Book on hepatitis from page 168 to 179

Book on hepatitis from page 168 to 179

168  Hepatology 2012
Special considerations in HIV/HBV coinfection
In patients with chronic hepatitis B and HIV coinfection, the first question to ask is
if there is an indication for antiretroviral therapy. In patients with no such indication
interferon or an HBV polymerase inhibitor without HIV activity are options. The
initially recommended monotherapy with entecavir is now considered obsolete – the
anti-HIV activity of entecavir has been described (M184V) in anecdotal cases
(MacMahon 2007). Currently, adefovir and telbivudine are recommended, based on
limited in vivo data for adefovir or in vitro data and some anecdotal case reports for
telbivudine (Delaugerre 2002, Sheldon 2005, Avilla 2009, Milazzo 2009). As both
drugs have limitations in the setting of HBV-monoinfected patients the initiation of
antiretroviral therapy allowing the use of tenofovir plus lamivudine/emtricitabine
should be considered, in particular in patients with advanced liver fibrosis.
In patients with an indication for antiretroviral therapy, a regimen containing
tenofovir with or without lamivudine or emtricitabine is favored in order to avoid
development of lamivudine or emtricitabine resistance in HBV. The incidence of
HBV resistance in patients treated with lamivudine after two years is about 50% in
HIV/HBV-coinfected patients (Benhamou 1999). In patients who have already
developed lamivudine-resistant HBV, tenofovir should be added to or replace
lamivudine for HBV treatment (Schmutz 2006). Whether entecavir should be added
in patients on tenofovir +/– emtricitabine/lamivudine or replace tenofovir in case of
renal impairment should be decided on an individual basis (Ratcliffe 2011).
A change of antiretroviral regimen in HBV/HIV-coinfected patients due to the
development of HIV resistance must take the HBV infection into consideration, as
the chronic hepatitis B may be exacerbated in the absence of an active HBV
polymerase inhibitor.
More information on this topic can be found in Chapter 17.
Immune escape and polymerase inhibitor
resistance
Another relevant but unexpected consequence of lamivudine resistance is the
induction of conformational changes in the HBs antigen due to an overlapping
reading frame in the genetic sequence of the HBV polymerase and the HBs antigen
(Figure 4). Because of this, mutations in the HBV polymerase may induce changes
in the envelope of the virus resulting in an altered immunogenicity. This may result
in vaccine escape mutants. In vitro and ex vivo studies support this hypothesis,
which may have important public health implications (Mathews 2006, Sheldon
2007). Studies in chimpanzees have indeed confirmed that infections with drug-induced HBV variants are possible despite the presence of high anti-HBs levels that
were considered protective in the vaccinated host (Kamili 2009).
In addition to humoral escape, lamivudine resistance may also affect cellular
immunity against HBV. As mentioned earlier, suboptimal antiviral therapy, e.g.,
with lamivudine, especially in high prevalence countries, could undermine the
success of vaccination efforts leading to a spread of HBV vaccine escape mutants.
The YMDD motif is also part of an MHC class I restricted CTL epitope. YMDD-specific cytotoxic T lymphocytes may partially cross-react with YVDD and YIDD
variants (Lin 2005) and thereby contribute to a prevention of emergence of
Management of Resistance in HBV Therapy  169
resistance. However, more studies are needed to explore in detail the consequences
of the development of viral resistance to polymerase inhibitors for T cell immunity
against HBV.
Conclusion
In summary, therapy with HBV polymerase inhibitors to date is limited to two
active subclasses with different resistance profiles. Resistance due to suboptimal
treatment, i.e., on only one drug, can eliminate or reduce the effect of other drugs
due to partial or complete cross-resistance. This sequence is well documented for
lamivudine, telbivudine and entecavir. The superiority of de novo  combination
therapy for HBV over sequential monotherapy may be likely for patients with very
high HBV viremia, but still has to be confirmed in well-designed prospective
clinical trials. In patients with low or intermediate viremia, the risk for development
of resistance is rather low when using drugs with a high genetic barrier and when a
rapid suppression of HBV replication is achieved (Figure 5).
The choice of first-line treatment strategy will determine future treatment options;
being judicious is paramount, as suboptimal therapeutic approaches can result in a
rapid exhaustion of options within just a few years.
Figure 5. Antiviral potency and genetic resistance barrier of currently approved HBV
polymerase inhibitors.
References
Benhamou Y, Bochet M, Thibault V, Di Martino V, Caumes E, Bricaire F, et al. Long-term
incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency
virus-infected patients. Hepatology. 1999;30(5):1302-6. (Abstract)
Berg T, Moller B, Trinh H, Chan S, Marcellin P, Suarez E, et al. Tenofovir disoproxil fumarate
(TDF) versus emtricitabine plus TDF for treatment of chronic Hepatitis B (CHB) in
170  Hepatology 2012
subjects with persistent viral replication receiving adefovir dipivoxil (ADV). Journal of
Hepatology. 2008; 48(Suppl.2): S34 (abstract 76).
Bonino F, Marcellin P, Lau GK, Hadziyannis S, Jin R, Piratvisuth T, et al. Peginterferon Alfa-2a
HBeAg-Negative Chronic Hepatitis B Study Group. Predicting response to
peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative
chronic hepatitis B. Gut. 2007; 56(5): 699-705. (Abstract)
Brunelle MN, Jacquard AC, Pichoud C, Durantel D, Carrouée-Durantel S, Villeneuve JP, et al.
Susceptibility to antivirals of a human HBV strain with mutations conferring resistance
to both lamivudine and adefovir. Hepatology. 2005; 41(6): 1391-8. (Abstract)
Chang T, Gish R, De Man R. A comparison of entecavir and lamivudine for HBeAg-positive
chronic hepatitis B. N Engl J Med 2006; 354: 1001-1010. (Abstract)
Chloe WH, Hong SP, Kim BK, Ko SY, Jung YK, Kim JH, et al. Evolution of hepatitis B virus
mutation during entecavir rescue therapy in patients with antiviral resistance to
lamivudine and adefovir. Antivir Ther 2009;14(7): 985-93. (Abstract)
Colonno RJ, Rose R, Baldick CJ, Levine S, Pokornowski K, Yu CF, et al. Entecavir resistance
is rare in nucleoside naive patients with hepatitis B. Hepatology. 2006;44(6):1656-65.
(Abstract)
Cornberg M, Protzer U, Dollinger MM, Petersen J, Wedemeyer H, Berg T, et al. Prophylaxis,
Diagnosis and Therapy of Hepatitis-B-Virus-(HBV-) Infection: upgrade of the
guideline. Z Gastroenterol. 2007; 45(6): 525-74.
Delaugerre C, Marcelin AG, Thibault V, Peytavin G, Bombled T, Bochet MV, et al. Human
immunodeficiency virus (HIV) Type 1 reverse transcriptase resistance mutations in
hepatitis B virus (HBV)-HIV-coinfected patients treated for HBV chronic infection
once daily with 10 milligrams of adefovir dipivoxil combined with lamivudine.
Antimicrob Agents Chemother. 2002;46(5):1586-8. (Abstract)
Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, et al. Italian
Association for the Study of the Liver (AISF) Lamivudine Study Group, Italy. Clinical
outcome of HBeAg-negative chronic hepatitis B in relation to virological response to
lamivudine. Hepatology. 2004; 40(4):883-91. (Abstract)
Erhardt A, Blondin D, Hauck K, Sagir A, Kohnle T, Heintges T, Haussinger D. Response to
interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive
to interferon than genotype D. Gut. 2005; 54(7):1009-13. (Abstract)
Erhardt A, Göbel T, Ludwig A, et al. Response to antiviral treatment in patients infected with
hepatitis B virus genotypes E-H. J Med Virol. 2009:1716-20 (Abstract)
Flink HJ, van Zonneveld M, Hansen BE, de Man RA, Schalm SW, Janssen HL. HBV 99-01
Study Group. Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic
hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol.
2006;101(2):297-303. (Abstract)
Fung SK, Andreone P, Han SH, et al. Adefovir-resistant hepatitis B can be associated with viral
rebound and hepatic decompensation. J Hepatol 2005; 43(6):937-43. (Abstract)
Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009; 461(7262):399-401. (Abstract)
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir Dipivoxil 438 Study Group.
Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for
up to 5 years. Gastroenterology. 2006;131(6):1743-51.
Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety nof tenofovir disoproxil
fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140(1):132-43Kamatani Y, Wattanapokayakit S, Ochi H, et al. A genome-wide association study
identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians.
Nat Genet. 2009; 41(5): 591-5.
Kamili S, Sozzi V, Thompson G, et al. Efficacy of hepatitis B vaccine against antiviral drug-resistant hepatitis B virus mutants in the chimpanzee model. Hepatology. 2009;
49(5):1483-91. (Abstract)
Kurashige N, Ohkawa K, Hiramatsu N, et al. Two types of drug-resistant hepatitis B viral strains
emerging alternately and their susceptibility to combination therapy with entecavir
and adefovir. Antivir Ther. 2009;14(6):873-7. (Abstract)
Lada O, Gervais A, Branger M, et al. Long-term outcome of primary non-responders to
tenofovir therapy in HIV/HBV-co-infected patients: impact of HBV genotype G. Liver
Int. 2012;32(1):93-101. (Abstract)
Management of Resistance in HBV Therapy  171
Lai CL, Leung N, Teo EK, et al. A 1-year trial of telbivudine, lamivudine, and the combination in
patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology.
2005; 129(2):528-36. (Abstract)
Lai C, Shouval D, Lok A, et al. Entecavir versus lamivudine for patients with HBeAg-negative
chronic hepatitis B. N Engl J Med 2006; 354:1011-20. (Abstract)
Lampertico P, Vigano M, Manenti E, et al. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology 2005;
42:1414-1419. (Abstract)
Lampertico P, Viganò M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to
adefovir combined with Lamivudine: a 3-year study of 145 Lamivudine-resistant
hepatitis B patients. Gastroenterology 2007; 133(5):1445-51. (Abstract)
Lampertico P, Vigano M, Facchetti F, Suter F, Minola E, Fracessetti O, et al. Entecavir
monotherapy in 418 NUC-naive patients with chronic hepatitis B from filed practice:
High efficacy and favourable safety profile over 3 years of treatmentHepatology 2011;
54(4):1043A
Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B
Study Group. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005; 30;352(26):2682-95. (Abstract)
Liaw YF, Gane E, Leung N, et al. 2-Year GLOBE trial results: telbivudine Is superior to
lamivudine in patients with chronic hepatitis B. Gastroenterology. 2009;136(2):486-95. (Abstract)
Lee YS, Suh DJ, Lim YS, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy.
Hepatology. 2006; 43(6):1385-91. (Abstract)
Liaw YF, Sung JJ, Chow WC, et al. Cirrhosis Asian Lamivudine Multicentre Study Group.
Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J
Med 2004; 351(15):1521-31. (Abstract)
Liaw YF, Gane E, Leung N, Zeuzem S, et al. GLOBE Study Group. 2-Year GLOBE trial results:
telbivudine Is superior to lamivudine in patients with chronic hepatitis B.
Gastroenterology. 2009;136(2):486-95. (Abstract)
Lim SG, Ng TM, Kung N, et al. Emtricitabine FTCB-301 Study Group. A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B. Arch Intern Med. 2006;
166(1):49-56. (Abstract)
Lin CL, Tsai SL, Lee TH, Chien RN, Liao SK, Liaw YF. High frequency of functional anti-YMDD
and -mutant cytotoxic T lymphocytes after in vitro expansion correlates with
successful response to lamivudine therapy for chronic hepatitis B. Gut. 2005; 54 (1):
152-61. (Abstract)
Locarnini S, Hatzakis A, Heathcote J, et al. Management of antiviral resistance in patients with
chronic hepatitis B. Antivir Ther. 2004; 9 (5): 679-93. (Abstract)
Lok A, Trinh HN, Carosi G, et al. Entecavir monotherapy for 96 weeks is comparable to
combination therapy with entecavir plus tenofovir in nucles(t)ide-naïve patients with
chronic hepatitis B: The be-low study. Hepatology 2011; 54(4):417A
Manns M, Jeffers L, Dalekos G, Berg T, Trepo C, et al. Safety and efficacy of 96 weeks of
tenofovir disoproxil fumarate therapy in lamivudine experienced patients. J Hepatol
2009; 50(1) : S335.
Marcellin P, Chang TT, Lim SG, et al. Adefovir Dipivoxil 437 Study Group. Adefovir dipivoxil for
the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J
Med.2003; 27;348(9):808-16.
Marcellin P, Lau GK, Bonino F, et al Peginterferon alfa-2a alone, lamivudine alone, and the two
in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med.
2004; 351(12):1206-17. (Abstract)
Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil
for chronic hepatitis B. N Engl J Med. 2008; 359(23):2442-55. (Abstract)
Marcellin P, Piratvisuth T, Brunetto MR, et al. A finite course of peginterferon alfa-2a results in
inactive chronic hepatitis B and HBsAg clearance 5 years Post treatment in patients
with HBeAg-negative disease: baseline characteristics and predictive factors of long-term response. Hepatology 2009; 50 (4): 487A.
Matthews GV, Bartholomeusz A, Locarnini S, et al. Characteristics of drug resistant HBV in an
international collaborative study of HIV-HBV-infected individuals on extended
lamivudine therapy. AIDS 2006;20(6):863-70. (Abstract)
172  Hepatology 2012
McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir - effects on HIV-1
replication and resistance. N Engl J Med 2007;356:2614-21. (Abstract)
Milazzo L, Caramma I, Lai A, et al. Telbivudine in the treatment of chronic hepatitis B:
experience in HIV type-1-infected patients naive for antiretroviral therapy. Antivir Ther
2009; 14(6):869-72. (Abstract)
Nguyen MH, Huy NT, Nguyen T, et al. Complete viral suppression and ALT normalization on
entecavir (ETV) therapy in patients who were previously treated with adefovir (ADV):
A multicenter study. Hepatology 2009; 50,4: 540A.
Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated
with interferon alfa for chronic hepatitis B. N Engl J Med 1996;30;334(22):1422-7.
(Abstract)
Nelson M, Portsmouth S, Stebbing J. An open-label study of tenofovir in HIV-1 and hepatitis B
virus co-infected individuals. AIDS 2003;17:F7-F10. (Abstract)
Núñez M, Pérez-Olmeda M, Díaz B, Ríos P, González-Lahoz J, Soriano V. Activity of tenofovir
on hepatitis B virus replication in HIV-co-infected patients failing or partially
responding to lamivudine. AIDS 2002;16:2352-54. (Abstract)
Petersen J, Ratziu V, Buti M, et al. Entecavir plus tenofovir combination as rescue therapy in
pre-treated chronic hepatitis B patients: An international multicenter cohort study. J
Hepatol. 2011 Oct 26. [Epub ahead of print]. (Abstract)
Petersen J, Buggisch P, Stoehr A, et al. Stopping long-termnucleosid(t)ide analogue therapy
before HbsAg loss or seroconversion in HbeAg negative chronic hepatitis B patients:
Experience from five referral centers in Germany. Hepatolog 2011 54(4):1033A.
Ratcliffe L, Beadsworth MB, Pennell A, Phillips M, Vilar FJ. Managing hepatitis B/HIV co-infected: adding entecavir to truvada (tenofovir disoproxil/emtricitabine) experienced
patients. AIDS. 2011 ;25(8):1051-6. (Abstract)
Reijnders JG, Deterding K, Petersen, et al. Antiviral effect of entecavir in chronic hepatitis B:
influence of prior exposure to nucleos(t)ide analogues. J Hepatol. 2010;52(4):493-500. (Abstract)
Reijnders JG, Perquin MJ, Zhang N, Hansen BE, Janssen HL. Nucleos(t)ide analogues only
induce temporary hepatitis B e antigen seroconversion in most patients with chronic
hepatitis B. Gastroenterology. 2010;139(2):491-8. (Abstract)
Schmutz G, Nelson M, Lutz T, et al. Combination of tenofovir and lamivudine versus tenofovir
after lamivudine failure for therapy of hepatitis B in HIV-coinfection. AIDS.
2006;20(15):1951-4.
Sheldon JA, Corral A, Rodés B, et al. Risk of selecting K65R in antiretroviral-naive HIV-infected
individuals with chronic hepatitis B treated with adefovir. AIDS 2005;19(17):2036-8.
(Abstract)
Sheldon J, Ramos B, Garcia-Samaniego J, et al. Selection of Hepatitis B Virus (HBV) Vaccine
Escape Mutants in HBV-Infected and HBV/HIV-Coinfected Patients Failing
Antiretroviral Drugs With Anti-HBV Activity. J Acquir Immune Defic Syndr. 2007;
46(3):279-82. (Abstract)
Shim JH, Suh DJ, Kim KM, et al. Efficacy of entecavir in patients with chronic hepatitis B
resistant to both lamivudine and adefovir or to lamivudine alone. Hepatology. 2009;
50(4):1064-71. (Abstract)
Snow-Lampart A, Chappell B, Curtis M, et al. No resistance to tenofovir disoproxil fumarate
detected after up to 144 weeks of therapy in patients monoinfected with chronic
hepatitis B virus. Hepatology. 2011;53(3):763-73.
Sung JJ, Lai JY, Zeuzem S, et al. Lamivudine compared with lamivudine and adefovir dipivoxil
for the treatment of HBeAg-positive chronic hepatitis B. J Hepatol. 2008;48(5):728-35. (Abstract)
Tenney DJ, Rose RE, Baldick CJ, et al. Two-year assessment of entecavir resistance in
Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes
depending on the resistance substitutions present. Antimicrob Agents Chemother.
2007;51(3):902-11. (Abstract)
Van Bommel F, Wunsche T, Mauss S, et al. Comparison of adefovir and tenofovir in the
treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 2004; 40:
1421-25. (Abstract)
Van Bömmel F, de Man RA, Wedemeyer H, et al. Long-term efficacy of tenofovir monotherapy
for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide
analogues. Hepatology. 2010; 51(1): 73-80. (Abstract)
Management of Resistance in HBV Therapy  173
Westland C, Delaney W, Yang H, et al. Hepatitis B virus genotypes and virologic response in
694 patients in phase III studies of adefovir dipivoxil1. Gastroenterology
2003;125(1):107-16. (Abstract)
Yuen MF, Seto WK, Fung J, Wong DK, Yuen JC, Lai CL. Three years of continuous entecavir
therapy in treatment-naïve chronic hepatitis B patients: VIRAL suppression, viral
resistance, and clinical safety. Am J Gastroenterol. 2011;106(7):1264-71. (Abstract)
Zeuzem S, Gane E, Liaw YF, Lim SG, DiBisceglie A, Buti M, et al. Baseline characteristics and
early on-treatment response predict the outcomes of 2 years of telbivudine treatment
of chronic hepatitis B. J Hepatol. 2009; 51(1):11-20. (Abstract)
174  Hepatology 2012
11. Hepatitis D – Diagnosis and Treatment
Heiner Wedemeyer
Introduction
Hepatitis delta is considered 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 2006). Hence, hepatitis delta occurs only in HBsAg-positive individuals
either as acute coinfection or as superinfection in patients with chronic hepatitis B
(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 fibrosis progression, possibly a slightly increased risk of
hepatocellular carcinoma and early decompensation in the setting of established
cirrhosis (Hughes 2011, Fattovich 2000, Fattovich 1987). 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
hepatitis delta, the baseline-event-anticipation (BEA) score (Calle Serrano 2011). So
far, only (pegylated) interferon α treatment has been shown to exert some antiviral
activity against HDV and has been linked to improve the long-term outcome. Data
on the use of pegylated interferon confirm earlier findings,  PEG-IFN leads to
sustained virological response rates in about one quarter of patients. Alternative
treatment options including HBV entry inhibitors and prenylation inhibitors are
currently in clinical development.
Hepatitis D – Diagnosis and Treatment  175
Figure 1. Courses of hepatitis delta.
Virology of hepatitis delta
The HDV virion is approximately 36 nm large, 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 2006). It is coated with the envelope protein derived from the pre-S and S
antigens of the hepatitis B virus. 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 2006).
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 autocatalytically cleaved to linear monomers and ligated
into the circular HDV RNA viral progeny.
Genetic analysis has revealed the presence of at least eight HDV genotypes
(Hughes 2011) (Figure 2). Genotype 1 is the most frequently seen genotype 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 Russia, 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 and
genotypes 5-8 in African countries. Genotype 1 is associated with both severe and
mild disease whereas genotype 2 causes a milder disease over a long-term course
(Su 2006). All patients who have been included in the large European HIDT-I
176  Hepatology 2012
treatment trial in Germany, Turkey and Greece were infected with HDV genotype I
(Zachou 2010).
Figure 2. Prevalence of HDV genotypes.
Epidemiology of hepatitis delta
Hepatitis delta 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 Western countries, high anti-HDV prevalence is found in HBsAg-positive intravenous drug users both in Europe
(Wedemeyer 2007, Gaeta 2000) and North America (Kurcirka 2010). Worldwide,
more than 350 million people are chronically infected with HBV and 15-20 million
of those are estimated to be anti-HDV positive (Wedemeyer 2010). Delta hepatitis
was endemic in Southern Europe. Several studies performed in the 1980s and 1990s
showed a prevalence of anti-HDV among HBsAg-positive individuals of more than
20%. As a result of the implementation of HBV vaccination programs, the incidence
of HDV infections significantly decreased in Southern Europe in the 1990s (Gaeta
2000) (Figure 3). In Turkey, HDV prevalence in HBsAg-positive patients range
from <5% in western Turkey to >27% in southeast Turkey (Degertekin 2008). Other
countries with a particularly high prevalence of hepatitis delta are Mongolia with up
to one third of chronic hepatitis cases being caused by HDV infection (Tsatsralt-Od
2005), some Central Asian republics, northwestern states of Brazil, and some
Polynesian islands (Hughes 2011). Of note, prevalence rates of HBV and HDV are
not linked - for example, HDV infections are rather rare in most parts of mainland
China despite very high frequencies of hepatitis B.
Hepatitis D – Diagnosis and Treatment  177
Figure 3. Prevalence of hepatitis D virus in Italy and Germany.
a)  Chronic Hepatitis D: a vanishing disease. From Gaeta GB, Hepatology 2000.
b)  Hepatitis D virus infection - Not a vanishing disease in Europe! From Wedemeyer,
Hepatology 2007.
Chronic delta hepatitis still represents a significant health burden in Central
Europe – in particular due to immigration from highly endemic areas (Wedemeyer
2007, Erhardt 2003) (Figure 4, Table 1). In our experience at a referral center for
liver disease, about 8-10% of HBsAg-positive patients still test positive for anti-HDV (Figure 3). More than three quarters of our delta hepatitis 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
significantly increased in recent years (Wedemeyer 2007) (Table 1). 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 HBsAg-positive HIV-infected individuals with about 14.6%
in different European regions (Soriano 2011).
178  Hepatology 2012
Figure 4. Diagnostic steps in delta hepatitis.
Table 1. Hepatitis D virus (HDV) detection in Germany between 1992–1996 vs 1997–
2006 compared to the country of birth of patients.
Origin of patients   HDV diagnosis*
1992–1996
n=45
HDV diagnosis*
1997–2006
n=100
p-value
Germany  20.9 (n=9)  19.2 (n=19)  n.s.
Turkey  42.0 (n=18)  20.2 (n=20)  0.009
Eastern Europe/NIS  14.0 (n=6)  37.3 (n=37)  0.005
* in %. From Heidrich, Journal of Viral Hepatitis, 2009; n.s., not significant; NIS, Newly Independent
States (ex-USSR)
Pathogenesis of HDV infection
Knowledge about the pathogenesis of delta hepatitis infection is limited. Clinical
observations have provided examples of mostly an immune-mediated process in
delta hepatitis disease. However, patterns suggesting a cytopathic viral disease have
occasionally been observed. A typical example of the latter were outbreaks of
severe hepatitis in the northern part of South America (Nakano 2001). These mostly
fulminant hepatitis cases were induced by genotype 3 delta virus. However, in the
usual case of delta hepatitis the liver histology is not different from a patient with
hepatitis B or hepatitis C with accompanying necroinflammatory lesions.
Importantly, HDV viremia is not directly associated with the stage of liver disease
(Zachou 2010). Cellular immune responses against the hepatitis D virus have been
described (Nisini 1997, Aslan 2003, Huang 2004, Grabowski 2011) suggesting that
the quantity and quality of T cell responses may be associated with some control of
the infection. Some data from our group indicate that the frequency of cytotoxic
CD4+ T cells is higher in delta hepatitis patients than in individuals with HBV or
Hepatitis D – Diagnosis and Treatment  179
HCV infection (Aslan 2006) and that HDV-specific IFN gamma and IL-2 responses
are more frequent in patients with low HDV viremia (Grabowski 2011). This still
limited information suggests that HDV is mainly an immune-mediated disease, at
least in HDV genotype 1 infection. Ideally, antiviral therapies should therefore also
aim to enhance anti-HDV immunity to confer long-term control of the infection.
Still, sterilizing immunity against HDV has not been demonstrated yet. Of note,
chimpanzees that have recovered from HDV infection were successfully reinfected
with HDV in one study performed in the 1980s (Negro 1988). Coinfections with
multiple hepatitis viruses are associated with diverse patterns of reciprocal
inhibition of viral replication (Raimondo 2006,  Wedemeyer 2010). HDV has
frequently been shown to suppress HBV replication (Jardi 2001, Sagnelli 2000).
Between 70% and 90% of delta hepatitis patients are HBeAg-negative with low
levels of HBV DNA. Humanized HBsAg-positve mice that become superinfected
HDV also show a decrease in HBV replication (Lutgehetmann 2011). A molecular
explanation for the suppression of HBV replication by HDV has been suggested as
HDV proteins p24 and p27 may repress HBV enhancers (Williams 2009). However,
viral dominance may change over time (Wedemeyer 2010) and about half of the
hepatitis delta patients showed significant HBV replication in one study (Schaper
2010).
There is increasing evidence that HDV not only suppresses HBV replication but
also HCV replication in triple-infected patients. In our experience, less than one
fifth of anti-HCV/HBsAg/anti-HDV-positive individuals are positive for HCV RNA
(Heidrich 2009). We even observed a case where acute HDV/HBV superinfection
led to clearance of chronic hepatitis C infection (Deterding 2009). It is not clear how
many anti-HCV-positive/HCV RNA-negative patients recover from HCV infection
and how many patients just show a suppressed HCV replication in the context of
viral coinfections.
Clinical course of delta hepatitis
Acute HBV/HDV coinfection
Acute HBV/HDV coinfection leads to recovery in more than 90% of cases but
frequently causes severe acute hepatitis with a high risk for developing a fulminant
course (Rizzetto 2009). In contrast, HDV is cleared spontaneously only in a
minority of patients with HDV superinfection of chronic HBsAg carriers (Figure 1).
The observation that histopathology of simultaneous HBV and HDV infection is
more severe than in infection with HBV alone has also been documented in
experiments with chimpanzees (Dienes 1990). Several outbreaks of very severe
courses of acute delta hepatitis in patients have been described in different regions
of the world (Casey 1996, Flodgren 2000, Tsatsralt-Od 2006). Fortunately, acute
delta hepatitis has become rather infrequent over the last two decades in Western
countries due to the introduction of vaccination programs.
Chronic delta hepatitis
Several studies have shown that chronic HDV infection leads to more severe liver
disease than chronic HBV monoinfection, with an accelerated course of fibrosis
progression, and early decompensation in the presence of cirrhosis (Fattovich 1987,
Jardi 2001, Sagnelli 2000, Rizzetto 2000, Uzunalimoglu 2001). HDV accounts for