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Keywords:

  • chronic hepatitis D;
  • hepatitis D therapy;
  • hepatitis D virus;
  • hepatitis therapy;
  • interferon;
  • peg-interferon

Abstract

  1. Top of page
  2. Abstract
  3. Problems in the therapeutic strategy
  4. No role for antivirals against HBV
  5. Treatment with standard IFN
  6. Treatment with pegylated IFNs
  7. Future therapies
  8. Liver transplantation
  9. Disclosure
  10. References

Interferon is the only therapy for chronic hepatitis D. Nucleos(t)ides are not effective against the helper hepatitis B virus. The current therapeutic recommendation is a weekly dose of pegylated interferon (PEG-IFN)-α, for 12–18 months. Serum HDV-RNA only becomes undetectable after 6 months of therapy in about a quarter of the patients. Hepatitis D virus (HDV) may relapse in patients if they remain HBsAg positive. Although the end-point of therapy is the clearance of the HBsAg, this is seldom achieved. Current management of HDV patients is based on standard practices which should be pragmatic and individualized.


Abbreviations
HDV

hepatitis D virus

PEG-IFN

peg-interferon

SVR

sustained viral response

Problems in the therapeutic strategy

  1. Top of page
  2. Abstract
  3. Problems in the therapeutic strategy
  4. No role for antivirals against HBV
  5. Treatment with standard IFN
  6. Treatment with pegylated IFNs
  7. Future therapies
  8. Liver transplantation
  9. Disclosure
  10. References

The therapeutic strategy for hepatitis D virus (HDV) is difficult because of the unique replication mechanism of HDV and because HDV must be associated with another viral infection, i.e. HBV infection.

Hepatitis D virus only requires the Hepatitis B surface antigen (HBsAg) coat from HBV to enter hepatocytes. The HD virion binds to a receptor on the liver cell via a domain in the N-terminal pre-S1 region of the large HBsAg [1]. HDV-RNA moves to the nucleus where it is replicated by redirected cellular RNA-polymerases [2, 3]. The rod-like structure which HDV-RNA is driven into by extensive base pairing, is probably recognized by host RNA polymerases as a self-DNA.

Replication via a rolling circle mechanism generates multimeric linear transcripts of the genome and antigenome which are cleaved to genome/antigenome size monomers and circularized into the infectious form by the HDV ribozyme [2].

HDV diverts the replicative machinery of the cell to its advantage and uses a structural part of its RNA as a catalyst rather than a protein. It offers no enzymatic target to antivirals, such as HCV and HBV proteases and polymerases.

As hepatitis D is the result of a double infection of HDV with HBV, therapeutic goals are defined in relation with both viral infections. Of note, the only reliable end-point of therapy appears to be the clearance of HBsAg. A sustained viral HDV response (i.e. negative HDV-RNA 6 months after therapy) may not apply to hepatitis D as a surrogate to cure. If HBsAg remains present, HDV may remain infectious and capable of reactivating the disease at levels well below the number of copies detectable with the most sensitive serum assays (10 copies/ml). In the chimpanzee model, HDV was transmitted to HBsAg-carrier animals with serum diluted up to 10−11 [4].

No role for antivirals against HBV

  1. Top of page
  2. Abstract
  3. Problems in the therapeutic strategy
  4. No role for antivirals against HBV
  5. Treatment with standard IFN
  6. Treatment with pegylated IFNs
  7. Future therapies
  8. Liver transplantation
  9. Disclosure
  10. References

Although HBV synthesis is spontaneously inhibited in most patients with chronic hepatitis D, the availability of antivirals against HBV suggested the hypothesis that further pharmacological repression of HBV might repress HBsAg synthesis long enough for the infected hepatocytes to die, leading to HDV eradication.

However, lamivudine 100 mg a day for 12 or 24 months had no effect on markers of HDV infection or on the clinical/histological features of hepatitis D [5] and adefovir monotherapy at a dose of 10 mg daily for 48 weeks was not effective [6].

Treatment with standard IFN

  1. Top of page
  2. Abstract
  3. Problems in the therapeutic strategy
  4. No role for antivirals against HBV
  5. Treatment with standard IFN
  6. Treatment with pegylated IFNs
  7. Future therapies
  8. Liver transplantation
  9. Disclosure
  10. References

Interferon-α, is the only therapy licensed for hepatitis D.

Standard IFN-α, for 6–12 months controlled liver enzymes in about 20–25% of patients and results were better with a high dose of IFN, 5 MU daily or 9 MU three times a week for 12 instead of 6 months [5].

However, the rate of HDV clearance was significantly lower than the rate of ALT normalization, and the virus persisted in many cases despite temporary control of aminotransferases. These studies were heterogeneous with only a few patients, different designs and therapy protocols.

Although none of 10 children treated in 1990 improved clinically or histologically after treatment for a year [5], in a recent report from Pakistan 80% of 25 children with chronic hepatitis D responded to conventional IFN [7].

It was suggested that results would improve if therapy was extended to 24 months. However, this approach did not increase the rate of a sustained response compared with that after 12 months [8].

Treatment with pegylated IFNs

  1. Top of page
  2. Abstract
  3. Problems in the therapeutic strategy
  4. No role for antivirals against HBV
  5. Treatment with standard IFN
  6. Treatment with pegylated IFNs
  7. Future therapies
  8. Liver transplantation
  9. Disclosure
  10. References

Sustained clearance of serum HDV-RNA was achieved in 43% of 14 patients treated with (PEG-IFN)-α, 2b 1.5 μg/kg weekly for 12 months [9] (Fig. 1). In three other groups of patients treated with the same PEG-IFN, a sustained viral response (SVR) was obtained in 17%, 21% and 25% respectively [10-12]. PEG-IFN was also effective in patients with cirrhosis [13]. In a recent study of 90 patients with HDV [6], 31 patients received 180 μg of (PEG-IFN)-α, 2a per week plus 10 mg of Adefovir daily, 29 received 180 μg of (PEG-IFN)-α, 2a per week plus placebo and 30 received 10 mg of adefovir alone daily. Treatment lasted for 48 weeks with 24 weeks of follow-up.

image

Figure 1. Chronic hepatitis D treated with PEG-IFN monotherapy or in combination with antivirals.

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At the end follow-up or 72 weeks after treatment began, HDV-RNA was negative in 26% of the patients treated with PEG-IFN plus adefovir, in 31% of those treated with PEG-IFN plus placebo and in none of those who received adefovir monotherapy. During follow-up, nine patients became HDV-RNA negative but two had a virological relapse. There was no difference in efficacy between PEG-IFN plus adefovir or PEG-IFN alone. There was a cumulative SVR of 28% between the two groups; however, liver biopsy results were not consistent, with more histological worsening in the PEG-IFN-alone groups.

Possible predictors of response to Peg-IFN therapy may be a low baseline HBsAg, low HDV-RNA titres and elevated ALT. The kinetics of HDV-RNA during therapy may also be a predictive factor. In one French study [9], HDV-RNA was negative after 6 months of therapy in 75% of the patients who achieved an end-of-therapy response vs. none of the non responders.

Future therapies

  1. Top of page
  2. Abstract
  3. Problems in the therapeutic strategy
  4. No role for antivirals against HBV
  5. Treatment with standard IFN
  6. Treatment with pegylated IFNs
  7. Future therapies
  8. Liver transplantation
  9. Disclosure
  10. References

Potential therapeutic targets are the mechanism of HDV attachment to the liver cell and of virion assembly.

Acylated pre-S peptides derived from the large HBsAg envelope protein are potent inhibitors of the HBV entry into hepatocytes. Myrcludex-B, a myristoylated pre S/2-48my2 peptide [14], has been shown to limit the establishment of HDV infection in vivo and delayed the increase in HBV viraemia.

Prenylation of the last four amino acids on the large-HDAg (the so-called CXXX box) is critical for the interaction of this viral antigen with HBsAg and disturbing prenylation has been a suggested therapeutic target [15]. In vitro and in vivo experiments have shown that inhibition of prenylation prevented HD virion assembly and resulted in clearance of HDV viraemia. However, there are no results as yet to show that this strategy is feasible and effective in humans.

Liver transplantation

  1. Top of page
  2. Abstract
  3. Problems in the therapeutic strategy
  4. No role for antivirals against HBV
  5. Treatment with standard IFN
  6. Treatment with pegylated IFNs
  7. Future therapies
  8. Liver transplantation
  9. Disclosure
  10. References

Liver transplantation is a valid therapeutic option for end-stage liver disease [16]. The risk of spontaneous graft reinfection is clearly lower for HDV than for HBV. Hepatitits B Virus must be present to support recurrent hepatitis D, but HBV replication is diminished in most HDV patients. Therefore, recurrent hepatitis D is prevented by the low HBV titres in HDV patients undergoing transplantation.

Current prophylaxis with hyperimmune serum against HBsAg and antivirals protect virtually every HDV transplant patient from reinfection, with very good survival rates. Shortage of donors might make it tempting to give an HBsAg-positive liver to an HDV patient. This should be avoided, two cases have been reported and HDV disease recurred in both [17, 18].

References

  1. Top of page
  2. Abstract
  3. Problems in the therapeutic strategy
  4. No role for antivirals against HBV
  5. Treatment with standard IFN
  6. Treatment with pegylated IFNs
  7. Future therapies
  8. Liver transplantation
  9. Disclosure
  10. References