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the HBV infection thereater. HBsAg levels of <2 log10 IU/mL at treatment
https://t.me/medicina_free
withdrawal were associated with a lower relapse rate ater 1–2 years (15%
vs. 85%) (Liang 2011).
The predictors of of-treatment response were recently assessed in a
meta-analysis including 25 studies with more than 1700 patients in whom
NAs were discontinued (Papatheodoridis 2016). The duration of suppression
of HBV DNA was shown to be the most important predictor of a durable
of-therapy, and the probability of a viral relapse was lower in patients
with suppression of HBV DNA for 24 months compared to 12 months (36%
vs. 75%). Low HBsAg levels at the time point of treatment cessation were
shown to be another positive predictor of treatment response (Wang 2016).
However, more prospective studies are certainly needed for validation
of these observations and for the reined deinition of termination of NA
treatment. Severe liver damage due to ALT lares was only observed in
patients with cirrhosis so far (Papatheodoridis 2016).
9. Treatment of hepatitis B infections
Figure 13. HBV DNA and alanine aminotransferase (ALT)* levels, HBsAg loss and retreatment
with TDF in 21 HBeAg- negative patients during 144 weeks after discontinuation of TDF
treatment (figure taken from Berg 2017). The number of patients with different post- NA
treatment are given in the bars. *ULN defined as 45 U/L. ALT, alanine aminotransferase;
HBsAg, hepatitis B sur face antigen; ULN, upper limit of normal
Figure 12 . Suggested association of NA treatment discontinuation and the arising of sustained
immune control. Af ter a temporar y increase, HBV DNA levels durably drop below the limit of
treatment indication (<2,000 IU/mL) and alanine aminotransferase (ALT) levels normalise.
HBsAg levels show some decline under increased immune control, in some patient s even to
undetectable levels (van Bömmel 2018).
200 201
Management of HBV resistance
Resistance development. The mechanism of action of NAs is a
competitive inhibition of the HBV polymerase. During treatment with these
substances, HBV variants bearing mutations within the HBV polymerase
gene may become selected from the HBV quasispecies, a phenomenon
which is deined as genotypic resistance.
Phenotypic resistance is deined as decreased susceptibility (in vitro
testing) to inhibition by antiviral drugs as sociated with genotypic resista nce
(Figure 15).
Cross-resistance of HBV to antiviral treatment has been described wit hin
the groups of nucleoside and nucleotide analogues, respectively (Figure 16).
If a resistant population becomes the majority in an individual, treatment
might fail and a viral breakthrough during treatment may appear which
may be associated with severe and sometimes fatal reactivation (Zoulim
2012).
9. Treatment of hepatitis B infections
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Figure 14. Cumulative incidence of HBV resistance. These numbers are average estimates
based on different studies. Overall, resistance rates have been higher in HBeAg positive
patients than in HBe antigen negative patients. Long-term data for ADV has only been
reported for HBeAg negative patients and thus resistance rates may be even higher for HBe
antigen positive individuals. Data for ET V is biased since both patients with best responses
(e.g., HBeAg seroconversion) and patients with suboptimal virologic responses (>700,000
copies/mL after one year of treatment) were withdrawn from the study. For TDF and TAF, no
viral breakthrough associated with HBV resistance has been described yet (modified from
[EASL 2017].
Theoretically, all available NAs may select resistant HBV strains.
However, resistance is very rare in treatment-naïve patients who receive
substances with strong antiviral activity, i.e., TDF or ETV, but resistance
rates against LdT, ADV and especially LAM are signiicantly higher (Figure
14).
Interestingly, for patients treated with TDF no resistance has ever been
reported, not even in patients who were pretreated with ADV, although
ADV resistance-associated mutations might slightly decrease response to
TDF (van Bömmel 2012, Kitrinos 2014, Berg 2014).
Detection of HBV resistance. Generally, a conirmed re-increase of
HBV DNA >1 log from nadir during treatment with nucleoside/nucleotide
analogues is considered being a potential viral breakthrough caused by
HBV resistance (Figure 10). Genotypic resistance testing is not available
to most treating physicians and is generally not recommended (Cornberg
2011, EASL 2017, Terrault 2016). However, genotypic resistance testing
might be helpful in individual cases. It has to be considered that most viral
breakthroughs in treatment-naïve patients receiving ETV or TDF are the
result of adherence issues. Therefore, patient adherence should be assessed
before genotypic resistance testing is done.
Figure 15. Resistance patterns of different antiviral drugs used for the treatment of chronic
hepatitis B. The numbers indicate the respective amino acid position in the HBV polymerase
gene. For ETV, resistance at positions rt204 plus an additional mutation at position rt184,
rt202 or rt250 is required to lead to clinically significant drug resistance. The mutations
rtA181V and rtN236T cause resistance against ADV and weaker response to TDF in some
patients; however, to date, viral breakthrough while on TDF treatment has not yet been
shown to be associated with HBV variants.
Avoidance of HBV resistance. HBV resistance occurs most frequently
in patients treated with LAM, LdT or ADV, therefore many guidelines
discourage physicians to use these NAs in irst line treatment. The selection
of resistant HBV strains becomes more likely if HBV DNA levels do not
become suppressed to undetectable levels within 6 months of treatment
with these NAs. Therefore, in patients undergoing treatment with these
substances, who show detectable HBV DNA ater 6 to 12 mont hs of treatment,
the treatment should be adjusted (Cornberg 2011, EASL 2017, Terrault 2016).
Also, patients with high viral load (>109 copies/mL) are at increased risk
of resistance and should not be treated with these substances. First-line
treatment with ETV or TDF is recommended by many guidelines to avoid
HBV resistance (Cornberg 2011, EASL 2017, Terrault 2016, WHO 2015).
Treatment of HBV resistance. Generally, resistance against a nucleoside
analogue should be treated with a nucleotide analogue and vice versa (Figure
13). In real life, treatment with TDF has been shown to suppress most kinds
of HBV variants associated with resistance against either nucleoside or
nucleotide analogues. Thus, a switch to a monotherapy with TDF was shown
to be very efective in patients with resistance to LAM and also in patients
with resistance to ADV in European and in Asian patients (van Bömmel
2010, Huang 2017). In a randomised study, it was shown that patients with
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9. Treatment of hepatitis B infections
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resistance to LAM did not show better response to a combination treatment
of TDF plus emtricitabine as compared to TDF monotherapy (Fung 2014). In
another study, it was observed that monotherapy with TDF was superior
to entecavir-adefovir combination treatment in NA resistant patients with
suboptimal response to lamivudine-adefovir (Lee 2017). However, some of
these patients with genotypic ADV resistance, especially those with HBV
DNA levels >107 copies/mL showed delayed or incomplete response to
TDF (van Bömmel 2010). ETV was shown to be efective as monotherapy
in patients with resistance to ADV. General recommendations for the
management of HBV resistance are given in Table 8.
Table 9. Recommendations for the treatment of HBV resistance
Resistance to nucleoside analogues Recommended therapeutic option
lamivudine tenofovir (TDF, TAF), ADV*
telbivudine tenofovir (TDF, TAF), ADV*
entecavir tenofovir (TDF, TAF), adefovir*
Resistance to nucleotide analogues Recommended therapeutic option
adefovir (LAM-naïve) entecavir, tenofovir (TDF, TAF), (telbivudine),
(lamivudine)
adefovir (LAM-resistant) tenofovir (TDF, TAF)
tenofovir (no in vivo data available) entecavir, (telbivudine), (lamivudine)
* in case tenofovir is not available
The combination of ADV and LAM in the presence of LAM resistance
delays the development of ADV resistance considerably compared to
switching to ADV monotherapy (Lampertico 2007). However, combination
treatment consisting of one nucleotide and one nucleoside analogue is
not necessary for the majority of patients if TDF is available. However
combination of TDF with a nucleoside analogue might be useful in patients
with multiple pre-treatments who have accumulated diferent resistance
mutations (Petersen 2012, van Bömmel 2012). In a therapeutic setting where
TDF is unavailable a combination treatment with ADV should be inititiated
if resistance to LAM, LdT or ETV occurs.
Treatment of HBV infections in special populations
Pr eg nancy. Globally, the vertical transmission from the mother to
the newborn is the most frequent cause of HBV infection, and the highest
risk is during delivery. A combination of hepatitis B immunoglobulin and
vaccination given within 12 hours ater birth can reduce the risk of perinatal
transmission from >90 to <10% (WHO 2015). Still for a neonate born to a
mother with high levels of HBV DNA (>200,000 IU/mL) the risk of perinatal
transmission is considerable. Therefore, antiviral treatment is generally
recommended in these women (Cornberg 2011, EASL 2017, Terrault 2016,
WHO 2015). PEG-IFN α is contraindicated in pregnant women. Antivirals
studied in pregnant women are LAM, LdT and TDF. In pregnant women
with high levels of HBV DNA, LAM treatment during the last trimester of
pregnancy was reported to reduce the risk of intrauterine and perinatal
transmission of HBV if given in addition to passive and active vaccination
by HBIg and HBV (van Zonneveld 2003). LdT administered for an average
of 15 weeks at the end of pregnancy plus active-passive immunisation to
neonates reduced vertical transmission rates from 23% to 4% compared to
immunisation alone (Han 2011). Because of its high antiviral potency, TDF is
oten considered the treatment of choice.
The risk of teratogenicity of NAs is assessed by a classiication based
on data gathered in clinical trials as well as through the FDA Pregnancy
Registry. TDF and LdT are listed as pregnancy category B drugs and LAM,
whereas ADV and ETV as category C drugs. However, other side efects
for the new born cannot completely be ruled out. A recent study reported
that bone mineral content of infants of HIV infected mothers exposed to
TDF (N=74) was 12% lower than that of infants not exposed to TDF (n=69)
(Siberry 2015). Although the signiicance of this observation is yet unclear,
antiviral treatment during pregnancy should be carefully monitored and
limited to the second and third trimester. However, the optimal treatment
duration has not been studied. As exacerbations of the HBV infection may
occur, women with HBV should be monitored closely ater delivery (ter
Borg 2008).
Immunosuppression. During immunosuppressive treatment, a
reactivation of an asymptomatic or inactive HBV infection can occur in 20%
to 50% of patients (Lok 2009). Reactivations can occur in HBsAg carriers,
but also in HBsAg negative but anti–hepatitis B core antibody (HBc)–
positive patients. These reactivations are characterised by an increase
in HBV replication followed by an increase in liver inlammation during
immune reconstitution resulting in liver damage or even liver failure in
some patients (Feld 2010, Roche 2011).
HBV reactivation was especially frequently observed during treatment
with corticosteroids and antitumour necrosis factor therapies (i.e.,
inliximab, etanercept, adalimumab), anti-CD20 therapies (i.e., rituximabcontaining chemotherapy) and trans-arterial chemoembolisation for HCC
(Vassilopoulos 2007, Moses 2006, Park 2005, utgeerts 2009, Mallet 2015).
Prior to initiating immunosuppressive therapies, screening for HBV
infection is recommended (Lok 2009, EASL 2017). Pre-emptive treatment
with nucleoside/nucleotide analogues should be initiated in all patients with
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9. Treatment of hepatitis B infections
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active HBV infection before any immunosuppressive treatment. HBsAg
positive inactive HBV carriers have a diminished risk of HBV reactivation
and mortality when pre-emptive treatment is conducted. Inactive carriers
receiving immunosuppressive treatment with methotr exate or azat hioprine
in monotherapy represent an exemption as these patients have a low risk of
HBV reactivation (Mallet 2016).
HBsAg negative/anti-HBc positive patients should only receive preemptive treatment if treatment with rituximab or human stem cell therapy
is planned (Lok 1991, Zurawska 2012).
If available, a highly potent antiviral as ETV or TDF should be used for
pre-emptive treatment. This recommendation is based on some recent
reports revealing lower rates of HBV reactivation in patients treated with
ETV as compared to patients treated with LAM. However, reactivations may
still occur albeit in a low frequency. This was recently demonstrated in a
randomised controlled trial of HBsAg negative/anti-HBc positive patients
receiving chemotherapy including an anti-CD20 agent. In these patients,
HBV reactivation occurred in 18% of the untreated compared to 2% of those
patients receiving prophylaxis with ETV (p<0.05) (Lau 2003).
Novel treatments for HBV infections
Figure 16. Novel approaches to treat HBV infections (selection). They include direct inhibition
of the viral life cycle by HBV polymerase inhibitors (1), inhibition of pgRNA encapsidation with
HBc allosteric modulators (CpAMs) (2), HBV RNA inter ference with siRNA molecules inhibition
of HBsAg secretion by nucleic acid polymers (3), inhibition of HBsAg secretion by nucleic acid
polymers (4), stimulation of the innate immune system as toll like or receptor stimulation or
the adaptive immune system as check point (e.g., programmed cell death (PD-1)) inhibitors (5),
cotransporting polypeptide degradation of cccDNA by APOBEC3A/B deminases or CRISPRassociated system 9 (Cas9) proteins (6) HBV entry through sodium taurocholate blocade (7).
Novel HBV serum markers are currently investigated for their value in treatment response
monitoring, including HBV RNA, HBV core related antigen (HBcrAg), quantitative HBeAg and
HBsAg components (8).
The complete eradication of HBV from infected individuals cannot be
achieved by any of the currently available treatment strategies, and this is
due to persistence of HBV cccDNA. Trials investigating the possibility of
improving outcomes in the treatment of HBV infections by combination
treatment of PEG-IFN α with NAs in diferent doses and durations and by
using novel NAs are ongoing. Besifovir (LB80380) is an acyclic nucleotide
phosphonate with a molecular structure similar to that of ADV and TDF.
In a phase IIb, open-label, multicentre study in114 treatment naïve patients
randomised to besifovir 90 mg or 150 mg daily or to ETV 0.5 mg daily for 48
weeks, an equally strong antiviral activity as compared to ETV was shown
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9. Treatment of hepatitis B infections
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for besifovir. Thus, suppression of HBV DNA to undetectable levels was found
in 64, 63 and 58 %, and HBeAg seroconversion in 11, 15 and 9.5 %, respectively
(Lai 2014). Of note, 94% of patients receiving besifovir had reduced serum
L-carnitine, but the L-carnitine levels returned to normal with supplement.
Numerous novel substances are under investigation which might ofer
more potent suppression of HBV replication and, ideally, even eradication
of the infection. Multiple strategies are being followed, some of which are
targeting the innate or the adaptive immune system and some targeting
the HBV replication cycle at diferent steps and to date it is not clear which
approach is more promising. (Figure 17). Some of these novel drugs are
investigated in pre-clinical or in early clinical studies and preliminary
results have already been published for some approaches.
Thus, restoring the production of antiviral cytokines, which is oten
impaired in HBV infected individuals is followed by stimulation of toll
like receptors (TLRs) which are located on plasmacytoid dendritic cells
and myeloid cells. In HBV infected woodchucks it has been shown that
treatment with the oral TL7 agonist GS-9620 was followed by a marked
decrease in serum HBsAg levels. HBsAg seroconversion occurred in several
of these animals (Menne 2015). In contrast, in a trial in 26 patients with
chronic HBV infection there was no efect of diferent doses of GS-9620 on
HBsAg levels when given over 24 weeks (Boni 2016). However, stimulating
efects of the HBV speciic immune response were demonstrated including
the acquisition of an activated natural killer cell type.
Interruption of HBV replication by interference with diferent key
mechanisms of the HBV replication cycle is also currently investigated. The
use of RNAi to inhibit the replication of HBV has been evaluated in animal
models.
The siRNA molecules AC-520 (phase II: NCT02604212 and
NCT02604199; Arrowhead Research Corporation, Pasadena, CA, USA),
ARB-1467 (phase II: NCT02631096; Arbutus Biopharma, Burnaby, British
Columbia, Canada) and ALN-HBV (phase I/II: NCT02826018; Alnylam,
Cambridge, MA, USA) are currently investigated in in clinical trials, The
compound AC-520 was shown to induce a durable and deep suppression
of HBV proteins and HBV DNA in a phase II study (Yuen 2015). The nucleic
acid polymer (NAP) Rep2139 (Replicor, Montreal, Quebec, Canada), has been
shown to inhibit the secretion of HBsAg by an unidentiied mechanism.
Its combination with pegIFN-α in clinical trials (NTC02233075) has been
shown to result in a signiicant suppression of HBsAg and HBV DNA levels
and a high rate of HBsAg seroconversion.
It is likely that these substances will be used in combination with either
NAs or PEG-IFN α and there is a need for new bio markers which relect the
level of HBV replication and the eicacy of these new compounds when HBV
DNA is suppressed to undetectable levels. For this purpose, new markers
such as quantitative HBeAg, HBV core-related antigen (HBVcrAg) and HBV
RNA are currently under investigation and these molecules might be useful
to tailor individual treatments and to increase response rates in the future.
An important goal for new drugs for treatment of HBV infections will
be to move patients closer towards complete eradication of HBV. To date it
seems, however, too early to predict the role of those novel compounds in
future HBV treatments, but this fast developing ield of research deserves
continuous attention.
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10. Hepatitis D –
https://t.me/medicina_free
diagnosis and treatment
Heiner Wedemeyer
Introduction
Hepatitis delta is the most severe form of viral hepatitis in humans.
The hepatitis delta virus (HDV) is a defective RNA virus which requires the
hepatitis B virus (HBV) surface antigen (HBsAg) for complete replication and
transmission, while the full extent of the HBV helper function is unexplored
(Rizzetto 1983, Taylor 2012). Hence, HDV occurs only in HBsAg positive
individuals either as acute coinfection or as superinfection in patients
with chronic HBV (Wedemeyer 2010) (Figure 1). Several studies have shown
that chronic HDV infection leads to more severe liver disease than chronic
HBV monoinfection, with an accelerated course of ibrosis progression,
possibly a slightly increased risk of hepatocellular carcinoma and early
decompensation in the setting of established cir rhosis (Hughes 2011, Manesis
2013, Beguelin 2017). Simultaneous HBV and HDV infection has also been
shown to be more severe than infection with HBV alone in chimpanzees
(Dienes 1990). An easy to apply clinical score has been suggested to predict
the likelihood of experiencing a clinical event for patients with HDV, the
baseline-event-anticipation (BEA) score (Calle-Serrano 2014). So far, only
interferon α treatment is recommended against HDV (Deterding 2019) and
has been linked to improve the clinical long-term outcome (Farci 2004,
Wranke 2017, Yurdaydin 2018). Data on the use of pegylated interferon (PEGIFN) conirm earlier indings, leading to prolonged virological of-treatment
responses in about one quarter of patients but long-term HDV RNA relapses
may occur (Heidrich 2014). Thus, HBsAg clearance should be the preferred
endpoint of interferon-based therapies of HDV. Still, suppression of HDV
RNA in the presence of HBsAg has been associated with improved clinical
outcomes. Alternative treatment options including HBV entry inhibitors
and prenylation inhibitors (www.clinicaltrials.gov) are currently in phase
3 clinical development.
215214
Figure 1. Courses of hepatitis delta
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Virology of HDV
The hepatitis D virion is approximately 36 nm in size, containing HDV
RNA and delta antigen. HDV RNA is single-stranded, highly base-paired,
circular and by far the smallest known genome of any animal virus,
containing close to 1700 nucleotides (Taylor 2012, Sureau 2016). It is coated
with the envelope protein derived from the pre-S and S antigens of HBV.
Other enveloped viruses including HCV and VSV can also propagate HDV
infection, both in vitro as well in humanized mice (Peres-Vargas 2019). Still,
it is currently unclear if viruses distinct from HBV induce dissemination
of HDV also in patients. The HDV RNA has six open reading frames (ORFs),
three on the genomic and three on the antigenomic strand. One ORF codes
for the hepatitis delta antigen (HDAg), while the other ORFs do not appear
to be actively transcribed. Two HDAgs exist: the small HDAg (24 kD) is 155
amino acids long and the large HDAg (27 kD) 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 genome synthesis, while
the large HDAg that inhibits HDV RNA synthesis is necessary for virion
morphogenesis (Taylor 2012). 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 then
10. Hepatitis D – diagnosis and treatment
autocatalytically cleaved to linear monomers and ligated into the circular
HDV RNA viral progeny (Sureau 2016). Recent work showed that the host
RNA polymerase II-is coactivated by S-HDAg using a histone mimicry
strategy (Abeywickrama-Samarakoon 2020).
Genetic analysis has revealed the presence of at least eight HDV
genotypes (Le Gal 2017) (Figure 2). Genotype 1 is the most frequently seen
and is distributed throughout the world, especially in Europe, the Middle
East, North America and North Africa. Genotype 2 is seen in East Asia
and the Yakutia region of ussia, and genotype 3 is seen exclusively in the
northern part of South America, especially in the Amazon basin. Genotype
4 is seen in Taiwan and Japan while genotypes 5–8 are found in Africa (Deny
2006). HDV genotype 1 is associated with both severe and mild disease
whereas genotype 2 causes a milder disease over a long-term course (Su
2006). HDV genotype 5 may also take a milder course and a better response
to PEG-IFNa treatment compared to genotype 1 (Spaan 2020).
HDV quasispecies evolution declines over time during HDV infection
even though a continuous adaptation of HDV occurs indicating ongoing
immune pressure in chronic HDV (Homs 2016).
HBV genotypes may also contribute to distinct clinical courses of HDV.
There is no evidence that speciic HDV genotypes may infect patients with
one speciic HBV genotype exclusively. However, recent data indicate that
distinct HDV mutations may facilitate association of certain HDV genotypes
with diferent HBV genotypes (Kay 2014). The global distribution of HBV
and HDV genotypes is shown in Table 1.
Table 1. HBV and HDV genotypes
Region HDV genotype HBV genotype
Europe 1 D/A
Brazil 1/3 F/A/D
China, Taiwan, Japan 1/2 /4 B/C
Turkey, Iran, Pakistan, India 1 D
Western Pacific 1/2 B/C/D
Africa 1, 5–8 D/A / E
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Figure 2. Prevalence of HDV genotypes
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Epidemiology of HDV
HDV is not an uncommon disease. Being linked to HBV, HDV is spread
in the same way as HBV, mainly through parenteral exposure (Niro 1999).
It is highly endemic in Mediterranean countries, the Middle East, Central
Africa, and northern parts of South America (Hughes 2011) (Figure 2).
In high-income countries, high anti-HDV prevalence is found in people
who inject drugs (PWID) who are HBsAg positive, both in Europe (Gaeta
2000, Heidrich 2009, Erhardt 2010) and North America (Kurcirka 2010).
Worldwide, more than 240 million people are chronically infected with
HBV and 15–25 million of those are estimated to be anti-HDV positive
(Wedemeyer 2010). Two systematic reviews suggested that the prevalence
of HDV may be even higher reaching up to 1% of the populations worldwide (Chen 2018, Miao 2019). This work has been criticized as systematic
reviews can only be as good as studies included (Wedemeyer 2018). but
HDV may still be more frequent than previously thought. HDV was
endemic in Southern Europe. Several studies performed in the 1980s and
1990s showed a prevalence of anti-HDV of more than 20% among HBsAg
positive individuals. As a result of the implementation of HBV vaccination
programmes, the incidence of HDV infections signiicantly decreased in
Southern Europe in the 1990s (Gaeta 2000, Degertekin 2008) (Figure 3).
Other countries with a particularly high prevalence of HDV are Mongolia
with up to one third of chronic hepatitis cases being caused by HDV
(Tsatsralt-Od 2005), some Central Asian republics, Pakistan (Abbas 2012),
10. Hepatitis D – diagnosis and treatment
northwestern states of Brazil (Kay 2014, Braga 2014), distinct regions
in Africa (Andernach 2014), and some Polynesian islands (Han 2014).
Of note, prevalence rates of HBV and HDV are not linked - for example,
HDV infections have been considered to be rather rare in most parts of
mainland China despite very high frequencies of HBV. However, some
studies revealed an HDV prevalence of up to 6.5%, suggesting that HDV may
be more frequent in China than previously thought (Lia 2014). HBV/HDV
coinfection was also associated with higher frequencies of end-stage liver
disease in that study. In Taiwan, a country with a well-established national
HBV vaccination program, the epidemiology of HDV changed over the last
20 years with PWID and HIV positive persons being particular risk groups
and representing a main reservoir for HDV infection (Hung 2014, Lin 2015,
Lee 2015).
One problem is that many HBsAg positive patients are not tested for
HDV. A study from Greece even suggests that HDV testing declined over
the last 10 years and only about one-third of people with HBV are currently
assessed for the presence of HDV antibodies (Manesis 2013). Similarly, the
HDV testing rate was low in four hospitals in London where people with
HDV frequently had severe disease and patients were of very diverse
ethnicity (El Bouzidi 2015). In the United States Veterans Afairs medical
system, only 8.5% of more than 25,000 HBsAg positive patients were tested
for HDV. Of those, 3.4% had evidence for HDV and HDV was associated with
a 2.9 fold higher HCC incidence and a higher risk of all-cause mortality
(Kushner 2015).
In our experience at a referral centre for liver disease, about 8–10% of
HBsAg positive patients test positive for anti-HDV as chronic HDV still
represents a signiicant health burden in Central Europe, which is a source
of immigration (Wedemeyer 2007, Heidrich 2009, Erhardt 2003, Erhardt
2010) (Figure 3, Table 1). More than three quarters of these HDV patients
were not born in Germany. However, the geographical origin of our patients
has changed during the last decade. While until the mid-1990s the majority
of HDV positive patients were born in Turkey, the proportion of Eastern
European patients has signiicantly increased in recent years (Wedemeyer
2007). Similarly, high HDV prevalence in immigrant populations has
been described in clinics in the UK (Cross 2008), France and Italy (Le Gal
2007, Mele 2007). HDV can also be found in high frequencies in people
living with HIV who are also HBsAg positive with about 14.6% in diferent
European regions (Soriano 2011). In France, the prevalence of HDV infection
has increased during the last 15 years, again mainly in pre-infected newly
arriving immigrants (Servant-Delmas 2013).
HDV prevalence is much lower in HBV patients without speciic risk
factors and cohorts excluding a referral bias. In this setting, less than 1–2%
of HBsAg positive individuals test anti-HDV positive, even in countries
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