doi: /hepr.12526

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1 bs_bs_banner doi: /hepr Original Article One-year extended, monthly vaccination prophylaxis combined with hepatitis B immune globulin for hepatitis B after liver transplantation Junichi Togashi, 1,3 Nobuhisa Akamatsu, 1 Yasuhiko Sugawara, 1 Junichi Kaneko, 1 Sumihito Tamura, 1 Tomohiro Tanaka, 2 Junichi Arita, 1 Yoshihiro Sakamoto, 1 Kiyoshi Hasegawa 1 and Norihiro Kokudo 1 1 Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, 2 Department of Organ Transplant Service, University of Tokyo and 3 Department of Surgery, Tokyo Rosai Hospital, Tokyo, Japan 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, ) 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. Key words: hepatitis B immune globulin, hepatitis B recurrence, hepatitis B virus, living donor liver transplantation, liver transplantation, vaccine INTRODUCTION THE INTRODUCTION OF passive immunoprophylaxis using long-term hepatitis B immune globulin (HBIG) Correspondence: Professor Norihiro Kokudo, Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate school of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo , Japan. KOKUDO-2SU@h.u-tokyo.ac.jp Author contribution: J. T, N. A., Y. S. and J. K. conducted the trial, collected the data, processed the data, wrote the manuscript and were responsible for proofreading the manuscript. S. T. and T. T. conducted the trial, collected the data and processed the data. J. A., Y. S. and K. H. conducted the trial and collected the data. N. K. conducted the trial and was responsible for proofreading the manuscript Financial support: Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports and Science of Japan. Conflict of interest: None to be declared. Received 1 March 2015; revision 3 April 2015; accepted 13 April in the early 1990s dramatically improved the outcome of liver transplantation for hepatitis B virus (HBV)-related chronic liver disease. 1 Additionally, during the last 15 years, the development of effective, well-tolerated and safe oral antiviral agents (nucleoside/nucleotide analogs [NA]) has allowed for successful management of HBVrelated liver disease, including liver transplant recipients. 2 Recent studies revealed that prophylaxis with a combination of HBIG and NA decreases the risk of HBV recurrence after liver transplantation to nearly negligible levels, 3,4 making HBV-related disease one of the best indications for liver transplantation with a higher rate of graft survival. 5 While there is no debate regarding the safety and efficacy of the combined prophylaxis with NA and high-dose HBIG, a disadvantage of this prophylaxis is the extremely high cost. 6,7 To maintain an adequate hepatitis E51

2 E52 J. Togashi et al. B surface antibody (HBsAb) titer, several vials of HBIG ($US 400/vial) must be administrated per month over the lifespan, the cost burden of which is quite large, not only for each individual but also for each country s national health-care budget. 8 To reduce the medical burden of HBIG, several trials have evaluated combined prophylaxis of low-dose HBIG with NA, 9,10 preparations for i.m. 11 /subcutaneous 12 administration, and monoprophylaxis with NA having a high genetic barrier. 4,13,14 Among these, active immunization for liver transplant recipients with the HBV vaccine is emerging as a useful approach, and seems attractive in terms of not only the medical cost but also the safety for recipients. 15 Unfortunately, the efficacy of the vaccination for liver transplant recipients has been controversial without an established protocol, and further studies are needed to evaluate the feasibility of this approach for liver transplant recipients. 6,16 Here, we report the results of a prospective investigation of a 1-year extended, monthly vaccination protocol with a second-generation recombinant vaccine for three types of liver transplant recipients: those with HBV-related chronic disease, those with HBV-related acute liver failure (ALF) and those with hepatitis B core antibody (HBcAb) positive grafts. METHODS ATOTAL OF 358 adult patients underwent liver transplantation (350 living donor liver transplantations and eight deceased donor liver transplantations) from 1996 to 2008 at the University of Tokyo Hospital. Among those, 78 were indicated for HBV recurrence prophylaxis with HBIG monotherapy. The initial disease of these recipients was as follows: 53 cases with cirrhosis with chronic HBV infection, nine cases with ALF due to HBV infection and 16 cases with HBcAb positive grafts. The inclusion criteria for the present study were as follows: HBV recurrence-free (absence of serum hepatitis B antigen [HBsAg] detection), stable condition for more than 1 year after liver transplantation, normal liver function in outpatient clinic and under fixed-dose HBIG monoprophylaxis without NA (i.e. recent cases with combined prophylaxis were excluded). Finally, 39 patients were enrolled and indicated for the present vaccination study. The patient selection flowchart is shown in Figure 1. The study protocol was approved by the institutional review board of the University of Tokyo (no. P X) and informed consent was obtained from each recipient. Pretransplant anti-hbv therapy and post-transplant prophylaxis protocol Lamivudine 100 mg/day (Zefix; GlaxoSmithKline Japan, Tokyo, Japan) was administrated p.o. to all HBV positive patients prior to liver transplantation. In patients in whom HBV DNA was detectable preoperatively, lamivudine administration was continued for 4 weeks Figure 1 Flow diagram of the patients enrolled in the present vaccination study. HBIG, human hepatitis B immune globulin; HBV, hepatitis B virus; LT, liver transplantation; NA, nucleoside/nucleotide analog.

3 HBV vaccination after liver transplantation E53 after liver transplantation and stopped after confirming negative HBV DNA. Prophylactic post-transplant treatment was based on HBIG monotherapy during this study period. 17 HBIG (Mitsubishi Tanabe Pharma; Hebsbulin-IH, Osaka, Japan) was administrated during the anhepatic phase ( units) and just after the end of the operation ( units). Thereafter, HBIG was administrated to maintain HBsAb levels at more than 1000 IU/L for 3 months and more than 500 IU/L within 1 year, and finally the HBsAb titer was maintained between 100 and 200 IU/L for more than 1 year after liver transplantation. All recipients included in the present study were administrated a fixed dose of i.v. HBIG ( units/month) at the outpatient clinic to maintain the above-mentioned HBsAb level. Immunosuppression protocol The details of the immunosuppression protocol are described elsewhere. 18 The post-transplant immunosuppression regimen consisted of steroid and tacrolimus, both of which were tapered gradually. The targeted serum trough level of tacrolimus was 5 ng/ml, and methylprednisolone was prescribed at a dose of 0.05 mg/kg more than 1 year after liver transplantation. Study protocol of vaccination and HBIG administration Low-dose yeast-derived recombinant hepatitis B vaccine (10 μg; Bimmugen; Astellas Pharma, Tokyo, Japan) was administrated s.c. every month for 12 months as the vaccination protocol. Without the established efficacy of the vaccination to maintain an adequate HBsAb level to prevent HBV recurrence, HBIG administration was never stopped during the study. Before starting the vaccination protocol, the dose of HBIG was adjusted to maintain the HBsAb level between 100 and 200 IU/L during the 3-month run-in period, and administration of the fixed dose of HBIG was continued throughout the study period (Fig. 2). The serum HBsAb titer was measured every month before the vaccination and HBIG administration. The efficacy of the vaccination was assessed by the response of the HBsAb titer. The increase in the HBsAb level at the end of vaccination protocol was calculated as the difference between that at the end of the study and that at the beginning of the study (i.e. [HBsAb titer at 12 months] [baseline HBsAb titer]), and an increase of more than 100 IU/L at the end of the vaccination was considered effective, with the patient classified as a good responder. Otherwise, patients were classified as poor responders. The minimum required HBsAb level was 100 IU/L, and HBsAb levels less than 100 IU/L over 2 months consecutively led to termination of the study with additional administration of HBIG, and patients were classified as poor responders. In contrast, patients with HBsAb levels of more than 1000 IU/L over 2 months consecutively were regarded as good responders, and vaccination and HBIG administration were terminated. After completion of the 1-year vaccination protocol, patients were followed for an additional 2 years, with monthly measurements of the HBsAb titer and records of the required dose of HBIG for each patient to clarify the long-term efficacy of vaccination (Fig. 2). Statistical analysis Non-parametric data was expressed as median (range). For comparison of the changes in HBsAb titers between the groups and analysis of factors associated with the response to HBV vaccine, the Mann Whitney U-test was used for interval values and the χ 2 -test was used for categorical values. A P-value less than 0.05 was considered statistically significant. All calculations were performed with SPSS statistical software (version 22.0 for Windows, Chicago, IL, USA). RESULTS ATOTAL OF 39 patients met the inclusion criteria and were enrolled into the study. Their initial diseases were HBV-related cirrhosis in 30 ( cirrhotic group ), ALF due to HBV infection in four ( ALF group ), and the remaining five patients were indicated for HBV prophylaxis due to the procurement of HBcAb positive grafts ( HBc+ group ). 19 The demographics of the patients are shown in Table 1, stratified by the indication for HBV prophylaxis. Figure 2 Study protocol. HBIG, hepatitis B immunoglobulin.

4 E54 J. Togashi et al. Table 1 Recipient demographics stratified by group Cirrhotic (n =30) ALF(n =4) HBcAb+(n =5) Increase in serum HBsAb level (IU/L) 42 ( 120 to 861) 14 ( 15 to 67) 129 ( 26 to 312) Recipient factors Sex (male : female) 27:3 2:2 2:3 Age (years) at transplantation 52 (38 59) 41 (30 62) 53 (45 59) MELD score 15.7 ( ) NA 16.6 (11 24) Bodyweight 66 (48 89) 55 (40 65) 54 (40 75) Preoperative coexistence of HCC 16 (53%) 0 (0%) 1 (20%) Preoperative positive HBV DNA 6 (20%) 2 (50%) Preoperative positive HBeAg 9 (30%) 0 (0%) Preoperative anti-hbv treatment Lamivudine 29 (97%) 4 (100%) Entecavir 1 (3%) 0 (0%) Adefovir 1 (3%) 1 (25%) Age (years) at vaccination 57 (41 67) 44 (32 66) 58 (53 64) Months to vaccination from transplantation 54 (16 124) 44 (20 65) 59 (13 113) Fixed dose of HBIG (IU/L) per month 1800 ( ) 1000 (100%) 1480 ( ) Serum creatinine level (mg/dl) at the start of vaccination 1.1( ) 1.37 ( ) 1.22 ( ) Tacrolimus trough level (ng/ml) during vaccination 6 ( ) 5.6 ( ) 7.1 ( ) Donor-related factors Age at transplantation 34 (19 58) 53 (33 65) 47 (29 57) Sex (male : female) 18: 12 2: 2 4: 1 Blood relation+ 18 (60%) 3 (75%) 3 (60%) Donor HBsAb+ 8 (27%) 1 (25%) 5 (100%) Donor HBeAb+ 5 (17%) 0 (0%) 2 (40%) Donor HBcAb+ 6 (20%) 1 (25%) 5 (100%) ALF, acute liver failure; HBcAb, hepatitis B core antibody; HBeAb, hepatitis B e-antibody; HBeAg, hepatitis B e-antigen; HBIG, human hepatitis B immunoglobulin; HBsAb, hepatitis B surface antibody; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease. Of the 39 recipients, 37 underwent living donor liver transplantation, while the other two underwent deceased donor liver transplantation. The study was initiated a mean of 54 months (range, ) after liver transplantation. All patients tolerated the protocol well without adverse reactions in the general condition or in laboratory examinations due to vaccination. During the study period, the overall HBV recurrence rate was 5% (2/39) when defined based on HBsAg positivity, and 2% (1/39) when defined based on HBV DNA detectability. HBsAb response and effects of HBV vaccination Cirrhotic group The increase in the HBsAb titer was 42 IU/L ( 120 to 861). Among 30 patients in the cirrhotic group, only four patients showed a good response to the vaccination with an increase in the HBsAb titer (196 IU/L [ ]). The remaining 26 patients were poor responders, including two patients who dropped out of the study requiring additional HBIG administration according to the lower limit criteria and one patient with HBV recurrence (HBsAg positive) at 4 months during the study period. ALF group The increase in the HBsAb titer in the ALF group was 14 IU/L ( 15 to 67). None of the patients in this group showed a good response, but there was no dropout or HBV recurrence. HBcAb+ group The increase in the HBsAb titer was 129 IU/L ( 26 to 312). Of five patients, two (40%) showed a good response to the vaccination with an increase in the HBsAb titer (312 and 244 IU/L), but one patient became serum HBV DNA positive.

5 HBV vaccination after liver transplantation E55 In terms of the response to the vaccination, there was no significant difference in the change in the serum HBsAb level between the three groups. Characteristics of the vaccination response in the cirrhotic group To elucidate the factors associated with a good response to the vaccination, we analyzed the variables assumed to be associated with the efficacy of vaccination in the cirrhotic group (Table 2). Although only univariate analyses were performed due to the small number of cases, we found a possible association between the preoperative existence of hepatocellular carcinoma (HCC) and a poor response. Long-term efficacy of 1-year vaccination Among six good responders (four in the cirrhotic group and two in the HBcAb+ group), three were completely free from HBIG for 2 years after the 12-month vaccination protocol with HBsAb of more than 500 IU/L, but the remaining three patients returned to the prevaccination HBsAb level and continued to require the same dose of HBIG. The changes in the HBsAb titers in these good responders are shown in Figure 3. Initial disease of the three long-term good responders was HBVrelated cirrhosis in two and the procurement of HBcAb positive graft in one. The efficacy of the current vaccination protocol was summarized in Table 3. Figure 3 Changes in serum hepatitis B surface antibody (HBsAb) levels of six good responders. Solid line: patients who demonstrated an adequate response. Dotted line: patients who returned to pre-vaccination level during the follow-up period. Table 2 Comparison between responders and non-responders in the cirrhotic group Good responder n = 4 Non-responder n =26 P-value Increase in serum HBsAb level (IU/L) 196 ( ) 4 ( 120 to 97) 0.01 Recipient factors Age (years) at transplantation 50 (47 53) 55 (38 59) 0.15 Sex (male : female) 3:1 24: MELD score 19 (13 25) 14 (3 33) 0.23 Bodyweight 60 (52 69) 67 (48 89) 0.33 Preoperative coexistence of HCC Preoperative positive HBV DNA 1 (25%) 5 (19%) 0.79 Preoperative positive HBeAg 0 (0%) 9 (35%) 0.17 Age (years) at the vaccination 56 (54 58) 58 (41 67) 0.30 Months to vaccination from transplantation 70 (46 95) 46 (16 124) 0.14 Fixed dose of HBIG (IU/L) per month 1000 ( ) 2000 ( ) 0.06 Serum creatinine level (mg/dl) at the start of vaccination 0.84 ( ) 1.05 ( ) 0.25 Tacrolimus trough level (ng/ml) during vaccination 5.1 ( ) 5.9 ( ) 0.56 Donor-related factors Age at transplantation 32 (20 47) 29 (19 58) 0.67 Sex (male : female) 1: 3 17: Blood relation Donor HBsAb Donor HBeAb Donor HBcAb HBcAb, hepatitis B core antibody; HBeAb, hepatitis B e-antibody; HBeAg, hepatitis B e-antigen; HBIG, human hepatitis B immunoglobulin; HBsAb, hepatitis B surface antibody; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease.

6 E56 J. Togashi et al. Table 3 Efficacy of the current vaccination protocol Good responders, n (%) All patients (n = 39) Cirrhotic (n =30) ALF(n = 4) HBcAb+(n = 5) End of the vaccination protocol (12 months) 6 (15%) 4 (13%) 0 (0%) 2 (40%) End of the follow up (36 months ) 3 (8%) 2 (7%) 0 (0%) 1 (20%) ALF, acute liver failure; HBcAb, hepatitis B core antibody. DISCUSSION PREVIOUSLY, WE REPORTED a vaccination trial for HBV among 20 liver transplant recipients under HBIG monotherapy with double-dose/double-phase use of a second-generation recombinant HBV vaccine, in which none of the patients developed an adequate HBsAb level at the end of the study. 20 In the present study, we investigated the efficacy of a 1-year extended, monthly vaccination protocol of a second-generation recombinant vaccine. At the end of the vaccination protocol (12 months), six recipients (15%) had responded well to the vaccination, but during the follow-up period of 24 months, only three (8%) maintained a sufficiently increased HBsAb level to spare HBIG administration. The recent established prophylaxis with the combination of HBIG (maintaining a serum HBsAb level of >100 IU/L) and NA with a high genetic barrier can prevent HBV reinfection in almost 100% patients. 4 Unfortunately, this approach, although highly effective, does not eradicate HBV, which may persist either in the graft liver and/or in extrahepatic sites in low replicating forms. Therefore, lifelong prophylaxis is required in liver transplant recipients unless an adequate specific immuneresponseis acquired. Accordingly, this approach has several problems, including the extremely high financial burden of lifelong passive immunoprophylaxis with HBIG, the emergence of HBIG-induced HBV escape mutants and/or NA resistance. With these considerations for the current combination prophylaxis, many centers have tried to establish active immunoprophylaxis with various vaccination protocols, but this approach is currently far from promising. 21 Studies of HBV vaccination for liver transplant recipients, which are summarized in Table 4, are controversial. 15,22 30 Due to differences in the vaccination protocol, not only in the dose and duration of the vaccination itself, but also in the underlying prophylaxis regimen, it is difficult to compare the results of each study. HBV vaccination for liver transplant recipients as a whole, however, is unsatisfactory and usually short-lasting, leading to the development of HBsAb protective titers in only 8% to 25% of recipients. 22,31 33 A recently introduced HBV vaccine, including 3-deacylated monophosphoryl lipid A as an adjuvant, was reported to achieve promising results in three studies with a success rate of 40 80%, 29,34 but opposite results were also reported. 25,26 Based on the present results and previous reports, some recipients can achieve adequate active immunity against HBV with the vaccination protocol after liver transplantation. Accordingly, it will be crucial to clarify the characteristics of those who respond well to the vaccination. To date, however, the small number of cases in each study as well as the present study makes it difficult to draw a conclusion. Recipients with liver failure due to acute HBV infection 30 and those with grafts from HBcAb positive donors 15,35,36 demonstrate a good response to vaccination. Unlike patients with pretransplant chronic HBV infection, these recipients can be expected to respond well to vaccination as they have not developed a tolerance to HBV. In contrast, the present findings did not provide the expected good response in the ALF group or in the HBcAb+ group. With regard to recipients with pretransplant chronic HBV infection, several possible factors associated with a good response are reported, such as younger recipient age (<50 years), 15,37 higher donor HBsAb level, 30 and absence of blood relation to the donor. 30 The present study also revealed the possible association of a good response with the absence of HCC at transplantation, although the clinical significance seems minimal. All of these findings were based on a small cohort with weak statistical power, and additional welldesigned studies are needed to determine significant factors. There are many limitations to these studies. First, as in the present study, each study enrolled only a small cohort, cases per study (Table 4), which makes it difficult to draw a convincing conclusion. Second, besides the differences in the vaccination protocol, the follow-up period after vaccination seems too short to evaluate the long-term efficacy of the vaccination protocol. Some studies defined the final response at the end of the study without follow up after the cessation of vaccination. We followed up for 2 years after the vaccination, during which half of the good responders returned to the pre-vaccination HBsAb titer and required the same dose of HBIG. It is essential to evaluate the long-term efficacy of the vaccination protocol

7 HBV vaccination after liver transplantation E57 Table 4 Studies of vaccination for hepatitis B among liver transplant recipients Follow-up period after vaccination (months) HBsAb 100 IU/L at the end of follow up Concomitant use of NA Immunomodulating adjuvant Concomitant use of HBIG Dose of HBV vaccine (μg) No. of vaccinations Preoperative HBV DNA detection- Negative cases (%) Acute/ chronic/ HBcAb+ Age (median) Reference n Sanchez-Fueyo et al. 22 (2000) /14/ No No Yes 23% 14 (3 54) Angelico et al. 23 (2002) /17/ No No Yes 12% 9 Bienzle et al. 24 (2003) /18/ Yes Yes Yes 80% 14 (6 22) Starkel et al. 25 (2005) /8/ Yes Yes No 40% 6 Rosenau et al. 26 (2006) /9/ Yes Yes Yes 8% 2 Soejima et al. 27 (2007) /0/8 NA 9 20 No No Yes 36% 9 Tahara et al. 28 (2010) /14/0 71 Non stop Yes No Yes 65% NA Di Paolo et al. 29 (2010) /18/ Yes (withdrawal) Yes Yes 44% 12 Ishigami et al. 15 (2011) /15/ Yes (withdrawal) No Yes 24% 9 Takaki et al. 30 (2013) /22/ Yes No Yes 52% NA Present study /30/ Yes No No 18% 24 HBcAb, hepatitis B core antibody; HBIG, human hepatitis B immune globulin; HBsAb, hepatitis B surface antibody; HBV, hepatitis B virus; NA, nucleoside/nucleotide analog. because we often experience the return of HBsAb titers to the pre-vaccination level in long-term recipients. However, due to the extremely small number of cases in the present study, it is difficult to retrieve some conclusive comments regarding the maintenance of the vaccination efficacy. In this regard, the role of HBV-specific immune response has been postulated by several authors, which may need further clinical evaluations. Further extension of the vaccination protocol might be an option to improve the efficacy of vaccination, but recently Ishigami et al. 38 reported the risk of an emergence of escape mutants after repeated vaccination. Finally, the present study was based on a previous cohort with HBIG monoprophylaxis, 17 although we used a combined approach for recent cases. Given the current availability of potent NA (entecavir and tenofovir) with a negligible risk for long-term viral resistance, at present it seems rational to begin the vaccination protocol in combination with such NA. Currently, the combination of HBIG (at least for a short period) and one NA appears to be the most reliable post-transplant approach, while monoprophylaxis with the new NA cannot be excluded in the future, particularly in patients with a low risk of recurrence. 39 In such trials of NA monoprophylaxis, a combination of the vaccination protocols may be useful for selected patients. In conclusion, the extended 1-year vaccination protocol resulted in an all-or-none response in liver transplant recipients, meaning that a limited number of patients were able to establish active immunity completely sparing HBIG, but the majority could never benefit from vaccination. Based on the present finding, we concluded that the clinical indication for the HBV vaccination in liver transplant recipients is currently minimal. The present finding, as well as those of previous studies, however, demonstrated that some recipients could establish active immunity after an extended vaccination protocol. A well-designed multicenter study with enrollment of a significantly greater number of patients should be performed before the introduction of this approach into clinical practice. Close monitoring of serum HBsAb levels (at least monthly), an extended vaccination protocol (e.g. 1 year), and combined administration of HBIG or NA are mandatory for HBV vaccination trials in liver transplant recipients. REFERENCES 1 Samuel D, Muller R, Alexander G et al. Liver transplantation in European patients with the hepatitis B surface antigen. The New England journal of medicine (25): Papatheodoridis GV, Cholongitas E, Archimandritis AJ, Burroughs AK. Current management of hepatitis B virus

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9 HBV vaccination after liver transplantation E59 28 Tahara H, Tanaka Y, Ishiyama K et al. Successful hepatitis B vaccination in liver transplant recipients with donor-specific hyporesponsiveness. Transplant international: official journal of the European Society for Organ Transplantation (8): Di Paolo D, Lenci I, Cerocchi C et al. One-year vaccination against hepatitis B virus with a MPL-vaccine in liver transplant patients for HBV-related cirrhosis. Transpl Int (11): Takaki A, Yagi T, Yasunaka T et al. Which patients respond best to hepatitis B vaccination after a hepatitis B virus-related liver transplantation? Journal of gastroenterology (12): Lo CM, Liu CL, Chan SC, Lau GK, Fan ST. Failure of hepatitis B vaccination in patients receiving lamivudine prophylaxis after liver transplantation for chronic hepatitis B. Journal of hepatology (2): Rosenau J, Hooman N, Hadem J et al. Failure of hepatitis B vaccination with conventional HBsAg vaccine in patients with continuous HBIG prophylaxis after liver transplantation. Liver transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society (3): Di Paolo D, Lenci I, Trinito MO et al. Extended doubledosage HBV vaccination after liver transplantation is ineffective, in the absence of lamivudine and prior wash-out of human Hepatitis B immunoglobulins. Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver (10): Bienzle U, Gunther M, Neuhaus R et al. Immunization with an adjuvant hepatitis B vaccine after liver transplantation for hepatitis B-related disease. Hepatology (Baltimore, Md) (4): Kwon CH, Suh KS, Yi NJ et al. Long-term protection against hepatitis B in pediatric liver recipients can be achieved effectively with vaccination after transplantation. Pediatr Transplant (4): Chang SH, Suh KS, Yi NJ et al. Active immunization against de novo hepatitis B virus infection in pediatric patients after liver transplantation. Hepatology (Baltimore, Md) (6): Lo CM, Lau GK, Chan SC, Fan ST, Wong J. Efficacy of a pre-s containing vaccine in patients receiving lamivudine prophylaxis after liver transplantation for chronic hepatitis B. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2): Ishigami M, Honda T, Ishizu Y et al. Frequent incidence of escape mutants after successful hepatitis B vaccine response and stopping of nucleos(t)ide analogues in liver transplant recipients. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society (10): Cholongitas E, Vasiliadis T, Antoniadis N, Goulis I, Papanikolaou V, Akriviadis E. Hepatitis B prophylaxis post liver transplantation with newer nucleos(t)ide analogues after hepatitis B immunoglobulin discontinuation. Transplant Infectious Disease: An Official Journal of the Transplantation Society (5):