Chronic hepatitis D (CHD) is a severe liver disease with worldwide distribution caused by the hepatitis D virus (HDV). Therapy of CHD is at a standstill. It still relies on interferon (IFN), introduced empirically in the 1980s; results are limited. With the peghilated IFNs that are now in use, only 25% of CHD reach a sustained viral response, that is, clear the HDV-RNA 6 months after stopping therapy. However, HDV remains infectious and ready to reactivate at very low titers undetectable by current assays, if the HBsAg persists in serum; relapses of hepatitis D post-therapy are frequent and further diminish the therapeutic response. The major obstacle to CHD therapy is the minimalist nature of the HDV. It does not encode for any enzymatic function but is replicated by host RNA polymerases deceived to recognize the viral RNA as it were a cellular DNA; therefore, it has no replicative machinery of its own to be targeted by antivirals. The only help required from hepatitis B virus (HBV) is the HBsAg coat to attach to hepatocytes and assembly in the virion; HBV antivirals that decrease HBV-DNA but leave HBsAg unaffected are of no avail in CHD. Novel therapeutic strategies are under evaluation. Myrcludex B, a peptidic inhibitor of HBV entry, was used with some success in vitro in the mouse to block the Na+-tauro chocolate cotransporting polypeptide and prevent entry of the HD virion into hepatocytes. The nuclei acid polymer REP-2139 was shown to distinctly diminish serum HBsAg and HDV-RNA by blocking HBsAg entry and inhibiting its intracellular synthesis. Prenylation of the large HD-antigen is critical for its interaction with the HBsAg in the assembly of the virion. A proof of concept study in humans has shown that the prenylation inhibitor lonafarnib reduced HDV-viremia.

Keywords:
Hepatitis D, Hepatitis D virus, IFN-therapy , Chronic hepatitis D therapy
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2016
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