Title: One-year extended, monthly vaccination prophylaxis combined with hepatitis B immune globulin for hepatitis B after liver transplantation
Short title: HBV vaccination after liver transplantation
Authors: Junichi Togashi1,3, Nobuhisa Akamastu1, Yasuhiko Sugawara1, Junichi Kaneko1, Sumihito Tamura1, Tomohiro Tanaka2, Junichi Arita1, Yoshihiro Sakamoto1, Kiyoshi Hasegawa1, Norihiro Kokudo1
Affiliations: 1Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; 2Department of Organ Transplant Service, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; 3Department of Surgery, Tokyo Rosai Hospital, 4-13-21 Omori-Minami, Ota-ku, Tokyo 143-0013, Japan
Corresponding author: Norihiro KOKUDO, Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate school of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Tel.: 81-3-3815-5411; fax: 81-3-5684-3989; e-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/hepr.12526
This article is protected by copyright. All rights reserved.
Authorship: JT, NA, YS, and JK conducted the trial, collected the data, processed the data, wrote the manuscript, and were responsible for proofreading the manuscript. ST and TT conducted the trial, collected the data, and processed the data. JA, YS, and KH conducted the trial and collected the data. NK 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 statement. None to be declared.
Abbreviations: HBs-Ab, hepatitis B surface antibody; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; NA, nucleos(t)ide analogue; ALF, acute liver failure; HBc-Ab, hepatitis B core antibody; HBs-Ag, hepatitis B surface antigen; HCC, hepatocellular; HBe-Ag, hepatitis B envelope antigen; HBe-Ab, hepatitis B envelope antibody; MELD, model for end-stage liver disease.
Key words: liver transplantation, living-donor liver transplantation, hepatitis B virus, hepatitis B recurrence, vaccine, hepatitis B immune globulin
This article is protected by copyright. All rights reserved.
Abstract 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; Bimmugen, Asteras Pharma Inc., Tokyo, Japan) was administered subcutaneously 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 (HBs-Ab, n=4), and those with hepatitis B core antibody positive grafts (n=5). A fixed dose of hepatitis B immune globulin (HBIG) was administered 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 54 (13-124) months 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 HBs-Ab titer greater than 100IU/L at the end of vaccination, but only 3 (8%) maintained an adequate HBs-Ab 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.
This article is protected by copyright. All rights reserved.
Introduction The introduction of passive immunoprophylaxis using long-term hepatitis B immune globulin (HBIG) 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 [nucleos(t)ide analogues (NAs)] has allowed for successful management of HBV-related liver disease, including liver transplant recipients (2). Recent studies revealed that prophylaxis with a combination of HBIG and NAs 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 NAs and high-dose HBIG, a disadvantage of this prophylaxis is the extremely high cost (6, 7). To maintain an adequate hepatitis B surface antibody (HBs-Ab) titer, several vials of HBIG ($400/vial) must be administered 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
NAs
(9,
10),
preparations
for
intramuscular(11)/subcutaneous(12) administration, and monoprophylaxis with NAs 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).
This article is protected by copyright. All rights reserved.
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 (HBc-Ab) positive grafts.
Methods A total of 358 adult patients underwent liver transplantation (350 living donor liver transplantations and 8 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, 9 cases with acute liver failure due to HBV infection, and 16 cases with HBc-Ab positive grafts. The inclusion criteria for the present study were as follows: HBV recurrence-free (absence of serum hepatitis B antigen [HBs-Ag] detection), stable condition for more than 1 year after liver transplantation, normal liver function in outpatient clinic, and under fixed-dose HBIG monoprophylaxis without NAs (i.e., recent cases with combined prophylaxis were excluded). Finally, 39 patients were enrolled and indicated for the present vaccination study. The patient selection flow-chart is shown in Figure 1. The study protocol was approved by the institutional review board of the University of Tokyo (No. P2008003-11X), and informed consent was obtained from each recipient.
Pretransplant anti-HBV therapy and posttransplant prophylaxis protocol Lamivudine 100 mg/day (Zefix, Glaxo Smith Kline Japan Co., Tokyo, Japan) was given orally to all HBV-positive patients prior to liver transplantation. In patients in whom HBV-DNA was detectable preoperatively, lamivudine administration was continued for 4
This article is protected by copyright. All rights reserved.
weeks after liver transplantation and stopped after confirming negative HBV-DNA. Prophylactic posttransplant treatment was based on HBIG monotherapy during this study period (17). HBIG (Mitsubishi Tanabe Pharma, Hebsbulin-IH, Osaka, Japan) was administered during the anhepatic phase (10,000 units) and just after the end of the operation (10,000 units). Thereafter, HBIG was administered to maintain Hbs-Ab levels at more than 1000 IU/L for 3 months and more than 500 IU/L within 1 year, and finally the HBs-Ab titer was maintained between 100 to 200 IU/L for more than 1 year after liver transplantation. All recipients included in the present study were administered a fixed dose of intravenous HBIG (1000 to 2000 units per month) at the outpatient clinic to maintain the above-mentioned HBs-Ab level.
Immunosuppression protocol The details of the immunosuppression protocol are described elsewhere (18). The posttransplant 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 Inc., Tokyo, Japan) was administered subcutaneously every month for 12 months as the vaccination protocol. Without the established efficacy of the vaccination to maintain an adequate HBs-Ab 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 HBs-Ab level between 100 to 200 IU/L during the 3-month run-in period, and
This article is protected by copyright. All rights reserved.
administration of the fixed dose of HBIG was continued throughout the study period (Figure2). The serum HBs-Ab titer was measured every month before the vaccination and HBIG administration. The efficacy of the vaccination was assessed by the response of the HBs-Ab titer. The increase in the HBs-Ab 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., [HBs-Ab titer at 12 months]- [baseline HBs-Ab 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 HBs-Ab level was 100 IU/L, and HBs-Ab levels less than 100 IU/L over 2 consecutive months led to termination of the study with additional administration of HBIG, and patients were classified as “poor responders”. In contrast, patients with HBs-Ab levels of more than 1000 IU/L over 2 consecutive months 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 HBs-Ab titer and records of the required dose of HBIG for each patient to clarify the long-term efficacy of vaccination (Figure2).
Statistical analysis Nonparametric data was expressed as median (range). For comparison of the changes in HBs-Ab 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 chi-square 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 (ver 22.0 for Windows, Chicago, IL, USA).
This article is protected by copyright. All rights reserved.
Results A total of 39 patients met the inclusion criteria and were enrolled into the study. Their initial diseases were HBV-related cirrhosis in 30 (“Cirrhotic group”), acute liver failure due to HBV infection in 4 (“ALF group”), and the remaining 5 patients were indicated for HBV prophylaxis due to the procurement of HBc-Ab positive grafts (“HBc+ group”)(19). The demographics of the patients are shown in Table 1, stratified by the indication for HBV prophylaxis. Of the 39 recipients, 37 underwent living donor liver transplantation, while the other 2 underwent deceased donor liver transplantation. The study was initiated a mean of 54 (range, 13-124) months 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 HBs-Ag positivity, and 2% (1/39) when defined based on HBV-DNA detectability.
The HBs-Ab response and effects of HBV vaccination Cirrhotic group The increase in the HBs-Ab titer was 42 (-120 - 861) IU/L. Among 30 patients in the Cirrhotic group, only 4 patients showed a good response to the vaccination with an increase in the HBs-Ab titer (196 [137 - 861] IU/L). The remaining 26 patients were poor responders, including 2 patients who dropped out of the study requiring additional HBIG administration according to the lower limit criteria and 1 patient with HBV recurrence (HBs-Ag positive) at 4 months during the study period. ALF group The increase in the HBs-Ab titer in the ALF group was 14 (-15 - 67) IU/L. None of the patients in this group showed a good response, but there was no dropout or HBV recurrence.
This article is protected by copyright. All rights reserved.
HBc-Ab+ group The increase in the HBs-Ab titer was 129 (-26 - 312) IU/L. Of five patients, two (40%) showed a good response to the vaccination with an increase in the HBs-Ab titer (312IU/L and 244IU/L), but one patient became serum HBV-DNA positive. In terms of the response to the vaccination, there was no significant difference in the change in the serum HBs-Ab 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 6 “good responders” (4 in the Cirrhotic group and 2 in HBc-Ab+ group), 3 were completely free from HBIG for 2 years after the 12-month vaccination protocol with HBs-Ab > 500 IU/L, but the remaining 3 patients returned to the pre-vaccination HBs-Ab level and continued to require the same dose of HBIG. The changes in the HBs-Ab titers in these good responders are shown in Figure3. Initial disease of the three long-term “good responders” was HBV-related cirrhosis in two and the procurement of HBc-Ab positive graft in one. The efficacy of the current vaccination protocol was summarized in Table 3.
Discussion Previously, we reported a vaccination trial for HBV among 20 liver transplant recipients under
This article is protected by copyright. All rights reserved.
HBIG monotherapy with double dose/double-phase use of a second-generation recombinant HBV vaccine, in which none of the patients developed an adequate HBs-Ab 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), 6 recipients (15%) had responded well to the vaccination, but during the follow-up period of 24 months, only 3 (8%) maintained a sufficiently increased HBs-Ab level to spare HBIG administration. The recent established prophylaxis with the combination of HBIG (maintaining a serum HBs-Ab level >100IU/L) and NAs 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, life-long prophylaxis is required in liver transplant recipients unless an adequate specific immune response is acquired. Accordingly, this approach has several problems, including the extremely high financial burden of life-long 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 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 HBs-Ab 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
This article is protected by copyright. All rights reserved.
achieve promising results in three studies with a success rate of 40% to 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 HBc-Ab 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 HBc-Ab+ 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 (
Short title: HBV vaccination after liver transplantation
Authors: Junichi Togashi1,3, Nobuhisa Akamastu1, Yasuhiko Sugawara1, Junichi Kaneko1, Sumihito Tamura1, Tomohiro Tanaka2, Junichi Arita1, Yoshihiro Sakamoto1, Kiyoshi Hasegawa1, Norihiro Kokudo1
Affiliations: 1Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; 2Department of Organ Transplant Service, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; 3Department of Surgery, Tokyo Rosai Hospital, 4-13-21 Omori-Minami, Ota-ku, Tokyo 143-0013, Japan
Corresponding author: Norihiro KOKUDO, Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate school of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Tel.: 81-3-3815-5411; fax: 81-3-5684-3989; e-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/hepr.12526
This article is protected by copyright. All rights reserved.
Authorship: JT, NA, YS, and JK conducted the trial, collected the data, processed the data, wrote the manuscript, and were responsible for proofreading the manuscript. ST and TT conducted the trial, collected the data, and processed the data. JA, YS, and KH conducted the trial and collected the data. NK 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 statement. None to be declared.
Abbreviations: HBs-Ab, hepatitis B surface antibody; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; NA, nucleos(t)ide analogue; ALF, acute liver failure; HBc-Ab, hepatitis B core antibody; HBs-Ag, hepatitis B surface antigen; HCC, hepatocellular; HBe-Ag, hepatitis B envelope antigen; HBe-Ab, hepatitis B envelope antibody; MELD, model for end-stage liver disease.
Key words: liver transplantation, living-donor liver transplantation, hepatitis B virus, hepatitis B recurrence, vaccine, hepatitis B immune globulin
This article is protected by copyright. All rights reserved.
Abstract 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; Bimmugen, Asteras Pharma Inc., Tokyo, Japan) was administered subcutaneously 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 (HBs-Ab, n=4), and those with hepatitis B core antibody positive grafts (n=5). A fixed dose of hepatitis B immune globulin (HBIG) was administered 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 54 (13-124) months 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 HBs-Ab titer greater than 100IU/L at the end of vaccination, but only 3 (8%) maintained an adequate HBs-Ab 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.
This article is protected by copyright. All rights reserved.
Introduction The introduction of passive immunoprophylaxis using long-term hepatitis B immune globulin (HBIG) 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 [nucleos(t)ide analogues (NAs)] has allowed for successful management of HBV-related liver disease, including liver transplant recipients (2). Recent studies revealed that prophylaxis with a combination of HBIG and NAs 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 NAs and high-dose HBIG, a disadvantage of this prophylaxis is the extremely high cost (6, 7). To maintain an adequate hepatitis B surface antibody (HBs-Ab) titer, several vials of HBIG ($400/vial) must be administered 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
NAs
(9,
10),
preparations
for
intramuscular(11)/subcutaneous(12) administration, and monoprophylaxis with NAs 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).
This article is protected by copyright. All rights reserved.
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 (HBc-Ab) positive grafts.
Methods A total of 358 adult patients underwent liver transplantation (350 living donor liver transplantations and 8 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, 9 cases with acute liver failure due to HBV infection, and 16 cases with HBc-Ab positive grafts. The inclusion criteria for the present study were as follows: HBV recurrence-free (absence of serum hepatitis B antigen [HBs-Ag] detection), stable condition for more than 1 year after liver transplantation, normal liver function in outpatient clinic, and under fixed-dose HBIG monoprophylaxis without NAs (i.e., recent cases with combined prophylaxis were excluded). Finally, 39 patients were enrolled and indicated for the present vaccination study. The patient selection flow-chart is shown in Figure 1. The study protocol was approved by the institutional review board of the University of Tokyo (No. P2008003-11X), and informed consent was obtained from each recipient.
Pretransplant anti-HBV therapy and posttransplant prophylaxis protocol Lamivudine 100 mg/day (Zefix, Glaxo Smith Kline Japan Co., Tokyo, Japan) was given orally to all HBV-positive patients prior to liver transplantation. In patients in whom HBV-DNA was detectable preoperatively, lamivudine administration was continued for 4
This article is protected by copyright. All rights reserved.
weeks after liver transplantation and stopped after confirming negative HBV-DNA. Prophylactic posttransplant treatment was based on HBIG monotherapy during this study period (17). HBIG (Mitsubishi Tanabe Pharma, Hebsbulin-IH, Osaka, Japan) was administered during the anhepatic phase (10,000 units) and just after the end of the operation (10,000 units). Thereafter, HBIG was administered to maintain Hbs-Ab levels at more than 1000 IU/L for 3 months and more than 500 IU/L within 1 year, and finally the HBs-Ab titer was maintained between 100 to 200 IU/L for more than 1 year after liver transplantation. All recipients included in the present study were administered a fixed dose of intravenous HBIG (1000 to 2000 units per month) at the outpatient clinic to maintain the above-mentioned HBs-Ab level.
Immunosuppression protocol The details of the immunosuppression protocol are described elsewhere (18). The posttransplant 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 Inc., Tokyo, Japan) was administered subcutaneously every month for 12 months as the vaccination protocol. Without the established efficacy of the vaccination to maintain an adequate HBs-Ab 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 HBs-Ab level between 100 to 200 IU/L during the 3-month run-in period, and
This article is protected by copyright. All rights reserved.
administration of the fixed dose of HBIG was continued throughout the study period (Figure2). The serum HBs-Ab titer was measured every month before the vaccination and HBIG administration. The efficacy of the vaccination was assessed by the response of the HBs-Ab titer. The increase in the HBs-Ab 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., [HBs-Ab titer at 12 months]- [baseline HBs-Ab 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 HBs-Ab level was 100 IU/L, and HBs-Ab levels less than 100 IU/L over 2 consecutive months led to termination of the study with additional administration of HBIG, and patients were classified as “poor responders”. In contrast, patients with HBs-Ab levels of more than 1000 IU/L over 2 consecutive months 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 HBs-Ab titer and records of the required dose of HBIG for each patient to clarify the long-term efficacy of vaccination (Figure2).
Statistical analysis Nonparametric data was expressed as median (range). For comparison of the changes in HBs-Ab 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 chi-square 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 (ver 22.0 for Windows, Chicago, IL, USA).
This article is protected by copyright. All rights reserved.
Results A total of 39 patients met the inclusion criteria and were enrolled into the study. Their initial diseases were HBV-related cirrhosis in 30 (“Cirrhotic group”), acute liver failure due to HBV infection in 4 (“ALF group”), and the remaining 5 patients were indicated for HBV prophylaxis due to the procurement of HBc-Ab positive grafts (“HBc+ group”)(19). The demographics of the patients are shown in Table 1, stratified by the indication for HBV prophylaxis. Of the 39 recipients, 37 underwent living donor liver transplantation, while the other 2 underwent deceased donor liver transplantation. The study was initiated a mean of 54 (range, 13-124) months 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 HBs-Ag positivity, and 2% (1/39) when defined based on HBV-DNA detectability.
The HBs-Ab response and effects of HBV vaccination Cirrhotic group The increase in the HBs-Ab titer was 42 (-120 - 861) IU/L. Among 30 patients in the Cirrhotic group, only 4 patients showed a good response to the vaccination with an increase in the HBs-Ab titer (196 [137 - 861] IU/L). The remaining 26 patients were poor responders, including 2 patients who dropped out of the study requiring additional HBIG administration according to the lower limit criteria and 1 patient with HBV recurrence (HBs-Ag positive) at 4 months during the study period. ALF group The increase in the HBs-Ab titer in the ALF group was 14 (-15 - 67) IU/L. None of the patients in this group showed a good response, but there was no dropout or HBV recurrence.
This article is protected by copyright. All rights reserved.
HBc-Ab+ group The increase in the HBs-Ab titer was 129 (-26 - 312) IU/L. Of five patients, two (40%) showed a good response to the vaccination with an increase in the HBs-Ab titer (312IU/L and 244IU/L), but one patient became serum HBV-DNA positive. In terms of the response to the vaccination, there was no significant difference in the change in the serum HBs-Ab 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 6 “good responders” (4 in the Cirrhotic group and 2 in HBc-Ab+ group), 3 were completely free from HBIG for 2 years after the 12-month vaccination protocol with HBs-Ab > 500 IU/L, but the remaining 3 patients returned to the pre-vaccination HBs-Ab level and continued to require the same dose of HBIG. The changes in the HBs-Ab titers in these good responders are shown in Figure3. Initial disease of the three long-term “good responders” was HBV-related cirrhosis in two and the procurement of HBc-Ab positive graft in one. The efficacy of the current vaccination protocol was summarized in Table 3.
Discussion Previously, we reported a vaccination trial for HBV among 20 liver transplant recipients under
This article is protected by copyright. All rights reserved.
HBIG monotherapy with double dose/double-phase use of a second-generation recombinant HBV vaccine, in which none of the patients developed an adequate HBs-Ab 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), 6 recipients (15%) had responded well to the vaccination, but during the follow-up period of 24 months, only 3 (8%) maintained a sufficiently increased HBs-Ab level to spare HBIG administration. The recent established prophylaxis with the combination of HBIG (maintaining a serum HBs-Ab level >100IU/L) and NAs 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, life-long prophylaxis is required in liver transplant recipients unless an adequate specific immune response is acquired. Accordingly, this approach has several problems, including the extremely high financial burden of life-long 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 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 HBs-Ab 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
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achieve promising results in three studies with a success rate of 40% to 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 HBc-Ab 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 HBc-Ab+ 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 (
