Efficacy of HBV Therapeutic Vaccine in Consolidation of Nucleos(t)Ide Analogues Therapy: a Pilot Study

Introduction Chronic hepatitis B virus (HBV) infection is a widely prevalent global health problem with estimate 350-400 million chronic HBV carriers worldwide. In China, Southeast Asia and sub-Saharan Africa, as many as 10-15% of the population are chronically infected with HBV. In North America and North Europe, HBV chronic carrier rates are much lower, usually below 1%. Intermediate HBV carrier rates of 1-7% are found in parts of Southern and Eastern Europe, Central America, the Middle East and parts of Japan (1-4).

HBV is highly infectious; many chronic HBsAg carriers were infected in their family shortly after birth or in early childhood (5-7). Recent genome-wide association studies revealed antigen presenting molecules, Human leukocyte antigen-DP (HLA-DP) and HLA-DQ, are associated with persistence HBV infection (8-10). HBV is actively replicated in chronic carriers during the initial immune tolerance phase (11). Impaired innate and adaptive immune responses to HBV can be found during this stage (12-16). They are generally asymptomatic until the immune clearance phase developed. At this stage, innate immunity, HBV-specific and non-specific T cells and other immune cells may orchestra an immune response and hepatic necroinflammation to clear HBV (17-19). The immune clearance phase is critical to the outcome of chronic HBsAg carriers. Those patients with prolonged HBV replication and repeated hepatic inflammation will run into liver cirrhosis and /or hepatocellular carcinoma (HCC) (20-23). How to terminate HBV replication is an important issue in management of chronic HBsAg carriers.

1.1 Therapy for chronic hepatitis B In the past 20 years, significant improvements in treatment of chronic hepatitis B (CHB) have been achieved by introducing regimen of interferon derivatives and nucleotide/nucleoside analogues (NA) (24-26). Interferon is a T helper cell type 1 cytokine that promotes immunity of host to clear HBV (27,28). NA inhibit HBV DNA synthesis by termination the nascent proviral DNA chain. About 30% patients may have complete response with normalization alanine aminotransferase (ALT) and HBV DNA lower than 10000 cps/mL one to three year after discontinued therapy (10,29-31). For the rest of patients a flare-up HBV replication occurred (10,29-31), a life-long therapy may be needed to eliminate covalently closed circular DNA (cccDNA) pool and achieved a sustained therapeutic response (32). Unfortunately, the prolonged use of NA need a lot of budgets and carried a substantial risk for emerging drug resistance mutants (33). The interferon derivatives regimens have similar efficacy with significant side effects (27,28). Therefore, Development of a safe and affordable anti-HBV agent/strategy is needed to further improve outcomes (34).

1.2 Rational for combine HBV vaccine with NA therapy NA therapy may suppress Serum HBV DNA to undetectable level (29-31). These drugs are acceptable to most of the patients because they are admitted orally, once daily and without significant side effect. The main problem is HBV DNA tends to relapse in approximately 70% of patients 1-3 years after discontinued therapy (10, 29-31).

When HBV was suppressed by NA therapy, the immune tolerance may also be suppressed. The post treatment relapse is an indirect evidence of losing immune tolerance in such patients (29-31). The post treatment clinical relapse is associated with enhanced Th1 response (35-37). T regulatory (Treg) cells, macrophages and other unidentified factors may play important roles on HBV tolerance (19, 38-41). One of an important phenomenon for patients receiving NA therapy is decrease of Treg cells level (42,43). The post treatment relapse of hepatic necroinflammation is an evidence of the restored HBV specific immune response (44,45).