REVIEWS

epidemiology, pathogenesis and management

of hepatitis D: update and challenges ahead
Heiner Wedemeyer and Michael P. Manns
abstract | Hepatitis D is caused by infection with the hepatitis D virus (HDV) and is considered to be the
most severe form of viral hepatitis in humans. Hepatitis D occurs only in individuals positive for the HBV
surface antigen (HBsAg) as HDV is a defective RNA viroid that requires HBsAg for transmission. At least
eight different HDV genotypes have been described and each has a characteristic geographic distribution
and a distinct clinical course. HDV and HBV coinfection can be associated with complex and dynamic viral
dominance patterns. Chronic HDV infection leads to more severe liver disease than HBV monoinfection and is
associated with accelerated fibrosis progression, earlier hepatic decompensation and an increased risk for the
development of hepatocellular carcinoma. So far, only IFN‑α treatment has proven antiviral activity against HDV
in humans and has been linked to improved long‑term outcomes. Studies conducted in the past 2 years on
the use of PEG‑IFN‑α show that a sustained virologic response to therapy, measured in terms of undetectable
serum HDV RNA levels, can be achieved in about one quarter of patients with hepatitis D. Novel alternative
treatment options including prenylation inhibitors are awaiting clinical development for use in hepatitis D.
Wedemeyer, H. & Manns, M. P. Nat. Rev. Gastroenterol. Hepatol. 7, 31–40 (2010); doi:10.1038/nrgastro.2009.205

Introduction
in 1977, mario rizzetto and colleagues described a
novel antigen in the nucleus of hepatocytes derived
from patients infected with HBv.1 antibodies against
the so-called ‘delta antigen’ were detected in patients
with a particularly severe course of HBv infection.2
subsequently, the hepatitis D virus (HDv) was identified
as the infectious agent causing hepatitis in the presence
of HBv infection.3 thus, hepatitis D can occur only in
individuals who are also infected with HBv as HDv uses
the hepatitis B surface antigen (HBsag) as its envelope
protein, which is essential for viral transmission. HDv
infection can therefore occur as either a superinfection
of chronic HBv infection or as simultaneous acute HBv
and HDv coinfection. in this review, we summarize the
knowledge available on the re-emerging epidemiology
of HDv infection, to briefly introduce concepts of HDv
virology and pathogenesis, and describe strategies to
treat this most severe form of viral hepatitis.
Virology
the HDv virion is a large particle, approximately 36 nm,
and contains HDv rna and hepatitis delta antigen
(HDag).4 HDv rna is single-stranded, highly base-
paired, circular, and by far the smallest genome of any
animal virus as it contains approximately 1,700 nucleo-
tides. HDv rna has six open reading frames, three on
the genomic strand and three on the antigenomic strand.
Competing interests
The authors declare associations with the following companies:
BMS, Gilead, Novartis and Roche. See the article online for full
details of the relationships.
one open reading frame encodes the HDag; the others
do not seem to be actively transcribed. two HDags exist:
the small HDag (24 kDa), which is 155 amino acids
long, and the large HDag (27 kDa), which is 214 amino
acids long. a single nucleotide change (a–G) in the
small HDag sequence leads to the synthesis of the large
HDag. the small HDag accelerates HDv rna synthesis
whereas the large HDag inhibits HDv rna synthesis but
is necessary for virion morphogenesis.4 replication of
HDv rna occurs through a ‘double rolling circle model’
in which the genomic strand is replicated by a host rna
polymerase to yield a multimeric linear structure that
is autocatalytically cleaved into linear monomers and
ligated into circular HDv rna viral progeny.
at least eight HDv genotypes have been identified.5,6
HDv genotype 1 is the most common genotype and is
distributed throughout the world, especially in europe,
the middle east, north america and north africa. By
contrast, genotype 2 is seen in the Far east, and geno-
type 3 is observed exclusively in the northern part of
south america. Genotypes 4–8 have primarily been
identified in african patients, for example, in preg- Department of
nant women in Gabun.7 HDv genotype 4–8 infection Gastroenterology,
Hepatology and
in africa is associated with HBv genotype a–e infec- Endocrinology,
tion.7 HDv genotype 1 is associated with both severe Hannover Medical
School, Carl Neuberg
and mild disease, whereas genotype 2 is associated with a Strasse 1, D‑30625
mild disease course.8 Hannover, Germany
(h. Wedemeyer,
M. p. Manns).
Epidemiology
HDv is spread in the same way as HBv, mainly through Correspondence to:
M. P. Manns
parenteral exposure. 9 the virus is highly endemic in manns.michael@
mediterranean countries, the middle east, Central mh‑hannover.de

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© 2010 Macmillan Publishers Limited. All rights reserved
revieWs
Key points
■ Hepatitis D occurs only in individuals positive for the HBV surface antigen
(HBsAg) as hepatitis D virus (HDV) is a defective RNA viroid that requires HBsAg
for transmission
■ Chronic HDV infection is associated with a severe course of hepatitis that
frequently leads to rapid fibrosis progression, hepatic decompensation and the
development of hepatocellular carcinoma
■ HDV infection is particularly frequent among immigrant populations from
regions where HDV is endemic, such as Central Africa, Eastern Turkey, Central
Asia, some Eastern European countries and the Amazonian region of Brazil
■ Only IFN‑α has proven antiviral activity against HDV and treatment with
PEG‑IFN‑α leads to HDV clearance in about 25% of patients
africa, and northern parts of south america. 5 in
western countries, there is a high prevalence of HDv
infection in intravenous drug addicts with HBv infec-
tion. 10,11 worldwide, more than 350 million people
are considered to have chronic HBv infection, and
15–20 million of these individuals are thought to be
coinfected or superinfected with HDv.12 HDv infection
has been highly endemic in southern europe. several
studies performed in the 1980s and 1990s showed the
prevalence of HDv infection among HBsag-positive
individuals to be >20%;13 however, the implementation
of HBv vaccination programs in the 1980s has signifi-
cantly decreased this incidence to 5–10%.11 in turkey, the
prevalence of HDv infection in HBsag-positive indivi-
duals ranges between <5% in western turkey to >27% in
south east turkey.14 another country with a particularly
high prevalence of HDv infection is mongolia where up
to one third of chronic hepatitis infections are attribut-
able to HDv.15 Figure 1 shows the global prevalence of
HDv infection according to viral genotype.
Despite the prevalence of hepatitis D falling in
southern europe, the disease still represents a major
health burden in Central europe where its prevalence
is mostly attributable to the immigration of individuals
from highly endemic areas.10,16 in our experience at a
German referral center for liver diseases, about 8–10%
of HBsag-positive patients test positive for anti-HDv
antibodies. more than three quarters of our patients with
hepatitis D are not born in Germany. the geographical
origin of our HDv-infected patients has changed during
the past decade. until the mid-1990s the majority of
HDv-positive patients at our center were born in turkey;
however, the proportion of HDv-infected patients born
in eastern europe and states of the previous soviet union
has significantly increased since the late 1990s.10 another
German hepatology center has also reported increased
numbers of patients with hepatitis D who were born in
eastern europe and Central asia.16 HDv infection is also
increasingly prevalent in south london. 82 (8.5%) of
almost 1,000 consecutive patients with chronic hepatitis B
tested positive for anti-HDv antibodies at King’s College
Hospital, london, between 2000 and 2006.17 in that study,
HDv-infected patients were born mainly in africa or
eastern europe. in line with the German and english
experience, immigrant populations in France also have
rather a high prevalence of HBsag-positive individuals
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© 2010 Macmillan Publishers Limited. All rights reserved
who test positive for anti-HDv antibodies.18 Despite these
findings, acute HDv infections may occur rarely in non-
immigrant populations. the main risk factors for HDv
infection in italy are attributed to promiscuous sexual
activity, beauty treatments and injection drug use.19
limited data are available on the epidemiology of hepa-
titis D in the us. studies published between 1985 and
1993 report the prevalence of HDv infection in the us
to be 2% in homosexual men,20 around 20% in hemo-
philiacs21 and female prostitutes,22 and up to 30% in indivi-
duals with HBv infection.23 However, no epidemiology
study with significantly large enough number of indivi-
duals has been published since. in particular, the preva-
lence of HDv infection in high-risk populations, such as
intravenous drug addicts, is unknown for the us.
Hepatitis D is also prevalent in HBsag-positive
populations of the amazonian region of western Brazil,24
mountainous regions of venezuela and in the western
Pacific population.25 very high frequencies of HDv infec-
tion and high morbidities and mortalities are described
in the amazonian region of western Brazil.24,26,27
Pathogenesis
Knowledge about the pathogenesis of HDv infection is
limited. Clinical observations indicate that hepatitis D
is mostly an immune-mediated disease process. However,
specific clinical cases indicating that HDv can be cyto-
pathic have been published. For example, outbreaks of
severe hepatitis D in the northern part of south america
have been linked to unusual histological features of liver
disease that could represent a cytopathic viral nature.28
these, mostly fulminant, cases of hepatitis were induced
by HDv genotype 3.
liver histology is not usually different in patients
with hepatitis D than in patients with hepatitis B or
hepatitis C. importantly, the level of HDv viremia is
not directly associated with the stage of liver disease.29
only serum levels of HBsag have shown a weak correla-
tion with histological activity of disease in patients with
hepatitis D in one international study.30
Cellular immune responses against HDv have been
described by few investigators, and these studies suggest
that the quantity and quality of host t-cell responses may
be associated with the degree of control of infection.31–33
in 2006, we showed that the level of cytotoxic CD4 +
t cells is higher in patients with HDv infection than
in individuals with HBv or HCv infection.34 of note, in
general, CD4+ t cells have a higher level in the liver than
in the blood and accumulate with age; this characteristic
might be one explanation for the more rapid progression
of hepatitis D in older patients.
taken together, these limited data suggest that hepa-
titis D is mainly an immune-mediated disease, at least
in patients with HDv genotype 1 and HDv genotype 2
infection. antiviral therapies should, therefore, aim
to enhance anti-HDv immunity and reduce viremia to
confer long-term control of infection. interestingly, in
our HiDit-1 trial, we reported the first evidence that
the quality of the HDv-specific t-cell response is able
to predict the response to PeG-iFn-α2a treatment in
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Genotype I
Genotype I

Genotype (I)/II/IV

Genotype V–VII
HDV prevalence
High Genotype III
Intermediate
Low
Very low

No data

Figure 1 | Global epidemiology of HDV infection according to viral genotype. HDV genotype 1 is the most frequent genotype
and is distributed throughout the world, especially in Europe, the Middle East, North America and North Africa. By contrast,
HDV genotype 2 is observed in the Far East, and HDV genotype 3 is seen exclusively in the northern part of South America.
Abbreviation: HDV, hepatitis D virus.

patients with HDv infection.35 of note, another study
published in 2009 identified that HDv interferes with
iFn-α signaling by blocking tyk2 activation, thereby
impairing the activation and translocation of stat1 and
stat2 to the nucleus and stopping the antiviral action
of therapy.36
Coinfections with multiple hepatitis viruses are
associated with diverse patterns of reciprocal inhibition
of viral replication.37 HDv has frequently been shown
to suppress HBv replication.38–40 70–90% of patients
with hepatitis D are hepatitis B early antigen (HBeag)
negative and have low serum levels of HBv Dna. early
cotransfection experiments showed that delta proteins
may reduce levels of intracellular 3.5 kB HBv rna and
2.1 kB HBv rna.41 one possible explanation for this
observation might be that both HDv p24 and HDv p27
proteins repress the HBv enhancers piie1 and piie2 and
inhibit HBv replication.42 in addition, williams et al.
showed that HDv p27 transactivates the iFn-α inducible
Mx1 gene (also known as MxA) thereby also inhibiting
HBv replication.42
Despite the influence of HDv on HBv, 15–30% of
patients with hepatitis D are HBeag and/or HBv Dna
positive. However, the course of disease in HBeag-positive
patients with hepatitis D has not been well studied.
importantly, it should be noted that even HBeag-positive
patients may be negative for HBv Dna in the context of
HDv coinfection.43 on the other hand, HBv pre-core
stop codons may develop in patients with hepatitis D,
and HBeag-negative patients can, therefore, have signifi-
cant levels of HBv Dna and require antiviral treatment
against hepatitis B.44 the level of HBv viremia is one of
the most important predictors of disease progression in
patients with HBv monoinfection.45,46 similarly, HBv
viremia should be monitored and treated if necessary in
patients with HBv and HDv coinfection as HBv viremia
may also contribute to the development of clinical end
points in patients with hepatitis D.47
up to one-third of european patients with hepatitis D
are coinfected with HCv.43 in this context it is important
to note that HDv cannot only suppress HBv replication
but also suppress HCv replication in patients with triple
infection.48 Chronic HCv infection may even be cleared in
patients who are superinfected with HBv and HDv.49
in our experience, less than one-fifth of individuals who
are anti-HCv antibody positive, HBsag positive, and
anti-HDv antibody positive are positive for HCv rna.43
However, it is not clear how many of the individuals who
are anti-HCv antibody positive and HCv rna nega-
tive have truly recovered from HCv infection or whether
HCv replication is just suppressed in the context of viral
coinfection. viral dominances may change over time.37
Patients with triple hepatitis infections should therefore
be followed up closely and, if indicated, treatment of the
dominant virus should be considered.
Diagnosis and management
every individual who is HBsag positive should be tested
for anti-HDv igG antibodies at least once. there is no
evidence that direct testing for HDv rna in the absence
of anti-HDv antibodies is of any use because anti-HDv
antibodies develop in every individual infected with
HDv. Cases of HDv viremia in immunocompromised
patients in the absence of anti-HDv antibodies have not
yet been reported to our knowledge. a positive result for
the presence of anti-HDv antibodies, however, does not
necessarily indicate active hepatitis D—HDv rna can
disappear indicating recovery from HDv infection. in
the long term, anti-HDv antibodies can disappear after
recovery from infection. However, anti-HDv antibodies

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© 2010 Macmillan Publishers Limited. All rights reserved
revieWs
may persist for years,24 even when the patient has experi-
enced HBsag seroconversion 50 or has undergone
liver transplantation.51
HDv infection should be confirmed by the detec-
tion of serum HDv rna. if an individual tests positive
for serum HDv rna, subsequent evaluation includ-
ing grading and staging of liver disease, surveillance
for hepatocellular carcinoma and consideration for
antiviral treatment is indicated. HDv rna quantifica-
tion is offered by some laboratories. However, there
is no evidence that serum HDv rna levels correlate
with any clinical marker of activity or stage of liver
disease,29 which is similar to HCv infection for which
no associations or even causal links between levels of
viremia and disease activity are evident.45 thus, HDv
rna quantification is only useful if antiviral treat-
ment is indicated. rules regarding the discontinuation
of antiviral treatment depending on the level of HDv
rna decline are under evaluation. erhardt et al. have
suggested that patients with less than a log 3 decline
in serum HDv rna levels after 24 weeks of treatment
with PeG-iFn-α2b do not benefit from continued treat-
ment.52 similarly, Yurdaydin et al. showed that patients
with HDv infection who achieve an svr with conven-
tional recombinant iFn-α usually show a decline in
serum HDv rna levels within the first 3–6 months of
treatment compared with patients who are not able to
clear HDv infection.53
HDv genotyping is performed by some research
laboratories and this may help to identify patients with
an increased or reduced risk of developing end-stage
liver disease.8 in western countries, almost all patients
are infected with HDv genotype 1, thus, viral genotyping
may be considered only for immigrants or populations
with a high prevalence of a variety of genotypes.
in the 1980s and 1990s the diagnosis of active hepa-
titis D was dependent on anti-HDv antibody igm
testing. anti-HDv antibody igm testing might still be
useful, particularly for patients who test negative for
HDv rna but have evidence of liver disease that cannot
be explained by other reasons. owing to the variability
of the HDv genome and the lack of standardization of
HDv rna assays, an HDv rna test may yield a false-
negative result, or the level of HDv rna may be under
that of the detection limit of the assay in cases of fluctu-
ating disease. in these cases, HDv rna testing should
be repeated and, if available, anti-HDv antibody igm
testing might be performed.
as hepatitis D occurs only in the context of super-
infection or coinfection with HBv, a solid work-up of
HBv infection, including HBv Dna quantification and
HBeag and anti-HBe antibody determination, is war-
ranted. similarly, testing for anti-HCv antibodies and
anti-Hiv antibodies is mandatory. in our experience, up
to one third of patients who test positive for anti-HDv
antibodies also test positive for anti-HCv antibodies,43 a
finding that is in line with those from other cohorts.54
adequate grading and staging of liver disease should
be part of the diagnostic work-up of every patient with
viral hepatitis, and is particularly important for patients
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© 2010 Macmillan Publishers Limited. All rights reserved
with hepatitis D as this disease can progress rapidly
and be severe in nature. as treatment options for hepa-
titis D are limited, the analysis of the risks and benefits
of initiating iFn therapy should consider the extent of
fibrosis in the liver. noninvasive serological markers
of fibrosis and elastography have been studied extensively
for hepatitis C and hepatitis B.55,56 However, very limited
information is available for hepatitis D. scores for staging
liver disease, such as the aspartate aminotransferase
(ast) to platelet ratio index (aPri),57 or the ast to
alanine aminotransferase ratio, do not differ significantly
between hepatitis D patients with or without fibrosis or
cirrhosis.30 to our knowledge, transient elastography
has not yet been studied in HDv-infected patients.
liver biopsies therefore remain a key component of the
diagnostic work-up of patients with HDv infection and
we perform a liver biopsy for almost every patient with
HDv infection at our center. a summary of diagnostics
tests for the evaluation of a patients with HDv infection
is presented in table 1.
Clinical course of hepatitis D
acute hBv and hDv coinfection
acute HBv and HDv coinfection leads to complete viral
clearance in more than 90% of cases but it may cause
severe acute hepatitis with the potential for a fulminant
disease course.58 By contrast, HDv is cleared spontane-
ously in only a minority of chronic HBsag carriers with
HDv superinfection.58 the observation that the histo-
pathology of patients with simultaneous HBv and HDv
infection is more severe than in patients with HBv infec-
tion alone has also been documented in chimpanzees.59
several outbreaks of very severe courses of acute hepa-
titis D have been described in different regions of the
world.60–62 However, and fortunately, acute hepatitis D
has become rather infrequent in western countries over
the past two decades due to the introduction of HBv
vaccination programs.
Chronic hDv infection
several studies have shown that chronic HDv infec-
tion leads to more severe liver disease than chronic
HBv monoinfection, and is associated with an acceler-
ated course of fibrosis progression, an increased risk of
hepato cellular carcinoma, and early decompensation
in the setting of cirrhosis.38,39,50,58,63,64 HDv accounts for
almost half of all cases of liver cirrhosis and hepatocellular
carcinoma in south east turkey.14,64,65 a 28-year follow-
up study of patients with hepatitis D in italy showed that
25% of patients with cirrhosis developed hepatocellular
carcinoma and that liver failure was the cause of death in
59% of patients.66 these data are in line with those from a
study in taiwan where the cumulative survival of patients
infected with HDv genotype 1 was reported to be low;
only 50% of patients survived after 15 years.8 HDv infec-
tion has also been associated with an increased risk of
developing liver cirrhosis in patients with HDv and
Hiv coinfection. 66% of patients coinfected with Hiv,
HBv, HCv and HDv, but only 6% of patients coinfected
with HBv, HCv, and Hiv, presented with liver cirrhosis
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Table 1 | A summary of diagnostic tests for the evaluation of patients with HDV infection
test purpose remarks
Anti‑HDV IgG Detects IgG antibodies against HDV, indicates Should be the first diagnostic screening test employed
antibody previous or ongoing contact with HDV and should be performed in all HBsAg‑positive patients
Anti‑HDV IgM Detects IgM antibodies against HDV, indicates Can be used to determine disease activity in patients who
antibody acute HDV infection or chronic HDV infection test positive for anti‑HDV IgG antibodies. Available tests are
with disease activity not standardized
HDV RNA Detects HDV RNA Indicates HDV replication Gold standard to determine HDV infection. Test can be
qualitative and active infection false‑negative if primers are not optimized for all HDV
genotypes
HDV RNA Determines the level of HDV RNA in the blood Can be useful in the context of antiviral treatment to predict
quantitative treatment response. There is no association between serum
HDV RNA levels and the grade or stage of liver disease
HDV genotyping Determines the HDV genotype Different HDV genotypes may be associated with distinct
clinical courses
HBsAg Determines the level of HBsAg in the blood HBsAg is associated with HDV RNA levels. HBsAg clearance
quantitative is associated with HDV eradication and thus HBsAg
monitoring can be useful during antiviral treatment
HBeAg/anti‑HBe Determines the presence of the HBeAg and the About 15–20% of patients with HDV infection test positive
antibody presence of anti‑HBe antibodies for HBeAg, which can be associated with HBV replication.
Treatment with HBV polymerase inhibitors might be indicated
if IFN‑α treatment is not possible
HBV DNA Determines the level of HBV DNA in the blood Indication for treatment with HBV polymerase inhibitors
quantitative depends on the amount of HBV DNA detectable in the blood
Anti‑HCV Determines the presence of the antibodies Up to one third of patients in Europe with HDV infection are
antibody/HCV against HCV and the presence of HCV RNA coinfected with HCV. Screening for HCV should be performed
RNA at least once. HCV RNA is frequently suppressed by
coinfection
Liver biopsy Histological evaluation of and grading or staging Should be performed in all patients with hepatitis D as
of liver disease noninvasive markers of liver fibrosis are not proven to be
able to accurately predict the stage of liver disease in
patients with HDV infection
Abbreviations: HBsAg, hepatitis B surface antigen; HBe; hepatitis B early antigen; HBeAg, hepatitis B e antigen; HDV, hepatitis D virus.

in a spanish cohort.67 similarly, hepatitis D was associ-
ated with reduced survival in a group of patients from
taiwan with HDv and Hiv coinfection.68
Treatment
Hepatitis D is the only form of viral hepatitis for which
there is not an established treatment. However, several
therapeutic strategies can be employed. a possible thera-
peutic algorithm for HDv-infected patients is suggested
in Figure 2. table 2 summarizes the outcomes of selected
therapeutic trials for patients with hepatitis D. we believe
that egular monitoring of HDv infection should be man-
datory. as mentioned above, different patterns of viral
dominance can be observed and these are associated with
different clinical outcomes and require distinct treatment
strategies. However, viral hierarchies are not necessar-
ily stable over time37 and therapeutic approaches might,
therefore, need to be adapted during patient follow-up.
nucleoside and nucleotide analogues
several nucleoside and nucleotide analogues used for
the treatment of HBv infection are shown to be ineffec-
tive against HDv. Famciclovir, which was under clini-
cal development for the treatment of hepatitis B in the
1990s,69 had no significant antiviral activity against HDv
in a turkish trial.70 similarly, lamivudine was ineffective in
trials for the treatment of hepatitis D.53,71–73 ribavirin
alone, or in combination with iFn, is also shown not to
increase rates of HDv rna clearance.74–76 However, a
long-term observational study of individuals coinfected
with Hiv, HBv and HDv and on antiretroviral treat-
ment, which included tenofovir, showed more promising
results.77 in this study, antiretroviral treatment lasted a
median of 6 years, and, during this period, the authors
observed an average decline in serum HDv rna levels
from 7 log10 to 5.8 log10, and 3 out of 16 patients became
HDv rna negative. thus, prolonged treatment with
potent HBv polymerase inhibitors may lead to bene-
ficial effects in patients with hepatitis D, possibly owing
to a reduction in serum HBsag levels. Future long-term
trials will need to confirm these data in individuals with
triple infections.
Clevudine, a nucleoside analogue in development
for the treatment of hepatitis B, has been shown to
inhibit HDv viremia in woodchucks. 78 However, no
data are yet available for clevudine treatment in patients
with hepatitis D. moreover, in 2009, the treatment of
chronic hepatitis B with clevudine was linked to cases
of severe myopathy characterized by depletion of mito-
chondrial Dna.79 Further clinical development of this
compound is, therefore, uncertain.
the selection of variants that are resistant to HBv
polymerase inhibitors and that may confer changes to
the structure of the HBsag must be considered if HBv

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Anti-HDV antibody positive

HDV RNA positive HDV RNA negative (repeatedly)

HBV DNA >2,000 IU/ml; Contraindication for HBV DNA >2,000 IU/ml; HBV DNA <2,000 IU/ml;
no contraindication for IFN-α + HBV DNA
HBV DNA <2,000 IU/ml liver cirrhosis no cirrhosis
IFN-α detectable

PEG-IFN-α HBV polymerase PEG-IFN-α HBV polymerase inhibitors Observation

Treatment duration should inhibitors Treatment duration Administer according to Initiate treatment only
be decided on the basis of Administer according should be decided HBV guidelines if serum HBV DNA
HDV RNA and HBsAg to HBV guidelines on the basis of Monitor serum HDV RNA levels increase or the
kinetics HDV RNA and levels; consider IFN-α patient tests positive
Consider the use of HBV HBsAg kinetics treatment if patient becomes for HDV RNA
polymerase inhibitors positive for HDV RNA
if serum level of HBV DNA
is very high and does not
decline sufficiently
during treatment
HBV DNA >2,000 IU/ml after
treatment or detectable
serum HBV DNA with
advanced fibrosis or cirrhosis

Patients should be monitored every 3–6 months after the initiation of treatment
as serum levels of HBV DNA and HDV RNA may fluctuate
If a patient is HCV RNA positive consider treatment for hepatitis C with PEG-IFN-α plus ribavirin

Figure 2 | A possible treatment algorithm for hepatitis D. The use of PEG‑IFN‑α or HBV polymerase inhibitors depends on
serum levels of HDV and HBV and on the presence or absence of liver cirrhosis. Abbreviations: HBsAg, hepatitis B surface
antigen; HDV, hepatitis D virus.

polymerase inhibitors are used for the treatment of hepa-
titis D, as the open reading frames for HBv polymerase
and HBsag overlap. in particular, the rtm204v HBv
polymerase variant, which frequently is selected for
during lamivudine therapy for HBv infection, has been
associated with changes in the gene encoding the HBv
small envelope protein at positions s195 and s196.80 HDv
is encapsidated by the envelope proteins of HBv. vieether
et al. demonstrated that the lamivudine-induced sw196l
or sw196s HBsag variants inhibited the secretion of
HDv particles.81 these data were confirmed by a French
group who showed that the sw196s HBsag variant was
deficient for HDv assembly as it could no longer interact
with the large delta antigen.82 the clinical consequences of
these observations are unclear as the nonsecretion
of HDv particles means that cells will be packed with
HDv antigen, which may cause cytopathology. these
data suggest that unnecessary nucleoside or nucleotide
treatment of hepatitis D should be avoided as the patho-
genicity of HDv may change if small HBsag variants
are induced.
recombinant iFn‑α
iFn-α has been used for the treatment of hepatitis D
since the mid 1980s.83 since then a large number of trials
have explored different durations and doses of iFn-α in
HDv-infected individuals. However, data are difficult
to compare as end points have differed between trials,
and few studies have studied serum levels of HDv rna
levels over time.84
one randomized italian study on the use of high-dose
iFn-α is of importance as it associated this treatment
with a beneficial long-term outcome in patients with
hepatitis D.85,86 some studies have investigated prolonged
iFn-α treatment, and it seems that 2 years of treatment
is superior to shorter durations of treatment in terms of
HDv rna clearance.84 in one case report from the niH,
12 years of iFn-α treatment led finally to resolution of
both HDv infection and HBsag clearance.87 However,
high doses of iFn-α, and prolonged treatment are tolerated
only by a minority of patients, and treatment options are
therefore still very limited for the majority of patients.88
peg‑iFn‑α
in 2006, PeG-iFn-α was evaluated for the treatment of
hepatitis D in three, small trials.52,74,89 these studies exam-
ined the use of PeG-iFn-α2b for 48 weeks or 72 weeks
(table 2). the French study by Castelnau et al. included
14 patients who were treated for 1 year. an svr (defined
as undetectable serum HDv rna 6 months after treat-
ment) was observed in 6 patients (43%).89 of note, the
second study by andreas erhardt and colleagues applied
a similar treatment protocol in 12 patients, but an svr
was achieved in only 2 patients.52 in this study the decline
in serum levels of HDv rna during the first 6 months of
treatment seemed to be predictive of svr. the third and
largest study included 38 patients who all received PeG-
iFn-α2b for 72 weeks;74 22 of these patients also received
ribavirin for the first 48 weeks. overall, 8 individuals
(21%) were HDv rna negative 24 weeks after the end of
therapy. importantly, ribavirin had no apparent beneficial
effect, which is in line with earlier, smaller trials that also
could not identify an anti-HDv activity of ribavirin.75,76
the HiDit-1 trial 90,91 included 90 patients from
Germany, turkey and Greece. Patients were randomly
allocated to receive either 180 μg of PeG-iFn-α2a weekly

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Table 2 | Summary of selected therapeutic studies for patients with hepatitis D

trial number of participants treatment outcome
patients
Yurdaydin 15 Chronic Famciclovir for 6 months No effect on serum HDV RNA levels
et al. (2002)70 hepatitis D
Niro et al. 31 Chronic Lamivudine (n = 20) vs no treatment No effect on serum HDV RNA levels
(2005)72 hepatitis D (n = 11) for 2 years
Yurdaydin 39 Chronic Lamivudine (n = 17) vs lamivudine SVR for HDV RNA in 9 patients (41%); no
et al. (2008)53 hepatitis D plus IFN‑α2a (n = 14) vs IFN‑α2a (n = 8) additional benefit of adding lamivudine
for 1 year
Gunsar et al. 31 Chronic IFN‑α2a plus ribavirin (n = 21) vs SVR for HDV RNA in 7 patients (23%); no
(2005)75 hepatitis D IFN‑α2a alone for 2 years additional benefit of adding ribavirin
Sheldon et al. 16 HDV and HIV Highly active antiretroviral therapy Median HDV RNA decline from 7 log
(2008)77 coinfection for 6.1 years copies/ml to 5.8 log copies/ml;
3 patients were HDV RNA negative
Rosina et al. 61 Chronic IFN‑α2b (n = 31) vs no treatment SVR for HDV RNA in 14 patients (45%)
(1991)99 hepatitis D (n = 30) for 2 years
Farci et al. 42 Chronic IFN‑α2a 9 million units three times 71% of patients in 9 million units arm were
(1994)85,86 hepatitis D a week (n = 14) vs IFN‑α2a 3 million HDV RNA negative by the end of
units three times a week (n = 14) vs treatment; relapse of HDV infection in all
no treatment (n = 14) for 1 year patients; improved long‑term survival after
>10 years in the 9 million units group
Castelnau 14 Chronic PEG‑IFN‑α2b for 48 weeks SVR for HDV RNA in 6 patients (43%)
et al. (2006)89 hepatitis D
Niro et al. 38 Chronic PEG‑IFN‑α2b for 72 weeks (n = 16) SVR for HDV RNA in 88 patients (21%); no
(2006)74 hepatitis D vs PEG‑IFN‑α2b for 72 weeks plus additional benefit of adding ribavirin
ribavirin for the first 48 weeks (n = 22)
Erhardt et al. 12 Chronic PEG‑IFN‑α2b for 48 weeks SVR for HDV RNA in 2 patients (17%)
(2006)52 hepatitis D
Wedemeyer 90 Chronic PEG‑IFN‑α2a (n = 29) vs PEG‑IFN‑α2a SVR for HDV RNA in 14 patients (23%);
et al. (2007)91 hepatitis D plus adefovir dipivoxil (n = 30) vs combination treatment was superior in
adefovir dipivoxil alone (n = 31) for terms of decline in serum HBsAg levels
48 weeks
Abbreviations: HDV, hepatitis D virus; SVR, sustained virologic response.

plus 10 mg adefovir dipivoxil daily, 180 μg PeG-iFn-α2a liver transplantation

weekly plus placebo daily, or 10 mg adefovir dipivoxil
daily for 48 weeks. Both PeG-iFn-α2a groups showed a
significantly higher reduction in mean serum HDv rna
levels than the adefovir dipivoxil monotherapy group by
week 48. HDv rna was undetectable after treatment
only in patients who received a regimen including PeG-
iFn-α2a. the PeG-iFn-α2a and adefovir dipivoxil
combination group showed a 1.1 log10 iu/ml decline
in serum HBsag levels by week 48. these data are in
line with a report from Greece that also found a signifi-
cant decline in serum Hbsag levels in patients with
hepatitis D receiving long-term treatment with iFn-α.92
overall the HiDit-1 trial showed several things. First,
PeG-iFn-α2a has a significant antiviral efficacy against
HDv in more than 40% of patients, with 25% achieving
an svr after 48 weeks of treatment. second, adefovir
dipivoxil has little efficacy in terms of reduction of serum
levels of HDv rna, but may be considered for patients
with marked levels HBv replication. third, combina-
tion therapy with PeG-iFn-α2a plus adefovir dipivoxil
has no advantages in terms of reduction of serum HBv
Dna levels or serum HDv rna levels. Finally, combina-
tion therapy with PeG-iFn plus a nucleotide analogue is
superior to either monotherapy in reducing serum levels
of HBsag in HDv-infected patients.93,94
liver transplantation is the only treatment option for
patients with end-stage liver cirrhosis resulting from
hepatitis D. as HBv re-infection after liver transplanta-
tion can be prevented in most individuals by passive
immunization with anti-HBsag antibodies and the
administration of HBv polymerase inhibitors,95 HDv
reinfection does not occur after transplantation. the
post-transplant course of patients with hepatitis D is,
therefore, very good, and 5-year survival rates are signifi-
cantly higher than in patients undergoing transplanta-
tion for most other causes of chronic liver failure.84 of
note, HDv rna rapidly disappears from the blood after
liver transplantation in parallel with the decline in serum
HBsag levels.51 studies in chimpanzees have also ruled
out the possibility that HDv can persist as an isolated
infection in the absence of HBv.96
Current recommendations and future options
most guidelines recommend treatment for chronic HDv
infection with PeG-iFn-α for at least 1 year.97 longer
treatment should be considered if patients are able to
tolerate the adverse effects of therapy, they show a bio-
chemical and virologic response to treatment, and are at
a high risk of developing clinical end points. measuring
the kinetics of HDv rna during treatment might help to

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© 2010 Macmillan Publishers Limited. All rights reserved
revieWs

identify patients who are true nonresponders to therapy
and individuals who could benefit from extended treat-
ment. 53 treatment with HBv polymerase inhibitors
is indicated only if iFn treatment is not possible and
marked levels of HBv replication can be detected. Data
on the efficacy of combination therapies including iFn
and HBv polymerase inhibitors are insufficient; however,
pronounced reductions in serum HBsag levels have been
observed during treatment with PeG-iFn-α2a plus
adefovir dipivoxil.91
trials are ongoing to optimize the efficacy of available
treatment options, for example, the long-term use of com-
bined therapy with PeG-iFn-α2a plus tenofovir. moreover,
alternative treatment options need to be explored. among
those, prenylation inhibitors may be promising.98 HDv
replication depends on a prenylation step and prenyla-
tion inhibitors have already been developed for the treat-
ment of malignancies and are shown to be safe in this
setting. it might be interesting to see if other compounds
with a broad antiviral efficacy, including nitazoxanide,
are also effective against HDv. Finally, several alterna-
tive iFns including iFn-λ are in clinical development
and these should be also be explored for use in patients
with hepatitis D. Continuous efforts to improve treat-
ment options available for hepatitis D are urgently needed
as HDv infection is a largely underestimated disease
with an enormous health burden in some countries.
Conclusions
Hepatitis D represents a major health burden in certain
areas of the world. in western countries, mainly immi-
grant populations have a high prevalence of HDv infec-
tion. Diagnosis is challenging and requires knowledge of
complex patterns of viral dominance between different
hepatitis viruses. treatment options are limited as only
iFn-α has proven antiviral efficacy against HDv and has
been linked with improved long-term outcome. ongoing
research is required to better understand the pathophysi-
ology of HDv infection and to develop novel treatment
options for this most severe form of viral hepatitis.
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Hepatitis” AND “treatment”. For selected topics such
as treatment for HDV infection, congress abstracts
presented at European or American Liver Meetings
between 2006 and 2009 were also considered.

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