declines in parallel.
94
Graft re-infection is prevented by
long-term administration of HBIg, which prevents
HBV re-infection; hence, propagation of HDV cannot
be supported.
95,96
Originally, HDV was thought to persist
as an isolated or latent infection after transplantation;
however, more advanced and sensitive serological
assays have shown that this latency does not occur.
97

Hence, the outcome of liver transplantation for HDV is
very good, with 5-year survival of more than 80%, and
better than the outcome noted with transplantation for
other causes of liver disease.
95,98
Although early studies identied that HDV genotype
aects the natural history of HDV, the more recently
identied genotypes 58, from Africa, are less well
characterised. A study from Taiwan
99
showed a lower rate
of remission and more adverse outcomes in patients with
genotype 1 than in those with genotype 2. Patients with
genotype 4 often have mild liver disease,
100
but a variant
of genotype 4 on the Miyako Island in Okinawa, Japan, is
associated with greater progression to cirrhosis than
genotype 4 is in Taiwan.
101
Genotype 3 has been linked to
outbreaks of severe, orid hepatitis (Labrea fever),
culminating in acute liver failure and death in the
Amazon Basin of South America.
44
Outbreaks of severe
hepatitis due to genotype 1 have also taken place, but
genotype 1 is associated with a wide range of disease,
102

thereby making the relation between genotype and
natural history di cult to interpret.
Although HBV genotype might also determine the
natural history of HDV, any eect is di cult to study
because in many co-infected individuals the serum level
of HBV DNA is too low for genotype analysis. Nonetheless,
Su and colleagues
99
showed a signicantly lower remission
rate and more adverse outcomes in patients with HDV
superinfection with HBV genotype C than with HBV
genotype B, in a population from Taiwan who were mostly
infected with HDV genotypes 1 and 2. A study from Brazil
A
B
Time after exposure (weeks)
C
Anti-HBc IgG
Anti-HBc IgM
Anti-HD IgG
Anti-HD IgM
HBsAg
HDV RNA
ALT
Figure 3: Typical evolution of serological and virological markers in HDV infection
(A) Simultaneous co-infection with HBV and HDV, resulting in clearance of both viruses in almost all patients. (B) HDV superinfection of an HBV carrier with
self-limited outcome. The spontaneous clearance of HDV RNA might take years to occur (indicated by break on x axis) and, in few cases, can herald the loss of HBsAg
(not depicted). (C) HDV superinfection of a HBV carrier with chronic persistent viral replication; the more common outcome after superinfection. HDV=hepatitis
delta virus. ALT=alanine aminotransferase. HBV=hepatitis B virus. HBsAg=hepatitis B surface antigen.
Seminar
78 www.thelancet.com Vol 378 July 2, 2011
has suggested that HBV genotype determines the severity
of liver inammation and the HDV viral load in
individuals with co-infection; however, the consequence
of this in relation to outcome is not clear.
103
Patterns of viral dominance
Co-infection and superinfection with HDV suppresses
HBV replication in patients and in model systems.
About 7090% of patients with HDV co-infection are
HBeAg negative, and most have low serum HBV
DNA.
73,104106
Evidence has indicated that the small (p24)
and large (p27) HDV proteins downregulate HBV repli-
cation by repressing activity of the two HBV enhancer
regions, and by transactivating the interferon-inducible
MxA gene, which inhibits HBV replication by reducing
the export of viral mRNA from the nucleus.
107,108
If HDV
infection is cleared either spontaneously or after
treatment with interferon alfa, then HBV replication
can reactivate.
109
Many patients with HBV and HDV have serological
evidence of exposure to hepatitis C virus (HCV)about
30% in European cohorts.
73,105
In those with triple
infection, HDV is the dominant virus because it not only
suppresses HBV replication, but also inhibits HCV
replication.
110
Indeed, HCV RNA was detected in less
than 19% of patients who were anti-HCV antibody
positive, HBsAg positive, and anti-HDV antibody posi-
tive.
73,105,110
Most patients who are HCV RNA negative have
probably cleared HCV infection, but further long-term
follow-up studies are needed, especially because patterns
of viral dominance evolve over time in HBV and HCV
co-infection.
111
A dynamic pattern of viral dominance also
exists in HBV and HDV co-infection.
112
Pathogenesis
The mechanisms that determine whether an individual
clears HDV spontaneously or becomes chronically
infected, and the processes that cause severe hepatitis
and rapid progression of brosis, remain unclear.
HDAg is not directly cytotoxic in human hepatocytes or
in transgenic mice.
113,114
Viral load of HDV was not
associated with severity of liver injury in a cohort of
patients in a clinical trial.
106
However, evidence from
observational cohort studies suggests that in the acute
phase of HDV infection, HDV viraemia is associated
with an increased level of alanine aminotransferase and
suppressed HBV. In the chronic phase, falling HDV
RNA, reactivation of HBV, and moderate trans aminitis
culminate in a late phase that is characterised by either
the development of cirrhosis and hepatocellular
carcinoma due to replication of HDV or HBV, or
remission with clearance of both viruses.
115
Hence, viral
load of HDV and HBV uctuates according to the stage
of viral infection. Whether this uctuation represents a
direct relation with the pathogenesis of disease
progression remains unclear, and other factors should
be considered.
Host immune response
The host immune response is thought to have an
important role in viral clearance and liver injury. An early
study
116
showed that the function of natural killer cells
was active in individuals who suppressed HDV RNA
during treatment with interferon, but further studies
investigating the innate immune response in the
pathogenesis of HDV are needed. The adaptive immune
response in HDV infection is also poorly dened. In one
study,
117
weak HDAg-specic responses of CD4 T cells
were elicited in patients with inactive HDV infection
(anti-HDV antibody positive but RNA negative), but
absent in those with chronic HDV infection. Further
studies
118
have shown that chronic HDV infection is
associated with a response that is dominated by T-helper-2
(Th-2) cells, with a high frequency of T cells secreting
interleukin-10. Furthermore, after antiviral therapy,
production of interleukin-10 that was HDV-peptide
specic remained higher in patients who did not respond
to treatment than in those who did. Secretion of
interferon-inducible protein-10 was, however, more
frequent in responders.
119
These ndings suggest that
HDV subverts the adaptive immune response away from
the Th-1-biased CD4 and CD8 T-cell response that is
needed for viral clearance. Indeed, Huang and
colleagues
120
showed that the responses of HDV-specic
CD8 cytotoxic T lymphocytes were detected in those with
past, but not active, infection.
CD4 T cells are essential to the antiviral immune
response because they help CD8 T cells and B cells by
stimulating antigen presenting cells and cytokine
secretion. However, cytotoxic CD4 T cells that are
perforin-positive might also have a role in directly
killing virus-infected cells. A higher frequency of these
cells were recorded in patients who were co-infected
with HBV and HDV than with HBV or HCV
mono-infection, and the frequency of perforin-positive
cells was positively correlated with disease activity.
These ndings suggest that such perforin-positive cells
are implicated in the pathogenesis of HDV liver
disease.
121
These studies suggest an important role for
the adaptive immune response, but the precise
mechanisms are unknown.
Role of HDV genotype in pathogenesis
E ciency of RNA editing is lower with genotype 2 than
with genotype 1, but this dierence is unlikely to account
for the reduced disease activity.
122
The sequence of the
C-terminal moiety in large-HDAg varies widely between
genotypes, with up to 74% divergence between the HDV
packaging signal domains of genotype 1 and other HDV
genotypes. The C-terminal sequence of the large antigen
in genotype 1 results in better packaging ability than in
genotype 2, which interacts weakly with clathrin, leading
to less e cient assembly of particles.
123125
However, all
HDV genotypes are able to bind clathrin to some degree,
which lends support to the role of clathrin binding in the
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assembly of HDV particles.
126
Which, if any, of these
mechanisms underpin the eect of genotype on the
natural history of HDV is unclear.
Diagnosis
The development of anti-HDV antibodies is universal in
individuals with HDV; therefore, every patient who is
HBsAg positive should be tested for anti-HDV IgG
antibodies, which persist even after the patient has
cleared HDV infection. Although active HDV infection
was diagnosed historically by the presence of anti-
HDV IgM antibodies, it is now conrmed by the detection
of serum HDV RNA with sensitive real-time PCR
assay.
127
Covert HDV infection has not been reported;
therefore, testing of HDV RNA in the absence of
anti-HDV antibodies is not indicated. Because of the
variability of the genome sequence, assays of HDV RNA
might produce false-negative results, and testing of anti-
HDV IgM antibodies still has a role in patients who
test negative for HDV RNA, but have clinical features
of HDV-related liver disease. International standard-
isation of the HDV RNA assay is needed. Some
laboratories undertake quantitative assays, but serum
concentrations of HDV RNA do not correlate with
disease activity or stage of liver brosis.
106
Serial
quantication of HDV RNA is used to determine the
response to antiviral treatment.
128,129
HDV genotyping is usually only available in specialist
centres, but is gaining acceptance as a useful diagnostic
test because patients with HDV genotype 1 are at a
higher risk of developing end-stage liver disease
99
and
have a lower response to treatment with pegylated
interferon than do patients with African genotypes
(unpublished data). All patients with HDV also need
investigation for HCV and HIV because co-infection
with these viruses is common.
73,105,130
The panel shows the
relevance of serological and virological markers in HDV.
Patients who test positive for serum HDV RNA should
be further investigated with liver biopsy to assess the
severity of liver disease. Studies have shown no
association between levels of HDV RNA, HBsAg titre,
values of liver tests, and the histological staging of liver
disease, thus reinforcing the pivotal part that liver biopsy
plays in the assessment of HDV-related liver disease.
Tests for non-invasively assessing the progression of
liver brosis, such as transient elastography, can be
useful for detecting advanced hepatic brosis, but have
not been validated in chronic HDV and therefore cannot
yet be recommended. The aspartate aminotransferase to
HBsAg
Anti-HDV IgG Ab
Treat as per local HBV
guidelines
HCV/HIV Ab
Add ribavirin
+ve
-ve
>1 -ve
+ve
+ve
HCV RNA+ve HBV DNA>2000 IU/mL
Reactivation of HBV after
successful control of HDV
HDV RNA
Liver biopsy
Consider PEG- IFN- for at
least 48 weeks
Consider addition of potent
nucleos(t)ide analogue
Add potent nucleos(t)ide
analogue
Figure 4: Suggested algorithm for the investigation and management of a patient with HDV
HBsAg=hepatitis B surface antigen. HBV=hepatitis B virus. HCV=hepatitis C virus. HDV=hepatitis delta virus.
PEG-IFN-=pegylated interferon alfa. Ab=antibody.
Panel: Diagnostic markers in HDV infection and their
importance
Anti-HDV IgG antibody
Positive in all individuals exposed to HDV, and persists
long-term, even after viral clearance.
Anti-HDV IgM antibody
Positive in acute infection, negative in past infection but
persists in a large proportion of patients with chronic
infection. Sometimes used as surrogate marker for HDV
replication but not 100% sensitive or specic.
HDV RNA qualitative
Marker of HDV replication. Positive in all patients with
chronic infection. Negative in spontaneous or
treatment-induced viral clearance.
HDV RNA quantitative
Useful method to predict or monitor treatment response.
HBsAg qualitative
Must be positive for HDV infectivity.
HBsAg quantitative
Positively correlated with HDV RNA. Might be useful to
predict or monitor treatment response, since falling titre
heralds HBsAg loss, and hence HDV clearance.
HBeAg
Negative in about 85% of patients; associated with
detectable anti-HBe.
HBV DNA quantitative
Usually negative or low level because suppressed by HDV.
Might be increased, especially in patients with detectable
HBeAg. Can reactivate after spontaneous or
treatment-induced clearance of HDV.
ALT
Usually increased but does not correlate well with degree of
histological liver damage.
HDV=hepatitis delta virus. HBsAg=hepatitis B surface antigen. HBeAg=hepatitis B early
antigen. HBV=hepatitis B virus. ALT=alanine aminotransferase
Seminar
80 www.thelancet.com Vol 378 July 2, 2011
platelet ratio index was shown to have no use in
predicting the stage of brosis in patients with HDV.
106

The assessment of patients with HDV infection is
summarised in gure 4.
Treatment
The ideal endpoint of any treatment for HDV is not only
clearance of HDV, but also of the helper virus HBV.
Hence, a major challenge of dening the optimum
therapy is the added complexity of targeting two persistent
viral infections. A meta-analysis of ve studies of
treatment with recombinant interferon concluded that
such treatment was benecial for HDV in terms of serum
aminotransferase reduction, but the response was poorly
sustained after discontinuation of treatment, and was not
necessarily associated with clearance of HDV RNA.
There were better results with higher doses of
interferonat least 5 MU daily or 9 MU thrice weekly for
12 months, rather than for 6 months.
131,132
High-dose
interferon induced delayed clearance of RNA, and
sometimes, loss of HBsAg with resultant improvement
in histological inammatory activity and stage of
brosis.
132
In a single-case study,
133
extended treatment for
12 years led to clearance of HDV RNA and loss of HBsAg
associated with complete regression of brosis.
Consequently, some have advocated prolonging treatment
duration,
47
but studies have shown no additional benet
in giving treatment for 24 months rather than for
12 months.
134,135
The potential benets of this approach
should be balanced with the side-eects, cost, and
logistical implications. Interferon-induced clearance of
HDV RNA has been associated with a fall in HBsAg
concentrations, and sometimes a loss of HBsAg, with
absence of HBsAg decline in patients who do not respond
to treatment.
128
However, the decrease in HBsAg often
lags behind that of HDV RNA, and hence the mechanism
behind this nding is unclear. More data will emerge as
quantication of HBsAg becomes more routinely used.
Investigators have examined the use of pegylated
interferon for chronic HDV. Series from Italy,
136
France,
109

Summary of therapy Regimen Number of
patients
Median age
(years)
Cirrhosis
(%)
Median baseline
HDV RNA
HDV
genotype
SVR
(%)
SBR (%)
Castelnau et al (2006)
109
Open label pilot PEG monotherapy PEG-IFN2b; 15g/kg per week;
12 months
14 42 29 5* 1=86%
5=14%
43 57
Niro et al (2006)
136
Multicentre randomised trial PEG vs PEG+rbv PEG-IFN2b; 15 g/kg per week;
72 weeks
+Rbv 800 mg per day for rst
48 weeks
16
22
45
43
75
73
..
..
..
..
25
18
25
27
Erhardt et al (2006)
137
Open label pilot PEG monotherapy PEG-IFN2b; 15 g/kg per week;
48 weeks
12 34 27 7* 1 or 2 17 17
Wedemeyer et al (2011)
138
Multicentre randomised trial PEG+placebo vs
PEG+adv vs adv
PEG-IFN2a; 180 g per week;
48 weeks
+Adv 10 mg; once daily
Adv 10 mg; once daily 48 weeks
29
31
30
38
42
33
20
14
24
6*
6*
6*
1
1
1
31
26
0
45
35
10
Yurdaydin et al (2008)
139
Multicentre randomised trial LAM vs LAM+IFN vs IFN LAM 100 mg; once daily;
12 months
+IFN2a; 9 MU three times per
week for last 10 months
IFN2a; 9 MU three times per
week; 12 months
17
14
8
38
35
46
..
..
..
6*
6*
6*
..
..
..
12
36
50
24
21
50
Gunsar et al (2005)
140
Single centre randomised trial IFN vs IFN+rbv IFN2a; 9 MU three times per
week 96 weeks
+Rbv 10001200 mg/day
10
21
39
38
30
24
..
..
..
..
20
20
235
235
Farci et al (2004)
132
Single centre randomised trial High-dose IFN vs
low-dose IFN vs no Rx
IFN2a; 9 MU three times per
week 48 weeks
IFN2a; 3 MU three times per
week 48 weeks
Untreated controls
14
14
13
35
35
38
71
64
61
6
6
6
1
1
1
0
0
0
50
7
8
SVR=sustained virological response (RNA negative 6 months after end of therapy). SBR=sustained biochemical response (normal aminotransferases 6 months after end of therapy). PEG=pegylated interferon.
IFN=interferon. Rbv=ribavirin. Adv=adefovir. LAM=lamivudine. Rx=prescription drug. *Log
10
copies per mL. Log
10
genome equivalents per mL.
Table: Summary of key trials of alpha-interferon for chronic hepatitis delta virus
Seminar
www.thelancet.com Vol 378 July 2, 2011 81
and Germany,
137
have shown sustained virological
responses in 21% of 38 patients, 43% of 14 patients, and
17% of 12 patients, respectively. In the HIDIT-1 trial,
138

which randomised 90 patients from Germany, Turkey,
and Greece, pegylated interferon led to a 28% sustained
virological response; the addition of adefovir did not
improve virological response but did lead to increased
suppression of HBsAg concentrations, whereas adefovir
monotherapy was ineective.
138
Why response rates vary
between series is not clear, but might relate to baseline
clinical, demographical, and virological characteristics
that are heterogeneous. The table shows data for the
main interferon trials.
The simplicity of the delta virus, particularly the lack of
viral polymerase, limits the targets for therapeutic
compounds. Investigators have studied nucleos(t)ide
analogues, which block the HBV polymerase, but
lamivudine alone was not eective at reducing
concentrations of HDV RNA and did not increase
sustained virological response when combined with
interferon.
139,141144
Famciclovir was also ineective.
145
Riba-
virin alone,
146
or combined with interferon
140,147
or pegylated
interferon
136
did not increase the virological response.
Entecavir did not reduce HDV viraemia, but did reduce
alanine aminotransferase and HBV DNA in a small
subset of patients who had low HDV RNA and high HBV
DNA.
148
One report has shown HDV clearance associated
with seroconversion of HBsAg in a man treated with
pegylated interferon plus tenofovir and emtricitabine,
who had high levels of both HBV DNA and HDV RNA.
149

In a long-term observational study
150
of 16 patients who
were co-infected with HIV, HBV, and HDV and on highly
active antiretroviral therapy with anti-HBV activity,
including tenofovir, a signicant reduction in HDV RNA
was noted for a median of 61 years, and three patients
became RNA negative. The mechanism for this reduction
is unclear, because it was not associated with a
corresponding decrease in concentrations of HBsAg.
Hence, treatment with nucleos(t)ide analogues is not
eective at reducing HDV replication, but might be useful
in patients with high concentrations of HBV replication,
and might be of potential benet when used long term by
gradually reducing HBsAg concentrations. The use of
older analogues of nucleos(t)ides to induce HBV
mutations is controversial. Lamivudine-induced muta-
tions in the polymerase gene at rtM204V or rtM204I are
associated with changes in the overlapping envelope gene
products, such as in sW196L/S, which inhibits secretion
of HDV particles.
151
There is insu cient evidence to show
whether the failure to package and secrete HDV is
benecial, or indeed whether the retention of HDV RNA
within cells is harmful.
Baseline and treatment factors predicting the outcome
of interferon treatment are poorly dened. HDV RNA is
correlated positively with HBsAg titre,
106,128
and baseline
values of both predict response to therapy (unpublished
data). HDV genotype 1 is associated with a reduced
response to pegylated interferon (unpublished data),
but whether this response relates to a property of the
HDV sequence itself, or merely to the nding that
patients with genotype 1 have increased viral loads, is
unknown. By contrast with treatment response in
patients with chronic HCV, in which rates of sustained
virological response to pegylated interferon are
substantially reduced by the presence of underlying
cirrhosis, cirrhosis associated with HDV infection did
not obviously aect the response to pegylated inter-
feron.
136,137,152
Baseline liver biochemical tests are also not
associated with treatment outcome.
109
Although the kinetics of HDV RNA in therapy have
been used to predict long-term virological outcome, data
are scarce.
128,129
Castelnau and colleagues
109
showed that
75% of patients achieving an end-of-treatment response
were HDV RNA negative by month 6 of treatment,
compared with no patients who did not respond to
treatment; however, undetectable mid-treatment RNA
did not protect against relapse. The investigators also
noted that HDV RNA values were lower at the end of
therapy than at baseline in some patients who did not
respond, which could justify extension of therapy in this
group. Yurdaydin and colleagues
139
dened three
virological patterns of response to interferon: complete,
in which RNA negativity at 6 months predicted sustained
virological response; partial, in which incomplete
suppression of RNA at 6 months predicted rebound are
in viral replication after discontinuation of therapy; and
non-response, in which viraemia persisted without
decline throughout treatment and follow-up. Liver
transplantation is the only treatment option for patients
who have end-stage liver disease due to co-infection with
HBV and HDV, and is appropriate for those with acute
liver failure that fulls criteria for poor prognosis.
153
Re-
infection of the graft is reduced by long-term
administration of immunoglobulins against the HBsAg
(HBIg) after transplantation,
95,96
creating an HBsAg-
negative environment in which HDV cannot survive.
97

The use of potent antivirals against HBV has further
reduced the risk of HBV re-infection.
The accepted practice for treatment of chronic HDV is
subcutaneous injections of pegylated interferon every
week for at least 48 weeks. This practice should be
considered in patients with active replication of HDV
RNA, and histological evidence of disease activity, and
with no contraindications to interferon therapy. We would
advocate an individualised approach to therapy in patients
who have not achieved clearance of HDV RNA by sensitive
PCR-based assay at 48 weeks. Those who have persistent,
high-level viraemia, with detectable anti-HDV IgM
antibody, and ongoing transaminitis, are unlikely to
respond to further therapy. By contrast, patients with a
falling viral load, declining IgM antibody titre, and
resolving transaminitis, or with progressive decline in
HBsAg titre, might benet from extending therapy to
72 weeks, and perhaps beyond, if improvement is
Seminar
82 www.thelancet.com Vol 378 July 2, 2011
sustained and if tolerability is favourable. In patients with
a high concentration of HBV DNA, addition of a potent
nucleos(t)ide analogue to inhibit HBV replication is
logical; however, the long-term eectiveness has yet to be
dened. Potent nucleos(t)ide analogues are the treatment
choice for patients in whom HBV replication is reactivated
after successful control of HDV replication. Such
analogues might also be used in patients with detectable
serum HBV DNA who cannot be treated with pegylated
interferon such as those with advanced liver disease.
Novel therapiesthe future
Increased understanding of the molecular virology of
HDV, and the poor overall response to conventional
antiviral therapy, has driven the search for alternative
antiviral targets. Prenylation of large-HDAg is essential
for viral assembly and secretion,
33
and in mouse models
prenylation inhibitors inhibited the assembly and
release of HDV, leading to rapid clearance of HDV
RNA from serum.
154
These compounds are in pre-
clinical development. Other forms of post-translational
modi cation of HDAg, such as acetylation, phos-
phorylation, and methylation, might also prove fruitful
as targets for novel therapeutic compounds, although
none are yet in development. Studies showing that
myristoylated synthetic peptides specic for the
N-terminal region of the pre-S1 domain of HBsAg are
able to inhibit viral attachment and hence HDV
infectivity, draw attention to an alternative therapeutic
target.
14,17,155,156
As we learn more about cell-signalling
pathways associated with the pathogenesis of HDV,
further targets might be exposed.
Therapy for HDV deserves the resurgence of interest
it has received. Treatment eectiveness remains unsatis-
factory, and developments have lagged behind those
achieved for the treatment of hepatitis B. The renement
of conventional antiviral regimens will continue with
larger collaborative trials, and drug development will
hopefully follow the advances in HDV biology. These
developments remain necessary while worldwide
measures to control the helper virus are inconsistent and
the prevalence of HDV does not decline in many areas,
resulting in a continuing and substantial health burden.
Contributors
All authors contributed to the conception and writing of the Seminar.
Sections were divided between SAH and PMH, and each author
undertook the relevant searches and wrote the assigned sections.
SAH assembled the sections and all authors revised the nal version.
Conicts of interest
PMH has received payment for board membership from Roche;
consultancy fees from Gilead, Bristol-Myers Squibb, and Phytopharm;
and payment for participation in a speakers bureau from Gilead and
Bristol-Myers Squibb. HW has received payment for board membership
from Roche, Gilead, Bristol-Myers Squibb, and Schering Plough;
consultancy fees from Roche and Novartis; grant support from Roche
and Gilead; payment for participation in a speakers bureau from Roche,
Gilead, Bristol-Myers Squibb, Schering Plough, and Novartis; and
payment for developing educational presentations from Roche. SAH
declares that she has no conicts of interest
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