A new promising combination therapy against hepatitis B outlined in a recent study, entitled, “Entecavir combined with turin inhibitor simultaneously reduces hepatitis B virus replication and e antigen secretion” published in Virology Journal by Hui Y Yang, the first author of the study, part of Dr. Xiao M Peng’s group from Hepatology Laboratory, the Hospital for Liver Disease, Sun Yat-Sen University, China, may offer a potential antiviral therapy for the chronic form of the disease.
Hepatitis B virus (HBV) infections cause 1 million deaths worldwide per year. Antiviral therapy is crucial to improve the prognoses of the patients. There are three main aims to be achieved in the antiviral therapy of chronic hepatitis B virus (HBV) infection, a virological response, undetectable levels of HBV DNA in the serum, and hepatitis B e antigen (HBeAg) seroconversion (HBeAg serological response). While the HBeAg persistence is an independent risk factor for hepatocellular carcinoma, the HBeAg seroconversion is thought to be important for a benign prognosis. The virological response plus HBeAg serological response have a low relapse probability, when patients are not under treatment with the current antiviral therapy, when compared with virological response alone. The current antiviral therapies include recombinant interferon and nucleoside/nucleoside analogs, like entecavir (ETV), which cannot rapidly achieve simultaneously the two main aims of the antiviral therapy. Nucleoside analog entecavir (ETV) inhibits HBV replication but may induce HBeAg seroconversion. For these reasons, ETV combined with some direct HBeAg secretion-inhibitory strategies seems a way to improve the current antiviral therapy of chronic hepatitis B.
The research team evaluated the efficacy of the combination therapy of nucleoside analog entecavir (ETV) with HBeAg secretion inhibitors, i.e. targeting furin activity, as antiviral therapy of chronic hepatitis B. Furin is a proprotein convertase involved in HBeAg maturation. In this study, the authors inhibited the activity of turin using the inhibitors decanoyl-RVKR-chloromethylketone (CMK) and hexa-D-arginine (D6R) or the expression of furin inhibitory prosegment. They assessed the effect of furin inhibition on HBV replication and the effect of CMK combined with nucleoside analog entecavir (ETV) on HBV replication and HBeAg secretion in human hepatoma cell line (HepG2.2.15 cells). All the inhibitors, CMK, D6R, and the expression of inhibitory pro segment, significantly reduced HBeAg secretion, but only CMK increased HBV replication and accumulated HBV replication-essential hepatitis B core antigen (HBcAg) in the cytosol of the cells. This last result is due to the CMK inhibitory effect on the trypsin-like activity of cellular proteasomes, enzymes responsible for the degradation of HBcAg. The effect of CMK on increased viral replication was inhibited by ETV and ETV in combination with CMK reduced simultaneously HBV replication and HBeAg secretion.
Overall, the authors conclude that the inhibition of furin does not enhance HBV replication. And importantly, the combination therapy of nucleotide/nucleoside analogs and turin inhibitors achieves the dual goal of the antiviral therapy for chronic hepatitis B and seems to be a potential and promising therapy against this infection.