The entry inhibitor Myrcludex-B efficiently blocks viral spreading in vivo in human liver chimeric uPA/SCID mice previously infected with Hepatitis B Virus
M. Lutgehetmann1, 2; J. Petersen3; T. Volz1; L. Allweiss1; A. W. Lohse1; S. Urban4; M. Dandri1
1. Internal Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany.
2. Medical Microbiology, University Hospital Hamburg Eppendorf, Hamburg, Germany.
3. Asklepiosklinik St. Georg, Liver Center Hamburg IFI Institute, Hamburg, Germany.
4. Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany.
Currently approved antiviral treatments based on interferon alpha or inhibitors of the hepatitis B virus (HBV) polymerase are generally not curative and additional therapeutic strategies interfering with other HBV replication steps are needed. We previously demonstrated prevention of de novo HBV infection by pre-treating uPA mice with Myrcludex-B, a lipopeptide derived from the preS1 domain of the HBV envelope (Nat. Biotech.2008). Aim of this study was to investigate the ability of this HBV entry inhibitor to block viral spreading post-infection, at a time when viremia is already detectable but only few human hepatocytes are infected. Experimental design: human liver chimeric uPA/SCID mice were injected with HBV-infectious serum (5x10E7 HBV DNA copies/mouse) and treatment with Myrcludex-B (2 mg/Kg/day; s.c. injection) was initiated either 3 days (group A, n=8) or 3 weeks (group B, n=7) post HBV-inoculation, while 8 sham-treated mice were used as control. Mice were analyzed serologically (HBV-DNA, HBsAg) and intrahepatically by quantitative RT-PCR measurements (cccDNA) and immunohistochemistry (human CK-18, HBcAg) at baseline, after 3 and 6 weeks of treatment. Results: In the first experimental setting, Myrcludex-B administration initiated 3-days after HBV-inoculation efficiently prevented viral spreading from the few initially infected human hepatocytes, as demonstrated by immunohistochemistry. Viremia and HBsAg levels remained below 10E5 HBV-DNA/ml and <10 IU/ml, respectively, while in untreated control mice median viremia increased to 3x10E7 and the majority of human hepatocytes stained HBcAg-positive within six weeks post-infection. Occurrence of viral spreading was also demonstrated in 2 mice after therapy discontinuation. Furthermore, Myrcludex-B blocked viral spreading even when treatment was first initiated at 3-weeks post-infection, at a time when median viremia was 2x10E6 HBV-DNA/ml. Notably, levels of viremia, HBsAg and intrahepatic cccDNA loads did not increase significantly after 6 weeks of treatment. Conclusions: Myrcludex-B showed strong capacities to prevent HBV spreading in vivo. Since maintenance of chronic HBV infection involves a dynamic turnover between cells that are cleared by the immune system and cells that become newly infected, the use of drugs preventing hepatocyte re-infection, possibly in combination with other HBV-drugs, may represent a new effective antiviral concept also in the setting of chronic infection.
yes it will be the first cure together with trl7 agonists and also rep9ac from replicors, the cures are there it is just a drug makers choice but they are forced now to market becuase Myrcludex-B is on trial in russia and they are less corrupt and willing to make money fast probably
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