Chronic hepatitis B (CHB) is the world’s most common serious liver infection and is a widespread global health issue that is under-diagnosed and under-treated. Although hepatitis B virus (HBV) infection is not currently curable, it can be effectively controlled using pegylated IFN-α (PegIFN-α) and/or nucleos(t)ide analogue antivirals  (NUCs). The next steps in the HBV therapeutic strategy are towards the cure of HBV infection according to Prof. Robert G. Gish, Stanford University, USA.

 

　　Right now, the antiviral regimens are limited for the strategy of HBV elimination.

 

　　PegIFN-α has the advantage of a fixed duration of therapy with the option of response-guided therapy based on HBsAg levels and can be an ideal option for some patients with high ALT and medium to low HBV DNA, but the rate of HBsAg seroconversion is lower than 20%. Entecavir and tenofovir treatment is indefinite for most patients but maintains extended virologic control over several years resulting in histologic improvement. There is also evidence that hepatic cccDNA levels can be modestly decreased with NUC therapy but without achieving cccDNA clearance.

 

　　The success of long-term NUC treatment prompts new questions for future HBV treatment strategies.

 

　　We can say “yes” to all these questions, Prof. Robert G. Gish said optimistically. It is possible to permanently eliminate HBV infection with therapies that specifically target the cccDNA pathway and we be aiming to achieve a “functional cure” using HBsAg elimination as an endpoint and thus, the ultimate maker that we are changing outcomes. We will have a new role for HBV RNA and HBcrAg testing and there will be new technologies for FNA and liver sampling for cccDNA and intracellular intermediates of HBV replication, including HBV pregenomic RNA (pgRNA) and mRNA testing.

 

　　The next step for antiviral therapy: new technologies and new anti-viral tools.

 

　　The new technologies and anti-viral tools include: iRNA, anti-sense, blocking viral entry, inhibiting viral release, using cellular mechanisms of viral replication such as cyclophilins, capsid inhibitors, and immune modulators including PD-L1 antagonists, TLR-7 agonists, Tarmogen-based vaccines, vaccines with adjuvants and extended preS1 epitopes; as well as attacking the virus in the nucleus using CRISPR/Cas9, changing histones, and acylation patterns are all new milestones towards the elimination of HBV infection.

 

　　The steps towards eliminating HBV.

 

　　“For the strategy of HBV elimination with anti-viral therapy, we are on the path and next need to clear HBsAg, then clear cccDNA, and finally clear all cells with HBV DNA integration and prevent HBV integration from occurring in those patients with early phases of disease”, said Prof. Gish.

 

　　The new concept of HBV therapy is usage of new combination therapeutic tools in combination and sequence.

 

　　The new Guidelines from APASL, AASLD and EASL will guide current therapy, but we need to further suppress the virus, stop the regeneration of cccDNA and awaken the host immune system so it will ultimately have the final “word” in viral control and clearance. The new therapies need to target multiple sites in the HBV genome and/or the immune system. The major concept moving forward with HBV therapeutics is the use of new combination therapies, and/or new therapies in sequence.

 

　　Prof. Gish concluded that it will be very exciting that we will have the chance to achieve a cure for HBV infection in our lifetime.