Download Natural history and treatment of chronic delta hepatitis

Journal of Viral Hepatitis, 2010
doi:10.1111/j.1365-2893.2010.01353.x
REVIEW
Natural history and treatment of chronic delta hepatitis
C. Yurdaydın,1,2 R. Idilman,1 H. Bozkaya1 and A. M. Bozdayi1,2
1
Gastroenterology Department, University of
2
Ankara Medical School and Hepatology Institute, University of Ankara, Ankara, Turkey
Received February 2010; accepted for publication April 2010
SUMMARY. Chronic delta hepatitis (CDH) represents a severe
form of chronic viral hepatitis, induced by the hepatitis delta
virus (HDV) in conjunction with the hepatitis B virus (HBV).
Delta hepatitis may lead to disease in humans through coinfection. The former leads to acute hepatitis which clinically
can range from mild hepatitis to fulminant hepatitis and
death. Severe or fulminant hepatitis is more often observed
with HBV-HDV co-infection compared to HBV mono-infection. Chronic infection after acute hepatitis B + D co-infection
is infrequent and similar to the rate in mono-infected patients.
CDH develops in 70–90% of patients with superinfection.
CDH runs a more progressive course than chronic hepatitis B
and may lead to cirrhosis within 2 years in 10–15% of
patients. However, as with any immune-mediated disease,
different patterns of progression, ranging from mild to severe
INTRODUCTION
Chronic delta hepatitis (CDH) represents a severe form of
chronic viral hepatitis and is mostly associated with rapid
progression of disease. The causative agent of CDH, the
hepatitis delta virus (HDV), discovered by Rizzetto et al. in the
1970s [1], has several unique features. It is not a virus per se
but can be described as a defective satellite virus that leads to
hepatitis only in the presence of the hepatitis B virus (HBV).
HDV has been isolated only from humans [2]. It comprises
a single-stranded, circular RNA genome of close to 1700
nucleotides, which is the smallest genome of any animal
virus [3]. Several features of HDV resemble those of plant
viroids such as the circular configuration of its RNA genome,
its RNA self-cleavage (ribozyme activity) property and its
Abbreviations: ALT, alanine aminotransferase; CDH, Chronic delta
hepatitis; CHB, chronic hepatitis B; CHD, chronic form of delta
hepatitis; CPEB3, cytoplasmic polyadenylation element-binding
protein 3; ER, endoplasmic reticulum; HCC, hepatocellular carcinoma; HDV, hepatitis delta virus.
Correspondence: Cihan Yurdaydın, MD, Ankara Üniversitesi Tıp
Fakültesi, Gastroenterology Kiliniği, Cebeci Tip Fakültesi Hastanesi,
Dikimevi, 06100 Ankara, Turkey. E-mail: cihan.yurdaydin@
medicine.ankara.edu.tr
2010 Blackwell Publishing Ltd
progressive disease, are observed. Active replication of both
HBV and HDV may be associated with a more progressive
disease pattern. Further, different HDV and HBV genotypes
may contribute to various disease outcomes. CDH may be
frequently associated with hepatocellular carcinoma development although recent studies provided conflicting results.
The only established therapy for CDH is treatment with
interferons for a duration of at least 1 year. On treatment,
6 month HDV RNA assessment may give clues as to whether
to stop treatment at 1 year or continue beyond 1 year. New
approaches to treatment of CDH are an urgent need of which
the use of prenylation inhibitors appears the most promising.
Keywords: chronic delta hepatitis, natural history, treatment.
RNA to RNA rolling circle replication, but there are also
important differences: (i) viroids are smaller, being 250–300
nucleotides in length; (ii) they do not require a helper virus
and (iii) viroids do not code for a protein [2]. Hence, HDV is
classified as a separate genus in the Deltaviridae family [4]. A
further interesting characteristic of this unique agent is the
recent postulate that HDV may have arisen from the human
transcriptosome. An in vitro human genome search for
ribozymes revealed the cytoplasmic polyadenylation elementbinding protein 3 (CPEB3) gene, which reportedly is structurally and biochemically related to the HDV ribozyme [5].
The CPEB3 ribozyme was found only in mammals. As CPEB3
was found not only in placental mammals but also in marsupials, it is likely that this ribozyme may have appeared at
least 150 million years ago before the two groups diverged,
and hence, it is postulated that HDV arose from the human
transcriptome, acquiring both the delta antigen protein and
the self-cleaving ribozyme from the host [5].
In recent years, several reports have suggested that with
the increased control of HBV infection achieved by intense
universal HBV vaccination programs, use of disposable
needles, screening blood donors for HBsAg and socioeconomic improvements, HDV infection has declined significantly in many endemic areas like Southern Europe and
Southeast Asia [6–9]. However, recent data suggest that this
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C. Yurdaydın et al.
decline may have reached a plateau, which is most likely
attributable to migration and increased travel [10–13].
The current review aims to summarize recent advances in
the natural history of the disease evoked by this fascinating
agent and discuss its treatment. For the latter, current
treatment as well as potential future treatment targets will
be discussed.
NATURAL HISTORY
Hepatitis delta virus can be acquired either by coinfection in
which an individual is confronted with both HDV and HBV
viruses simultaneously, or by superinfection of individuals
who are already chronically infected with HBV. HDV infection is in general associated with suppression of HBV infection as has been shown by a decline or disappearance of
HBcAg in liver tissue and a decrease in HBsAg levels in early
chimpanzee experiments [14].
ACUTE DELTA HEPATITIS
By definition, acute delta hepatitis can only be caused by
coinfection of HBV with HDV where patients are confronted
with both viruses. This may lead to a biphasic type of hepatitis, possibly related to sequential expression of the two
viruses, which has been observed both in early chimpanzee
studies [14] and prospectively in intravenous drug addicts
[15]. The acute hepatitis can clinically range from
mild hepatitis to fulminant hepatitis leading to death. The
variable course may be a reflection of the variation in the
immune response of the host or the helper function of HBV:
the wider the spread of HBV to hepatocytes, the more severe
the coinfection will be. In most cases, acute delta hepatitis
resembles a typical self-limited hepatitis that is clinically and
histologically indistinguishable from hepatitis B or other
types of acute viral hepatitis. Early studies have shown that
coinfection of HBV-HDV more often leads to severe or fulminant hepatitis compared to patients monoinfected with
hepatitis B (Table 1). In two separate studies from Europe
and the United States, the proportion of patients with evidence of delta coinfection among patients with fulminant
hepatitis B and acute non-fulminant hepatitis B was 34%
and 39% vs 4.2% and 19%, respectively [16,17]. In another
study performed among drug addicts, patients with acute
hepatitis B+D were compared to HBV monoinfected patients.
Of 86 coinfected patients, 15 (17.4%) developed severe
hepatitis, whereas severe hepatitis was encountered in only
2 of 50 (4%) monoinfected patients. Chronic infection
developed infrequently after acute hepatitis B+D coinfection,
similar to the rate in monoinfected adult patients: of 208
coinfected patients, CDH developed in 5 (2.4%) patients [18].
CHRONIC DELTA HEPATITIS
The chronic form of delta hepatitis (CHD) is most often the
result of superinfection with HDV of a patient with chronic
HBV infection, but as pointed out earlier, some infrequent
cases of HBV-HDV coinfection may also evolve to chronic
hepatitis. These two forms can not be differentiated on
clinical or morphological grounds [19]. Superinfection with
HDV may lead to clearance of both viruses in the minority of
patients; in 70–90% of cases, chronic hepatitis will develop.
An interesting feature of CHD mentioned in early reports is
that a history of an acute hepatitis episode is frequently
obtained. In an Italian cohort of 101 patients, 71 patients
(70%) reported such an episode [20]. It is likely that such an
episode represents the time of superinfection with HDV in a
high proportion of cases. In general, CHD runs a more
progressive course than chronic hepatitis B (CHB). Of 75
patients with CHD who at initial biopsy had chronic hepatitis, cirrhosis or liver failure developed in 29 patients (39%)
within a follow-up of 2–6 years [20]. In a further analysis,
the prevalence of histological cirrhosis showed a linear
increase over the years following a reported acute hepatitis
episode, reaching 23% (10/43), 41% (9/22) and 77% (9/13)
after 10, 20 and 30 years, respectively [21]. However, as
expected in an immune-mediated disease [22,23], CHD may
run different disease courses in different individuals ranging
from mildly progressive disease to a severe progressive
course, which may lead to acute on chronic liver failure
and death within weeks or months [24,25]. In 10–15% of
patients, rapid progression to cirrhosis within 2 years has
been reported [26]. The rapidly progressing form was mostly
observed in intravenous drug users. This has been attributed
to emergence of more pathogenic strains of HDV as a result
of rapid passage of HDV from person to person in the iv drug
community reminiscent of serial passage experiments of
HDV in HBV carrier chimpanzees, which resulted in more
severe hepatitis [27]. Further, active viral replication of both
HBV and HDV has been reported to be associated with poor
prognosis [28,29].
However, although severe disease in the acute setting of
HDV superinfection is universally observed, the more progressive course of CHD after this acute setting has not been
Table 1 Proportion of patients with serological evidence of delta infection among patients with acute self-limited vs acute
fulminant hepatitis B
Europe [16]
USA [17]
Fulminant hepatitis B
Acute hepatitis B
P value
43/111 (39%)
24/71 (34%)
101/532 (19%)
5/118 (4%)
<0.000001
0.000016
2010 Blackwell Publishing Ltd
Chronic delta hepatitis
observed everywhere. In series from the Far East, a more
protracted course of CHD has been reported [30]. This may
be linked to different HDV genotypes prevalent in these
areas. Currently, eight genotypes of HDV have been
described based on sequence variation of 19–38% [31,32].
Genotype 1 is distributed worldwide [33] with a variable
disease course and genotypes 5–8 are seen in Central and
West Africa. Genotype 3 has been observed in northern
South American countries, such as Columbia, Venezuela,
Peru and Ecuador, and is associated with a particularly
severe disease [34] whereas genotypes 2 and 4, encountered
in the Far East, have been associated with milder disease
than genotype1 [35,36]; a subtype of genotype 2 however
has been associated with a fast progressive course [37]. The
importance of HDV genotypes have been further substantiated in two recent publications, which have also pointed out
the potential importance of HBV genotypes in CHD [29,38].
In a study from Brasil, HDV viral load was lower in genotype
A patients compared to patients with genotype D or F HBV
[38]. This difference was however not reflected in the outcome of the patients, which may have been confounded by
the low number of HDV patients. In a longitudinal follow-up
study of a cohort of 194 CHD patients from Taiwan with
mostly genotypes B and C HBV and genotypes 1 and 2 HDV,
the incidence of acute liver failure was significantly higher in
genotype 1 than in genotype 2 HDV patients and on longterm follow-up genotype 1 HDV was associated with a lower
remission and a higher adverse outcome rate than genotype
2. Similarly, genotype C HBV was also associated with a
lower remission and a higher adverse outcome rate than
genotype B. By multivariate analysis, age, genotype C HBV
and genotype 1 HDV were independent factors for adverse
outcome [29]. Differences in virion assembly and HDV replication may account for the variable disease course between
genotype 1 and genotype 2 HDV. In in vitro experiments,
virion assembly efficiency has been reported to be higher
with genotype 1 than with genotype 2 HDV [39]. In a cell
culture assay, a genotype 2 clone of Taiwanese origin had
100-fold less RNA replication when compared with a
genotype 1 clone of Italian origin [40].
More recent studies on the natural history of CHD from
Italy also challenge the impression of CHD being a disease
with an ominous prognosis [41,42]. It appears that CHD
runs a severe course towards early development of cirrhosis
in parallel with high HDV replication after which the pace of
HDV replication may decrease associated with slowing of
disease progression [41].
EFFECT OF CHRONIC DELTA HEPATITIS ON
ADVERSE OUTCOMES SUCH AS
HEPATOCELLULAR CARCINOMA AND HEPATIC
DECOMPENSATION
Early reports suggested an infrequent association of CHD
with hepatocellular carcinoma (HCC), explained by a
2010 Blackwell Publishing Ltd
3
diminished life expectancy of patients with CHD [43]. A
European wide study has changed this view: it has reported
a 3.2-fold increased risk of HCC development in patients with
CHD compared to HBV monoinfected patients [44]. The
same study also found a 2.2-fold risk of hepatic decompensation that was however not significant. In contrast, Romeo
et al. [42], reported that hepatic decompensation and not
HCC was the dominant complication of CHD-induced compensated cirrhosis. Two studies from Taiwan and England
also failed to show an increased risk for HCC development in
CHD [13,25]. Further studies on CHD-induced liver related
complications are awaited for clarification.
TREATMENT OF CHD
The only evidence-based effective treatment of CHD consists
of the use of interferon. No other medication of proven efficacy against CHD exists. The main reason behind this is that
delta hepatitis-specific treatment, treatment oriented at different steps of the HDV life cycle, has not been developed. It
is hoped that the first example of such an approach will be
seen within one or 2 years with the use of prenylation
inhibitors for the treatment of CHD in humans.
CURRENT TREATMENT OF CHD
The only established therapy for CDH, interferon (IFN), has
to be administered for at least 1 year at high doses [45]. In
the early 1990s, controlled clinical trials showed that IFNalpha is effective in chronic hepatitis D, but relapse is high
and its efficacy is related to dose and duration of therapy
[45–47]. High doses (9 million units (MU) thrice weekly
or 5 MU daily) for at least 1 year were required to achieve
an improved outcome as determined by a biochemical and
virological response [alanine aminotransferase (ALT)
normalization and loss of HDV viremia measured by PCR]
both of which correlate with improvement in liver histology
[45,47]. Therapy with interferon is expensive and troublesome side effects are common. At the end of treatment,
biochemical response may be as high as 70%, but virological
response is seen in no more than 50% of patients. Despite a
high rate of relapse, high dose interferon may favourably
affect the natural history of the disease in the long run [47].
Long-term follow-up (median 13.0, range 2–14.8 years) of
patients from the landmark study by Farci et al. [45] indicates that in patients who have received high dose INF,
survival is significantly longer compared to both the low
dose group and the untreated control group [48]. Seven of
the 10 patients with end of treatment biochemical response,
continued to have a normal ALT. However, only three
patients lost HDV RNA by PCR, all of whom also lost HBsAg.
It is likely that a very sensitive PCR assay had been used in
this study, and the virological results may not be directly
comparable to virological outcomes of other studies
suggesting the importance of standardization of HDV RNA
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C. Yurdaydın et al.
PCR assays. Persistent ALT normalization was also associated with significant improvement in liver histology and
includes complete reversal of liver cirrhosis and fibrosis in
some patients.
Some patients may need treatment beyond 1 year. This
has been already shown in HBeAg-negative CHB where
2 years of IFN-alpha treatment appears to improve outcome over 1 year of therapy [49]. Common sense would
suggest that patients with a partial biochemical and virological response and those who relapse after treatment
discontinuation would be the typical candidates for prolonged treatment. Successful eradication of both HBV and
HDV in a patient treated daily with interferon for 12 years
supports this view [50]. Despite this, pilot studies of the use
of INF-alpha for 2 years failed to show superiority over
1 year of therapy [51–53]. However, all of these studies
were small cohort studies and did not have a comparator
arm of standard 1- year treatment. Side effects decreasing
compliance to treatment appears to be a problem in prolonged courses of treatment.
Experience with PEG-IFN-alpha has been reported recently
by four groups [54–57]. A sustained virological response,
defined as negative HDV RNA 6 months after treatment
cessation was reported in 17–47% of patients. Differences in
drop out rates, in the sensitivities of HDV RNA PCR assays
used, in the proportion of patients who had used interferon
in the past and who were cirrhotic at baseline, may account
for the divergent results. Several studies emphasize the
importance of measuring HDV RNA at month 6 of treatment
[54,55,58]. In an analysis of baseline factors predicting
response to treatment, patients who were treatment naı̈ve at
baseline or who had a low baseline GGT tended to respond
better compared to patients who had used IFN in the past or
whose baseline GGT was high [58]. In this study and previous studies [59], disease of short duration was predictive of
response to treatment.
Nucleoside analogues (NAs) have been tested in CHD. In
the past, ribavirin had been used because it had been
associated with the inhibition of HDV replication in primary woodchuck hepatocyte cultures infected with HDV
[60]. However, these in vitro results were not reproduced in
vivo in a pilot study of nine patients with chronic hepatitis
D who were given ribavirin monotherapy at a dose of
15 mg/kg daily for 16 weeks [61]. Famciclovir, lamivudine,
adefovir and entecavir have also been assessed for the
treatment of CHD. Unfortunately, all of them appear to be
without effect in chronic hepatitis delta [57,58,62–65].
These disappointing results were to be anticipated because
HDV replication does not possess a reverse transcription
step [2,3]. The studies have thus confirmed the fact that
CHD depends solely on HBsAg production from the helper B
virus.
The best and most widely studied of the NAs is lamivudine. In the two randomized trials, lamivudine was associated with a response rate of around 10%, which may be
considered as a placebo effect [63]. NAs were also without
effect in terms of HDV RNA negativization in patients with
HBeAg-positive CHD where higher HBV DNA levels are
expected [66]. However, HBeAg-positive CHD does not
represent a homogenous cohort with high HBV DNA levels;
in a large European database, a quarter of HBeAg-positive
CHD were actually associated with HBV DNA of <2000 IU/
mL [67]. Further, HBsAg levels in HBeAg-positive CHD were
higher than in HBeAg-negative CHD [67], which may
account for the disappointing results of NA treatment even
in HBeAg-positive CDH treated with NAs. A pilot study
suggests that NAs may be beneficial in a subset of patients
with high HBV DNA and very low HDV RNA [65]. Finally,
another NA, clevudine, drew attention because in the
woodchuck hepatitis model, it significantly inhibited the
production of the surface antigen, the only HBV function on
which HDV depends, in a dose-dependent manner [68]. and
in a preliminary study, clevudine was able to significantly
decrease HDV RNA in woodchucks infected with HDV [69].
However, development of clevudine in the international
market has been put on hold because of mitochondrial
toxicity [70].
Several nucleoside analogues have been used in combination with interferons for the treatment of chronic hepatitis
delta. Lamivudin–interferon combination treatment did not
show superiority over interferon monotherapy in two randomized studies and one pilot study [58,71,72]. Both conventional and pegylated interferon have been used in
combination with ribavirin [53,54,73]. In these studies,
an advantage of combination treatment over IFN as
monotherapy could not be shown. Finally, adefovir-pegylated IFN combination was assessed recently in the largest
multicenter–multinational study so far in CHD [57]. In this
study, Peg-IFN based treatment led to a 6 months posttreatment virological response rate in a quarter of patients.
Although combination treatment was not more effective
than peg-IFN monotherapy, combination treatment appeared to be significantly more effective compared to peg-IFN
monotherapy in reducing HBsAg levels. In a subanalysis of
the patient cohort from this study, quantitative HBsAg levels
correlated with HDV viremia [74]. On-treatment HBsAg
quantification could potentially be an important adjunct for
treatment assessment [75], as is now suggested for treatment monitoring in patients with CHB treated with pegylated interferon [76].
Other substances tried for the treatment of CHD include
thymic humoral factor-gamma 2 (THFc-2), a synthetic
thymus-derived peptide known to have a variety of
immunomodulatory effects. It has been reported as being
effective in chronic hepatitis B. However, no virological or
biochemical effect was seen in CHD [77]. The antihelminthic drug levamisole, because of its immunomodulatory
properties, was also tried but was without effect in CHD
[78]. A list of drugs used so far in CHD in humans is
provided in Table 2.
2010 Blackwell Publishing Ltd
Chronic delta hepatitis
Table 2 Medications used to treat chronic hepatitis delta in
humans. Therapy with proven efficacy has been reported
only for interferon alpha or pegylated interferon alpha. The
others were either not effective or in the case of Combination
did not provid additional benefit over interferon
monotherapy
Interferon alpha
Pegylated interferon alpha
Thymic humoral factor-gamma 2
Levamisole
Ribavirin
Lamivudine
Adefovir
Entecavir
Interferon alpha + lamivudine
Interferon alpha + ribavirin
Pegylated Interferon alpha + ribavirin
Pegylated Interferon alpha + adefovir
POTENTIAL NEW TREATMENT TARGETS
Potential treatment targets can be found by investigating the
life cycle of HDV. Four events can be segregated [79]:
(i) attachment of the HDV virion to the hepatocyte and
entrance into the hepatocyte; (ii) translocation to the nucleus;
(iii) genome replication and (iv) virion assembly. Of these four
steps of the HDV life cycle, two steps, the first and the last steps,
are under investigation as potential treatment targets.
For the step of cellular attachment, the HBV envelope
consisting of the large (L), middle (M) and small (S) surface
proteins, is of importance. These proteins are all coded by a
single open reading frame on the HBV genome using three
different sites for initiation of translation. Recently, the
hepatocyte-associated heparin sulphate proteoglycans have
been identified as attachment receptors for both HBV and
HDV [80,81]. Studies have highlighted the importance of the
preS1 domain within the L HBsAg protein: the integrity of
the N-terminal 77 amino acids in the preS1 domain and
myristoylation of glycine in the preS1 domain appear to be
crucial. Abolishment of HBV infection by interfering with
these two properties has been shown both in vitro [80,81]
and in vivo [82]. A phase I study of the use of hepatocyte
entry inhibitors is being planned in Germany.
Two approaches have been developed for potential treatment of HDV through inhibition of virion assembly and
secretion. One involves the use of glucosidase inhibitors [83].
In hepatocytes infected with HBV or HDV, HBsAg leaves the
hepatocyte through the endoplasmic reticulum (ER) where
glucosidase enzymes of the ER modify the envelop glycoproteins so that these glycoproteins are appropriately folded
for translocation through the ER. Glucosidase inhibitors by
Chronic hepatitis B, anti delta (+) patient
HDV RNA(+)
ALT normal
HDV RNA(+)
ALT↑
HDV RNA(–)
ALT normal
Check ALT, HDV RNA,
q3 months.
Repeat, if same
follow-up q6 months with US
Treat if ALT↑, HDV RNA(+)
Treatment with IFNα↓2a or 2b,
9 or 10 million units, tid or peg-IFNα 2a,
180 µg, qw for 1 year
Response:
HDV RNA(–)
ALT normal
Dc treatement, follow-up
q2 months for 6 months.
Partial response:
HDV RNA ↓ >2log
ALT↑ or normal
No response:
HDV RNA no change or
decline < 2log and ALT↑
Consider treatement continuation
for an additional year. If treatement
continued consider this algorithm
also at end of 2nd year
Consider experimental
treatement
If ALT↑, HDV RNA(+)
If ALT normal, HDV RNA(–)
If HDV RNA(+), ALT normal
Consider restarting
treatement
Check ALT, HDV RNA
q3-6 months, HB serology
q6 months.
Check HDV RNA, ALT q3 months
Consider restarting treatement if ALT↑
Fig. 1 Treatment algorithm suggestion for patients with chronic delta hepatitis.
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C. Yurdaydın et al.
causing misfolding of envelop proteins prevent secretion of
virions. Although the use of glucosidase inhibitors seemed to
be an attractive strategy a serious concern is the possibility
that retained HBV envelop proteins may stimulate oncogenic
pathways and lead to the development of HCC [84,85].
Another approach would be the use of prenylation
inhibitors. The large delta antigen contains at its carboxyl
terminus a cystein containing four amino acid motif serving
as substrate for prenyl transferases, which add a prenyl
group to the large delta antigen [86]. It has been shown that
prenylation of the large delta antigen is necessary for virion
morphogenesis. Prenylation inhibitors have been shown to
specifically abolish HDV-like particle production in vitro
[87,88] and in vivo [89], which supports its use in human
delta infection because these appear to be without major side
effects in humans [90].
These novel treatment strategies need testing in the
human condition. For the time being however, the only
management available for CHD is treatment with interferons. Based on available data mentioned in this review, we
suggest the use of the algorithm outlined in Fig. 1 for the
treatment of patients with CHD.
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