Liver transplantation for acute-on-chronic liver failure / 器官移植

Acute-on-chronic liver failure (ACLF) is a specific category of liver failure, which is mainly characterized by rapid progression and multiple organ failure. At present, patients with ACLF are mainly given with systematic and comprehensive medical therapy to promote liver regeneration. However, liver transplantation is the only potentially curative treatment for patients who failed to respond to medical treatment and rapidly progress into multiple organ failure. Considering the differences of disease progression and clinical prognosis, and the shortage of donor liver in China, it is necessary to actively prevent the triggering factors of ACLF in patients with chronic liver diseases, screen out the recipients who are most likely to benefit from liver transplantation and deliver precision management during perioperative period of liver transplantation. In this article, the application of liver transplantation in ACLF was illustrated from the perspectives of accurate evaluation of ACLF, proper control of liver transplantation indications and meticulous perioperative management, aiming to optimize the therapeutic strategy of liver transplantation in patients with ACLF.

Comments on“2019 Chinese practice guideline for the prevention and treatment of hepatitis B virus mothertochild transmission” / 临床肝胆病杂志

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.

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 / 中华肝脏病杂志

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.

Study on the efficacy of neonatal HBsAg content in venous blood to predict mother-to-children transmission of hepatitis B virus / 中华实验和临床病毒学杂志

Objective@#To investigate the role of HBsAg status and content in neonatal venous blood to predict HBV mother-to-children transmission.@*Methods@#The study candidates from a prospective study about HBV mother-to-children transmission blocking who were hepatitis B surface antigen (HBsAg) positivity, hepatitis B e antigen (HBeAg) positivity, and HBV DNA levels >105 IU/ml.All of their infants were enrolled.200 IU of hepatitis B immunoglobulin (HBIG)was injected within 6 hours after birth, and 200 IU HBIG was voluntarily selected 1 month after birth.All infants according to 0-1-6 month standard procedure were given 10 or 20 μg of hepatitis B vaccine. Pregnancy women before birth, and infants at the time of birth, 1-month and 7-month after birth, venous blood was tested for HBV virus and serological markers to assess the association with success of mother-to-children transmission blocking.@*Results@#530 pregnant women and 530 neonates were enrolled. 60.75% at birth and 86.02% at birth for one month children were HBsAg-negative. The successful transmission in HBsAg-negative neonates was 100.00%. According to the receiver operating characteristic curve, the AUC of HBsAg content≥0.35 IU/ml at birth predicted to block failure was 0.979. The sensitivity was 85.60%, and the specificity was 100.00%. The AUC of HBsAg content≥0.18 IU/ ml at one month after birth predicted to block failure was 0.988, the sensitivity was 89.40%, and the specificity was 100.00%.@*Conclusions@#The HBsAg level in venous blood at birth and 1 month after birth can predict the failure of HBV mother-to-children transmission, and the neonates with HBsAg positivity in venous blood are a high-risk group that may block failure.

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.

Getting to zero mother-to-child transmission of hepatitis B virus: dream and challenge / 中华肝脏病杂志

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.

Research progress on the application of human hepatitis B immunoglobulin in preventing hepatitis B recurrence after liver transplantation / 中华肝胆外科杂志

Patients who suffer from HBV-related endstage liver disease are the majority of liver transplantation (LT) recipients,and hence HBV recurrence post-LT is the key for the treatment success.HBIG was no longer solely used in clinical practice because of high cost and unavoidable drug-resistance.Nowadays,the standard prophylaxis regimen is the combination of low-dose HBIG and nucleoside analogues (NAs).Recently,the necessity of HBIG usage has been often questioned,and the novel prophylaxis of HBIG-withdrawn and HBIG-free regimen have been carried out in several transplant centers with encouraging results.In this review,we summarized the application of HBIG in the prophylaxis of HBV recurrence,and then evaluated the prospect of the prophylaxis of HBIG-withdrawn and HBIG-free regimen.

Efficacy of two injections of hepatitis B immunoglobulin in infants to interrupt mother-to-children transmission of hepatitis B virus / 中华实验和临床病毒学杂志

Objective@#To investigate the efficacy of 200IU hepatitis B immunoglobulin (HBIG) injection at 1 month after birth to interrupt the mother-to-children transmission (MTCT) of hepatitis B virus (HBV).@*Methods@#Infants born to mothers who were hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) positive, with HBV DNA load ≥1.0×106 IU/ml and who did not receive antiviral drug treatment during pregnancy, were randomly divided into 2 groups. Infants in the control group were treated with standard immunoprophylaxis: 200 IU HBIG and 10 μg recombinant hepatitis B vaccine injection within 2 h after birth and a vaccine booster at 1 and 6 months after birth. For infants in the HBIG group the standard immunoprophylaxis and an additional 200 IU HBIG were administered at 1 month. HBsAg, the antibody to HBsAg (anti-HBs), and HBV DNA load were measured at birth and after 7 months. later.Immunoprophylaxis failure was defined as the presence of HBV DNA and HBsAg positivity or the presence of HBV DNA and HBsAg negativity at 7 months.@*Results@#In this prospective cohort study, of the 280 infants enrolled, 14 infants (HBIG/control: 6/8) were lost to follow-up and 266 subjects (HBIG/control: 134/132) completed the 7-month study. The log10HBV DNA load of mothers in the HBIG group and control group were (7.31±0.66) log10IU/ml and (7.32±0.74) log10IU/ml, respectively (P=0.92). The MTCT rate of the two groups was similar (5.97% vs. 7.58%, P=0.63). At 7 months, the HBsAg positive rate and the level of anti-HBs in the two groups were 94.03%(126/134)vs. 91.67% (121/132) and 623.60±412.93 mIU/mL vs. 620.38±399.10 mIU/ml, respectively with no significant difference (P=0.48 and P=0.95, respectively). The log10 HBV DNA load of mothers in immunoprophylaxis failure group and success group was similar (P=0.09). The number of infants who were serum HBsAg positive and HBV DNA positive at birth in the immunoprophylaxis failure group were higher than those in the success group (100% and 100% vs. 35.89% and 31.85%, P<0.01, respectively). The serum HBsAg levels in infants at birth was the only independent relevant factor for HBV MTCT, with risk rates of 11.18 (95% Confidence interval (CI), 1.23-101.88), 352.00 (95%CI, 15.82-7833.20), and 968.00 (95%CI 81.35-11519.19) for HBsAg levels of 0.05-< 1, 1-< 10, and ≥ 10 IU/ml, respectively, compared to infants with HBsAg levels < 0.05 IU/ml.@*Conclusions@#Administering 200IU HBIG injection at 1 month did not reduce the risk of HBV MTCT.

Treatment of HBV recurrence after liver transplantation for HBV related liver diseases / 中华器官移植杂志

Objective To analyze the HBV recurrence and summarize the experiences in treatment of HBV recurrence after liver transplantation for HBV related liver diseases.Method A total of 650 patients subject to liver transplantation for HBV related liver diseases from September 2002 to February 2007 were included,and the clinical data were retrospectively analyzed.Result Twenty-five (3.85％) of 650 patients experienced HBV recurrence.All liver functions recovered to normal after nucleoside or nucleotide analogs treatment.Two cases lost to follow-up,2 cases were died of tumor recurrence,and 1 case died of tumor recurrence after re-transplantation.Eleven cases were positive for serum HBsAg,and HBV DNA was converted to undetectable levels in 10 cases.One case developed to decompensated liver cirrhosis,and HBsAg was negative after re-transplantation.In 7 cases,after nucleos(t)ide analogs treatment,HBsAg titer was decreased gradually to a lower level,and continuous intravenous drip of large doses of HBIG for 3 to 5 days achieved anti-HBs seroconversion.Conclusion Nucleos(t) ide analogs can effectively suppress viral replication of HBV recurrence after liver transplantation.When the HBsAg titer is decreased to a lower level,large doses of HBIG can achieve anti-HBs seroconversion.

Quality investigation of insoluble particles in freeze-dried and liquid human immunoglobulin for intravenous injection / 中国药学杂志

OBJECTIVE: To determine the insoluble particles in human immunoglobulin (pH 4) for intravenous injection and human hepatitis B immunoglobulin(pH 4) for intravenous injection in both liquid and freeze-dried forms from 14 domestic manufacturers. METHODS: Thirty-two batches of human immunoglobulin products including 19 batches of human immunoglobulin (pH 4) for intravenous injection, 5 batches of human immunoglobulin (pH 4) for intravenous injection (freeze-dried), 5 batches of human hepatitis B immunoglobulin (pH 4) for intravenous injection, and 3 batches of human hepatitis B immunoglobulin(pH 4) for intravenous injection (freeze-dried) were tested by light obscuration particle count test method recommend by appendix of 2010 CHP by GWF-8JA laser particle size analyzers. Insoluble particles greater than 10 and 25 μm were counted, respectively. Microscopy counting was carried out if the test results from light blockage method did not meet the qualification criteria in 2010 ChP. Trend analysis and comparison of the results from NIFDC and enterprises were done. RESULTS: The test results of insoluble particles in 32 batches of human immunoglobulin products indicate that 90.6%(29/32) of the products complied with the requirement of 2010 ChP and the results were in agreement between NIFDC and enterprises. Unfortunately, 3 batches of human immunoglobulin(pH 4) for intravenous injection(freeze-dried) failed in light obscuration particle count test, however, they met the requirement of 2010 ChP when microscopy counting method was used. CONCLUSION: The quality control of human immunoglobulin products in China market is generally fine, and the test results from different laboratories are basically consistent. Test result of insoluble particles in freeze-dried IVIG by microscopy counting method and light obscuration particle count test method show significant difference.

Risk factors of hepatitis B virus re-infection after orthotopic liver transplantation / 中华临床感染病杂志

Objective To investigate the risk factors of hepatitis B virus(HBV) re-infection after orthotopic liver transplantation(OLT)and to evaluate the therapeutic efficacy of hepatitis B immunoglobulin(HBIG)combined with nucleos(t)ide analogues. Methods The study included 160 patients with HBVrelated liver diseases who underwent OLT in the Third Affiliated Hospital of Sun Yat-sen University from October 2003 to Augest 2007, 117 of whom were treated with nucleos(t)ide analogues before OLT;and all patients were received HBIG i. m and nucleos(t)ide analogues treatment after OLT. Preoperative data of the patients were retrospectively reviewed, and HBV re-infection was assessed prospectively. Independent t test was used to compare normally distributed data and Fisher's exact test was used for the comparison of rates among groups. Results HBV re-infection Was observed in 19 patients after OLT with a rate of 11. 88%(19/160), which was not correlated with HBV DNA loads, HBeAg and the duration of antiviral therapy before OLT(r=0.108, 0.127 and 0.033, P>0.05). Of 19 patients with HBV re-infection, 17 were treated with lamivudine after OLT, and HBV YMDD mutants were detected in 8. The YMDD positive group had a higher HBV DNA level than YMDD negative group(7.0 ± 2.0 log copies/mL vs 3.2 ± 2.5 log copies/mL, t = 3.531, P=0.003). Among above 17 patients, 12 received adefovir add-on treatment, and3 received entecavir instead of lamivadine; all achieved satisfactory responses. Conclusions Low dose of HBIG combined with long-term use of nucleos(t)ide analogues can effectively prevent HBV re-infection after OLT. HBV YMDD mutation may be the primary reason for HBV re-infection in the patients treated with lamivudine after OLT.

Comparison of Preventive Effect of Maternal-Infant Hepatitis B Virus Vertical Transmission by Symphysial Immunoprophylaxis / 实用儿科临床杂志

Objective To investigate the efficacy by inoculated with hepatitis B immunoglobulin(HBIG) and hepatitis B vaccine in dif-ferent doses and time points to prevent maternal-infant vertical transmission of hepatitis B virus(HBV).Methods Gravidas positive for HBV were selected and measured HBV DNA,according to difference HBV DNA degrees divided into A,B,C groups.Every group was randomly divided into 4 groups using a variety of combined immunity methods to compare its efficacies.Results There were no significant differences in the positive rate of HBV and HBsAb in A,B groups by statistics analysis.There were significant differences in the positive rate of HBV and HBsAb in group C by statistics analysis.Conclusion According to the different HBV DNA take different combined immunodeficiency approach to prevent maternal-infant vertical transmission.

Prevention and Treatment for Recurrence of Hepatitis B after Liver Transplantation / 中国普外基础与临床杂志

Objective To investigate the prevention and treatment for recurrence of hepatitis B after liver transplantation on HBV related diseases.Methods Making a literature summarization based on published papers review.Results Acute and chronic HBV related diseases are the main indications of liver transplantation.Recurrence rate of hepatitis B is from 80% to 100% in the untreated patients after liver transplantation,and it affects the survivals of patients seriously.It has become a focus to prevent and treat the recurrence of hepatitis B.After a series of explotation and application,there have been a lot of drugs of preventing and treating HBV reinfection, including hepatitis B immunoglobulin,interferon and nucleotide analog antivirus drugs(lamivudine, famcyclovir, adefovir),etc.The therapeutic characteristics of them are different. Their utilizations of dividing or alliance are developing rapidly Conclusion Liver transplatation is an effective therapy for HBV related disease. Anti HBV treatments perioperation play an important role in the improvement of succeed of liver transplantation.

The Change of Anti-HBs Titer after Injection of HBIG and HBV in Newborn Delivered from HBsAg Carrier Mothers

PURPOSE: We studied prevention effects of vertical transmission of Hepatitis B with follow-up, through the change of Anti-HBs titers during 9 months after injection of Hepatitis B immunoglobulin (HBIG) and Hepatitis B vaccine (HBV) at birth in newborn delivered from Hepatitis antigen carrier mothers. METHODS: This study was performed on newborn delivered from HBsAg carrier mothers at Hae Sung Hospital from Feb. 1995 to May 1996. These newborn were injected intramuscularly with HBV and HBIG after evaluation of HBsAg and Anti-HBs titer directly at birth. Regular Hepatitis vaccination was given at 1 month, 6 months as well as HBsAg and Anti-HBs titer were evaluated at 24 hours, 1 month, 3 months, 6 months, and 9 months. RESULTS: The incidence of Hepatitis B carrier mothers is 5.6%, and newborn babies born to HBsAg carrier mothers showed HBsAg in 10.6%. In most newborn, Anti-HBs titer maintained in 100-1,000mIU/ml after injection of HBIG and HBV at birth, and mean Anti-HBs titer decreased a little at 1 month, but therafter increased gradually by regular Hepatitis vaccination. HBsAg positive newborn maintained mean HBsAg titers below 2 (S/N) until 9 months old after injection of HBIG and HBV. CONCLUSIONS: A screening test for Hepatitis B must be performed on all pregnant women, and that infants of Hepatitis B carrier mothers must be immunized by HBIG and HBV directly at birth.