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Emerging Issues in Hepatitis D

Maria Claudia Stefanoli, MD

Zaigham Abbas, MBBS, FCPS, FRCP, FRCPI, FACP, FACG, AGAF
Professor and Head, Department of Gastroenterology
Ziauddin University Hospital Clifton
Karachi, Pakistan

Hepatitis D is the most severe form of viral hepatitis, leading to early cirrhosis and decompensation 1. Hepatitis D or delta virus (HDV) can be acquired either by co-infection with hepatitis B virus (HBV) or by super-infection of someone already harboring chronic hepatitis B. Like HBV, hepatitis D is transmitted parenterally through exposure to infected blood or body fluids. Worldwide, about 15-20 million HBsAg positive patients are co-infected with HDV. The disease continues to be a major medical menace in the Asia Pacific region, especially Pakistan, Mongolia, and Eastern Europe 2.

Hepatitis B virus surface antigen (HBsAg) helps HDV to enter hepatocytes through the same receptors as of HBV and later to assemble the virion in the hepatocyte. The liver bile acids transporter sodium taurocholate co-transporting polypeptide (NTCP), which is responsible for the majority of sodium-dependent bile salts uptake by hepatocytes, also functions as a cellular receptor for viral entry of HBV and HDV through a specific interaction with the pre-S1 domain of HBV large envelope protein 3. HDV does not have replicative machinery of its own. The virus is replicated by host RNA polymerases. Host mediated post-translational changes of proteins, such as prenylation of large delta antigen, is crucial for interaction with the HBsAg in the assembly of the virion.

The baseline-event-anticipation score (BEA score) has been developed based on variables associated with the development of progressive HDV related disease and liver-related clinical complications 4. The score is useful for the management of hepatitis D to decide which patients most urgently require antiviral therapy or need closer monitoring. The BEA score included age, sex, and region of origin, as well as bilirubin, platelets, and international normalized ratio (INR). The BEA score is easy to apply. The score can be used to identify subjects with a low, moderate, or high risk for disease progression. Anti-HDV IgM testing is a relatively easy and robust marker which can provide important clinical information as IgM values are associated with disease activity, development of clinical event, and poor long-term outcome 5.

There is currently no satisfactory treatment available for this infection. In a meta-analysis, standard interferon alpha resulted in end of treatment response in only 33% of patients 6. This response could only be maintained in 17% of the cases six months post treatment. Treatment with pegylated interferon alpha for one year is able to maintain six months post treatment virologic response in only one quarter of the patients 7. Undetectable HDV RNA level at 24 weeks of treatment can predict a possible maintained virologic response post treatment. However, an undetectable HDV RNA at week 24 post treatment is not ‘sustained’ virologic response, as in one study 56% of patients with virologic response at 24 weeks post-treatment became HDV RNA positive in the long term follow up 8. HBV polymerase inhibitors alone or in combination with pegylated interferon are ineffective against HDV. Patients with Hepatitis D who respond to interferon based therapies and achieve sustained suppression of the virus, have favorable outcomes compared to those untreated or treated with nucleos(t)ide analogues 9.

Delta antigen prenylation can be inhibited by the prenylation inhibitors. Lonafarnib is an orally active inhibitor of farnesyl transferase, an enzyme involved in the prenylation. In a phase 2A double-blind, randomized, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up 10. Both groups enrolled six treatment participants and two placebo participants. At day 28, compared with placebo, there were significant mean log HDV RNA declines from baseline. LOWR HDV-4 (Lonafarnib with ritonavir in hepatitis Delta Virus-4) is an ongoing open label, dose titration study designed to evaluate the efficacy and tolerability of lonafarnib combined with ritonavir for a total of 24 weeks in fifteen patients with chronic hepatitis delta.

Myrcludex B, a 47 amino acid peptidic inhibitor of HBV entry, was used with some success in vitro in mice to block the sodium taurocholate cotransporting polypeptide and prevent entry of the hepatitis D virion into hepatocytes. In a prospective open first-in-human, phase I clinical trial, single ascending doses of myrcludex B were administered up to 20 mg intravenously and 10 mg subcutaneously to 36 healthy volunteers. Myrcludex B showed excellent tolerability up to high doses and pharmacologic properties followed a 2-compartment target-mediated drug disposition model 11. In another study, 24 patients with chronic hepatitis D infection were equally randomized (1:1:1) to receive myrcludex B, or pegylated interferon α-2a, or their combination. Patients were evaluated for virological and biochemical response and tolerability of the study drugs at weeks 12 and 24. HDV RNA significantly declined at week 24 in all cohorts. HDV RNA became negative in two patients each in the myrcludex and interferon cohort, and in five patients of the myrcludex-interferon combination cohort. Synergistic antiviral effects on HDV RNA and HBV DNA in the combination cohort indicated a benefit of the combination of entry inhibition with pegylated interferon to treat hepatitis D patients 12.

Pegylated-interferon-lambda (PEG-IFN-λ) is a well-characterized, late-stage, first in class, type III interferon that stimulates cell-mediated immune responses that are critical for the development of host protection during viral infections. A phase II study to evaluate the safety, tolerability, and pharmacodynamics of pegylated interferon lambda 180 ug weekly for 48 weeks will commence soon. Nucleic acid polymers therapy in patients with chronic HDV infection may block HDV entry and the production of HDV derived from a subviral particle related assembly mechanism. The nuclei acid polymer REP-2139 was shown to significantly reduce serum HBsAg and HDV-RNA levels 13.

In conclusion, there is no approved medication for HDV. Interferon alpha is the only available therapy for HDV. It has limited efficacy, prolonged treatment is required, and relapses are common. The only way to abrogate HDV infection will be to eradicate HBsAg, a goal difficult to achieve. Understanding the virology of this virus has advanced the development of innovative therapies, which may be available for clinical use in the near future.

References

  1. Wedemeyer H. Hepatitis D revival. Liver Int 2011;31 Suppl 1:140-4.
  2. Abbas Z, Jafri W, Raza S. Hepatitis D: Scenario in the Asia-Pacific region. World J Gastroenterol 2010;16:554-62.
  3. Yan H, Zhong G, Xu G, He W, Jing Z, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 2012 Nov 13;1:e00049.
  4. Calle Serrano B, Großhennig A, Homs M, Heidrich B, Erhardt A, et al. Development and evaluation of a baseline-event-anticipation score for hepatitis delta. J Viral Hepat 2014 Nov;21(11):e154-63.
  5. Wranke A, Heidrich B, Ernst S, Calle Serrano B, Caruntu FA, et al. Anti-HDV IgM as a marker of disease activity in hepatitis delta. PLoS One 2014;9(7):e101002 014 Nov;21(11):e154-63.
  6. Abbas Z1, Khan MA, Salih M, Jafri W. Interferon alpha for chronic hepatitis D. Cochrane Database Syst Rev 2011 Dec 7;(12):CD006002.
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  8. Heidrich B, Yurdaydın C, Kabaçam G, Ratsch BA, Zachou K, et al; HIDIT-1. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology 2014;60:87-97.
  9. Wranke A, Serrano BC, Heidrich B, Kirschner J, Bremer B, et al, Does antiviral treatment affect the clinical long-term outcome of hepatitis delta? J Hepatol 2016;64: S163.
  10. Koh C, Canini L, Dahari H, Zhao X, Uprichard SL, et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis 2015;15:1167-74.
  11. Blank A, Markert C, Hohmann N, Carls A, Mikus G, et al. First-in-human application of the first-in-class hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol 2016 Apr 27. pii: S0168-8278(16)30145-3.
  12. Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B - first results of a Phase Ib/IIa study. J Hepatol 2016 Apr 27. pii: S0168-8278(16)30148-9.
  13. Bazinet M, Pantea V, Cebotarescu V, Cojuhari L, Jimbei P, et al. Update on the safety and efficacy of REP 2139 monotherapy and subsequent combination therapy with pegylated interferon alpha-2a in caucasian patients with chronic HBV/HDV co-infection J Hepatol 2016;64:S584.