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Chapter 11: Hepatitis D Diagnostic procedures and therapy 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 (Farci 2003) (Figure 1). Several studies have shown that chronic HDV infection leads to more severe liver disease than chronic HBV mono-infection with an accelerated course of fibrosis progression, an increased risk of hepatocellular carcinoma and early decompensation in the setting of established cirrhosis (Farci 2003; 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). So far, only interferon alpha treatment has been shown to exert significant antiviral activity against HDV and has been linked to improve the long-term outcome. Recent data on the use of pegylated interferon confirm earlier findings - PEG-IFN leads to sustained virological response rates in about one quarter of patients.

Simultaneous coinfection Acute HBV Acute HDV

95% recovery More frequent fulminant

HDV Super Infection Acute HDV Chronic hepatitis B

90% chronic More severe disease

Figure 1. Courses of delta hepatitis.

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Virology of delta hepatitis

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 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 seven HDV genotypes (Radjef 2004) (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 genotype 3 is seen exclusively in the northern part of South America. 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 treatment trial in Germany, Turkey and Greece were proven to be infected with HDV genotype I (Zachou 2006).

Figure 2. Prevalence of HDV genotypes.

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Epidemiology of delta hepatitis

Delta hepatitis 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 (Radjef 2004) (Figure 2). In Western countries, high prevalence can be found in HBsAg-positive intravenous drug users (Wedemeyer 2007; Gaeta 2000). Worldwide, more than 350 million people are considered to be chronically infected with HBV and 15-20 million of those are estimated to be anti-HDV positive (Hadziyannis 1997). Delta hepatitis is highly 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% (Farci 2003). In Turkey, HDV prevalences in HBsAg-positive patients ranged between <5% in Western Turkey to >27% in South East Turkey (Degertekin 2008). Another country with a particular high prevalence of delta hepatitis is Mongolia with up to one third of chronic hepatitis cases being caused by HDV infection (Tsatsralt-Od 2005). 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).

Gaeta et al., Hepatology 2000

Wedemeyer et al., Hepatology 2007

Figure 3. Prevalence of hepatitis D virus in Italy and Germany.

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Chronic delta hepatitis still represents a significant health burden in Central Europe â&#x20AC;&#x201C; 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 was born in Turkey, the proportion of Eastern European patients has significantly increased in recent years (Wedemeyer 2007) (Table 1).

Figure 4. Diagnostic steps in delta hepatitis.

Origin of patients

HDV diagnosis 1992 - 1996 N=3

HDV diagnosis 1997 - 2006 N=101

p-value

Germany (%)

23.2 (N=10)

17.8 (N=18)

n.s.

Turkey (%)

41.8 (N=18)

19.8 (N=20)

0.006

Eastern Europe/NIS (%)

16.6 (N=5)

34.6 (N=35)

0.003

Table 1. Country of birth in patients with delta hepatitis at Hannover Medical School.

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Limited data is available on the epidemiology of delta hepatitis in the USA. Earlier studies published between 1985 and 1993 reported HDV prevalences of 2% in homosexual men (Weisfuse 1989), around 20% in haemophiliacs (Rizzetto 1983) and female prostitutes (Troisi 1993) and up to 30% in hepatitis B carriers in Illinois (Hershow 1989). However, no study including a significant number of individuals has been published since 1993. In particular, the prevalence of HDV in high-risk populations such as IV drug users is unknown in US populations.

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 2006). Cellular immune responses against the hepatitis D virus have been described by few investigators (Nisini 1997; Aslan 2003; Huang 2004) suggesting that the quantity and quality of T cell responses may be associated with some control of the infection. We have recently shown that the frequency of cytotoxic CD4+ T cells is higher in delta hepatitis patients than in individuals with HBV or HCV infection (Aslan 2006). This limited information taken together suggests that HDV is mainly an immune-mediated disease, at least in HDV genotype 1 infection. Antiviral therapies should therefore also aim to enhance anti-HDV immunity to confer long-term control of the infection. Interestingly, we have seen that the quality of the HDV-specific T cell response is able to predict the response to PEG-IFN a-2a treatment (Wedemeyer 2007). Coinfections with multiple hepatitis viruses are associated with diverse patterns of reciprocal inhibition of viral replication (Raimondo 2006). 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. However, the course of HBeAg-positive delta hepatitis has not been well studied. It is of importance to note that even HBeAg-positive patients may be negative for HBV DNA in the context of HDV coinfection. On the other hand, HBV pre-core stop codons may also develop in delta hepatitis patients and thus HBeAgnegative patients can display significant levels of HBV DNA requiring antiviral treatment against hepatitis B. There is also increasing evidence that HDV can not only suppress HBV replication but also HCV replication in tri-infected patients (Wedemeyer 2001). In our experience, less than one fifth of anti-HCV/HBsAg/anti-HDV-positive individuals are positive for HCV RNA. It is not clear how many of the anti-HCV-positive/HCV RNA-negative patients have recovered from HCV infection and how many patients just show a suppressed HCV replication in the context of viral coinfections. It is

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interesting to note that viral dominance may change over time. Thus triple infected patients should be followed closely and, if indicated, treatment of the dominant virus needs to be considered.

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 2000). 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). However, 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, an increased risk of hepatocellular carcinoma and early decompensation in the presence of cirrhosis (Fattovich 1987; Jardi 2001; Sagnelli 2000; Rizzetto 2000; Uzunalimoglu 2001; Wedemeyer 2007). HDV accounts for almost half of all cases of liver cirrhosis and hepatocellular carcinoma in South East Turkey (Degertekin 2008; Uzunalimoglu 2001; Yurdaydin 2006a). A recent long-term 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). 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).

Diagnosis of delta hepatitis Every HBsAg-positive patient must 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 treat-

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ment 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 2006). Thus, HDV RNA quantification is currently only useful 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 log decline of HDV RNA after 24 weeks of treatment will not benefit from antiviral treatment with PEG-IFN a-2b (Erhardt 2006). 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 prevalences. 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 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. 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. 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.

Treatment of Delta Hepatitis Nucleoside and nucleotide analogues Several nucleoside and nucleotide analogues used for the treatment of HBV infection have been shown to be ineffective against HDV (Table 2). Famcyclovir, 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 2005; Yurdaydin 2008; Lau 1999b). Ribavirin alone or in combination with interferon also did not lead to increased rates of HDV RNA clearance (Niro 2006a; Gunsar 2005; Garripoli 1994). However, a longterm 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. Another promising and surprising alternative to the currently approved HBV polymerase inhibitors may be clevudine. Clevudine, a nucleoside analogue currently in

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development for the treatment of hepatitis B, has recently been shown to inhibit delta virus viremia in woodchucks. No data are available yet in humans treated with clevudine for HDV (Casey 2005). Nucleos(t)ide analogues Famciclovir ineffective Lamivudine ineffective

Yurdaydin et al., Hepatol 2002 Wolters et al., J Viral Hepatitis 2000; Lau et al., Hepatology 1999; Niro, Aliment Pharmacol Ther. 2005; Niro et al., J Viral Hepatitis 2008 Yurdaydin et al., J Viral Hepatitis 2008

Ribavirin ineffective

Niro et al., Hepatology 2006 Garripoli et al., Liver 1994 Gunsar et al., Antiv Therapy 2005

Interferon a Sustained biochemical responses in 0-36% of patients Few studies with virologic endpoints Treatment for>12 months may be requiered

Farci et al., NEJM 1994 Di Marco et al., J Viral Hepatitis 1996 Niro et al., J Viral Hepatitis 2005; Yurdaydin et al., J Viral Hepatitis 2008

Higher IFN doses were associated with better survival in small cohort study

Gunsar et al., Antiv Therapy 2005

Table 2. Treatment options in delta hepatitis.

Recombinant interferon alpha

Interferon a 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 alpha 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 2005). One randomized Italian study on the use of high dose interferon alpha is especially important as interferon treatment has been associated with a beneficial long-term outcome in delta hepatitis patients (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 2005). In one case report from NIH, 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 option are very limited for the majority of patients (Manns 2006).

Pegylated interferon alpha Recently, pegylated interferon has also 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).

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Castelnau, Gault et al. Hepatology 2006 14 patients, 12 months of PEG-IFN a-2b Niro, Rizzetto et al. Hepatology 2006 38 patients, 72 weeks PEG-IFN a-2b 16 patients monotherapy 22 patients + ribavirin (first 48 weeks) Erhardt, Häussinger et al. Liver Int 2006 12 patients, 48 weeks of PEG-IFN a-2b

SVR in 6 patients (43%)

SVR: 8 patients (21%) Ribavirin had no additional effect

SVR in 2 patients (17%)

Table 3. Pegylated interferon in delta hepatitis.

In 2004, the Hep-Net International Delta hepatitis Intervention Trial (HIDIT-1) began. 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 a-2a QW plus 10 mg adefovir dipivoxil QD (group A, N=31), 180 µg PEGIFN a-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 realtime PCR. Ten patients did not complete 48 weeks of therapy because of disease progression (N=6) or interferon-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 became negative in 21%, 30% and 8% of patients, respectively (PEG-IFN vs. adefovir, p=0.06). While patients receiving PEGIFN a-2a alone or adefovir monotherapy had similar mean HBsAg levels at week 0 and week 48, the PEG-IFN a-2a/adefovir combination group showed a 1.1 log10 IU/ ml decline of HBsAg levels by week 48 (p<0.001). 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 alpha (Manesis 2007). Overall the HIDIT-1 study showed that (i) PEG-IFN a-2a displays a significant antiviral efficacy against HDV in more than 40% of patients with 25% 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 a-2a plus adefovir has no advantages for HBV DNA or HDV RNA reduction; (iv) a combination therapy of pegylated interferon with a nucleotide is superior to either monotherapy in reducing HBsAg levels in HBV-infected patients (Wedemeyer 2007; Yurdaydin 2006b). Currently, additional trials are ongoing to investigate the efficacy of PEG-IFN a-2a in combination with tenofovir for the treatment of delta hepatitis. Moreover, alternative treatment options need to be 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.

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