Book on hepatitis from page 180 to 185

Book on hepatitis from page 180 to 185

180  Hepatology 2012
almost half of all cases of liver cirrhosis and hepatocellular carcinoma in southeast
Turkey (Degertekin 2008, Uzunalimoglu 2001, Yurdaydin 2006a). An observational
study from Taiwan has reported a cumulative survival of HDV genotype 1-infected
patients of as low as 50% after 15 years (Su 2006). Long-term follow-up data from
Italy confirm the particularly severe course of hepatitis delta (Romeo 2009; Niro
2010). HDV infection has also been associated with a higher risk of developing
liver cirrhosis in HIV-coinfected patients as 66% of HIV/HBV/HCV/HDV-infected
patients but only 6% of HBV/HCV/HIV-infected patients present with liver
cirrhosis in a Spanish cohort (Castellares 2008). Similarly, delta hepatitis was
associated with poorer survival in HIV-infected patients in Taiwan (Sheng 2007).
An easy to apply clinical score, the baseline-event anticipation (BEA) score, has
been suggested to predict the risk of developing liver-related morbidity and
mortality (Calle Serrano 2011). Factors associated with a poor long-term outcome
included age above 40, male sex, low platelet counts, high bilirubin and INR values
and southeast Mediterranean origin.
Diagnosis of delta hepatitis
We recommend that  every HBsAg-positive patient  be tested for anti-HDV
antibodies at least once. There is currently no evidence that direct testing for HDV
RNA in the absence of anti-HDV is of any use. A positive result for anti-HDV does
not necessarily indicate “active” delta hepatitis, as HDV RNA can become negative
indicating recovery from HDV infection. Over the long term as well, anti-HDV
antibodies can be lost after recovery. However, anti-HDV may persist for years
even when the patient has experienced HBsAg seroconversion (Wedemeyer 2007).
“Active” replicative delta hepatitis should be confirmed by the detection of HDV
RNA. If HDV RNA is positive, subsequent evaluation of grading and staging of
liver disease, surveillance for hepatocellular carcinoma and consideration of
antiviral treatment is  indicated. HDV RNA quantification is offered by some
laboratories. However, so far there is no evidence that HDV RNA levels correlate
with any clinical marker of liver disease (Zachou 2010). HDV RNA quantification
is useful in particular if antiviral treatment is indicated. Stopping rules during
antiviral treatment depending on the level of antiviral decline are currently being
evaluated. Patients with less than a 3 log10 decline of HDV RNA after 24 weeks of
treatment will not benefit from antiviral treatment with PEG-IFN α-2b (Erhardt
2006). There is currently no WHO standard for HDV. Various PCR assays have
been presented recently, however, the performance of these assays may differ
significantly and detection rates for rare HDV genotypes may be low (Mederacke
2010, Niro 2011).
HDV genotyping is performed by some research labs and may help to identify
patients with a higher or lower risk of developing end-stage liver disease (Su 2006).
In Western countries almost all patients are infected with HDV-genotype 1, thus
genotyping may be considered only in immigrants or populations with mixed
genotype prevalence.
In the 1980s and 1990s the diagnosis of active delta hepatitis was dependent on
anti-HDV IgM testing. Anti-HDV IgM testing might still be useful in patients who
test HDV RNA negative but have evidence of liver disease, which cannot be
explained by other reasons. Due to the variability of the HDV genome and the lack
Hepatitis D – Diagnosis and Treatment  181
of standardization of HDV RNA assays, HDV RNA may test false negative or be
under the detection limit of the assay in the case of fluctuating viral load. In these
cases, HDV RNA testing should be repeated and anti-HDV IgM testing might be
performed, if available. Anti-HDV IgM levels also correlate with disease activity
and may be predictive for response to IFN α-based antiviral therapy (Mederacke
2012, in press).
As delta hepatitis only occurs in the context of HBV coinfection, a solid work-up
of HBV infection including HBV DNA quantification and HBeAg/anti-HBe
determination is warranted. Most hepatitis delta patients in Europe are infected with
HBV genotype D but infection with genotype A can also occur (Soriano 2011)
which may have significant implications for treatment decisions as HBV genotype
A shows a better responses to interferon α therapy (Janssen 2005). Similarly, testing
for anti-HCV and anti-HIV is mandatory. In our experience, up to one third of anti-HDV-positive patients also test positive for anti-HCV (Heidrich 2009).
Treatment of delta hepatitis
Nucleoside and nucleotide analogs
Several nucleoside and nucleotide analogs used for the treatment of HBV infection
have been shown to be ineffective against HDV (Table 2). Famciclovir, used in the
1990s to treat HBV infection (Wedemeyer 1999), had no significant antiviral
activity against HDV in a Turkish trial (Yurdaydin 2002). Similarly, lamivudine
was ineffective in trials of delta hepatitis (Wolters 2000, Niro 2005a, Yurdaydin
2008, Lau 1999b). Ribavirin alone or in combination with interferon also did not
lead to increased rates of HDV RNA clearance (Niro 2005a, Gunsar 2005, Garripoli
1994). However, a long-term observational study of HIV-infected individuals
receiving HAART followed HBV/HDV/HIV-coinfected individuals for a median of
more than 6 years; over this time, a decline of HDV RNA from 7 log10 to 5.8 log10
was observed and 3 out of 16 patients became HDV RNA-negative (Sheldon 2008).
Thus, very long treatment with HBV polymerase inhibitors may lead to beneficial
effects in delta hepatitis possibly due to a reduction of HBsAg levels. Future long-term trials will need to confirm these data in triple-infected individuals.
Table 2. Treatment options in delta hepatitis.
Nucleos(t)ide Analogs
Famciclovir ineffective  Yurdaydin 2002
Lamivudine ineffective  Wolters 2000, Lau 1999, Niro 2005a,
Niro 2008, Yurdaydin 2008
Ribavirin ineffective  Niro 2006, Garripoli 1994, Gunsar 2005
Interferon α
Sustained biochemical responses in 0-36% of patients
Few studies with virological endpoints
Treatment >12 months may be required
Farci 1994, Di Marco 1996, Niro 2005b,
Yurdaydin 2008
Higher IFN doses were associated with better survival
in small study cohort
Farci 2004
Another promising and surprising alternative to the currently approved HBV
polymerase inhibitors may be clevudine. Clevudine, a nucleoside analog currently
182  Hepatology 2012
in development for the treatment of hepatitis B, has recently been shown to inhibit
delta virus viremia in woodchucks (Casey 2005). However, a first pilot trial showed
no significant HDV RNA declines (Yakut 2010).
Recombinant interferon α
Interferon α has been used for the treatment of delta hepatitis since the mid 1980s
(Rizzetto 1986). Since then, many trials have explored different durations and doses
of interferon α in HDV-infected patients. However, data are difficult to compare as
endpoints are different in the trials and few studies have followed HDV RNA levels
over time (Niro 2005b).
One randomized Italian study on the use of high dose interferon α associated a
beneficial long-term outcome in delta hepatitis patients with high dose interferon
treatment (Farci 1994, Farci 2004). Some studies have used extended doses of
interferon treatment and it seems that two years of treatment is superior in terms of
HDV RNA clearance (Niro 2005b). In one NIH case report, 12 years of interferon
treatment led finally to resolution of both HDV infection and HBsAg clearance (Lau
1999a). High doses of interferon and extended treatment are tolerated by only a
minority of patients and treatment options are very limited for the majority (Manns
2006).
Pegylated interferon α
Pegylated interferon has been used in small trials to treat delta hepatitis, with
sustained virological response rates of about 20% (Castelnau 2006, Niro 2006,
Erhardt 2006) (Table 3).
Table 3. Pegylated interferon in delta hepatitis.
Study    Outcome
Castelnau, Hepatology
2006
12 months of PEG-IFN α-2b (n=14)  SVR in 6 patients (43%)
Niro, Hepatology 2006  72 weeks of PEG-IFN α-2b (n=38)
– Monotherapy: n=16
– PEG-INF + ribavirin during first 48
weeks: n=22
SVR in 8 patients (21%)
Ribavirin had no
additional effect
Erhardt, Liver Int 2006  48 weeks of PEG-IFN α-2b (n=12) SVR in 2 patients (17%)
Wedemeyer, NEJM 2011  a) 48 weeks PEG-IFN α-2a
+ adefovir (n=31) or
b) PEG-IFN α-2a + placebo (n=29) or
c) Adefovir (n=30)
HDV RNA-negative
Group a) 23%
Group b) 24%
Group c) 0%
Results of the Hep-Net International Delta hepatitis Intervention Trial (HIDIT-1)
were published in 2011 (Wedemeyer 2011). 90 patients (42 in Germany, 39 in
Turkey and 9 in Greece) with chronic HDV infection and compensated liver disease
were randomized to receive either 180 µg PEG-IFN α-2a QW plus 10 mg adefovir
dipivoxil QD (group A, N=31), 180 µg PEG-IFN α-2a QW plus placebo (group B,
N = 29) or 10 mg adefovir dipivoxil qd alone (group C, N=30) for 48 weeks. HBV
DNA and HDV RNA were investigated by real-time PCR. Ten patients did not
complete 48 weeks of therapy because of disease progression (N=6) or interferon-
Hepatitis D – Diagnosis and Treatment  183
associated side effects (N=4). Both PEG-IFN groups showed a significantly higher
reduction in mean HDV RNA levels than the adefovir monotherapy group by week
48. HDV RNA was negative 24 weeks after the end of treatment in 28% of patients
receiving PEG-IFN but in none of patients treated with adefovir alone. While
patients receiving PEG-IFN α-2a alone or adefovir monotherapy had similar mean
HBsAg levels at week 0 and week 48, the PEG-IFN α-2a/adefovir combination
group showed a 1.1 log10 IU/ml decline of HBsAg levels by week 48 (p <0.001)
with 10/30 patients achieving a decline in HBsAg of more than 1 log (10) IU/ml.
These data are in line with a report from Greece of a significant decline in HbsAg
levels in delta hepatitis patients receiving long-term treatment with interferon α
(Manesis 2007).
Overall the HIDIT-1 study showed that (i) PEG-IFN α-2a displays a significant
antiviral efficacy against HDV in more than 40% of patients with 24% becoming
HDV RNA negative after 48 weeks; (ii) adefovir dipivoxil has little efficacy in
terms of HDV RNA reduction but may be considered for patients with significant
HBV replication; (iii) combination therapy of PEG-IFN α-2a plus adefovir has no
advantages for HBV DNA or HDV RNA reduction; (iv) a combination therapy of
pegylated interferon with adefovir was superior to either monotherapy in reducing
HBsAg levels in HBV-infected patients (Wedemeyer 2011). However, adefovir
treatment was associated with a decline in glomerular filtration rates (Mederacke
2012, in press) and thus PEG-IFN α/adefovir combination treatment cannot be
recommended as the first-line treatment for all patients with hepatitis delta.
Currently, additional trials are ongoing to investigate the efficacy of PEG-IFN α-2a in combination with tenofovir for the treatment of delta hepatitis. First data of the
HIDIT-2 trial are expected in 2012. Moreover, alternative treatment options are
currently being explored. Among these, prenylation inhibitors may be promising
(Bordier 2003). HDV replication depends on a prenylation step and prenylation
inhibitors have already been developed for the treatment of malignancies. The HBV
entry inhibitor Myrcludex-B is also being developed for hepatitis delta. Myrcludex-B is a lipopeptide derived from the preS1 domain of the HBV envelope (Petersen
2008) and has been shown to hinder HDV infection in uPA/SCID mice transplanted
with human hepatocytes (Lütgehetmann 2011).
Liver transplantation for hepatitis delta
Liver transplantation remains the ultimate treatment option for many hepatitis delta
patients with end-stage liver disease. Hepatitis delta patients have lower risk for
reinfection after transplantation than HBV monoinfected patients (Samuel 1993). If
prophylaxis by passive immunization with anti-HBs antibodies and administration
of HBV polymerase is applied, HBV/HDV reinfection can be prevented in all
individuals (Rosenau 2007) leading to an excellent long-term outcome after
transplantation. HDV RNA levels rapidly decline during the first days after
transplantation (Mederacke 2011) but HDAg may persist in the transplanted liver
for several years (Smedile 1998,  Mederacke 2011). Long-term prophylaxis to
prevent HBV reinfection should be recommended in patients transplanted for
hepatitis delta patients as reinfection may lead to HDV reactivation for which
treatment options are very limited.
More information on hepatitis delta for physicians and patients can be found on
the website of the Heptitis Delta International Network: www.hepatitis-delta.org 
184  Hepatology 2012
Figure 5. Treatment algorithm for hepatitis delta.
References
Aslan N, Yurdaydin C, Bozkaya H, Baglan P, Bozdayi AM, Tillmann HL, et al. Analysis and
function of delta-hepatitis virus-specific cellular immune responses. J Hepatol
2003;38:15-6.
Aslan N, Yurdaydin C, Wiegand J, Greten T, Ciner A, Meyer MF, et al. Cytotoxic CD4 T cells in
viral hepatitis. J Viral Hepat 2006;13:505-14. (Abstract)
Bordier BB, Ohkanda J, Liu P, Lee SY, Salazar FH, Marion PL, et al. In vivo antiviral efficacy of
prenylation inhibitors against hepatitis delta virus. J Clin Invest 2003;112:407-14.
(Abstract)
Calle Serrano B, Heidrich B, Homs M, et al. Development and Evaluation of a Baseline Event-Anticipation (BEA)-Score for Hepatitis Delta. 62nd Annual Meeting of the American
Association for the Study of Liver Disease (AASLD 2011). San Francisco, November
4-8. 2011. Abstract 171.
Casey J, Cote PJ, Toshkov IA, Chu CK, Gerin JL, Hornbuckle WE, et al. Clevudine inhibits
hepatitis delta virus viremia: a pilot study of chronically infected woodchucks.
Antimicrob Agents Chemother 2005;49:4396-9. (Abstract)
Casey JL, Niro GA, Engle RE, Vega A, Gomez H, McCarthy M, et al. Hepatitis B virus
(HBV)/hepatitis D virus (HDV) coinfection in outbreaks of acute hepatitis in the
Peruvian Amazon basin: the roles of HDV genotype III and HBV genotype F. J Infect
Dis 1996;174:920-6. (Abstract)
Castellares C, Barreiro P, Martin-Carbonero L, Labarga P, Vispo ME, Casado R, et al. Liver
cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome. J Viral
Hepat 2008;15:165-72. (Abstract)
Hepatitis D – Diagnosis and Treatment  185
Castelnau C, Le Gal F, Ripault MP, Gordien E, Martinot-Peignoux M, Boyer N, et al. Efficacy of
peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR
for follow-up. Hepatology 2006;44:728-35. (Abstract)
Cross TJ, Rizzi P, Horner M, et al. The increasing prevalence of hepatitis delta virus (HDV)
infection in South London. J Med Virol 2008;80:277-82. (Abstract)
Dienes HP, Purcell RH, Popper H, Ponzetto A. The significance of infections with two types of
viral hepatitis demonstrated by histologic features in chimpanzees. J Hepatol
1990;10:77-84. (Abstract)
Degertekin H, Yalcin K, Yakut M, Yurdaydin C. Seropositivity for delta hepatitis in patients with
chronic hepatitis B and liver cirrhosis in Turkey: a meta-analysis. Liver Int
2008;28:494-98. (Abstract)
Deterding K, Pothakamuri SV, Schlaphoff V, et al. Clearance of chronic HCV infection during
acute delta hepatitis. Infection 2009;37:159-62. (Abstract)
Erhardt A, Knuth R, Sagir A, Kirschberg O, Heintges T, Haussinger D. Socioepidemiological
data on hepatitis delta in a German university clinic--increase in patients from
Eastern Europe and the former Soviet Union. Z Gastroenterol 2003;41:523-6.
(Abstract)
Erhardt A, Gerlich W, Starke C, Wend U, Donner A, Sagir A, et al. Treatment of chronic
hepatitis delta with pegylated interferon-alpha2b. Liver Int 2006;26:805-10. (Abstract)
Farci P, Mandas A, Coiana A, Lai ME, Desmet V, Van Eyken P, et al. Treatment of chronic
hepatitis D with interferon alfa-2a. N Engl J Med 1994;330:88-94. (Abstract)
Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al. Long-term benefit of
interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic
fibrosis. Gastroenterology 2004;126:1740-9. (Abstract)
Fattovich G, Boscaro S, Noventa F, Pornaro E, Stenico D, Alberti A, et al. Influence of hepatitis
delta virus infection on progression to cirrhosis in chronic hepatitis type B. J Infect Dis
1987;155:931-5. (Abstract)
Fattovich G, Giustina G, Christensen E, Pantalena M, Zagni I, Realdi G, et al. Influence of
hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type
B. The European Concerted Action on Viral Hepatitis (Eurohep). Gut 2000;46:420-6.
(Abstract)
Flodgren E, Bengtsson S, Knutsson M, Strebkova EA, Kidd AH, Alexeyev OA, et al. Recent
high incidence of fulminant hepatitis in Samara, Russia: molecular analysis of
prevailing hepatitis B and D virus strains. J Clin Microbiol 2000;38:3311-6. (Abstract)
Gaeta GB, Stroffolini T, Chiaramonte M, Ascione T, Stornaiuolo G, Lobello S, et al. Chronic
hepatitis D: a vanishing Disease? An Italian multicenter study. Hepatology 2000;32(4
Pt 1):824-7. (Abstract)
Garripoli A, Di Marco V, Cozzolongo R, et al. Ribavirin treatment for chronic hepatitis D: a pilot
study. Liver 1994;14:154-7. (Abstract)
Grabowski J, Yurdaydin C, Zachou K, et al. Hepatitis D virus-specific cytokine responses in
patients with chronic hepatitis delta before and during interferon alfa-treatment. Liver
Int 2011;31:1395-405. (Abstract)
Gunsar F, Akarca US, Ersoz G, Kobak AC, Karasu Z, Yuce G, et al. Two-year interferon
therapy with or without ribavirin in chronic delta hepatitis. Antivir Ther 2005;10:721-6.
(Abstract)
Hadziyannis SJ. Review: hepatitis delta. J Gastroenterol Hepatol 1997;12:289-98. (Abstract)
Heidrich B, Deterding K, Tillmann HL, Raupach R, Manns MP, Wedemeyer H. Virological and
clinical characteristics of delta hepatitis in Central Europe. J Viral Hepat 2009;16:883-94. (Abstract)
Hershow RC, Chomel BB, Graham DR, Schyve PM, Mandel EJ, Kane MA, et al. Hepatitis D
virus infection in Illinois state facilities for the developmentally disabled. Epidemiology
and clinical manifestations. Ann Intern Med 1989;110:779-85. (Abstract)
Huang YH, Tao MH, Hu CP, Syu WJ, Wu JC. Identification of novel HLA-A*0201-restricted
CD8+ T-cell epitopes on hepatitis delta virus. J Gen Virol 2004;85(Pt 10):3089-3098.
(Abstract)
Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet 2011;378:73-85.
(Abstract)
Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in
combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised
trial. Lancet 2005;365:123-9. (Abstract)