Despite the major progress made in HBV therapy, there remain various challenges. One is cost, about $60,000–$72,000 for 5-year TDF therapy. Pharmacy claims show that adherence is a problem; doses used are less than doses prescribed. There is a lack of accurate prediction of how HBV disease will progress in individuals. HBV DNA can be integrated into the human genome at an early stage of infection. Fortunately, the integrated

viral DNA is usually not the complete viral genome and patients, who achieve HBsAg loss, rarely relapse. Stefan Mehrle, TSA HDAC in vitro University of Heidelberg, Germany (Stephan Urban, Head of Hepatitis B Research Group, University of Heidelberg, was originally scheduled to give this presentation). Some chronic HBV-infected subjects are co-infected with hepatitis delta virus (HDV). This is a defective virus that replicates only in the presence of HBV. Current antiviral drugs do not inhibit HDV. Recently, heparan sulphate proteoglycan (HSPG) has been shown to be essential for binding both HBV and HDV to primary hepatocytes. In 2012, human sodium taurocholate co-transporting polypeptide (hNTCP) was Akt assay identified as a functional receptor for HBV and HDV. hNTCP is also designated as a solute carrier protein 10A1 (SLC10A1). hNTCP was shown to be a binding factor for the preS1 domain of the HBV L envelope protein. This interaction

was found to be essential for HBV and HDV infection. Whereas HBV replication is poor in cell lines derived from hepatocytes (e.g. HepG2 and Huh-7) in which hNTCP is usually weakly expressed, HBV replication is possible in primary human hepatocytes. The critical discovery was that over-expression of hNTCP in HepG2 or Huh-7 cells conferred susceptibility to HBV and HDV infection. Myrcludex-B is a lipopeptide derived from amino acid residues 2–48 of the preS1 region of the HBV L protein. Because it quickly (within 5 min) targets the liver, it is being developed for liver imaging and for drug targeting. It also

acts as an entry inhibitor for HBV and HDV by Glutamate dehydrogenase interrupting binding between the HBV L protein and hNTCP. It specifically inhibits hNTCP-mediated taurocholate transport but the effect on HBV replication is much greater. Myrcludex-B activity has been investigated in vivo using SCID mice reconstituted with human hepatocytes. With prophylactic treatment, not one infected hepatocyte was seen. Following therapeutic treatment, at week 6 post-infection, there were a few isolated infected cells. After the end of therapy, the infection seems to spread but only to neighboring cells. Myrcludex-B has been synthesised on a 100 g scale. Toxicology evaluation in 3 chimpanzees has been completed and clinical trials have been initiated. In a Phase I trial using a 20 mg dose, myrcludex-B was well tolerated. Results of a further Phase I trial are due to be reported later this year (2014). A dose-ranging Phase II trial has been started.