Commentary
Devil hepatitis D: an orphan disease or
largely underdiagnosed?
Heiner Wedemeyer,1 Francesco Negro2
Hepatotropic viruses can infect hepato-
cytes causing a host defence reaction and
subsequently scaring of the liver—if the
infection is not cleared. The threats of
chronic viral hepatitis partially vanished
due to the revolution of antiviral treat-
ment options first for hepatitis B and more
recently for hepatitis C. Persistent HCV
infection can nowadays be cleared with
direct acting antiviral agents leading to
impressive improvements in the clinical
long-term outcome with reduced inci-
dences of hepatic decompensation and
hepatocellular carcinoma. Similarly,
durable suppression of HBV replication
has been shown to prevent disease progres-
sion and even to normalise life expectancy
unless hepatocellular carcinoma appears.1
Unfortunately, the scenario is completely
different for hepatitis D virus (HDV)
infection. Coinfection of HBsAg-positive
individuals with HDV causes the most
severe form of chronic viral hepatitis with
earlier development of liver cirrhosis,
higher incidence of hepatocellular carci-
noma and increased liver-related and
overall mortality.2 3 In addition, treatment
options for hepatitis D are currently
limited. Pegylated interferon alpha has
been shown to suppress HDV replication
in about 25% of patients but only a
minority of patients can be treated with
interferon-based therapies and late
relapses after initial viral control occur
frequently.4 Still, the extent of the global
disease burden caused by HDV infection is
a matter of debate. The WHO Global
Hepatitis Report 2017 highlighted the
issue of uncertainty regarding the HDV
burden.5 While both the European Medi-
cines Agency and the Food and Drug
Administration granted new compounds
to treat hepatitis D an orphan drug status
(meaning that less than 5 or less than 7.5
out of 10 000 individuals are suffering
from hepatitis D), a well-conducted
1
Department of Gastroenterology and Hepatology,
Essen University Hospital, University of Duisburg-Essen,
Essen, Germany
2
Divisions of Gastroenterology and Hepatology of
Clinical Pathology, University Hospital of Geneva,
Geneva, Switzerland
Correspondence to Professor Heiner Wedemeyer,
Department of Gastroenterology and Hepatology, Essen
University Hospital, University of Duisburg-Essen, Essen
47057, Germany; ​Heiner.​Wedemeyer@​uk-​essen.​de
systematic review published in Gut
suggests that up to more than 60 million
individuals worldwide (!!) could be
infected with HDV.6 This would mean that
the global HDV prevalence would be at
least twofold to threefold higher of what
has been estimated before. Is this really a
reliable assumption and do we have to
modify hepatology textbooks?
HDV infection occurs in HBsAg-pos-
itive individuals only as the viroid-like
self-complementary RNA HDV depends
on a helper virus (ie, HBV in the human
infection), which provides the envelope
for assembly and transmission.7 Simul-
taneous coinfection of HBV and HDV
leads to severe acute hepatitis with spon-
taneous resolution of both HBV and
HDV infections. In contrast, HDV super-
infection of chronic HBV carriers evolves
towards persistency. Patients with HDV
infection show HBsAg levels similar to
HBV-monoinfected individuals but HBV
DNA is frequently low or completely
suppressed in hepatitis D.7 Subsequently,
vertical transmission of HDV occurs
infrequently8 and the majority of patients
have therefore acquired HDV infection
during childhood. At least eight different
HDV genotypes are known with distinct
global distributions. Countries with high
HDV prevalences are located in Central
Asia, Eastern Europe, West Africa
and the Amazonian region. However,
patients show a heterogeneous clinical
presentation with more severe courses of
liver disease in South America and older
patient’s age in European cohorts.9
The epidemiology of HDV infec-
tion is still only partially understood.
It is unclear why HDV prevalence may
differ between neighbouring countries,
for example, more than 10%–15% of
HBsAg-positive patients are seropositive
for HDV in Romania while much lower
rates have been reported in Bulgaria
or Hungary. Even within a territory,
unexplained ‘hotspots’ can exist. In the
Amazon basin, between 60% and 100%
of individuals may be anti-HDV positive
in distinct villages while HDV cannot be
detectable at all in nearby settlements.10
Few population-based studies on
HDV incidence and prevalence are
available. Previous estimates on the
global number of individuals with HDV
Wedemeyer H, Negro F. Gut Month 2018 Vol 0 No 0
infection provided figures ranging
from 5 to 20  million. However, no
recent systematic review was available
Gut: first published as 10.1136/gutjnl-2018-317403 on 27 October 2018. Downloaded from http://gut.bmj.com/ on 3 December 2018 by guest. Protected by copyright.
supporting these assumptions. There-
fore, the present paper by Chen and
colleagues is of interest to stimulate the
discussion. 6 Key findings of this study
are as follows: (1) the global HDV
prevalence is underestimated, with new
proposed figures going from 10.5% of
all hepatitis B surface antigen-positive
persons to a staggering 1% of the global
population (!); (2) the current HDV
epidemic is mainly driven by injecting
illicit drugs, with three times higher
HDV seroprevalence in the intravenous
drug use than in the general popula-
tion; (3) high-risk sexual behaviour has
to be considered as an additional risk
factor for hepatitis D, at variance with
previous studies and may affect both
the homosexual and the heterosexual
populations; (4) the HDV prevalence
differed significantly between asymp-
tomatic HBsAg carriers and patients
with significant hepatitis activity, again
supporting that HDV per se is a major
driver of liver disease; and (5) despite
the availability of vaccines against hepa-
titis B, HDV prevalence rates increased
during the last 20 years in several coun-
tries due to immigration.
The systematic review was well
conducted even though several limita-
tions need to be considered. The
authors do not discuss the significant
problem of ascertainment and referral
bias for many studies, bearing the risk
that reported hyperendemicity could
have been artefactual. In this regard,
the existing data on HDV epidemiology
should be regarded insufficient and
in some cases misleading. Regarding
methodology, it has to be noted that
only one author (not two independent
investigators) searched for articles
while two authors extracted data. Iden-
tifying studies is, however, critical as
in particular for a rare disease such as
HDV infection many articles may have
been published in regional journals
only. Inclusion or exclusion of studies
may be justified based on prespeci-
fied criteria but even if high standards
are applied the outcome of systematic
reviews can be surprisingly different.
This is also the case here where data for
Africa suggested by Chen et al differed
from a recent systematic review and
meta-analysis focusing on Africa. 11 In
that study, two publications from Benin
and Somalia reporting higher HDV
seroprevalences were not considered.
Another issue is that anti-HDV assays
   1
Commentary
differ in performance characteristics
and assays are not as standardised as
for other viral infections. Both false
negative and false positive anti-HDV
test results could not be considered
here. Moreover, the authors could
study HDV seroprevalence rates only
but not the true number of viraemic
HDV infections. About one-third of
anti-HDV-positive patients have unde-
tectable HDV RNA6—which could
indicate resolved hepatitis D, persistent
infection with very low viraemia or a
false negative PCR test result. Only
recently, commercial HDV RNA assays
became available with high sensitivity
and reliable coverage of all known
HDV genotypes. However, a meta-anal-
ysis can only rely on published litera-
ture and earlier studies frequently used
home-made assays which were not well
standardised.
So what can we learn from this
study? The number of HDV-infected
individuals is likely much higher than
previously thought—even though the
true HDV prevalence still remains a
matter of debate. Already based on
the numbers presented in the paper by
Chen et al one may calculate highly
conflicting and unprecedented figures.
Still, even adopting a very conserva-
tive attitude, for example, considering
only those patients who have detect-
able viraemia (ie, two-thirds of all
those anti-HDV positive), the global
disease burden caused by HDV would
be higher than previously estimated,
2 Wedemeyer H, Negro F. Gut Month 2018 Vol 0 No 0
urgently warranting new and more
effective treatment options. Luckily,
several new drugs including prenylation
inhibitors, entry inhibitors and nucleic
acid polymers are currently explored in
clinical trials.4 The first phase 3 studies
are expected to enrol patients in 2019.
Hopefully, the devil hepatitis D will be
as successfully challenged as hepatitis B
and C. Until then, preventive measures
should be implemented, in particular in
vulnerable high-risk populations. This
includes needle exchange programmes
as well as broader vaccination coverage.
Contributors  Both authors contributed equally to the
commentary.
Funding  This study was funded by German Center
for Infection Research (DZIF), partner site Hannover-
Braunschweig, external partner Essen, project 05.807.
Competing interests  None declared.
Patient consent  Not required.
Provenance and peer review  Commissioned;
internally peer reviewed.
© Author(s) (or their employer(s)) 2018. No commercial
re-use. See rights and permissions. Published by BMJ.
To cite Wedemeyer H, Negro F. Gut Epub ahead of
print: [please include Day Month Year]. doi:10.1136/
gutjnl-2018-317403
Received 9 October 2018
Accepted 12 October 2018
►► http://​dx.​doi.​org/​10.​1136/​gutjnl-​2018-​316601
Gut 2018;0:1–2.
doi:10.1136/gutjnl-2018-317403
Gut: first published as 10.1136/gutjnl-2018-317403 on 27 October 2018. Downloaded from http://gut.bmj.com/ on 3 December 2018 by guest. Protected by copyright.
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