Treatment of hepatitis D: an unmet medical need

Background: Therapy of chronic hepatitis D (CHD) is still based on interferon alpha (IFN alpha), introduced in clinical practice 30 years ago: results are modest and better therapies are an urgent medical need. Aims: This article provides a critical overview of the new therapies under investigation for CHD. Sources: Review of the recently published medical literature. Content: New therapeutic efforts aim to deprive the hepatitis D virus (HDV) of functions provided to its life cycle by the hepatitis B Virus (HBV) or by the host. Three therapeutic strategies are in evaluation: a) Myrcludex B, a myristolated lipopeptide of the pre -S1 domain of the HBsAg that blocks the entry of the HDV into hepatocyes and controls infection by preventing the spreading of the virus to liver cells not infected by the HBV; b) Lonafarnib, an inhibitor of a host farnesyl-transferase that hinders morpho- genesis of the HDV by preventing the farnesylation of the large HD -antigen, necessary for virion as- sembly; c) REP 2139, a nucleic acid polymer that prevents export of the mature HDV by the presumed inhibition of the synthesis of subviral HBsAg particles with which the virion is coated. Myrcludex B and Lonafarnib increase therapeutic ef ficacy in combination with Peg-IFN alpha. In a pilot study, REP 2139 in combination with Peg-IFN alpha induced the clearance of serum HDV RNA and of the HBsAg in about half of 12 treated patients. Implications: Long-term therapies with either Myrcludex B or Lonafarnib in combination with Peg-IFN alpha are required to achieve clinical control of CHD. However, with prolonged therapies tolerance becomes a problem; studies are on the way to determine whether Peg-IFN lambda may be better tolerated that Peg- IFN alpha. The promising preliminary data of REP 2139 in combination with Peg-IFN alpha await con firmation of the original pilot study. (c) 2020 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.