Intramuscular hepatitis B immune globulin combined with lamivudine in prevention of hepatitis B recurrence after liver transplantation

BACKGROUND: Combined hepatitis B immune globulin (HBIg) and lamivudine in prophylaxis of the recurrence of hepatitis B after liver transplantation has significantly improved the survival of HBsAg positive patients. This study was undertaken to evaluate the outcomes of liver transplantation for patients with hepatitis B virus (HBV). METHODS: A retrospective chart analysis and a review of the organ transplant database identified 51 patients (43 men and 8 women) transplanted for benign HBV-related cirrhotic diseases between June 2002 and December 2004 who had survived more than 3 months. HBIg was administered intravenously during the first week and intramuscularly thereafter. RESULTS: At a median follow-up of 14.1 months, the overall recurrence rate in the 51 patients was 3.9% (2/51). The overall patient survival was 88.3%, and 82.4% after 1 and 2 years, respectively. A daily oral dose of 100 mg lamivudine for 2 weeks before transplantation for 10 patients enabled 57.1% (4/7) and 62.5% (5/8) of HBV-DNA and HBeAg positive patients respectively to convert to be negative. Intramuscular HBIg was well tolerated in all patients. CONCLUSION: Lamivudine combined with intramuscular HBIg can effectively prevent allograft from the recurrence of HBV after liver transplantation.

Adaptive immune response during hepatitis C virus infection

Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma.HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control.Liver damage and disease progression during HCV infection are driven by both viral and host factors.Specifically,adaptive immune response carries out an essential task in controllingnon-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery.HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion.To impair HCV-specific T cell reactivity,HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro-and antiapoptotic proteins.In this review,the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

Cellular immune function and liver damage in post hepatitic cirrhosis

AIM To study the cellular immune function in patients with post hepatitic cirrhosis (PHC) and its relation with different liver damages.

Prevention of vertical transmission of hepatitis B virus infection

Hepatitis B virus(HBV)is the leading cause of chronic viral hepatitis.Annually,almost two million children younger than 5 years acquire the infection,mostly through vertical or horizontal transmission in early life.Vertical transmission of HBV is a high efficacy phenomenon ranging,in the absence of any preventive interventions,from 70%to 90%for hepatitis e antigen positive mothers and from 10%to 40%for hepatitis e antigen-negative mothers.Maternal viraemia is a preeminent risk factor for vertical transmission of HBV.Maternal screening is the first step to prevent vertical transmission of HBV.Hepatitis B passive and active immunoprophylaxis at birth together with antiviral treatment of highly viraemic mothers are the key strategies for global elimination of HBV infection.Strategies are needed to promote implementation of birth-dose vaccination and hepatitis B immunoglobulins in low-and middle-income countries where the prevalence of the infection is at the highest.

Host genetic factors affecting hepatitis B infection outcomes:Insights from genome-wide association studies

The clinical outcome of hepatitis B virus(HBV) infection depends on the success or failure of the immune responses to HBV,and varies widely among individuals,ranging from asymptomatic self-limited infection,inactive carrier state,chronic hepatitis,cirrhosis,hepatocellular carcinoma,to liver failure,depending on the success or failure of immune response to HBV.Genome-wide association studies(GWAS) identified key genetic factors influencing the pathogenesis of HBV-related traits.In this review,we discuss GWAS for persistence of HBV infection,antibody response to hepatitis B vaccine,and HBV-related advanced liver diseases.HBV persistence is associated with multiple genes with diverse roles in immune mechanisms.The strongest associations are found within the classical human leukocyte antigen(HLA) genes,highlighting the central role of antigen presentation in the immune response to HBV.Associated variants affect both epitope binding specificities and expression levels of HLA molecules.Several other susceptibility genes regulate the magnitude of adaptive immune responses,determining immunity vs tolerance.HBV persistence and nonresponse to vaccine share the same risk variants,implying overlapping genetic bases.On the other hand,the risk variants for HBV-related advanced liver diseases are largely different,suggesting different host-virus dynamics in acute vs chronic HBV infections.The findings of these GWAS are likely to pave the way for developing more effective preventive and therapeutic interventions by personalizing the management of HBV infection.

Hepatitis B virus: Where do we stand and what is the next step for eradication?

Hepatitis B(HB) virus(HBV) infection, which causes liver cirrhosis and hepatocellular carcinoma, is endemic worldwide. Hepatitis B vaccines became commercially available in the 1980 s. The World Health Organization recommended the integration of the HB vaccine into the national immunisation programs in all countries. HBV prevention strategies are classified into three groups:(1) universal vaccination alone;(2) universal vaccination with screening of pregnant women plus HB immune globulin(HBIG) at birth; and(3) selective vaccination with screening of pregnant women plus HBIG at birth. Most low-income countries have adopted universal vaccine programs without screening of pregnant women. However, HB vaccines are not widely used in low-income countries. The Global Alliance for Vaccine and Immunization was launched in 2000, and by 2012, the global coverage of a three-dose HB vaccine had increased to 79%. The next challenges are to further increase the coverage rate, close the gap between recommendations and routine practices, approach highrisk individuals, screen and treat chronically infected individuals, and prevent breakthrough infections. To eradicate HBV infections, strenuous efforts are required to overcome socioeconomic barriers to the HB vaccine; this task is expected to take several decades to complete.

High-dose hepatitis B immunoglobulin therapy in hepatocellular carcinoma with hepatitis B virus-DNA/hepatitis B e antigen-positive patients after living donor liver transplantation

AIM: To investigate the impact of high-dose hepatitis B immunoglobulin(HBIG) on hepatocellular carcinoma(HCC) and hepatitis B virus(HBV) recurrence and overall survival after living donor liver transplantation(LDLT).METHODS: We investigated 168 patients who underwent LDLT due to HCC, and who were HBV-DNA/hepatitis B e antigen(HBe Ag)-positive, from January 2008 to December 2013. After assessing whether the patients met the Milan criteria, they were assigned to the low-dose HBIG group and high-dose HBIG group. Using the propensity score 1:1 matching method, 38 and 18 pairs were defined as adhering to and not adhering to the Milan criteria. For each pair, HCC recurrence, HBV recurrence and overall survival were analyzed by the Kaplan-Meier method and the log rank test according to the HBIG dose. RESULTS: Among those who met the Milan criteria, the 6-mo, 1-year, and 3-year HCC recurrence-free survival rates were 88.9%, 83.2%, and 83.2% in the low-dose HBIG group and 97.2%, 97.2%, and 97.2% in the high-dose HBIG group, respectively(P = 0.042).In contrast, among those who did not meet the Milan criteria, HCC recurrence did not differ according to the HBIG dose(P = 0.937). Moreover, HBV recurrence and overall survival did not differ according to the HBIG dose among those who met(P = 0.317 and 0.190, respectively) and did not meet(P = 0.350 and 0.987, respectively) the Milan criteria. CONCLUSION: High-dose HBIG therapy can reduce HCC recurrence in HBV-DNA/HBe Ag-positive patients after LDLT.

Prevention of recurrent hepatitis B infection after liver transplantation

BACKGROUND:Recurrence of hepatitis B virus(HBV) infection after liver transplantation can lead to graft loss and a reduction in long-term survival.The purpose of this review is to summarize the current therapeutic options for preventing HBV recurrence in liver transplant recipients.DATA SOURCES:Up to January 2013,studies that were published in MEDLINE and EMBASE on prevention of HBV recurrence after liver transplantation were reviewed.RESULTS:There have been remarkable advancements in the past two decades on the prevention of HBV recurrence after liver transplantation,from the discovery of hepatitis B immune globulin(HBIG) and lamivudine monotherapy to the combination therapy using HBIG and lamivudine.With the development of newer and stronger antiviral agents,the need for life-long HBIG is doubtful.With their low resistance profile,oral antiviral prophylaxis using these new agents alone is sufficient and is associated with excellent outcome.CONCLUSIONS:Restoration of host HBV immunity with adoptive immunity transfer and vaccination may represent the ultimate strategy to withdraw prophylactic treatment and to achieve a drug free regimen against HBV recurrence after liver transplantation.

Prevention and treatment of hepatitis B recurrence after liver transplantation

OBJECTIVE: To study the efficacy of liver transplantation on end-stage hepatitis B related liver diseases, and the prevention and treatment strategies of hepatitis B recurrence after the transplantation. METHODS: The efficacy of combined treatment of lamivudine and hepatitis B immune globulin (HBIG) therapy on 24 patients who had received liver transplantation was retrospectively studied. RESULTS: All the 24 patients with end-stage hepatitis B-related liver diseases treated with lamivudine alone or combined therapy of lamivudine and HBIG showed normal liver function and 21 of them lost hepatitis B virus (HBV) markers. However, the remaining 3 patients became HBsAg positive again soon after liver transplantation. CONCLUSIONS: Liver transplantation is effective for patients with end-stage hepatitis B-related liver diseases. Combined treatment of lamivudine and HBIG may prevent the recurrence of hepatitis B after the operation.

T-cell allorecognition of donor glutathione S-transferase T1 in plasma cell-rich rejection

AIM To investigate the role of glutathione S-transferase T1 donor-specific T lymphocytes in plasma cell-rich rejection of liver allografts.METHODS The study group included 22 liver transplant patients. Among them, 18 patients were mismatched for the glutathione S-transferase T1(GSTT1) alleles(don+/rec-), and 4 were matched(don+/rec+). Seven of the mismatched patients produced anti-GSTT1 antibodies and developed plasma cell-rich rejection(former de novo immune hepatitis). For the detection of specific Tlymphocytes, peripheral blood mononuclear cells were collected and stored in liquid nitrogen. The memory T cell response was studied by adding to the cell cultures to a mix of 39 custom-made, 15-mer overlapping peptides, which covered the entire GSTT1 amino acid sequence. The specific cellular response to peptides was analyzed by flow cytometry using the markers CD8, CD4, IL-4 and IFNγ.RESULTS Activation of CD8^+ T cells with different peptides was observed exclusively in the group of patients with plasma-cell rich rejection(3 out of 7), with production of IL-4 and/or IFNγ at a rate of 1%-4.92% depending on the peptides. The CD4^+ response was most common and not exclusive for patients with the disease, where 5 out of 7 showed percentages of activated cells from 1.24% to 31.34%. Additionally, two patients without the disease but with the mismatch had cells that became stimulated with some peptides(1.45%-5.18%). Highly unexpected was the finding of a double positive CD4^+CD8^(low) T cell population that showed the highest degree of activation with some of the peptides in 7 patients with the mismatch, in 4 patients with plasma cell-rich rejection and in 3 patients without the disease. Unfortunately, CD4^+CD8^(low) cells represent 1% of the total number of lymphocytes, and stimulation could not be analyzed in 9 patients due to the low number of gated cells. Cells from the 4 patients included as controls did not show activation with any of the peptides. CONCLUSION Patients with GSTT1 mismatch can develop a specific T-cell response, but the potential role of this response in the pathogenesis of plasma cell-rich rejection is unknown.

Prevention of intrauterine infection by hepatitis B virus with hepatitis B immune globulin:efficacy and mechanism

Objective To evaluate the efficacy of hepatitis B immune globulin (HBIG) in preventing intrauterine infection by hepatitis B virus (HBV) and to investigate its mechanism. Methods Forty eight pregnant women positive for hepatitis B surface antigen (HBsAg) were randomly divided into 2 groups. The 34 women in the study group were injected with HBIG during pregnancy; the other 14 women were controls. Maternal blood samples were taken before HBIG injection and at delivery. Neonatal blood samples were taken within 24 hours after birth before HBIG and hepatitis B vaccine were given. HBsAg and antibody to HBsAg (anti HBs) were tested by radioimmunoassay. Results None of the 35 newborns (including 2 twins) in the study group was positive for HBsAg, but 3 (21%) in the control group were positive (P=0.02). The HBsAg titers in the women in the study group decreased after HBIG injection. Of the 35 newborns in the study group, 32 (91%) were positive for anti HBs. Conclusion Systematic injections of HBIG during pregnancy may prevent intrauterine HBV infection, the mechanism of which may be reduction of maternal HBV viremia and production of fetal passive immunity.

Impact of Hepatits B Vaccination as an Important Indicator for Immunization Program in Albania

Albania has been a country with a high prevalence of hepatitis B virus. Hepatitis B vaccine has been introduced nationwide in Albanian Immunization Program in 1994. Hepatitis B is given at birth, as a separate antigen, followed by three doses at 2, 4 and 6 months, where Hepatitis B, starting from 2009, is part of pentavalent vaccine of DTP-HepB-Hib. The aim of this study was to evaluate Immunization Program with Hepatitis B vaccination in order to prove program efficacy, increase public confidence in immunizations and advocate for sustainable immunization programs. Methodology was based on three components such as Immunization coverage surveys, serologic surveys and surveillance for acute cases of Hepatitis B. Results of this study showed that vaccination coverage is really high, more than 95% all over the country and with drop-out rates less than 10%. Anti-HBs levels in immunized children were very high in comparison with unimmunized ones. Incidence of HBV in children 0-14 years old is almost zero. Such results tell us that Hepatitis B vaccination is one of the most fruitful strategies for long term control of Hepatitis B disease.

The expressions and clinical significance of CD107a and CD107b in chronic hepatitis B patients with different immune status

Objective To investigate the expressions of CD107a and CD107b on CD8+T lymphocytes in chronic hepatitis B(CHB)patients with different immune status.Methods Forty-three CHB patients were collected and classified according to the immune status(23 cases of atypical status,10 cases of immune tolerance and 10 cases of immune clearance).Another 10 cases were selected

Changes of Color and Blood Flow of the Tongue in the Mini-swine of Immune Hepatic Injury

Objective:To investigate color and microvascular blood flow of the tongue in the mini-swine with immune hepatic injury. Methods: Six Chinese mini-swine for experimental use, 3 males and 3 females, were randomly divided into two groups, normal group and model group, 3 swine in each group. The swine in the model group was administrated by injection of 5 mg/kg ConA into the vein of auricular back, once every other day, 3 times each week, for 2 weeks in total. The animal in the control group was administrated with equal volume of saline. At 9 o’clock in the morning of the 15th day of the experiment, each swine was anesthetized with intramuscular injection of 9 ml 2.5% pentobarbital sodium and 3 ml Maleate, and then picture of the tongue was taken, microvascular blood flow on the tongue and the liver was detected with a laser Doppler blood flowmeter; Blood was taken from the precaval vein. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST),total bilirubin (Tbil) and total protein (TP) were determined; Pathological changes of the liver and tongue tissues were investigated by means of HE staining; Serum TNF-α content was detected with ELISA assay. Results: In the mini-swine with immune hepatic injury induced by ConA, the tongue color showed cyanotic color, microvascular perfusion in the liver and the tongue, and partial pressure of oxygen in the tongue tissue significantly decreased; and the microcirculatory perfusion of the tongue was significantly correlated with that of the liver and the HIS color spatial value of the tongue; Serum TNF-α content significantly increased. Conclusion: The mini-swine with immune hepatic injury induced by ConA conforms to pathological characteristics of immune hepatic injury. Formation of the cyanotic tongue is related with microcirculatory disturbance of the tongue, which can indirectly reflect hepatic microcirculatory state in the immune hepatic injury.