The role of HBIG in real life for patients undergoing liver transplantation due to HDV-related cirrhosis.

Recommended post-liver transplant (LT) prophylaxis in patients with hepatitis delta includes a nucleos(t)ide analogue (NA) and anti-hepatitis B immunoglobulin (HBIG) indefinitely. We analysed the use of HBIG in real-life clinical practice and its impact on HBV/HDV recurrence in 174 HDV-related LT patients from 10 Spanish liver transplant centres (1988-2018). Median post-LT follow-up was 7.8 (2.3-15.1) years and patient survival at 5 years was 90%. Most patients (97%) received HBIG in the immediate post-LT, but only 42% were on HBIG at the last control. Among those discontinuing HBIG, the median time on treatment was 18 (7-52) months. Post-LT HBsAg+ was detected in 16 (9%) patients and HBV-DNA in 12 (7%). Despite HBsAg positivity, HDV recurrence was reported only in three patients (1.7%), all of whom were not receiving NA and had discontinued HBIG. Our data suggest that a finite HBIG prophylaxis in HDV-LT is feasible, especially if high-barrier NAs are used.

Prevention of vertical transmission of hepatitis B: A retrospective review of a 5-year maternal-infant cohort in London.

AIMS: The World Health Organization (WHO) estimates that 3.5% of the population live with hepatitis B virus (HBV); migrants to Europe are disproportionately affected. UK birth dose HBV vaccination is limited to infants born to those living with HBV (LWHBV). High-risk infants (high maternal infectivity, low birthweight) also receive HBV immunoglobulin (HBIG). The Family Hepatitis Clinic follows infants and those LWHBV working towards WHO goals of combating viral hepatitis by 2030. METHODS: A trust-wide electronic note review of outcomes for infants born to those LWHBV (2016-2020). RESULTS: Two hundred and eighty-three infants, 134 (47%) females, born to those LWHBV were referred. Two hundred and thirty-one (82%) attended follow-up with a vertical transmission rate of 0%. Twenty (7%) individuals LWHBV received tenofovir disoproxil fumerate in pregnancy; median viral load (VL) at initiation 125 416 376 DNA IU/mL, one having birth VL. Twenty-eight (10%) infants were stratified as high risk and all received HBIG and birth dose vaccination with 9 (32%) subsequently lost to follow-up, compared to 48 (19%) low-risk infants. 267/283 (94%) had birth dose vaccination documented and 206/283 (73%) received at least four vaccine doses. 215/283 (76%) infants had serology by 24 months; 17 (6%) with suboptimal vaccine responses: hepatitis B surface antibody <100 IU/mL. Serology before 18 months resulted in higher rates of maternal hepatitis B core antibody detection (15% vs. 3%). CONCLUSION: Prevention of vertical transmission of HBV was universal in those attending, although high-risk infants were more likely lost to follow up. HBV post-vaccine serological protection was comparable with national data from 2021 (77% >4 doses, 77% HBsAb >100).

[17-year study on the curative effect of treatment to prevent the recurrence of hepatitis B in different risk groups after liver transplantation].

Objective: To observe the recurrence condition of hepatitis B in different risk groups after liver transplantation in an attempt to provide useful information on whether to discontinue hepatitis B immunoglobulin (HBIG) in the future at an early stage. Methods: The patient population was divided into high, low-risk, and special groups [especially primary hepatocellular carcinoma (HCC)] according to the guidelines for the prevention and treatment of hepatitis B recurrence after liver transplantation. The recurrence condition and risk factors in this population were observed for hepatitis B. Measurement data were analyzed using a t-test and a rank-sum test. Count data were compared using a χ(2) test between groups. Results: This study finally included 532 hepatitis B-related liver transplant cases. A total of 35 cases had HBV recurrence after liver transplantation, including 34 cases that were HBsAg positive, one case that was HBsAg negative, and 10 cases that were hepatitis B virus (HBV) DNA positive. The overall HBV recurrence rate was 6.6%. The recurrence rate of HBV was 9.2% and 4.8% in the high- and low-risk HBV DNA positive and negative groups before surgery (P = 0.057). Among the 293 cases diagnosed with HCC before liver transplantation, 30 had hepatitis B recurrence after surgery, with a recurrence rate of 10.2%. The independent related factors for the recurrence of hepatitis B in patients with HCC after liver transplantation were HCC recurrence (HR =181.92, 95%CI 15.99~2 069.96, P < 0.001), a high postoperative dose of mycophenolate mofetil dispersible tablets (MMF) ( HR =5.190, 95%CI 1.289~20.889, P = 0.020), and a high dosage of HBIG (HR = 1.012, 95%CI 1.001~1.023, P = 0.035). Among the 239 cases who were non-HCC before liver transplantation, five cases (recurrence rate of 2.1%) arouse postoperative hepatitis B recurrence. Lamivudine was used in all cases, combined with on-demand HBIG prophylaxis after surgery. There was no hepatitis B recurrence in non-HCC patients who treated with entecavir combined with HBIG after surgery. Conclusion: High-barrier-to-resistance nucleotide analogues combined with long-term HBIG have a good effect on preventing the recurrence of hepatitis B after liver transplantation. The discontinuation of HBIG may be considered at an early stage after administration of a high-barrier-to-resistance nucleotide analogue in low-risk patients. Domestically, the HBV infection rate is high, so further research is still required to explore the timing of HBIG discontinuation for high-risk patients, especially those with HCC.

A collaborative study to establish the second national standard for hepatitis B immunoglobulin in Korea.

This study aimed to establish a second national standard for hepatitis B immunoglobulin (HBIG) that can be used for potency assays of hepatitis B and normal immunoglobulin. The candidate material was manufactured using a process approved as Good Manufacturing Practice. The freeze-dried candidate preparation was tested for physicochemical and biological properties, including pH, residual moisture, molecular size distribution, and potency. A collaborative study was performed involving four laboratories, including the National Institute of Food and Drug Safety Evaluation, as an official national control laboratory in Korea and manufacturers. The potency was calibrated against the second international standard for HBIG using two enzyme immunoassays: enzyme-linked immunosorbent assay and electrochemiluminescence immunoassay. Results from 240 assays were obtained from four laboratories, and combined potency estimates were obtained by calculating the geometric means. Intra- and inter-laboratory variability showed acceptable geometric coefficients of variation of 1.3-6.0 and 3.2-3.6%, respectively. The candidate preparation showed satisfactory stability in accelerated thermal degradation and real-time stability tests. Based on these results, the potency value of 105 IU/vial was assigned (95% confidence intervals: 100.0-109.2 IU/vial), and it was deemed suitable to serve as the Korean national standard for HBIG.

Antiviral prophylaxis against hepatitis B recurrence after liver transplantation: Current concepts.

The advance in treatment against hepatitis B virus (HBV) infection with the development of nucleos(t)ide analogues (NAs) with high genetic barrier to resistance, including entecavir and tenofovir, has improved clinical outcomes of patients transplanted for HBV infection, by preventing HBV recurrence after liver transplantation (LT) effectively. Currently, after LT, the combination of hepatitis B immunoglobulin (HBIG) and a high-barrier NA is considered as the standard of care for prophylaxis against HBV recurrence. However, because of the high cost of intravenous high-dose HBIG, other routes of HBIG administration, such as intramuscular or subcutaneous, have come to the foreground. In addition, several transplant centres tend to use a NA as monoprophylaxis, following a short post-LT period of HBIG and NA combination. Lately, studies using HBIG-free prophylactic regimens with entecavir or tenofovir have shown promising outcomes in preventing HBV recurrence, mostly regarding patients with undetectable HBV DNA at the time of LT. Although vaccination against HBV has been an attractive prophylactic approach, its efficacy has been controversial. Moreover, further studies are needed regarding long-term outcomes of complete withdrawal anti-HBV prophylaxis. For patients transplanted for HBV/HDV co-infection, combined regimen should be administered for a longer period post-LT. Finally, the use of grafts from hepatitis B core antibody-positive donors is safe for HBV-negative recipients, with the administration of lifelong antiviral prophylaxis.

Hepatitis B Prophylaxis after Liver Transplantation in Korea: Analysis of the KOTRY Database.

BACKGROUND: Prophylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. We conducted real-world analysis of HBV prophylaxis after LT in the Korean population. METHODS: Korean Organ Transplantation Registry (KOTRY) database and additionally collected data (n = 326) were analyzed with special reference to types of HBV prophylaxis. RESULTS: The study cohort comprised 267 cases of living-donor LT and 59 cases of deceased-donor LT. Hepatocellular carcinoma (HCC) was diagnosed in 232 (71.2%) of these subjects. Antiviral agents were used in 255 patients (78.2%) prior to LT. HBV DNA was undetectable in 69 cases (21.2%) and detectable over wide concentrations in the other 257 patients (78.8%) prior to LT. Polymerase chain reaction analysis of the store blood samples detected HBV DNA in all patients, with 159 patients (48.9%) showing concentrations > 100 IU/mL. Post-transplant HBV regimens during the first year included combination therapy in 196 (60.1%), hepatitis B immunoglobulin (HBIG) monotherapy in 121 (37.1%), and antiviral monotherapy in 9 (2.8%). In the second post-transplant year, these regimens had changed to combination therapy in 187 (57.4%), HBIG monotherapy in 112 (34.4%), and antiviral monotherapy in 27 (8.3%). Trough antibody to hepatitis B surface antigen titers > 500 IU/mL and >1,000 IU/mL were observed in 61.7% and 25.2%, respectively. The mean simulative half-life of HBIG was 21.6 ± 4.3 days with a median 17.7 days. Up to 2-year follow-up period, HCC recurrence and HBV recurrence developed in 18 (5.5%) and 6 (1.8%), respectively. HCC recurrence developed in 3 of 6 patients with HBV recurrence. CONCLUSION: Combination therapy is the mainstay of HBV prophylaxis protocols in a majority of Korean LT centers, but HBIG was often administered excessively. Individualized optimization of HBIG treatments using SHL is necessary to adjust the HBIG infusion interval.

[Comments on 2019 Chinese practice guideline for the prevention and treatment of hepatitis B virus mother-to-child transmission].

Recently, the Society of Infectious Diseases of Chinese Medical Association and Chinese GRADE Center jointly released the "2019 Chinese practice guideline for the prevention and treatment of hepatitis B virus mother-to-child transmission" . We concerned several issues in the Guideline, including the improper citation of some references, no recommendations for some key strategies for the prevention of hepatitis B virus mother-to-child transmission, insufficient or even lack of evidence for some recommendations and others. Based on the principle of academic contention, we present in this article our comments on the Guideline to discuss these issues with the Guideline's authors and readers.

Efficacy of antepartum administration of hepatitis B immunoglobulin in preventing mother-to-child transmission of hepatitis B virus.

The aim of this study was to investigate the efficacy of antepartum administration of three doses of hepatitis B immunoglobulin (HBIG) in interrupting mother-to-child transmission (MTCT) of hepatitis B virus (HBV). In this trial, a total of 728 HBeAg-positive pregnant women with chronic HBV infection who had an HBV DNA level higher than 6log10  copies/mL were enrolled. They were divided into three groups based on individual preference. Subjects in group A and group B received 200 IU (unit) HBIG and 400 IU (unit) HBIG intramuscularly once a month at the third, second and first month before delivery, respectively. Subjects in the control group (C) received no special treatment. All the infants received passive-active immunoprophylaxis. The HBsAg-positive rate of all infants at 7-12 months of age was 5.1% (37/728). Specifically, the HBsAg-positive rate of infants was comparable in all three groups (5.3% vs 5.1% vs 5%, P = 0.988). No significant difference was found in anti-HBs levels between the infants aged 7-12 months in the three groups (P = 0.469). HBV DNA levels of the umbilical cord blood in the HBV-infected group were higher than those in the uninfected group (5.2 vs 3.4log10  copies/mL, P < 0.001), and these with family history of HBV infection were also higher (45.9% vs 28.5%, P = 0.034). To conclude, administration of passive-active immunoprophylaxis to infants contributed to effective prevention of the MTCT of HBV; extra antepartum administration of HBIG during pregnancy could not decrease the rate of MTCT or increase the anti-HBs levels of infants born to HBsAg-positive mothers with HBV DNA higher than 6log10  copies/mL.

Study of the distribution of hepatitis B immunoglobulin in pregnant mice using small-animal imaging technology.

BACKGROUND: The safety and necessity of hepatitis B immunoglobulin (HBIG) in preventing the mother-to-child transmission of hepatitis B virus (HBV) are still controversial because of its unclear mechanism of action and the inconsistent injection programs used during gestation. OBJECTIVES: This study aimed to show the dynamic transportation and distribution of HBIG in the maternal body and to provide evidence for its clinical efficacy in preventing mother-to-child HBV transmission. STUDY DESIGN: Pregnant mice were injected with Cy7-labeled mouse anti-human monoclonal hepatitis B surface antibodies through the tail vein. In vivo imaging technology was used to observe the dynamic transportation and distribution of HBIG in the pregnant mice. RESULTS: HBIG fluorescence signals were higher in the uterus than in the liver, spleen, and kidneys. Fluorescence signals in the uterine region were obviously higher at the third trimester than at early and mid pregnancy. CONCLUSIONS: HBIG is gradually deposited in the mouse placenta during pregnancy, with the phenomenon being more significant in the third trimester.

Low-dose anti-hepatitis B immunoglobulin regimen as prophylaxis for hepatitis B recurrence after liver transplantation.

BACKGROUND: Combination of anti-hepatitis B immunoglobulin (HBIg) and antiviral nucleotide/nucleoside is the most common regimen for prophylaxis against hepatitis B virus (HBV) recurrence. However, what the optimal regimen is for HBIg administration remains subject to debate. METHODS: Two hundred and thirty-two HBV patients who had liver transplantation were included in this study. According to the decline rate of HBIg, the patients were divided into quick (group Q, n = 95) and slow decline groups (group S, n = 137). Quick HBIg decline was defined as anti-HBs titer <200 IU/mL at postoperative month (POM) 1, when 24 000 IU of HBIg was given perioperatively. HBV recurrence was defined as reappearance of hepatitis B surface antigen (HBsAg). RESULTS: After a mean (range) follow-up of 42.2 (24.1-76.8) months, the HBV recurrence rate was 12.1% for all 232 patients. The median (interquartile) HBIg titer was 96.2 (41.0-158.0) IU in group Q patients, compared to 418.0 (298.8-692.8) IU in group S patients at POM 1 (P < .001). For the patients in group Q, 18 patients (18.9%) had HBV recurrence; this was higher than the 10 (7.3%) patients in group S (P = .013). Multivariate analysis showed that quick HBIg decline and hepatocellular carcinoma recurrence were the risk factors for HBV recurrence. CONCLUSION: Perioperative low-dose HBIg and antiviral nucleotide/nucleoside can effectively prevent HBV recurrence in patients with slow HBIg decline. For patients with quick HBIg decline, the idealized HBIg and antiviral agent regimen should be adjusted to establish an effective regimen as prophylaxis against HBV recurrence.

Determination of Hepatitis B Immunoglobulin Infusion Interval Using Pharmacokinetic Half-life Simulation for Posttransplant Hepatitis B Prophylaxis.

BACKGROUND: Prophylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. This study established an individualized HBV prophylaxis protocol, through optimization of hepatitis B immunoglobulin (HBIG) administration, with application of simulative half-life (SHL). METHODS: This study involved five parts: Part 1 developed the SHL estimation method with 20 patients; Parts 2 and 3 assessed the SHL variability and developed a simulation model to apply SHL in 100 patients; Part 4 validated the simulation model in 114 patients, and Part 5 was a cross-sectional study on the current status of HBIG infusion intervals in 660 patients. RESULTS: In Part 1, infusion of 10,000 IU HBIG induced add-on rise hepatitis B surface antibody (anti-HBs) titer of 5,252.5 ± 873.7 IU/L, which was 4.4% lower than actual measurement. Mean SHL of 20.0 ± 3.7 days was 2.2% longer than actual measurement. In Part 2, the medians of the intra- and inter-individual coefficient of variation in SHL were 13.5% and 18.5%, respectively. Pretransplant HBV DNA load and posttransplant antiviral therapy did not affect SHL. In Part 3, a simulation model was developed to determine the interval of HBIG infusion, by using SHL. In Part 4, all 114 patients were successfully managed with regular HBIG infusion intervals of ≥ 8 weeks, and the interval was prolonged to ≥ 12 weeks in 89.4%, with a target trough anti-HBs titer ≥ 200 IU/L. In Part 5, 47.4% of our patients received HBIG excessively, at a target trough titer of 500 IU/L. CONCLUSION: SHL estimation using only clinically available parameters seems to be reliably accurate when compared with actual measurements. We believe that SHL estimation is helpful to establish a personalized HBV prophylaxis protocol for optimizing HBIG administration.

The efficiency of low-dose hepatitis B immunoglobulin plus nucleos(t)ide analogs in preventing posttransplant hepatitis B virus recurrence

Background/aim: In this study, the efficiency of using low-dose hepatitis B immunoglobulin (HBIG) plus antiviral treatment according to individual needs has been evaluated in posttransplant hepatitis B virus (HBV) patients. Materials and methods: We retrospectively evaluated 179 patients who were admitted between 2009 and 2014. Five thousand IU intravenous HBIG was given in the anhepatic phase, and 400 IU/day intramuscular (IM) HBIG was given in the posttransplant period. After HBsAg seroconversion, 400 IU IM HBIG was continued as prophylaxis every two weeks. Results: The average follow-up period was 26 (2­65) months. Seventy patients had hepatocellular carcinoma (HCC). The HBV recurrence was 4.5% in the first year, and 5.8% in the third year. The HBsAg became negative in 11 (2­63) days, and anti-HBs became positive in 9 (1­31) days. HBsAg positivity occurred in 6 patients during the follow-up period. Five of these patients were those who underwent transplantation due to HCC. In 5 of the HCC patients, in whom HBsAg became positive, tumor recurrence was observed after 0.3­9.9 months. HBsAg positivity was more frequently detected in patients with HCC (P = 0.009). Conclusion: The HBV recurrence should be evaluated as a predictor of the HCC recurrence in patients who were transplanted due to HCC.

The use of hepatitis B immunoglobulin with or without hepatitis B vaccine to prevent de novo hepatitis B in pediatric recipients of anti-HBc-positive livers.

Prophylactic measures are used to reduce DNHB after HBsAg-negative patients receive anti-HBc-positive liver grafts. This study investigated the incidence of DNHB and clinical outcomes in pediatric LT recipients under HBIG prophylaxis, with or without hepatitis B vaccination. Between 1995 and 2013, 51 HBsAg-negative pediatric recipients underwent living-donor LT from anti-HBc-positive donors. The median (range) age was 4 (0.1-17) years, 23 (45%) were male, and 71% were negative for both anti-HBc and anti-HBc. During a median follow-up of 12.1 (0.06-19.9) years, 13 (25.4%) developed DNHB; 7 of the 13 achieved HBsAg seroconversion after administration of LAM or ETV. Among studied patients, 20 (39%) received hepatitis B vaccination, and 2 of them (10%) developed DNHB. At last follow-up, 41% (21/51) discontinued HBIG either after successful HBV vaccination (n = 17) or retransplantation with anti-HBc-negative grafts (n = 4). In conclusion, pediatric LT recipients of anti-HBc-positive grafts, most of them were naïve to HBV infection, were at high risk of DNHB, and consistent monitoring for the early detection of DNHB was necessary. A combination use of post-LT vaccination is promising prophylactic strategy against DNHB.

[Getting to zero mother-to-child transmission of hepatitis B virus: dream and challenge].

To eliminate viral hepatitis as a public health threat, the World Health Organization has set the ambitious goal of reducing the prevalence of hepatitis B surface antigen (HBsAg) in children to 0.1% by 2030, and the key to this grand goal is cutting off hepatitis B virus (HBV) transmission from mother-to-child. Previously, national and international guidelines for the management of chronic hepatitis B recommended the use of hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) or combination of any in neonates and antiviral drugs for pregnant women with high viral load in late pregnancy. However, a recent study in Thailand found that the addition of antiviral drugs in pregnant women with high viral load in the third trimester did not significantly lower the incidence of mother-to-child HBV transmission, but no case of chronic HBV infection was seen with strict standards hepatitis B vaccine and HBIG combined immunoprophylaxis and the use of tenofovir disoproxil in pregnant women with high viral load in the third trimester. In addition, the incidence of mother -to- child transmission of HBV in the antiviral group was 0, while the incidence of HBV transmission in the placebo group was 2%. Therefore, it is not possible to deny the efficacy of adding antiviral drugs in treating pregnant women with high viral load in the third trimester with combined immunoprophylaxis. There is an urgent need for more real-world studies in clinical practice to further reveal the principles and existing problems of mother- to- child transmission of HBV.

Antenatal maternal hepatitis B care is a predictor of timely perinatal administration of hepatitis B immunoglobulin.

BACKGROUND: Mother-to-child transmission of hepatitis B virus continues to occur despite universal recommendations for neonatal immune prophylaxis therapy (IPT) and infant vaccination. AIM: To characterise the risk factors for failure to provide timely IPT and completion of the infant hepatitis B vaccination schedule for children born to mothers with chronic hepatitis B (CHB). METHODS: We conducted a retrospective cohort study to assess compliance with universal guidelines for neonatal IPT for children born to CHB mothers at Monash Health, Australia from 2008 to 2013. These mothers were invited to participate in a telephone interview regarding post-partum hepatitis B virus (HBV) care and infant vaccination status. Multivariate logistic regression analysis was utilised to identify the predictors for engagement with specialist HBV care, timely administration of IPT, completion of HBV vaccination schedule and serological testing of the baby. RESULTS: A total of 451 CHB mothers delivered 454 live births. HBV immunoglobulin (HBIg) was dispensed within 12 h in 79.52% of births. HBIg was not administered to eight neonates. Of the 451 women, 125 were interviewed: 88.8% of babies completed the vaccine schedule, and 19.2% of infants had post-vaccination testing. Antenatal HBV care was independently associated with a greater likelihood of timely HBIg administration (odds ratio 1.64, P = 0.04, 95% CI: 1.03-2.61). There were no significant predictors for engagement with specialist HBV care, vaccine coverage or serological testing of the baby. CONCLUSION: Targeted interventions to improve timely HBIg and completion of the vaccine schedule are recommended. All pregnant women with CHB should be referred for HBV-specific antenatal care regardless of viral replicative status.

Occult hepatitis B virus infection in immunized children born to carrier mothers.

BACKGROUND: The prevalence of occult hepatitis B virus (HBV) infection (OBI) in children due to mother-to-child transmission (MTCT) despite immunoprophylaxis remains controversial and is still unknown in Japan. The aim of this study was to determine the OBI prevalence in such children in Japan and identify the genomic mutations that might be associated with the pathogenesis of OBI in children. METHODS: The data on 158 children born to HBV carrier mothers and who received complete passive-active immunoprophylaxis after birth in 2002-2014 were reviewed. HBV markers were detected using commercial enzyme-linked immunosorbent assay kits. HBV-DNA was detected using real-time and nested polymerase chain reaction. Complete genomic sequences were determined. RESULTS: Among the 158 children studied, three had HBV MTCT: two had OBI, and one had resolved HBV infection (RBI). The prevalence of OBI and RBI was estimated to be 1.3% and 0.6%, respectively. The HBV genomes of the two OBI children were wild type and 100% identical to those of their mothers. Of these two children, one received repeated hepatitis B immunoglobulin (HBIG) and developed overt HBV infection. Her HBV genome had a G145R mutation in the S gene that might have been induced by HBIG treatment. The RBI child was persistently positive for antibody to HBV core antigen (10-12 signal/cut-off ratio; S/CO). CONCLUSIONS: A low prevalence of OBI was observed in children who received immunoprophylaxis for preventing MTCT in Japan. The development of overt HBV infection in infants with OBI indicates the necessity of close and long-term monitoring.

The long-term efficacy of combining nucleos(t)ide analog and low-dose hepatitis B immunoglobulin on post-transplant hepatitis B virus recurrence.

BACKGROUND: The aim of this study was to determine the long-term efficacy of nucleos(t)ide analog (NA) and low-dose hepatitis B immunoglobulin (HBIG) combination treatment for preventing post-transplant hepatitis B virus (HBV) recurrence. METHODS: A total of 296 patients with HBV-associated liver disease who underwent liver transplantation (LT) were enrolled. A combination of a daily NA and low-dose HBIG was used after LT. RESULTS: The median follow-up period was 46 months. HBV recurrence occurred in eight patients. The cumulative probability of HBV recurrence at 1, 3, 5, and 7 years was 1%, 3%, 3%, and 4%, respectively. Seven were on lamivudine (LMV) or adefovir dipivoxil (ADV), or LMV and ADV and HBIG combination treatment and one entecavir (ETV) and HBIG. With Cox regression analysis, HBV recurrence was determined to be associated with the presence of hepatocellular cancer (HCC) prior to LT (HR: 12.3, P=.02). Overall, 44 patients died. Survival was significantly better in the ETV or tenofovir disoproxil fumarate (TDF) and HBIG group than the other group (P<.001). CONCLUSION: The combination of ETV or TDF and low-dose HBIG achieved a more favorable prophylaxis against HBV recurrence after LT. The presence of HCC prior to LT was associated with post-transplant HBV recurrence.

Extended survival of patients with persistently suppressed hepatitis B transplanted for hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has become a major cause of liver-related death and indication to liver transplantation (LT) in patients with chronic hepatitis B virus (HBV) infection following the widespread adoption of antiviral therapy with nucleos(t)ide analogs (NUCs). Yet, the long-term outcome of patients undergoing liver transplantation for an HCC developed during effective NUC treatment is unknown. METHODS: We evaluated 101 patients with persistently compensated cirrhosis who were consecutively transplanted for HCC in two centers in Milan. At LT, 91 (90%) patients had undetectable serum HBV DNA (<12 IU/ml) and 90 (89%) were within Milan criteria (MC). All patients received post-transplant HBV prophylaxis with specific immunoglobulins (HBIgs) and NUCs. End-points were long-term patient survival and recurrence of HCC and HBV. RESULTS: During 106 (range 3-165) months following LT, HCC recurred in 11 (11%) patients (nine beyond MC at explant, two with HBV recurrence). Age (HR 1.1, 95%CI 1.0-1.2, P = 0.04) and exceeding MC (HR 9.6, 95%CI 2.9-32, P < 0.0001) were the only independent pretransplant predictors of tumour recurrence. The 10-year cumulative rate of HCC recurrence was 7% among patients transplanted within MC compared with 45% among those beyond MC at LT (P = 0.004). Overall, 18 patients (18%, nine HCC, nine non liver-related events) died with a 10-year cumulative probability of overall and liver-related survival of 79% and 89% respectively. CONCLUSIONS: Extended survival of HBV cirrhotics transplanted for HCC can be achieved by coupling MC at listing with persistent pharmacological suppression of HBV.

Transmission route and genotype of chronic hepatitis B virus infection in children in Japan between 1976 and 2010: A retrospective, multicenter study.

AIM: The aim of this study was to clarify the trends of the infectious source of chronic hepatitis B virus (HBV) infection and the HBV genotype in the Japanese pediatric population over the last three decades. METHODS: The present study was a retrospective, nationwide, multicenter study. Patients who were under 20 years of age when diagnosed with chronic HBV infection were eligible for enrollment in this study. A total of 430 patients (male/female, 256/174; age at the time of writing, 1-37 years; median age, 14 years; birth year, 1976-2010) from 11 hospitals were evaluated. RESULTS: The incidence of chronic HBV infection from 1976 to 1980, 1981-1985, 1986-1990, 1991-1995, 1996-2000, 2001-2005 and 2006-2010 was 56, 52, 34, 37, 81, 92 and 78, respectively. Of the 430 patients, 304 (71%), 61 (14%), 11 (3%) and 54 (13%) were infected via mother-to-child transmission, close contact, blood transfusion and unknown source, respectively. After the introduction of perinatal immunoprophylaxis, the rate of mother-to-child transmission increased from 62% during the 1991-1995 period to 86% during the 2006-2010 period. The distributions of genotypes A, B, C, D and F were 3%, 9%, 86%, 2% and 1%, respectively. No obvious change was observed in the distribution of genotypes. Genotype C was significantly associated with mother-to-child transmission. CONCLUSION: Mother-to-child transmission remains the primary source of chronic HBV infection after the introduction of immunoprophylaxis. Taking measures to prevent immunoprophylaxis failure is essential to reduce pediatric chronic HBV infection in Japan.

Risk factors for hepatitis B virus recurrence after living donor liver transplantation: A 17-year experience at a single center.

AIM: The incidence of hepatitis B virus (HBV) recurrence after liver transplantation (LT) has been reduced by prophylaxis with hepatitis B immunoglobulin (HBIG) and nucleoside analogs, but the factors associated with HBV recurrence are unclear. The aim of this study was to determine the risk factors associated with HBV recurrence after living donor LT (LDLT). METHODS: A retrospective review was performed for 45 patients (28 male and 17 female; median age, 54 years) who underwent LDLT for HBV-related liver disease and were followed up for at least 6 months between October 1996 and June 2013. The virological data, tumor burden, antiviral therapy and immunosuppressive therapy were evaluated and compared between the HBV recurrence ad non-recurrence groups. RESULTS: Seven of the 45 patients (15.6%) developed post-LT HBV recurrence. The median interval between LDLT and HBV recurrence was 23.7 months (range, 0.8-35.9). Three of the seven patients (42.9%) developed recurrence after cessation of HBIG, and three (42.9%) were cases with hepatocellular carcinoma (HCC) recurrence after LDLT. The remaining case underwent transplantation from a donor with positive hepatitis B surface antigen. Based on the univariate and multivariate analyses, HBIG cessation (hazard ratio [HR], 20.17; 95% confidence interval [95% CI], 2.091-194.593; P = 0.009) and HCC recurrence (HR, 30.835; 95% CI, 3.132-303.593; P = 0.003) were independent risk factors for HBV recurrence after LDLT. CONCLUSION: In LDLT patients, cessation of HBIG and HCC recurrence were risk factors associated with HBV recurrence, so careful monitoring for serological HBV markers is needed in patients with these factors.