Andrew Vaillant, presenting at AASLD 2016. Photo by Liz Highleyman, hivandhepatitis.com
Today there is no cure for hepatitis B infection. Current treatment consists of prolonged antiviral treatment, preferably using either tenofovir or entecavir, to control viral replication. Owing to the integration of hepatitis B virus (HBV) DNA into the cellular nucleus in a form called cccDNA, it is not possible to eradicate the virus with antiviral drugs available today. New drugs are needed that will either interrupt the production of new cccDNA in the liver, or target other steps in the viral lifecycle, leading to loss of HBsAg. Ultimately the aim of experimental treatment for HBV is either to eradicate the virus entirely, or to achieve a 'functional' cure, meaning that the immune system is able to control any residual HBV infection without ongoing damage to the liver and without further antiviral treatment.
One approach to targeting a new step in the HBV lifecycle is to block the release of HBV viral subparticles from infected hepatocytes. Montreal-based Replicor, Inc. is developing nucleic acid polymers (NAPs) that interfere with the assembly and block the release of these particles. At the 2016 Liver Meeting, organised by the American Association for the Study of Liver Diseases (AASLD), the company presented promising preliminary results of a study of two nucleic acid polymers – REP 2139 and REP 2165 – used in combination with tenofovir disoproxil fumarate and pegylated interferon for the treatment of hepatitis B 'e' antigen (HBeAg)-negative chronic hepatitis. The study found that all people who received REP 2139 and six of the nine who received REP 2165 experienced a reduction of 90% or more in HBsAg levels after 12 weeks of treatment. People in the study also experienced large increases in ALT (alanine transaminase) levels during treatment; this may be a sign of immune restoration but will need careful observation in future studies to ensure patient safety. This study will continue, and will test whether people who receive the experimental drugs are able to control HBV replication after stopping all treatment for at least six months. Larger studies will be needed to determine whether this form of treatment can deliver a functional cure.
Improving the immune system’s ability to control HBV and recognise HBV-infected cells might also assist in controlling the infection, even if it cannot be eradicated. Therapeutic vaccines are one means of improving immune responses to a viral infection. By presenting an inactive sequence of the virus in the form of a vaccination, researchers try to stimulate improved immune responses that will lead to better control of HBV.
At the AASLD Liver Meeting Gilead Sciences reported the results of a phase II study of a therapeutic vaccine, GS-4774, designed to improve HBV-specific immune responses. The vaccine was tested in a randomised study of 195 people taking tenofovir as antiviral treatment. The study found no significant difference in HBsAg levels between those receiving the vaccine and those receiving tenofovir alone after 24 weeks. The study investigators say that this is not the end of HBV therapeutic vaccine research; the study findings will inform how future therapeutic vaccines will be designed, and in particular, which immune responses need to be improved in order to control HBV.
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