Impact of Hepatitis B Vaccination on HBs Antigenemia
Condition: HBV
MeSH terms: Hepatitis B
Study type: Interventional

Summary: 
      -  HBV is not curable with persistent HBsAg even after the disappearance of HBV DNA.

        -  HBsAg > 1000 IU/ml is associated with the risk of virological recurrence and HCC.

        -  There is an impaired immune response to HBsAg and HBV vaccine is an easily available,
           cost-effective, non-harmful method of stimulating immunity.
    

Detailed description: 
      Persistent HBs antigenemia >1000 IU/ml has a possibility of viral reactivation and hepatoma
      in 8%; the effect of HBV vaccine on HBsAg was investigated, recurrence of viremia, insulin
      resistance, and fibrosis regression.

      From August 2011 to October 2016, 220 participants with chronic hepatitis B were evaluated at
      the hepatology clinic-Internal medicine department-Zagazig university-Egypt. They were
      enrolled after approval of the ethical committee of Zagazig university hospital. Written
      informed consent was obtained for the interview, clinical evaluation, and blood sampling.

      participants were divided into two groups:

        -  Inactive carriers (n=100) who were presented with persistent HBsAg, undetected HBV DNA,
           normal liver enzymes, positive HBeAb and had never been exposed to antiviral therapy.

        -  Patients exposed to NAs (n=120): tenofovir 300mg (n=65) or Entecavir 1mg (n=55): A-
           HBeAg-positive patients (n=60) who received NAs until 1 year after HBe seroconversion
           and disappearance of HBV DNA with persistent HBsAg B- HBeAg-negative patients (n=60) who
           received NAs till 3 years after the disappearance of HBV DNA; all showed persistent
           HBsAg.

        -  Exclusion criteria Clinically decompensated liver cirrhosis; hepatocellular carcinoma;
           other causes of liver disease or mixed causes (excessive alcohol consumption, autoimmune
           liver disease, immunosuppressive drugs, or who had been infected with hepatitis C virus.

      B- Vaccination schedule

        -  All the participants had received 30 µg of recombinant HBV vaccine which contains
           Purified HBsAg produced by recombinant DNA technology (Euvax-B, LG Life Sciences, Korea)
           intramuscularly in the deltoid region at three different time intervals (0, 1, 6
           months). The first dose of the vaccine was initiated 1 year after HBe seroconversion and
           disappearance of HBV DNA in HBe +ve or 3 years after the disappearance of HBV DNA in HBe
           -ve patients or immediately after diagnosis of inactive carriers. NAs were stopped three
           months after the 3rd dose of HBV vaccine

        -  Three months after the last dose of vaccine, the participants were evaluated for IP-10
           level, the production of protective HBsAb, recurrence of viremia by regular HBV DNA,
           HBsAg quantification.

      Patients who failed to produce HBsAb i.e. HBsAb titer < 10 IU/ml, were given a fourth booster
      dose of vaccination immediately after confirmation of vaccine non-response.

      C- Control Group It included 100 participants who had CHB, with undetectable HBV DNA with
      persistence of HBsAg and they did not receive HBV vaccine. They were divided into treatment
      naïve (n=50) and treatment experienced (n=50) who were given tenofovir (n=30) or entecavir
      (n=20) which were stopped 3 years after HBV DNA disappearance and HBeAg seroconversion and
      followed for 3 years by evaluation of HBsAg level and HBV DNA every 6 months to detect the
      natural rate of HBV reactivation.

      D- Laboratory analysis It included complete Blood Count, liver function tests, prothrombin
      time, prothrombin concentration (%), kidney function tests.

        -  HCV antibody, HBeAg, HBeAb, HBcAb.

        -  Real-time Quantitative PCR for HBV DNA was done at the baseline and then every 6 months
           after the last dose of HBV vaccine for 3 years (COBAS AMPLICOR HBV MONITOR, with a
           detection limit of 15 IU/ml; Roche Diagnostic Systems).

        -  Insulin resistance was done before initiation of vaccination and 3 months after the last
           dose of vaccination. It was calculated by HOMA-IR, a value greater than 2 indicates
           insulin resistance [20].

        -  HBV genotyping was performed using INNO-LiPA HBV Genotyping assay; Innogenetics NV,
           Ghent, Belgium.

        -  Determination of HBsAg titer (Elecsys HBsAg II assay, Roche Diagnostics, USA) [21]. It
           was done before vaccination and 3 months after the last dose of vaccine then every 6
           months for 3 years.

        -  Anti-HBs antibodies were performed 3 months following the third dose of the vaccine or 3
           months after the 4th booster dose. Seroconversion was considered if anti-HBs levels were
           above 10 IU/ml and non-response if anti-HBs levels were below 10 IU/ml [22].

        -  Serum IP-10 levels were determined in serum before vaccination and 3 months after the
           last dose of vaccine, by a solid-phase sandwich ELISA (Quantikine, R&D Systems, USA)
           (reference value: 7.8-500 pg/ml).

      E- Abdominal ultrasonography participants were examined after 6 hours fast. Criteria of
      cirrhosis, portal hypertension, and the presence of fatty liver disease were documented.

      F- Liver stiffness assessment (LSM) Fibroscan was performed to measure liver stiffness before
      antiviral therapy and 3 months after the last dose of HBV vaccine, with the number of shots
      is 10, interquartile range≤ 25%. Liver stiffness 2.5-7 kPa denotes (F0-1), 7-9.5 kPa (F2),
      9.5-12.5 kPa (F3), >12.5 kPa denotes cirrhosis.
    

Intervention name(s): HBV vaccine
Intervention type(s): Biological
Intervention description(s): HBV vaccine which contains Purified HBsAg produced by recombinant DNA technology (Euvax-B, LG Life sciences, Korea) intramuscularly in deltoid region at three different time intervals (0, 1, 6 months).
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Group I: inactive carriers (n=100). Group II: CHB exposed to nucleos(t)ides (n=120) till 6 months after HBe seroconversion and HBV DNA disappearance in HBeAg positive (n=60) or DNA disappearance in HBeAg negative patients (n=60). All showed persistent HBs antigenemia.
-A control group (n=100) did not receive HBV vaccine
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HBV vaccine; persistent; HBsAg; IP-10