4 WORLD GASTROENTEROLOGY NEWS JULY 2016 Editorial | Expert Point of View | Gastro 2016: EGHS-WGO | WDHD News | WGO & WGOF News | WGO Global Guidelines | Calendar of Events Anti-HDV IgM testing is a relatively easy and robust marker which can provide important clinical informa-tion 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 re-sponse 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 ‘sus-tained’ 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 poly-merase inhibitors alone or in combi-nation with pegylated interferon are ineffective against HDV. Patients with Hepatitis D who respond to inter-feron based therapies and achieve sus-tained 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 in-hibitors. Lonafarnib is an orally active inhibitor of farnesyl transferase, an enzyme involved in the prenylation. In a phase 2A double-blind, random-ized, placebo-controlled study, pa-tients aged 18 years or older with chronic HDV infection were random-ly 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 six 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 ongo-ing 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 hepati-tis delta. Myrcludex B, a 47 amino acid pep-tidic inhibitor of HBV entry, was used with some success in vitro in mice to block the sodium taurocholate co-transporting 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 intra-venously and 10 mg subcutaneously to 36 healthy volunteers. Myrcludex B showed excellent tolerability up to high doses and pharmacologic proper-ties 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 dur-ing viral infections. A phase II study to evaluate the safety, tolerability, and pharmacodynamics of pegylated in-terferon 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. Hepa-titis D: Scenario in the Asia-Pa-cific 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. Continued from first page.
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