Auxiliary Liver Graft Can Be Protected From HBV Infection in HBsAg Positive Blood Circulation.

Auxiliary grafts have a high risk of Hepatitis B virus (HBV) infection in patients with chronic HBV-related diseases. Hepatitis B virus-related auxiliary partial orthotopic liver transplantation (APOLT) cases were reviewed to show the results of current methods to block native-to-graft HBV transmission. Three patients received APOLT for HBV-related liver cirrhosis and a recurrent upper gastrointestinal hemorrhage between April 2015 and January 2017 by the liver transplant team of Beijing Friendship Hospital affiliated with Capital Medical University. All three patients were positive for HBV surface antigen (HBsAg) and had a negative HBV DNA test result before transplantation. After auxiliary transplantations, HBsAg was found to be positive in two patients and negative in one patient. To avoid graft infection of HBV, entecavir-based therapy was employed and the remnant native livers of the recipients were removed 51-878 days after liver transplantation. Then, serum conversions of HBsAg were found in all three cases. For the first time, this case series shows the possibility of blocking the transmission of HBV from a native liver to a graft in auxiliary transplantation by entecavir-based therapy. Among the cases, a left lobe graft was successfully implanted as a replacement of the right lobe of the recipient, which is also discussed.

Research progress on molecular mechanism of hepatitis B virus reactivation after liver transplantation / 器官移植

Liver transplantation is the most effective method for hepatitis B-related liver failure, liver cirrhosis and hepatocellular carcinoma. However, the reactivation of hepatitis B virus (HBV) after liver transplantation is not conducive to the recovery of liver function and leads to poor clinical prognosis. The prevention and treatment of HBV reactivation is currently the focus of research by physicians and surgeons. The current viral suppression strategies can not completely eradicate HBV nor completely prevent the recurrence of HBV infection in the future. This article aims to explore the molecular mechanism of HBV reactivation after liver transplantation, in order to more effectively prevent the recurrence of hepatitis B after liver transplantation.

Nucleos(t)ide analog(s) prophylaxis after hepatitis B immunoglobulin withdrawal against hepatitis B and D recurrence after liver transplantation.

BACKGROUND/AIMS: Nucleos(t)ide analogs (NAs) have made a hepatitis B immunoglobulin (HBIG)-sparing protocol an attractive approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, this approach is considered controversial in patients transplanted for HBV and hepatitis D (HDV) co-infection. MATERIAL/METHODS: All patients transplanted for HBV/HDV cirrhosis were evaluated. After LT, each patient received HBIG + NAs and then continued with NAs prophylaxis. All patients were followed up with HBV serum markers and HBV DNA, while anti-HDV/HDV RNA was performed in those with HBV recurrence. RESULTS: A total of 34 recipients were included (22 men, age: 46.7 ± 16 years). After HBIG discontinuation, NAs were received as monoprophylaxis (lamivudine [LAM]: 2, adefovir [AFV]: 1, entecavir: 9, tenofovir [TDF]: 12) or dual prophylaxis (LAM + AFV [or TDF]: 10 patients). Two (5.8%) of the 34 patients had HBV/HDV recurrence after HBIG withdrawal (median follow-up: 28 [range, 12-58] months). These 2 patients had undetectable HBV DNA at LT. Statistical analysis revealed that those with recurrence had received HBIG for shorter period, compared to those without recurrence (median: 9 vs. 28 months, P = 0.008). CONCLUSIONS: We showed for the first time, to our knowledge, that maintenance therapy with NAs prophylaxis after HBIG discontinuation was effective against HBV/HDV recurrence, but it seems that a longer period of HBIG administration might be needed before it is withdrawn after LT.

One-year extended, monthly vaccination prophylaxis combined with hepatitis B immune globulin for hepatitis B after liver transplantation.

AIM: The feasibility of vaccination in liver transplant recipients is highly controversial, and the present study aimed to investigate the efficacy of a 1-year extended, monthly vaccine prophylaxis protocol of a second-generation recombinant vaccine for transplant recipients. METHODS: The recombinant hepatitis B vaccine (10 µg) was administrated s.c. every month for 12 months as the vaccination protocol to 39 liver transplant recipients in stable condition, including those with hepatitis B-related chronic liver disease (n = 30), those with acute hepatitis B liver failure (hepatitis B surface antibody [HBsAb], n = 4), and those with hepatitis B core antibody positive grafts (n = 5). A fixed dose of hepatitis B immune globulin (HBIG) was administrated during the study based on the monoprophylaxis approach, and the increase in the hepatitis B surface antibody titer was measured to evaluate the efficacy of the vaccination. RESULTS: The vaccination protocol was initiated a mean of 54 months (range, 13-124) after liver transplantation, and all patients tolerated the vaccination well without adverse effects. The overall hepatitis B virus (HBV) recurrence rate was 5% (2/39) based on hepatitis B surface antigen positivity, and 2% (1/39) based on HBV DNA detectability. Six (15%) patients showed a good response to vaccination with an increase in the HBsAb titer greater than 100 IU/L at the end of vaccination, but only three (8%) maintained an adequate HBsAb level to spare HBIG during the 2-year observation period. CONCLUSION: While a few patients demonstrated an adequate response to vaccination, the clinical indication for the HBV vaccination for liver transplant recipients is currently minimal.

Pharmaceutical management of hepatitis B and C in liver and kidney transplant recipients.

The combination of hepatitis B immune globulin with entecavir or tenofovir (at least for a certain period of time) seems to be the most reasonable prophylaxis against recurrent hepatitis B after liver transplantation. Entecavir represents an attractive option for treatment of naïve kidney transplant recipients, because of its high efficacy and the low rates of resistance. However antiviral treatment should be individualized in the view of kidney function and the previous resistance. To date, new captivating therapeutic strategies could make interferon-free regimens viable for treatment of hepatitis C virus positive liver transplant recipients. The recent combinations of sofosbuvir with simeprevir or daclatasvir or ledipasvir plus/minus ribavirin have boosted the on treatment and sustained virological response to rates approaching 100% within liver transplant recipients with recurrent chronic hepatitis C (CHC). Preliminary data showed that the second generation direct oral antivirals could result to high treatment rates of recurrent CHC in kidney transplant recipients as well. Ongoing studies will clarify the optimal treatment of recurrent CHC in kidney transplant recipients.

Tenofovir/entecavir monotherapy after hepatitis B immunoglobulin withdrawal is safe and effective in the prevention of hepatitis B in liver transplant recipients.

BACKGROUND AND AIMS: Combination of hepatitis B immunoglobulin (HBIG) and a nucleos(t)ide analog (NA) is considered the standard of care for prophylaxis of hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, use of lifelong HBIG has significant limitations. We evaluated the efficacy and safety of entecavir (ETV) or tenofovir disoproxil fumarate (TDF) after withdrawal of HBIG in patients who had been under HBIG-regimen prophylaxis post LT. METHODS: Patients at low risk of recurrence were eligible for HBIG discontinuation (fulminant HBV hepatitis, co-infection with hepatitis D virus, and hepatitis B e antigen-negative cirrhotic patients with HBV DNA levels <300 copies/mL). All patients had received HBIG, with or without NA, for at least 12 months after LT. After HBIG discontinuation, they continued with ETV or TDF monotherapy. Patients were followed up with HBV serum markers and evaluation of renal function. RESULTS: Between September 2011 and June 2014, 58 liver transplant recipients were converted to TDF (31, 53%) or ETV (27, 47%). Mean follow-up after conversion was 28 ± 5 months (range 13-36 months). Five patients (8.6%) developed detectable hepatitis B surface antigen at 7, 9, 13, 15, and 22 months after HBIG discontinuation. However, in every case seroconversion was transitory, serum HBV DNA was undetectable, with no clinical manifestations of HBV recurrence. No adverse effects were observed or dose reductions required associated with ETV or TDF. CONCLUSIONS: Maintenance therapy with newer NAs, after discontinuation of HBIG prophylaxis, was safe and effective, with a low rate of serological recurrence and no evident clinical, biochemical, or virological consequences.

Efficacy and effectiveness of anti-HBV therapy with early withdrawal of HBIG prophylaxis to prevent HBV recurrence following liver transplantation.

INTRODUCTION: The traditional regimen for prophylaxis of hepatitis B recurrence post-liver transplantation is to use hepatitis B immune globulin (HBIG) along with oral antiviral therapy; however, it is unclear when it is safe to discontinue HBIG after certain time point and to maintain patients with only oral antiviral therapy. Several studies have suggested that maintenance with oral anti-hepatitis B virus (HBV) therapy following short-term or no HBIG following the immediate post-transplantation period may also be safe and effective in prevention of HBV recurrence. AREAS COVERED: We reviewed relevant literature to determine the effectiveness of early withdrawal of HBIG after liver transplantation and its effect on prevention of HBV recurrence. We used PubMed to search for any studies that used HBIG-free or short-term HBIG protocols with continued anti-HBV therapy. Short-term is defined as 12 months or less, and it is an evolving concept as new data on shorter and shorter duration becomes available. Additionally, a mini-quantitative analysis of the studies was performed using studies that involved the use of entecavir and tenofovir as anti-HBV therapy with or without HBIG. EXPERT OPINION: Patients who are considered low risk for HBV recurrence at the time of liver transplant may safely be able to utilize a short-term duration of HBIG with indefinite antiviral maintenance therapy afterwards, whereas high-risk patients will likely need long-term HBIG in combination with antiviral therapy.

Recent advances in prevention of hepatitis B recurrence after liver transplantation.

Liver transplantation is the only effective treatment for hepatitis B virus (HBV)-related end-stage liver disease. However, without antiviral prophylaxis, the recurrence rate of hepatitis B is as high as 80%-100%, which leads to a 50% mortality rate in the first 2 years after liver transplantation. Combination therapy of hepatitis B immunoglobulin (HBIG) and lamivudine demonstrated a higher efficacy of prophylaxis and further reduced the rate of recurrence to < 10%. The strategy of HBIG combined with lamivudine has been the standard treatment in many centers. However, the high rate of lamivudine resistance and the many disadvantages of HBIG have compelled surgeons to reconsider the long-term efficacy of this strategy for the prevention of HBV reinfection. Recently, new nucleos(t)ide analogues, such as entecavir and tenofovir, have been approved as first-line monotherapies for the treatment of chronic hepatitis B infection. These antiviral medicines have replaced lamivudine as the first choice in the prevention of HBV recurrence after liver transplantation. Various therapies that are composed of entecavir, tenofovir, and lamivudine plus adefovir, with or without HBIG have been adopted in several liver transplant centers. This article reviews the recent advances in prophylaxis for the recurrence of hepatitis B after liver transplantation.

Hepatitis B vaccination: a new strategy to prevent hepatitis B recurrence after liver transplantation for hepatitis B virus-related recipients / 中华肝胆外科杂志

Objective To investigate the efficacy of hepatitis B vaccination in preventing hepatitis B (HBV) recurrence after liver transplantation for hepatitis B virus-related (HBV-related) recipients.Methods 30 healthy recipients who survived for more than 2 years after liver transplantation received vaccination using hepatitis B surface antigen (HBsAg)-containing vaccine.There were a total of 5 injections at 0 month, 1 month, 2 months, 3 months and 6 months respectively, and each dose was 40 μg.Thirty healthy adults who received hepatitis B vaccination during the same period were selected into the control group.The antibody of hepatitis B surface (Anti-HBs) titer was tested at 1 month, 2 months, 3 months, 6 months, 9 months and 12 months after the first vaccination.Results 6.7％ (2/30) of the liver transplantation recipients had good response (defined as a rise of Anti-HBs titer of more than 100 IU/L at 12 months after the primary vaccination), and 16.7％ of recipients (5/30) had partial response (Anti-HBs titer in 3 patients at less than 100 IU/L, Anti-HBs titer in 2 patients at more than 100 IU/L at first, then less than 100 IU/L after 12 months).For the 9 patients who received liver transplantation for acute liver failure, 2 had good response (22.2％) and another 2 patients (22.2％) had partial response.For the liver transplant recipients who survived for more than 5 years, 2 had good response (22.2％) and another patient (11.1％) had partial response.In the healthy control group, the good response rate was 73.3％ (22/30), and the partial response rate was 10％ (3/30).Conclusions Some HBV-related liver transplant recipients could acquire Anti-HBs by vaccination.Good response rate was lower in the HBV-related group of liver transplant recipients than in the healthy control group of people.Recipients for liver transplantation carried out for acute liver failure and recipients who survived for more than 5 years had higher response rates to HBV vaccination.HBV vaccination can be a way to prevent HBV recurrence in some liver transplant recipients.

New nucleos(t)ide analogue monoprophylaxis after cessation of hepatitis B immunoglobulin is effective against hepatitis B recurrence.

New nucleos(t)ide agents (NAs) [entecavir (ETV) and tenofovir (TDF)] have made hepatitis B immunoglobulin (HBIG)-sparing protocols an attractive approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). Twenty-eight patients transplanted for HBV cirrhosis in our centre were prospectively evaluated. After LT, each patient received HBIG (1000 IU IM/day for 7 days and then monthly for 6 months) plus ETV or TDF and then continued with ETV or TDF monoprophylaxis. All patients had undetectable HBV DNA at the time of LT, and they were followed up with laboratory tests including glomerular filtration rate (GFR) after LT. All patients (11 under ETV and 17 under TDF) remained HBsAg/HBV DNA negative during the follow-up period [median: 21 (range 9-43) months]. GFR was not different between TDF and ETV groups of patients at 6 and 12 months and last follow-up (P value >0.05 for all comparisons). The two groups of patients were similar regarding their ratio of maximum rate of tubular phosphate reabsorption to the GFR (TmP/GFR). In conclusion, in this prospective study, we showed for the first time that maintenance therapy with ETV or TDF monoprophylaxis after 6 months of low-dose HBIG plus ETV or TDF after LT is highly effective and safe.

The influence factors for hepatitis B virus re-infection after liver transplantation / 中国实用内科杂志

Objective To study the influence factors for HBV reinfection following liver transplantation.Methods 92 cases of liver transplantation were enrolled for open non-randomized clinical study.Given conventional OLTx and immunosuppressive agents and antibiotics to prevent infection etc,patients are divided into lamivudine alone and HBIG combined with lamivudine group.Observation of postoperative liver function,HBV serum markers,HBV DNA in PBMC,YMDD and HBV S gene mutation,liver tissue IH etc.Results In 92 cases of liver transplantation with HBV-related liver disease,hepatitis B recurrence rate was 4.35%(4/92).In lamivudine group the HBV infection rate was 35%(7/20);In combined therapy group the HBV infection rate was 6.94%(5/72).With preoperatively negative HBV DNA negative the hepatitis B recurrence rate was 0;With preoperatively positive HBV DNA,the postoperative HBV infection rate was 17.39%(12/69),which had cases with S gene or YMDD mutation.In patients with negative HBV DNA before and after operation,the HBV re-infection rate was 11.11%(1/9);In 5 cases with preoperative HBV DNA positive,the HBV infection rate was 4/5 after LTx;before and after operation HBV DNA are positive,the HBV infection rate was 100%(3/3);the preoperative HBV DNA positive and postoperative HBV DNA negative,the HBV infection rate was 50%(1/2).Conclusion To prevent HBV infection after LTx,lamivudine group easily leads to HBV re-infection than HBIG combined with lamivudine group.Preoperative serum HBV DNA positive,preoperative and postoperative HBV YMDD and S gene mutation are the primary factors affecting the HBV re-infection after operation.HBV DNA positive in PBMC is the source of HBV re-infection,but also the factor of recurrence of hepatitis B.

Therapeutic progress on the treatment of hepatitis B recurrence after liver transplantation / 中国临床药理学与治疗学

Hepatitis B recurrence is an important factor to show whether liver transplantation is successful or not. Recrrrence rate is nearly 80% in the patients liver transplantation, and HBV reinfection is the main cause of death. After the operation, HBV may copy very quickly, because of taking in immunosuppressant therapy and graft diseases develop rapidly. Recently, the exploitation and application of therapy has become a focus. Now the drugs of preventing and treating HBV reinfection are mainly sorted into passive immunity agents(Hepatitis B immunoglobulin) and antivirus therapeutic agents(interferon and nucleotide analog antivirus drugs, etc.). Lamivudine is considered the most promising new drug of treating HBV infection. This article introduced the therapeutic characteristic of these drugs.