Hepatitis B Reactivation Clinical Trial
Official title:
Hepatitis B Vaccination in Liver Transplant Reecipients Who Received a Liver From an Anti-core Positive Donor. H
Anti-HBc positive liver donors frequently have occult HBV infection, and several studies in
HBsAg-negative subjects have shown that there is often the detection in the liver of
covalently closed circular DNA (cccDNA). In the setting of liver transplantation and
immunosuppresion, grafts from antiHBc positive donors may cause de novo HBV infection
(defined by the development of positive HBsAg and/or detectable serum or liver HBV DNA in
previously HBsAg recipients).
Active immunization may be successful in up to 20% of patients who received an anti-HBc+
liver during transplantation after the first vaccination schedule, and up to 30% after a
second vaccination course. Responders to vaccination could safely halt nucleos(t)ide analog
prophylactic therapy with no risk of HBV reactivation during follow-up.
We also hypothesize that an impaired antigen-specific adaptive cell-mediated immunity at
baseline explain the lack of response
Primary objective:
1. To investigate the efficacy of HBV vaccination in liver transplant recipients who
received a liver from an anti-HBc positive donor.
2. To assess the safety of nucleos(t)ide treatment interruption in those patients achieving
a response to HBV vaccination
HYPOTHESIS The hypothesis of the study is that active immunization may be successful in up to
20% of patients who received an anti-HBc+ liver during transplantation after the first
vaccination schedule, and up to 30% after a second vaccination course. Responders to
vaccination could safely halt nucleos(t)ide analog prophylactic therapy with no risk of HBV
reactivation during follow-up.
Thus, an impaired antigen-specific adaptive cell-mediated immunity at baseline may explain
the lack of response.
OBJECTIVES
Primary objective:
1. To investigate the efficacy of HBV vaccination in liver transplant recipients who
received a liver from an anti-HBc positive donor.
2. To assess the safety of nucleos(t)ide treatment interruption in those patients achieving
a response to HBV vaccination
Secondary objectives:
1. To investigate which clinical and virological variables are associated with a protective
response to HBV vaccination (including time from liver transplant, type of
immunosuppressive therapy and vaccination prior liver transplantation)
2. To assess the role of HBV specific CD8 responses in developing a protective response to
vaccination
3. To assess the relationship between intrahepatic cccDNA-HBV levels and the outcome after
vaccination
STUDY DESIGN This is a multi-center, open-label study in liver transplant recipients.
Four transplant centers will include non-HBV liver transplant recipients who received a
graft from an HBV anti-core positive donor. All patients should be under prophylactic
nucleos(t)ide treatment (NA). Individuals will undergo HBV vaccination with double dosis
vaccine (40 ug) and protective response will be evaluated at the end of a first course
of vaccination. Response will be defined as anti-HBs levels > 100 IU/L. In patients who
do not respond to a first course of vaccination, a second course will be administered.
In patients achieving a protective immune response, prophylactic NA treatment will be
interrupted and follow-up will be extended until 2 years after treatment interruption.
Among those patients achieving vaccination response, a booster dose will be given if
antiHBs levels fall below 100 IU/L during follow-up.
Sample size calculation Sample size has been calculated in order to be able to identify
variables that able to predict response/non response. The estimated number of anti-core
positive recipients in all centers according to anti-core prevalence in general
population is 160 patients (40 patients/center). According to previous reported data,
around 20% would achieve a response to a first course of vaccination and an additional
30% would achieve response after a second course. With a confidance interval of 95% and
accepting a precision level of 5% and an estimated loss rate of 15%, the calculated
sample size would be 114 patients.
Study flowchart All patients will receive 40 ug of HBV vaccine, at 0, 1 and 3 months
time points.
In patients not achieving protective anti-HBs titers (≥ 100 IU/L) 1 month after the last
HBV vaccine dose, the same vaccine schedule will be repeated (40 ug of vaccine 0, 1 and
3 months).
Patients not achieving protective anti-HBs titers (≥ 100 IU/L) 1 month after last HBV
vaccine dose will be considered non-responders and will continue on NA therapy.
In patients achieving protective anti-HBs titers, prophylaxis with nucleoside analogues
will be interrupted and patients will be followed for a minimum period of 24 months.
Blood tests will be performed every 6 months including liver tests, markers of HBV
reactivation and anti-HBs. If anti-HBs levels fall below <100 IU/L at any time point of
follow-up, a single boost (40 ug) will be repeated.
In case of HBV reactivation (HBsAg or HBV-DNA positive) during follow-up, oral NA
therapy will be restarted with high barrier to resistance drugs such as entecavir or
tenofovir.
Study procedures All patients Screening visit
- Medical history and physical examination.
- Review inclusion and exclusion criteria.
- Obtain written informed consent.
- Complete blood tets
- Hematology, chemistry and coagulation tests.
- Serologies: HBsAg, IgG HBV anti-core (HBc), anti-HBs, HIV antibody, IgG HCV
- HBV-DNA, HCV-RNA (only if anti-HCV positive)
- Liver biopsy (if the patient signs an additional inform consent)
- Extraction of 40 ml of blood to process PBMC (Hospital Clínic Barcelona and Padova
University Hospital)
- Liver Biopsy (Hospital Clínic Barcelona) in order to exclude the presence of liver
fibrosis (or other lesions) and to obtain frozen tissue and evaluate the presence
of cccDNA and its correlation with study outcomes.
Baseline (day 1):
The following procedures will be completed prior to treatment administration:
- Perform a complete physical examination.
- Extraction of 40 ml of blood to process PBMC Thereafter, the first dose of vaccine
(GSK 40 ug) will be administered Week 4: 2nd dose of vaccine Week 12: 3rd dose of
vaccine
Week 16:
- Medical history and physical examination.
- Complete blood tets
o Hematology, chemistry and coagulation tests.
- Serologies: HBsAg, anti-HBc, anti-HBs,
- HBV-DNA
- Extraction of 40 ml of blood to process PBMC (Hospital Clínic Barcelona and Padova
University Hospital) a) Responders If anti-HBs ≥ 100 IU/L Interruption of
nucleoside analogue* (in patients who qualify for NA interruption, a specific
follow-up will continue, as described below) b) Non-responders If anti-HBs < 100
IU/L First dose of second course of vaccination Week 20: 2nd dose of vaccine Week
32: 3rd dose of vaccine
Week 38:
- Medical history and physical examination.
- Complete blood tets o Hematology, chemistry and coagulation tests.
o Serologies: HBsAg, anti-HBc, anti-HBs,
o HBV-DNA
- Extraction of 40 ml of blood to process PBMC (Hospital Clínic Barcelona and Padova
University Hospital)
1. Responders If anti-HBs ≥ 100 IU/L Interruption of nucleoside analogue (in
patients who qualify for NA interruption, a specific follow-up will continue,
as described below)
2. Non-responders If anti-HBs < 100 IU/L will continue NA therapy
- Responders to vaccination and NA withdrawal: follow-up every 2 months
during the first 6 months and every 6 months until 2 years of follow-up
At each visit:
Medical history and physical examination.
Complete blood tets:
- Hematology, chemistry and coagulation tests.
- Serologies: HBsAg, Anti-HBs
- HBV-DNA If anti-HBs < 100 IU/L : a vaccine booster (40 ug) will be administered If
HBsAg+ or HBV-DNA+ confirmed in two occasions 2 weeks apart: NA therapy with
entecavir or tenofovir will be introduced.
Statistical analysis Statistical analysis will be performed using SPSS, version 22
(SPSS, Chicago, IL). Categorical data will be analyzed using the chi-square test;
continuous data will be analyzed using the Student T test. The survival rates were
calculated using the Kaplan-Meier method with log- rank test for significance. A P value
of<0.05 will be considered
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