Successful Active Immunization Using a Hepatitis B Virus Vaccination Protocol for a Recipient With Hepatitis B Core AntibodyePositive Liver Graft Y. Ohno, A. Mita, T. Ikegami, Y. Masuda, K. Urata, Y. Nakazawa, A. Kobayashi, and S. Miyagawa ABSTRACT Introduction. Donor shortages occasionally necessitate the use of hepatic allografts from hepatitis B core antibodyepositive (HBcAbþ) donors, with an attendant risk of posttransplantation hepatitis B virus (HBV) infection. The aim of the present study was to develop and evaluate a protocol of active immunization for prevention of posttransplantation de novo HBV infection in patients receiving liver grafts from HBcAbþ donors. Patients and Methods. Ten patients who had received HBcAbþ liver grafts at Shinshu University Hospital between October 1996 and December 2012 were enrolled. All the recipients were negative for HBV serological tests, and HBV-DNA. Hepatitis B immunoglobulin (HBIG) was given routinely in the peritransplantation and post-transplantation periods, without antiviral drugs. Subcutaneous vaccination with recombinant HBV was given at a dosage of 20 mg in adults and 5 mg in children concomitant with HBIG until acquisition of active immunization. The timing to start HBV vaccination was dependent on the condition of the patient. Results. The median follow-up period after liver transplantation was 140 months, and the median period after transplantation until the start of vaccination was 7.0 months. Nine patients (90%) acquired active immunity after a median number of 4 (range, 2e13) vaccinations (hepatitis B surface antibody >300 mIU/mL for 1 year, or >100 mIU/mL thereafter), and did not require HBIG administration thereafter. None had any side effects of HBV vaccination or developed hepatitis B infection during the study period. Four fast responders who achieved antibody high titers by active immunization within 9 months received pretransplantation vaccinations, whereas 5 slow responders did not. Conclusions. Our vaccination protocol provides a new effective strategy for prevention of de novo hepatitis B infection after liver transplantation in recipients with HBcAbþ liver grafts. Pretransplantation HBV vaccination was helpful for the post-transplantation vaccine response.
D
ONOR organ shortages occasionally necessitate the use of hepatic allografts from donors with antibody positivity for hepatitis B core antigen (HBcAb). However, transplantation of HBcAb-positive (HBcAbþ) livers carries a risk of transmitting hepatitis B virus (HBV) to recipients, with an incidence of 25%e95% [1e7]. Although hepatitis B immunoglobulin (HBIG) and/or nucleotide analogue have been used worldwide to prevent de novo HBV infection in recipients with HBcAbþ liver grafts [1,2,8], life-long administration of HBIG is costly and inconvenient. Once ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 721e725 (2014)
patients acquire active immunization by HBV vaccination, they can maintain their hepatitis B surface antibody (HBsAb)
From the Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan. Address reprint requests to Atsuyoshi Mita, MD, PhD, Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. E-mail: [email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.12.005 721
722
titer for a longer period than after receiving passive immunization, such as HBIG. Active immunization might be a better strategy than the use of HBIG, but previous reports have indicated unsatisfactory vaccination response rates after liver transplantation [9,10]. Recently, good results have been reported for active immunization in pediatric patients with HBcAbþ liver grafts [11,12]. On the other hand, the efficacy of HBV vaccination for HBcAb-negative (HBcAb) adult recipients with HBcAbþ liver grafts still remains unclear, and the rate of acquisition of active immunization is not satisfactory [13]. The aim of the present study was to develop an active immunization protocol and to evaluate its usefulness for preventing de novo HBV infection in adult and pediatric patients undergoing liver transplantation. PATIENTS AND METHODS Between December 1996 and December 2012, liver transplantations were performed for 300 patients at Shinshu University Hospital. Among them, 15 patients obtained liver grafts from HBcAbþ donors. For the purposes of this study, we excluded 5 recipients, 4 of whom had already showed HBcAb positivity at the time of liver transplantation and the remaining 1 was not administered immunosuppressants because of her graft from an identical twin. The remaining 10 patients, comprising 7 adults (age 18 years) and 3 infants, were adopted as the study subjects. Prior to transplantation, all recipients and donors were evaluated for hepatitis B using serological testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), HBcAb, hepatitis B envelope antigen (HBeAg), hepatitis B envelope antibody (HBeAb), and HBV-DNA.
Immunosuppression The immunosuppression protocol for the recipients has been described elsewhere [14]. The initial immunosuppressive regimen consisted of tacrolimus and steroids. Patients who had been rejection-free under a stable tacrolimus-based regimen for 6 months were offered the option of steroid withdrawal.
Post-Transplantation Prophylaxis for HBV Infection The prophylaxis protocol for HBcAb recipients with a HBcAbþ liver graft was initiated with HBIG alone. HBIG was intravenously given at 10,000 IU in the anhepatic period during liver transplantation. Postoperatively, the serum HBsAb titer was maintained at >300 mIU/mL for 1 year, and >100 mIU/mL thereafter by administration of HBIG. Subsequently, we added a subcutaneous injection of recombinant HBV vaccine (Bemmugen INJ[Vial]; Astellas, Tokyo, Japan) with a dose of 20 mg in adult cases and 5 mg in pediatric cases while maintaining HBsAb by HBIG. The timing to start HBV vaccination was dependent on the condition of the patient. The interval of the vaccinations was basically longer than 1 month, and depended on the serum HBsAb titer when introducing the HBV vaccination protocol. The HBV vaccine was initially administered together with intravenous HBIG administration. We defined a positive vaccination response as an increase in the serum HBsAb titer more than expected when administering HBIG alone. Nonresponders needed to continue HBIG administration, maintaining their serum HBsAb level. We did not define an upper limit for the frequency of vaccinations in our protocol. We investigated the success rate of vaccination, the periods of introducing HBV
OHNO, MITA, IKEGAMI ET AL vaccination, the frequency of vaccinations to acquire active immunization, and the factors for successful active immunization.
Statistical Analysis Univariate analysis was performed for categorical variables with the use of the chi-square test. We analyzed continuous variables with a 2-tailed unpaired t test. A P < .05 was considered statistically significant.
RESULTS
Characteristics of the recipients and donors at the first medical examination in our hospital are presented in Tables 1 and 2. The median age of the recipients was 41 (range, 0.5e61) years, and 6 of them were women. The underlying diseases for liver transplantation were biliary atresia in 3 cases, primary biliary cirrhosis in 2, hepatitis C in 2 (both had hepatocellular carcinoma concomitantly), familial amyloid polyneuropathy in 2, and autoimmune hepatitis in 1. Seven cases involved transplantation from living donors (3 parents, 3 siblings, and 1 child), and 3 from deceased donors. The median follow-up period after liver transplantation was 140 (range, 74e193) months. At the initial evaluation for liver transplantation, all recipients were negative for HBsAb. All the recipients were negative for HBsAg, HBcAb, HBeAg, HBeAb, and HBV-DNA. All donors were positive for HBcAb and negative for HBsAg, HBeAg and HBV-DNA. Among 4 recipients who were vaccinated against HBV before transplantation, 3 preoperatively showed a positive serum HBsAb titer with a median of 17.3 (range, 16e227) mIU/mL. At the liver transplantation, HBsAb was positive (>10 mIU/mL) in 3 of 9 patients. Vaccination was postoperatively performed in all 10 recipients. Nine patients acquired active immunity with a median number of 4 vaccinations (range, 2e13; HbsAb >300 mIU/mL for 1 year, or >100 mIU/mL thereafter). Vaccination was started 7.5 (range, 2e29) months after transplantation. In 1 nonresponder who was a 54-year-old woman with primary biliary cirrhosis, vaccination was started 16 months after deceased donor liver transplantation and still continued in the interval between outpatient visits. She was administered prednisolone (5 mg/d), tacrolimus, and mycophenolate mofetil (750 mg/d) at the time of observation. No patients showed a conversion to HBsAgþ or HBV-DNAþ postoperatively without HBIG administration in the median follow-up period of 112 months after they had acquired active immunity. The patients have still maintained the HBsAb level >100 mIU/mL by vaccination once or twice per year. No obvious side effects (fever, exanthema, nausea, diarrhea, anorexia, or headache) were seen in our series. One patient died of liver cirrhosis due to recurrent autoimmune hepatitis 5 years after liver transplantation. In this study, 2 types of response were observed among the patients who acquired active immunity. Four of 9 patients (44%; case 140, 195, 233, and 245) achieved antibody titers >100 mIU/mL within 9 months after induction of
723
þ þ þ þ þ þ þ þ þ þ
vaccination, allowing complete discontinuation of HBIG substitution (fast responders), and none of them had resumed HBIG administration by December 2012. The remaining 5 patients needed more than 18 months to achieve an antibody titer >100 IU/L without HBIG administration (slow responders). The mean age of the fast responders was 11.8 years, which was significantly younger than that of slow responders (42.5 years; P < .05). All of the fast responders received vaccinations before liver transplantation, whereas the slow responders did not (P < .05; Table 3). Abbreviations: FAP, familial amyloid polyneuropathy; HC, hepatitis C; PBC, primary biliary cirrhosis; BA, biliary atresia; AIH, autoimmune hepatitis; ne, not evaluated.
þ þ þ ne þ þ ne ne ne þ þ þ þ þ þ þ þ þ 46 41 61 39 0.8 23 43 2 2.5 54 65 101 116 137 140 167 195 233 245 252
M M M F F F M M F F
FAP FAP HC PBC BA AIH HC BA BA PBC
47 41 33 41 39 42 40 35 37 59
M F F M M M M M F M
Deceased Deceased Daughter Brother Father Deceased Brother Father Mother Deceased
HBeA HBsAb HBsA HBsAb HBsAg Primary Disease Gender Age No
Recipient
HBeAg
HBeAb
HBcAb
Age
Gender
Table 1. Patient and Donor Demographics and HBV Serology
Relationship
Donor
HBeAb
HBcAb
HBV VACCINATION PROTOCOL
DISCUSSION
We successfully prevented de novo HBV infection in HBcAb recipients with a HBcAbþ liver graft by using a prophylactic protocol. Our HBV prophylactic protocol is characterized by how to use vaccination with HBIG. We added vaccination while maintaining HBsAb by HBIG, and repeated vaccination until obtaining a response. De novo HBV infection after liver transplantation has been reported to be associated with donors who have serological markers of past HBV infection (HBcAbþ and HBsAg) [1e6]. Likewise, 3 recipients who received HBcAbþ liver grafts developed de novo HBV infection before the beginning of the prophylaxis protocol for de novo HBV infection at our institute until 1996. Among them, 1 recipient died of liver cirrhosis, and the other 2 have seroconverted to HBsAb positivity and have been well for 17 and 21 years of follow-up, respectively. To resolve this kind of problem, Uemoto et al reported that the use of daily intravenous administration of 10,000 IU HBIG for the first week after liver transplantation, followed by intermittent administration of 10,000 IU HBIG to maintain serum HBsAb at a level >100 mIU/mL, resulted in no patients developing de novo HBV infection [1]. Currently, it is considered acceptable to use liver grafts from HBcAbþ donors for HBcAb recipients when prophylactic protocols to prevent HBV infection are used [8,15,16]. However, these patients require life-long administration of very costly HBIG ($400 per 1000 IU) at intervals depending on their serum HBsAb level. Therefore, development of a simple and inexpensive prophylactic regimen has been required. As an alternative, artificial active immunization (HBV vaccination) is inexpensive and produces a relatively long-term protective response; patients need only a booster vaccination to sustain an adequate level of HBsAb. Because recipients are under immunosuppression following organ transplantation, they usually do not mount adequate immune responses to vaccine in comparison with nonimmunosuppressed individuals. Recently, SanchezFueyo et al [17] and Bienzle et al [18] have reported good results with active immunization after liver transplantation for the patients who underwent transplantation for HBVrelated cirrhosis. With regard to post-transplantation vaccination for pediatric patients receiving HBcAbþ liver
724
OHNO, MITA, IKEGAMI ET AL Table 2. Vaccination in Patients Who Received Grafts From Anti-HBcD Donors
No.
Vaccination Before LT
First Vaccination (mo After LT)
Total No. of Vaccinations
Time for Acquisition of Active Immunization
Titer on Last Visit (mIU/mL)
Follow-Up After LT (mo)
De Novo HBV
65 101 116 137 140 167 195 233 245 252
þ þ þ þ
15 26 29 2 3 2 7 8 6 16
2 9 7 2 3 13 6 4 2 13
29 84 41 18 9 16 14 12 13 e
406 632 551 376 927 2951 528 981 6345 145
193 166 157 147 145 61 119 89 80 74
Abbreviation: LT, liver transplantation.
grafts, Chang et al reported that young children successfully acquired active immunization, thus protecting them from de novo HBV infection [11]. They maintained an HBsAb titer of >20 mIU/mL, and 1 nonresponder developed de novo HBV infection in their series of 19 recipients. The median follow-up, however, was only 10 months, and thus a longer follow-up would be needed to validate the results because de novo HBV can occur beyond this time frame. Lin et al have reported that active immunization is effective for protecting young children receiving HBcAbþ liver grafts from de novo HBV infection by maintaining the HBsAb titer at levels >1000 mIU/mL [12]. Among 30 recipients, 1 whose HBsAb titers were >100 mIU/mL but 300 mIU/mL for 1 year and >100 mIU/mL thereafter. We considered that the patients had acquired active immunization when the serum HBsAb level reached our target level without administration of HBIG. Patients who underwent vaccination prior to transplantation acquired active immunity earlier than the patients who did not in our series. As Kwon et al suggested [20], pretransplantation vaccination can be important because it may influence the post-transplantation vaccine response, regardless of pretransplantation serological status or response. In living donor liver transplantation, information about donor HBV-related serology is obtained earlier than for deceased donor liver transplantation. Therefore, pretransplantation HBV vaccination is recommended when the living donor candidate is HBcAbþ. Although the incidence of HBV mutation after HBV vaccination to prevent de novo HBV infection is uncertain, it might be lower than for the regimen of HBIG used in other centers. We believe that the benefits of HBV vaccination for prophylaxis of de novo hepatitis overcome its potential side effects. With regard to recipient age, we found that younger patients had significantly better responses to HBV vaccination after liver transplantation. Similar observations have been
HBV VACCINATION PROTOCOL
reported in a transplant setting [13], in patients on hemodialysis [21,22], and in health care workers [19]. In conclusion, we successfully prevented de novo HBV infection in HBcAb recipients with a HBcAbþ liver graft by acquiring active immunization using a HBV vaccination protocol. Our protocol provides a new effective strategy for prevention of de novo HBV infection after liver transplantation in recipients with HBcAbþ liver grafts. Pretransplantation HBV vaccination was helpful for the post-transplantation vaccine response. REFERENCES [1] Uemoto S, Sugiyama K, Marusawa H, Inomata Y, Asonuma K, Egawa H, et al. Transmission of hepatitis B virus from hepatitis B core antibody- positive donors in living related liver transplants. Transplantation 1998;65:494e9. [2] Dodson SF, Issa S, Araya V, Gayowski T, Pinna A, Eghesad B, et al. Infectivity of hepatic allografts with antibodies to hepatitis B virus. Transplantation 1997;64:1582e4. [3] Dickson RC, Everhart JE, Lake JR, Yuling W, Seaberg E, Wiesner R, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. Gastroenterology 1997;113:1668e74. [4] Wachs ME, Amend WJ, Ascher NL, et al. The risk of transmission of hepatitis B from HBsAg(-), HBcAbþ, HBIgM(-) organ donors. Transplantation 1995;59:230e4. [5] Prieto M, Gomez MD, Berenguer M, Cordoba J, Rayon JM, Pastor M, et al. De novo hepatitis B after liver transplantation from hepatitis B core antibody-positive donors in an area with high prevalence of anti-HBc positivity in the donor population. Liver Transpl 2001;7:51e8. [6] Manzarbeitia C, Reich D, Oritz J, Rothstein K, Araya V, Munoz SJ, et al. Safe use of liver donors with positive hepatitis B core antibody. Liver Transpl 2002;8:556e61. [7] Douglas DD, Rakela J, Wright TL, Krow RA, Wiesner RH. The clinical course of transplantation-associated de novo hepatitis B infection in the liver transplant recipient. Liver Transpl Surg 1997;3:105e11. [8] Holt D, Thomas R, Van Thiel D, Brems JJ. Use of hepatitis B core antibody-positive donors in orthotopic liver transplantation. Arch Surg 2002;137:572e5. [9] Angelico M, Di Paolo D, Trinito MO, Petrolati A, Araco A, Zazza S, et al. Failure of a reinforced triple course of hepatitis B vaccination in patients transplanted for HBV-related cirrhosis. Hepatology 2002;35:176e81.
725 [10] Loinaz C, de Juanes JR, Gonzalez EM, Lopez A, Lumbreras C, Gomez R, et al. Hepatitis B vaccination results in 140 liver transplant recipients. Hepatogastroenterology 1997;44:235e8. [11] Chang SH, Suh KS, Yi NJ, Choi SH, Lee HJ, Seo JK, et al. Active immunization against de novo hepatitis B virus infection in pediatric patients after liver transplantation. Hepatology 2003;37: 1329e34. [12] Lin CC, Chen CL, Concejero A, Wang CC, Wang SH, Lie YW, et al. Active immunization to prevent de novo hepatitis B virus infection in pediatric live donor liver recipients. Am J Transplant 2007;7:195e200. [13] Soejima Y, Ikegami T, Taketomi A, Yoshizumi T, Uchiyama H, Harada N, et al. Hepatitis B vaccination after living donor liver transplantation. Liver Int 2007;27:977e82. [14] Hashikura Y, Kawasaki S, Matsunami H, Terada M, Ikegami T, Nakazawa Y, et al. Immunosuppressant switching between cyclosporine and tacrolimus after liver transplantation. Transplant Proc 1996;28:1034e5. [15] Dodson SF, Bonham CA, Geller DA, Cacciarelli TV, Rakela J, Fung JJ. Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors. Transplantation 1999;68:1058e61. [16] Chung RT, Feng S, Delmonico FL. Approach to the management of allograft recipients following the detection of hepatitis B virus in the prospective organ donor. Am J Transplant 2001;1:185e91. [17] Sanchez-Fueyo A, Rimola A, Grande L, Costa J, Mas A, Navasa M, et al. Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination: a new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation. Hepatology 2000;31:496e501. [18] Bienzle U, Gunther M, Neuhaus R, Neuhaus P. Successful hepatitis B vaccination in patients who underwent transplantation for hepatitis B virus-related cirrhosis: preliminary results. Liver Transpl 2002;8:562e4. [19] Wood RC, MacDonald KL, White KE, Hedberg CW, Hanson M, Osterholm MT. Risk factors for lack of detectable antibody following hepatitis B vaccination of Minnesota healthcare workers. JAMA 1993;270:2935e9. [20] Kwon CHD, Suh K-S, Yi N-J, Chang SH, Cho YB, Cho JY, et al. Long-term protection against hepatitis B in pediatric liver recipients can be achieved effectively with vaccination after transplantation. Pediatr Transplant 2006;10:479e86. [21] DaRoza G, Loewen A, Djurdjev O, Love J, Kempston C, Burnett S, et al. Stage of chronic kidney disease predicts seroconversion after hepatitis B immunization: earlier is better. Am J Kidney Dis 2003;42:1184e92. [22] Liu YL, Kao MT, Huang CC. A comparison of responsiveness to hepatitis B vaccination in patients on hemodialysis and peritoneal dialysis. Vaccine 2005;23:3957e60.
D
ONOR organ shortages occasionally necessitate the use of hepatic allografts from donors with antibody positivity for hepatitis B core antigen (HBcAb). However, transplantation of HBcAb-positive (HBcAbþ) livers carries a risk of transmitting hepatitis B virus (HBV) to recipients, with an incidence of 25%e95% [1e7]. Although hepatitis B immunoglobulin (HBIG) and/or nucleotide analogue have been used worldwide to prevent de novo HBV infection in recipients with HBcAbþ liver grafts [1,2,8], life-long administration of HBIG is costly and inconvenient. Once ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 721e725 (2014)
patients acquire active immunization by HBV vaccination, they can maintain their hepatitis B surface antibody (HBsAb)
From the Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan. Address reprint requests to Atsuyoshi Mita, MD, PhD, Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. E-mail: [email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.12.005 721
722
titer for a longer period than after receiving passive immunization, such as HBIG. Active immunization might be a better strategy than the use of HBIG, but previous reports have indicated unsatisfactory vaccination response rates after liver transplantation [9,10]. Recently, good results have been reported for active immunization in pediatric patients with HBcAbþ liver grafts [11,12]. On the other hand, the efficacy of HBV vaccination for HBcAb-negative (HBcAb) adult recipients with HBcAbþ liver grafts still remains unclear, and the rate of acquisition of active immunization is not satisfactory [13]. The aim of the present study was to develop an active immunization protocol and to evaluate its usefulness for preventing de novo HBV infection in adult and pediatric patients undergoing liver transplantation. PATIENTS AND METHODS Between December 1996 and December 2012, liver transplantations were performed for 300 patients at Shinshu University Hospital. Among them, 15 patients obtained liver grafts from HBcAbþ donors. For the purposes of this study, we excluded 5 recipients, 4 of whom had already showed HBcAb positivity at the time of liver transplantation and the remaining 1 was not administered immunosuppressants because of her graft from an identical twin. The remaining 10 patients, comprising 7 adults (age 18 years) and 3 infants, were adopted as the study subjects. Prior to transplantation, all recipients and donors were evaluated for hepatitis B using serological testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), HBcAb, hepatitis B envelope antigen (HBeAg), hepatitis B envelope antibody (HBeAb), and HBV-DNA.
Immunosuppression The immunosuppression protocol for the recipients has been described elsewhere [14]. The initial immunosuppressive regimen consisted of tacrolimus and steroids. Patients who had been rejection-free under a stable tacrolimus-based regimen for 6 months were offered the option of steroid withdrawal.
Post-Transplantation Prophylaxis for HBV Infection The prophylaxis protocol for HBcAb recipients with a HBcAbþ liver graft was initiated with HBIG alone. HBIG was intravenously given at 10,000 IU in the anhepatic period during liver transplantation. Postoperatively, the serum HBsAb titer was maintained at >300 mIU/mL for 1 year, and >100 mIU/mL thereafter by administration of HBIG. Subsequently, we added a subcutaneous injection of recombinant HBV vaccine (Bemmugen INJ[Vial]; Astellas, Tokyo, Japan) with a dose of 20 mg in adult cases and 5 mg in pediatric cases while maintaining HBsAb by HBIG. The timing to start HBV vaccination was dependent on the condition of the patient. The interval of the vaccinations was basically longer than 1 month, and depended on the serum HBsAb titer when introducing the HBV vaccination protocol. The HBV vaccine was initially administered together with intravenous HBIG administration. We defined a positive vaccination response as an increase in the serum HBsAb titer more than expected when administering HBIG alone. Nonresponders needed to continue HBIG administration, maintaining their serum HBsAb level. We did not define an upper limit for the frequency of vaccinations in our protocol. We investigated the success rate of vaccination, the periods of introducing HBV
OHNO, MITA, IKEGAMI ET AL vaccination, the frequency of vaccinations to acquire active immunization, and the factors for successful active immunization.
Statistical Analysis Univariate analysis was performed for categorical variables with the use of the chi-square test. We analyzed continuous variables with a 2-tailed unpaired t test. A P < .05 was considered statistically significant.
RESULTS
Characteristics of the recipients and donors at the first medical examination in our hospital are presented in Tables 1 and 2. The median age of the recipients was 41 (range, 0.5e61) years, and 6 of them were women. The underlying diseases for liver transplantation were biliary atresia in 3 cases, primary biliary cirrhosis in 2, hepatitis C in 2 (both had hepatocellular carcinoma concomitantly), familial amyloid polyneuropathy in 2, and autoimmune hepatitis in 1. Seven cases involved transplantation from living donors (3 parents, 3 siblings, and 1 child), and 3 from deceased donors. The median follow-up period after liver transplantation was 140 (range, 74e193) months. At the initial evaluation for liver transplantation, all recipients were negative for HBsAb. All the recipients were negative for HBsAg, HBcAb, HBeAg, HBeAb, and HBV-DNA. All donors were positive for HBcAb and negative for HBsAg, HBeAg and HBV-DNA. Among 4 recipients who were vaccinated against HBV before transplantation, 3 preoperatively showed a positive serum HBsAb titer with a median of 17.3 (range, 16e227) mIU/mL. At the liver transplantation, HBsAb was positive (>10 mIU/mL) in 3 of 9 patients. Vaccination was postoperatively performed in all 10 recipients. Nine patients acquired active immunity with a median number of 4 vaccinations (range, 2e13; HbsAb >300 mIU/mL for 1 year, or >100 mIU/mL thereafter). Vaccination was started 7.5 (range, 2e29) months after transplantation. In 1 nonresponder who was a 54-year-old woman with primary biliary cirrhosis, vaccination was started 16 months after deceased donor liver transplantation and still continued in the interval between outpatient visits. She was administered prednisolone (5 mg/d), tacrolimus, and mycophenolate mofetil (750 mg/d) at the time of observation. No patients showed a conversion to HBsAgþ or HBV-DNAþ postoperatively without HBIG administration in the median follow-up period of 112 months after they had acquired active immunity. The patients have still maintained the HBsAb level >100 mIU/mL by vaccination once or twice per year. No obvious side effects (fever, exanthema, nausea, diarrhea, anorexia, or headache) were seen in our series. One patient died of liver cirrhosis due to recurrent autoimmune hepatitis 5 years after liver transplantation. In this study, 2 types of response were observed among the patients who acquired active immunity. Four of 9 patients (44%; case 140, 195, 233, and 245) achieved antibody titers >100 mIU/mL within 9 months after induction of
723
þ þ þ þ þ þ þ þ þ þ
vaccination, allowing complete discontinuation of HBIG substitution (fast responders), and none of them had resumed HBIG administration by December 2012. The remaining 5 patients needed more than 18 months to achieve an antibody titer >100 IU/L without HBIG administration (slow responders). The mean age of the fast responders was 11.8 years, which was significantly younger than that of slow responders (42.5 years; P < .05). All of the fast responders received vaccinations before liver transplantation, whereas the slow responders did not (P < .05; Table 3). Abbreviations: FAP, familial amyloid polyneuropathy; HC, hepatitis C; PBC, primary biliary cirrhosis; BA, biliary atresia; AIH, autoimmune hepatitis; ne, not evaluated.
þ þ þ ne þ þ ne ne ne þ þ þ þ þ þ þ þ þ 46 41 61 39 0.8 23 43 2 2.5 54 65 101 116 137 140 167 195 233 245 252
M M M F F F M M F F
FAP FAP HC PBC BA AIH HC BA BA PBC
47 41 33 41 39 42 40 35 37 59
M F F M M M M M F M
Deceased Deceased Daughter Brother Father Deceased Brother Father Mother Deceased
HBeA HBsAb HBsA HBsAb HBsAg Primary Disease Gender Age No
Recipient
HBeAg
HBeAb
HBcAb
Age
Gender
Table 1. Patient and Donor Demographics and HBV Serology
Relationship
Donor
HBeAb
HBcAb
HBV VACCINATION PROTOCOL
DISCUSSION
We successfully prevented de novo HBV infection in HBcAb recipients with a HBcAbþ liver graft by using a prophylactic protocol. Our HBV prophylactic protocol is characterized by how to use vaccination with HBIG. We added vaccination while maintaining HBsAb by HBIG, and repeated vaccination until obtaining a response. De novo HBV infection after liver transplantation has been reported to be associated with donors who have serological markers of past HBV infection (HBcAbþ and HBsAg) [1e6]. Likewise, 3 recipients who received HBcAbþ liver grafts developed de novo HBV infection before the beginning of the prophylaxis protocol for de novo HBV infection at our institute until 1996. Among them, 1 recipient died of liver cirrhosis, and the other 2 have seroconverted to HBsAb positivity and have been well for 17 and 21 years of follow-up, respectively. To resolve this kind of problem, Uemoto et al reported that the use of daily intravenous administration of 10,000 IU HBIG for the first week after liver transplantation, followed by intermittent administration of 10,000 IU HBIG to maintain serum HBsAb at a level >100 mIU/mL, resulted in no patients developing de novo HBV infection [1]. Currently, it is considered acceptable to use liver grafts from HBcAbþ donors for HBcAb recipients when prophylactic protocols to prevent HBV infection are used [8,15,16]. However, these patients require life-long administration of very costly HBIG ($400 per 1000 IU) at intervals depending on their serum HBsAb level. Therefore, development of a simple and inexpensive prophylactic regimen has been required. As an alternative, artificial active immunization (HBV vaccination) is inexpensive and produces a relatively long-term protective response; patients need only a booster vaccination to sustain an adequate level of HBsAb. Because recipients are under immunosuppression following organ transplantation, they usually do not mount adequate immune responses to vaccine in comparison with nonimmunosuppressed individuals. Recently, SanchezFueyo et al [17] and Bienzle et al [18] have reported good results with active immunization after liver transplantation for the patients who underwent transplantation for HBVrelated cirrhosis. With regard to post-transplantation vaccination for pediatric patients receiving HBcAbþ liver
724
OHNO, MITA, IKEGAMI ET AL Table 2. Vaccination in Patients Who Received Grafts From Anti-HBcD Donors
No.
Vaccination Before LT
First Vaccination (mo After LT)
Total No. of Vaccinations
Time for Acquisition of Active Immunization
Titer on Last Visit (mIU/mL)
Follow-Up After LT (mo)
De Novo HBV
65 101 116 137 140 167 195 233 245 252
þ þ þ þ
15 26 29 2 3 2 7 8 6 16
2 9 7 2 3 13 6 4 2 13
29 84 41 18 9 16 14 12 13 e
406 632 551 376 927 2951 528 981 6345 145
193 166 157 147 145 61 119 89 80 74
Abbreviation: LT, liver transplantation.
grafts, Chang et al reported that young children successfully acquired active immunization, thus protecting them from de novo HBV infection [11]. They maintained an HBsAb titer of >20 mIU/mL, and 1 nonresponder developed de novo HBV infection in their series of 19 recipients. The median follow-up, however, was only 10 months, and thus a longer follow-up would be needed to validate the results because de novo HBV can occur beyond this time frame. Lin et al have reported that active immunization is effective for protecting young children receiving HBcAbþ liver grafts from de novo HBV infection by maintaining the HBsAb titer at levels >1000 mIU/mL [12]. Among 30 recipients, 1 whose HBsAb titers were >100 mIU/mL but 300 mIU/mL for 1 year and >100 mIU/mL thereafter. We considered that the patients had acquired active immunization when the serum HBsAb level reached our target level without administration of HBIG. Patients who underwent vaccination prior to transplantation acquired active immunity earlier than the patients who did not in our series. As Kwon et al suggested [20], pretransplantation vaccination can be important because it may influence the post-transplantation vaccine response, regardless of pretransplantation serological status or response. In living donor liver transplantation, information about donor HBV-related serology is obtained earlier than for deceased donor liver transplantation. Therefore, pretransplantation HBV vaccination is recommended when the living donor candidate is HBcAbþ. Although the incidence of HBV mutation after HBV vaccination to prevent de novo HBV infection is uncertain, it might be lower than for the regimen of HBIG used in other centers. We believe that the benefits of HBV vaccination for prophylaxis of de novo hepatitis overcome its potential side effects. With regard to recipient age, we found that younger patients had significantly better responses to HBV vaccination after liver transplantation. Similar observations have been
HBV VACCINATION PROTOCOL
reported in a transplant setting [13], in patients on hemodialysis [21,22], and in health care workers [19]. In conclusion, we successfully prevented de novo HBV infection in HBcAb recipients with a HBcAbþ liver graft by acquiring active immunization using a HBV vaccination protocol. Our protocol provides a new effective strategy for prevention of de novo HBV infection after liver transplantation in recipients with HBcAbþ liver grafts. Pretransplantation HBV vaccination was helpful for the post-transplantation vaccine response. REFERENCES [1] Uemoto S, Sugiyama K, Marusawa H, Inomata Y, Asonuma K, Egawa H, et al. Transmission of hepatitis B virus from hepatitis B core antibody- positive donors in living related liver transplants. Transplantation 1998;65:494e9. [2] Dodson SF, Issa S, Araya V, Gayowski T, Pinna A, Eghesad B, et al. Infectivity of hepatic allografts with antibodies to hepatitis B virus. Transplantation 1997;64:1582e4. [3] Dickson RC, Everhart JE, Lake JR, Yuling W, Seaberg E, Wiesner R, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. Gastroenterology 1997;113:1668e74. [4] Wachs ME, Amend WJ, Ascher NL, et al. The risk of transmission of hepatitis B from HBsAg(-), HBcAbþ, HBIgM(-) organ donors. Transplantation 1995;59:230e4. [5] Prieto M, Gomez MD, Berenguer M, Cordoba J, Rayon JM, Pastor M, et al. De novo hepatitis B after liver transplantation from hepatitis B core antibody-positive donors in an area with high prevalence of anti-HBc positivity in the donor population. Liver Transpl 2001;7:51e8. [6] Manzarbeitia C, Reich D, Oritz J, Rothstein K, Araya V, Munoz SJ, et al. Safe use of liver donors with positive hepatitis B core antibody. Liver Transpl 2002;8:556e61. [7] Douglas DD, Rakela J, Wright TL, Krow RA, Wiesner RH. The clinical course of transplantation-associated de novo hepatitis B infection in the liver transplant recipient. Liver Transpl Surg 1997;3:105e11. [8] Holt D, Thomas R, Van Thiel D, Brems JJ. Use of hepatitis B core antibody-positive donors in orthotopic liver transplantation. Arch Surg 2002;137:572e5. [9] Angelico M, Di Paolo D, Trinito MO, Petrolati A, Araco A, Zazza S, et al. Failure of a reinforced triple course of hepatitis B vaccination in patients transplanted for HBV-related cirrhosis. Hepatology 2002;35:176e81.
725 [10] Loinaz C, de Juanes JR, Gonzalez EM, Lopez A, Lumbreras C, Gomez R, et al. Hepatitis B vaccination results in 140 liver transplant recipients. Hepatogastroenterology 1997;44:235e8. [11] Chang SH, Suh KS, Yi NJ, Choi SH, Lee HJ, Seo JK, et al. Active immunization against de novo hepatitis B virus infection in pediatric patients after liver transplantation. Hepatology 2003;37: 1329e34. [12] Lin CC, Chen CL, Concejero A, Wang CC, Wang SH, Lie YW, et al. Active immunization to prevent de novo hepatitis B virus infection in pediatric live donor liver recipients. Am J Transplant 2007;7:195e200. [13] Soejima Y, Ikegami T, Taketomi A, Yoshizumi T, Uchiyama H, Harada N, et al. Hepatitis B vaccination after living donor liver transplantation. Liver Int 2007;27:977e82. [14] Hashikura Y, Kawasaki S, Matsunami H, Terada M, Ikegami T, Nakazawa Y, et al. Immunosuppressant switching between cyclosporine and tacrolimus after liver transplantation. Transplant Proc 1996;28:1034e5. [15] Dodson SF, Bonham CA, Geller DA, Cacciarelli TV, Rakela J, Fung JJ. Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors. Transplantation 1999;68:1058e61. [16] Chung RT, Feng S, Delmonico FL. Approach to the management of allograft recipients following the detection of hepatitis B virus in the prospective organ donor. Am J Transplant 2001;1:185e91. [17] Sanchez-Fueyo A, Rimola A, Grande L, Costa J, Mas A, Navasa M, et al. Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination: a new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation. Hepatology 2000;31:496e501. [18] Bienzle U, Gunther M, Neuhaus R, Neuhaus P. Successful hepatitis B vaccination in patients who underwent transplantation for hepatitis B virus-related cirrhosis: preliminary results. Liver Transpl 2002;8:562e4. [19] Wood RC, MacDonald KL, White KE, Hedberg CW, Hanson M, Osterholm MT. Risk factors for lack of detectable antibody following hepatitis B vaccination of Minnesota healthcare workers. JAMA 1993;270:2935e9. [20] Kwon CHD, Suh K-S, Yi N-J, Chang SH, Cho YB, Cho JY, et al. Long-term protection against hepatitis B in pediatric liver recipients can be achieved effectively with vaccination after transplantation. Pediatr Transplant 2006;10:479e86. [21] DaRoza G, Loewen A, Djurdjev O, Love J, Kempston C, Burnett S, et al. Stage of chronic kidney disease predicts seroconversion after hepatitis B immunization: earlier is better. Am J Kidney Dis 2003;42:1184e92. [22] Liu YL, Kao MT, Huang CC. A comparison of responsiveness to hepatitis B vaccination in patients on hemodialysis and peritoneal dialysis. Vaccine 2005;23:3957e60.
