Efficacy of HBV Vaccine in Consolidation of Nucleos(t)Ide Analogues Therapy
Condition: Chronic Hepatitis B
MeSH terms: Hepatitis B; Hepatitis B, Chronic
Study type: Interventional
Phase: Phase 4

Summary: 
      Background and aims: Nucleos(t)ide analogues may suppress HBV DNA to undetectable level, but
      only about 30-40% remain sustained response 1-3 years after discontinued therapy. The
      investigators will try to improve the sustained response rate by given a course of HBV
      vaccination during the last 6 months on patients receiving a 3-year entecavir or tenofovir
      therapy.

      Rational: The host may response to HBV vaccine when HBV DNA and immune tolerance are
      suppressed during entecavir or tenofovir therapy.

      Patients: Patients who have been receiving entecavir or tenofovir therapy for at least 30
      months will be invited to this study. The case group will receive 5 Engerix-B injections
      during the last 6 months of entecavir or tenofovir therapy. Arm A-entecavir pretreated group:
      75 cases will be enrolled to receive Engerix-B injection and compared with histological
      non-vaccine treated controls; Arm B-tenofovir pretreated group: 50 patients will be
      randomized into case (vaccine) and control group according to age, gender, pretreatment HBV
      DNA level.

      Therapy: Both case and control groups will receive a 3 year or longer entecavir or tenofovir
      therapy. Patients will be screen at 24-30 months and enrolled at 30 months after entecavir or
      tenofovir therapy. They will receive 5 Engerix-B injections at 0,1st ,2nd,3rd and 6th month
      [30-36 +/-1 month post nucleos(t)ide therapy] post enrollment. Both drugs will be
      discontinued after completed therapy.

      Follow-up: Both groups will be monitoring by biochemistry, alpha-fetoprotein, quantitative
      HBsAg, HBV DNA levels and immunological parameter periodically for 2 years after therapy.

      Efficacy: Those patients with persistent normal ALT and HBV DNA lower than 1*100000 cps/mL
      after discontinued nucleos(t)ide analogues therapy will be considered to have sustained
      response. Patients with transient elevation of HBV DNA and ALT, but normalized spontaneously
      without further therapy will be defined as delayed response. Patients with persistent HBV DNA
      greater than 1*100000 cps/mL will be considered to have non-sustained response.

      Study duration: The enrollment will be completed in one year and keep on observation for
      additional 2 years.

      Expected goals of the study: HBV vaccine and nucleos(t)ide analogues combination therapy may
      decrease the HBV relapse rate at 1 and 2 year after completed therapy.
    

Detailed description: 
      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).

      In addition to the relief of immune tolerance, NA may suppress the HBsAg production from free
      virus, but no effect is expected for those HBsAg produced by integrated HBV genome. These two
      types of HBsAg may have some differences on protein conformation and behavior (46,47). The
      vaccine is produced according to free virus. Therefore, when the HBsAg produced by free virus
      is suppressed by NA to a low level, the vaccine may be recognized as a new antigen. The
      immune response elicited by the therapeutic vaccine may have a potential on suppression of
      free virus.

      1.3 Combined HBV vaccine and NA therapy in animal study A Woodchuck animal study suggest
      entecavir therapy followed by Woodchuck surface (WHs) and core (WHc) DNA vaccination 7 weeks
      later may induce WHc and WHs specific T cell responses. Two of the 6 animals clear Woodchuck
      surface antigen (WHBsAg) and product anti-WHBs (48). Similar results can be found in HBV
      transgenic mice model. Hepatitis B surface (HBs) and hepatitis B core (HBc) specific cellular
      and humoral response was identified after HBc and HBs protein vaccine therapy (49). In a
      mouse model with sustained HBV viremia after infection with a recombinant adeno-associated
      virus carrying a replicable HBV genome. Immunization with the conventional HBV vaccine in the
      presence of aluminum adjuvant failed to elicit an immune response,but vaccination of mice
      with HBsAg/CpG induced strong antibody production and T-cell responses(50)

      1.4 Combined HBV vaccine and NA therapy in liver transplantation Prevention of HBV
      reinfection is an important issue in chronic hepatitis B received liver transplantation.
      HBsAg immunoglobulin (HBIG) is the choice of therapy with evident of good protection (51).
      However, HBIG is quite expensive and long term therapy is needed. Combination of HBV vaccine
      and NA therapy had been done in patients received liver transplantation. The initial reports
      were not good (52-54), but recent studies suggest up to 50% patients response to lamivudine
      and HBV vaccination combination therapy (55,56) after adjusted dose of HBIG. All these
      studies did not report severe adverse event using lamivudine and HBV vaccine combination
      therapy.

      1.5 Combined HBV vaccine and NA therapy in patients with chronic hepatitis B To increase
      response rate many HBV vaccines has been developed by increase immune epitope or
      posttranslation modifications (57,58) Combination of Lamivudine with therapeutic HBsAg DNA
      vaccination led to the persistence of T-cell responses (59). An HBV therapeutic vaccine
      clinical trial studies showed a decrease of HBV replication in hepatitis B e antigen (HBeAg)
      positive patients received HBV vaccine and lamivudine combination therapy (60).

      2. Study objectives To understand the efficacy of combining a 3-year NA and Engerix-B therapy
      in sustained viral suppression.

      3. Investigational plan 3.1 Overall study design This trials will examine the efficacy of NA
      and Engerix-B combination therapy in chronic hepatitis B.

      3.2 Study design Arm A-entecavir pretreated group: Case vs. histological control study. Arm
      B-tenofovir pretreated group: randomized case and control study. 3.3. Therapy 3.3.1 Entecavir
      0.5 mg daily for at least 3 years. 3.3.2 Tenofovir 300 mg daily for at least 3 years. 3.3.3
      Five doses of Engerix-B 20 ug during the last 6 month of NA therapy in case group.

      Both case and control groups will complete a 3-year NA therapy. The vaccination group will
      receive a course of Engerix-B vaccination. They will be enrolled at the last 6 months of the
      NA therapy. Engerix-B will be given at the 0,1st ,2nd 3rd and 6th month after the enrollment.
    

Intervention name(s): Engerix-B; Tenofovir; Entecavir
Intervention type(s): Drug; Drug; Drug
Intervention description(s): The case group will receive 5 Engerix-B injections during the last 6 months of a 3-year NA therapy.; Both case and control will receive 300 mg Tenofovir for at least 3 years; Both case and control will receive 0.5 mg entecavir therapy for at least 3 years
Intervention MeSH terms: Tenofovir; Entecavir
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Therapeutic Uses; Entecavir; Tenofovir; Engerix-B; DNA Virus Infections; Antiviral Agents; Vaccination