Donor organ shortages occasionally mandate the

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1 Active Immunization Against De Novo Hepatitis B Virus Infection in Pediatric Patients After Liver Transplantation Seong-Hwan Chang, 1 Kyung-Suk Suh, 1 Nam-Joon Yi, 1 Seok Ho Choi, 1 Hoan Jong Lee, 2 Jeong Kee Seo, 2 and Kuhn Uk Lee 1 The shortage of donor organs occasionally mandates the use of hepatic allografts from anti-hbc ( ) donors. HBIG and/or lamivudine are recommended for the prevention of de novo HBV infection in naive patients, but there are attendant problems, such as mutant strain emergence and high cost. Active immunization presents a better alternative than the use of HBIG or lamivudine, if it can be proven to be effective. Accordingly, we investigated the outcome of HBV vaccination in pediatric hepatic transplant recipients. Between July 1999 and October 2001, 19 pediatric recipients were administered HBV vaccinations after liver transplantation at Seoul National University Hospital. Nine patients received a graft from anti-hbc ( ) donors and 10 from anti-hbc ( ) donors. When steroid was withdrawn, recombinant HBV vaccine was administered. The median follow-up period after vaccination was months. Seventeen of the 19 patients showed a positive response to vaccination. In 9 patients who received grafts from anti-hbc ( ) donors, 2 patients showed no response, 4 patients low response (peak HBsAb titer <1,000 IU/L), and 3 patients high response (peak HBsAb titer >1,000 IU/L). De novo HBV infection developed in 1 of 2 patients who showed no response to vaccination. In 10 patients who received grafts from anti-hbc ( ) donors, 5 showed a low response and 5 a high response. In conclusion, HBV vaccination in pediatric patients after liver transplantation appeared to exhibit some effectiveness at protecting young children that received a graft from anti-hbc ( ) donors from de novo HBV infection. (HEPATOLOGY 2003;37: ) Donor organ shortages occasionally mandate the use of hepatic allografts from antibody to hepatitis B core antigen (anti-hbc) ( ) donors. The transplantation of anti-hbc ( ) livers carries a 25% to 95% risk of transmitting hepatitis B virus (HBV) to recipients, 1-6 although some of these studies showed lower rates of HBV infection in recipients who are anti-hbc/ Abbreviations: anti-hbc, antibody to hepatitis B core antigen; HBV, hepatitis B virus; anti-hbs, antibody to hepatitis B surface antigen; HBIG, hepatitis B immunoglobulin; HBsAb, hepatitis B surface antibody; UNOS, United Network for Organ Sharing; HBsAg, hepatitis B surface antigen. From the 1 Department of Surgery and 2 Department of Pediatrics, Seoul National University College of Medicine, Seoul; and Clinical Research Institute, Seoul National University Hospital, Seoul, Korea. Received October 24, 2002; accepted March 13, Supported by the Clinical Research Institute, Seoul National University Hospital, Seoul, Korea. Address reprint requests to: Kyung-Suk Suh, M.D., Department of Surgery, Seoul National University College of Medicine, 28 Yongon-Dong, Chongro-Gu, Seoul , Korea. kssuh@plaza.snu.ac.kr; fax: (82) Copyright 2003 by the American Association for the Study of Liver Diseases /03/ $30.00/0 doi: /jhep anti-hbs (antibody to hepatitis B surface antigen) positive. 2,3,5,6 Several reports have recommended that some forms of prophylaxis should be undertaken to prevent de novo hepatitis B infection in recipients who received a graft from anti-hbc ( ) donors. 1,7-9 Hepatitis B immunoglobulin (HBIG) and/or lamivudine have been used for prophylaxis, but their life-long administration presents problems, such as a mutant strain emergence, high cost, and several side effects. Thus, active immunization is a better strategy than HBIG or lamivudine, if it is effective. Reports issued to date on the active immunization of patients waiting for liver transplantation and who have undergone liver transplantation have not been satisfactory. 13,14 A poor response rate with vaccination and rapid decline in serum hepatitis B surface antibody (HBsAb) titer have been reported. 14 Recently, good results have been reported for the active immunization of selected patients after liver transplantation. 15,16 Thus, we undertook this study to elucidate whether posttransplantation HBV vaccination is effective in the prophylaxis of de novo HBV infection in pediatric 1329

2 1330 CHANG ET AL. HEPATOLOGY, June 2003 liver transplant recipients who have received a graft from anti-hbc ( ) donors. Patients and Methods Between October 1999 and May 2001, 19 pediatric patients received HBV vaccinations after liver transplantation at the Seoul National University Hospital. The patients included 9 boys and 10 girls of mean age (11 months to 9 years). The original diseases of the recipients included biliary atresia (16), inflammatory pseudotumor (1), neonatal hepatitis (1), and hepatoblastoma (1). All cases involved living donor liver transplant. Nine patients received liver grafts from anti-hbc ( ) donors, and 10 patients received liver grafts from anti- HBc ( ) donors. Immunosuppression was performed with FK 506 and steroid. The prophylaxis protocol used in patients who received a graft from anti-hbc ( ) donors was 100 IU/kg of HBIG injected intravenous and intraoperatively, and this was repeated daily for 3 days after transplantation. Subsequently the serum HBsAb titer was checked and maintained above 20 IU/L by HBIG injection. No prophylaxis was administered to patients who received liver from an anti-hbc ( ) donor, although prophylaxis was performed in 1 anti-hbc ( ) patient. From this patient (liver transplantation was performed in December 2000), prophylaxis was performed as normally for patients who are anti-hbc ( ). When steroid was withdrawn ( months postoperatively) from the 19 patients, HBV vaccination was administered weeks after discontinuing HBIG. The HBV vaccination protocol involved an intramuscular injection of recombinant HBV vaccine (HEPAVAX-GENE INJ[Vial] 10 g/ 0.5 ml; Yongin-si, Kyunggi-do, Korea or EUVAX B INJ[Vial] 10 g/0.5 ml; Seoul, Korea). Sequential injections were administered based on the monitored results of serum HBsAb titer. The dosage (0.5 ml or 1 ml) and interval (1 week or 1 month) of the vaccinations were determined according to the serum HBsAb titer. The median follow-up period after liver transplantation was (12-33) months, and the median follow-up period after the starting vaccination was (3-18) months. Nineteen patients all had received HBV vaccination after birth according to the routine newborn immunization program for HBV infection before this study. Anti-HBs was positive in 13 of 19 patients before liver transplantation and negative in 6 of 19 patients after vaccination. We defined a positive response as an increase in the serum HBsAb titer or its maintenance above 20 IU/L after vaccination. Nonresponders resumed HBIG. We divided the subjects into 2 groups according to the donors anti-hbc status and compared the results of vaccination. No differences between the 2 groups were observed in terms of sex ratio, mean age, preoperative United Network for Organ Status (UNOS) status, ABO cross match, preoperative donor HBsAb status, or preoperative recipient anti-hbc or HBsAb status. Characteristics of the patients are described in Table 1. Results Table 1. Characteristics of Patients Anti-HBc ( ) Donor Group Anti-HBc ( ) Sex ratio (M:F) 5:4 6:4 Mean age (y) Preoperative UNOS status 2B ABO match Identical 6 8 Compatible 3 2 Donors HBsAb ( : ) 1:8 2:8 Preoperative recipients Anti-HBc ( : ) 4:5 5:5 HBsAb ( : ) 4:5 2:8 In 9 patients who received grafts from anti-hbc ( ) donors (Table 2), 7 patients (77.8%) showed a positive response to vaccination. Three (75%) of the 4 anti-hbs ( ) patients preoperatively and 4 (80%) of the 5 anti- HBs ( ) patients preoperatively showed positive response. Among these patients who received grafts from anti-hbc ( ) donors, 2 patients had no response (Fig. 1), 4 patients low response (Fig. 2, peak serum HBsAb titer 1,000 IU/L), and 3 patients high response (Fig. 3, peak serum HBsAb titer 1,000 IU/L). De novo hepatitis B infection developed in 1 (11.1%, anti-hbs ( ) preoperatively) of the 9 patients, and this patient was 1 of the 2 patients who showed no response. In this particular patient, the serum HBsAb titer was not maintained well by HBIG before vaccination, and, when vaccination was started, there was no response. This patient resumed HBIG after no response to vaccination. Hepatitis B surface antigen (HBsAg) was found to be positive after the second HBIG injection, which was at 23 months postoperatively. But this patient showed no abnormal serum liver function test results, up to the time of writing. In 10 patients who received a graft from anti-hbc ( ) donors (Table 3), all patients responded positively; 5 patients showed a low response (Fig. 4) and 5 a high response (Fig. 5). No statistical difference in terms of the response to vaccination was found between the 2 groups. Overall, 17 (89.5%) of the 19 transplant patients showed a positive response, and 2 showed no response. Nine of the 17 positive responders showed a low response and 8 a high response. Anti-HBs was positive in 13 of the

3 HEPATOLOGY, Vol. 37, No. 6, 2003 CHANG ET AL Table 2. in Patients Who Received a Graft From Anti-HBc ( ) Donors No. Age Sex Preoperative HBsAb Status Peak Titer After HBIG Time of After Last HBIG (wk) Titer Before Total No. Peak Titer After Titer on Last Visit F/U After F/U After Last 1 1 F Negative 1, , F Positive F Negative 1, M Negative F Positive 7, M Negative ,000* M Positive 1, M Positive 2, , M Positive 1, *After second vaccination schedule. After HBIG. 19 patients before liver transplantation. Twelve (7 with low response and 5 with high response) of the 13 anti- HBs positive recipients responded to vaccination after liver transplantation, and 5 (2 with low response and 3 with high response) of the 6 anti-hbs negative recipients responded to vaccination. No statistical differences among the 3 groups were observed in terms of sex ratio, mean age, ABO cross match, donor anti-hbc and HBsAb status, preoperative recipient anti-hbc and HBsAb status, vaccination method, rejection or no rejection, and HBIG administration or not. There were no complications after vaccination. Three patients of the 17 positive responders responded to vaccination during the second vaccination course. For 1 patient (diamond in Fig. 3), the vaccine was changed from HEPAVAX-GENE INJ to EUVAX B INJ, which is a recombinant vaccine from a different company. Another patient (circle in Fig. 3) had his dose increased from single to double. The last patient (circle in Fig. 5) had his vaccination frequency changed from monthly to weekly. All of these 3 patients were high responders. Additional vaccinations were needed in 4 patients after an initial positive response, namely, patient 2 (circle in Fig. 2) and patient 8 (diamond in Fig. 3) in Table 2 and patient 2 (diamond in Fig. 4) and patient 8 (circle in Fig. 4) in Table 3. The intervals between the first successful vaccination and the additional vaccination were 10.5, 6.5, 8.5, and 5 months, respectively. Discussion Several reports have recommended that some form of prophylaxis should be administered to prevent de novo Fig. 1. Two no responders in the anti-hbc ( ) donor group. De novo hepatitis B infection developed in 1 patient ({) who received a graft from an anti-hbc ( ) donor. In this particular patient, the serum HBsAb titer was not maintained well by HBIG before vaccination, and when vaccination was started, there was no response. This patient resumed HBIG after no response to vaccination. HBsAg was found to be positive after the second HBIG injection. One patient (E) also did not respond to vaccination and resumed HBIG after no response to vaccination. Fig. 2. Four low responders in the anti-hbc ( ) donor group. Three patients had peak serum HBsAb titers of around 500 IU/L after the vaccination, and additional vaccination was needed in 1 patient (E). One patient s ( ) serum HBsAb titer increased to 76 IU/L, but no additional vaccination was required.

4 1332 CHANG ET AL. HEPATOLOGY, June 2003 Fig. 3. Three high responders in the anti-hbc ( ) donor group. Peak serum HBsAb titers were at around 1,000 to 2,000 IU/L. Two patients (E and {) responded to vaccination during the second vaccination course, and additional vaccination was needed in 1 patient ({). hepatitis B infection in the recipients who have the liver graft of an anti-hbc ( ) donor. 1,7-9 However, it is not clear whether such prophylaxis should be administered to all recipients. Furthermore, there is no consensus about the type (i.e., HBIG alone, HBIG plus lamivudine, or lamivudine alone), dosage, or duration of such a prophylaxis regimen. Uemoto et al. reported that HBIG doses of 10,000 IU/d were administered intravenously for the first week (started intraoperatively during the anhepatic phase) and that these were followed by 10,000 IU intermittently, with the aim of maintaining the serum HBsAb level at greater than 100 IU/L. 1 Dodson et al. reported that recipients who were anti-hbs negative, HBsAg negative, and had a liver graft from an anti-hbc ( ) donor received HBIG 10,000 IU intravenously daily for 7 days and then monthly for 6 months. After 6 months, 1,000 IU of HBIG was given intramuscularly every 2 weeks for 18 months. 7 Holt et al. reported that recipients received Fig. 4. Five low responders in the anti-hbc ( ) donor group. Three patients had peak serum HBsAb titers of around 200 to 300 IU/L. Two patients had peak serum HBsAb titers of below 100 IU/L. Additional vaccinations after a positive response were needed in 2 patients (E and {). One patient ({) needed additional vaccination. 10,000 U/d of intravenous HBIG for 7 days. In addition, they administered 300 mg/d of lamivudine in divided doses. 8 The protective anti-hbs titer is known to be 10 IU/L for protection from hepatitis B virus infection in the general population. However, in cases of immunosuppression, there have been no guidelines until now. We decided to maintain anti-hbs titer above 20 IU/L, and, during HBIG prophylaxis, no de novo HBV infection developed. Prophylaxis was performed in 1 patient who was anti- HBc ( ). In general, for anti-hbc ( ) recipients, low frequencies of HBV reactivation (0% to 13%) have been reported. 2,3,5,6 Therefore, we recommended HBV prophylaxis from December 2000 for patients who were anti- HBc ( ) even though the donor was anti-hbc ( ). However, the long-term use of these strategies has problems. Prophylaxis of de novo HBV infection in pa- Table 3. in Patients Who Received a Graft From Anti-HBc ( ) Donors No. Age Sex Preoperative HBsAb Status Peak Titer After HBIG Titer Before Total No. Peak Titer After Titer on Last Visit F/U After F/U After 1 2 F Positive ,300 1, M Negative F Positive Not checked F Positive 2, , M Positive ,300* F Positive 5 1 3, M Positive F Positive M Negative F Positive , *After second vaccination schedule.

5 HEPATOLOGY, Vol. 37, No. 6, 2003 CHANG ET AL Fig. 5. Five high responders in the anti-hbc ( ) donor group. Their peak serum HBsAb titers were between 1,000 and 5,000 IU/L. One patient (E) responded to vaccination during the second vaccination course. However, there was no need for additional vaccination. tients who have received a graft from an anti-hbc ( ) donor was achieved by administering HBIG derived from HBsAg-vaccinated subjects. Anti-HBs-mediated immune pressure on HBV, however, seems to be associated with the emergence and/or the selection of immune escape HBV mutants that enable viral persistence in spite of adequate antibody titers Lamivudine offers a major breakthrough in the care of patients with hepatitis B. However, the development of resistance to lamivudine is being increasingly recognized for prolonged monotherapy, and this limits the long-term efficacy of this nucleoside analogue As mentioned above, prophylaxis using HBIG and/or lamivudine in the prevention of de novo hepatitis B infection after liver transplantation with allografts from anti- HBc ( ) donors is not only cumbersome but it is also very expensive, and it is not free of potential adverse events. Especially in children, life-long preventive treatment should be easier, more effective, and cheaper. In Korea, which is in an area with a high prevalence of anti-hbc positivity in the donor population, we need a protocol to prevent de novo hepatitis B infection after liver transplantation involving allografts from anti-hbc ( ) donors. Active immunization presents a much simpler and cheaper alternative, if it is effective. To the present, studies on the active immunization to patients who are waiting for liver transplantation and who have undergone liver transplantation have not been satisfactory. 13,14 A poor response rate with vaccination and a rapid decline in the serum HBsAb titer 14 has been reported. A routine newborn immunization program for HBV infection is underway in Korea. All patients enrolled in this study received recombinant HBV vaccines after birth. Anti-HBs was positive in 13 of the 19 patients before liver transplantation and negative in 6 of the 19 patients after vaccination. It is controversial whether the preoperative presence of HBsAb in recipients may be a protective factor against HBV reactivation after liver transplantation with anti-hbc ( ) livers. Although 3 series have shown no HBV reactivation in HBsAb positive recipients who received liver from anti-hbc ( ) donors, 2,5,6 Chen et al. reported that HBV reactivation apparently developed in 1 of 3 HBsAb positive recipients who received a liver from anti-hbc ( ) donors, 23 and we know that serum anti- HBs titer cannot be maintained above the protective level to prevent HBV reactivation after transplantation. Recently, a number of studies have reported good results for the active immunization of selected patients after liver transplantation. Sanchez-Fueyo et al. 15 described a vaccination protocol that involved the administration of a double dose of recombinant HBV vaccine at 0, 1, and 6 months. The median time to the start of the vaccination protocol was 30 months (18-76 months) after transplantation and 1 to 4 weeks after the last dose of HBIG. Moreover, Bienzle et al. 16 reported a vaccination protocol that involved the administration of a single-dose recombinant HBV vaccine with a new adjuvant, AS02, at 0, 2, 4, 16, and 18 weeks. The time for starting the vaccination was 2 to 10 years after transplantation, and, if antibody titers exceeded 500 IU/L, HBIG substitution was discontinued. Titers were always determined before HBIG administration, and vaccination was performed at least 2 days before HBIG administration. The patients in these reports were recipients who underwent transplantation for hepatitis B virus-related cirrhosis. In the present study, we examined hepatitis B vaccination in pediatric recipients as a potentially new strategy for the prevention of de novo hepatitis B infection after liver transplantation in pediatric recipients with allografts from anti-hbc ( ) donors and achieved an antibody response in 7 of 9 such patients. Our prophylaxis protocol in pediatric patients who received a graft from anti-hbc ( ) donors involved the sequential injection of recombinant HBV vaccine. The dosage and vaccination interval was determined according to the serum HBsAb titer. Subsequently, the serum HBsAb titer was checked and maintained above 20 IU/L by additional vaccination. In the present study, vaccination was performed after steroid withdrawal because immunosuppressive therapy may have reduced the response to hepatitis B vaccination. Moreover, we vaccinated some period after discontinuing HBIG because we consider that concomitant HBIG and hepatitis B vaccination might reduce the response to the hepatitis B vaccination.

6 1334 CHANG ET AL. HEPATOLOGY, June 2003 We did categorize responders as low or high according to an anti-hbs titer of 1,000 IU/L, to examine different factors associated with patient response to vaccination. However, we were unable to identify factors that contributed to response to vaccination. In 9 of 17 responders, antibody responses were above 1,000 IU/L, 3 of the 17 patients responded to a second vaccination course, and 4 of the 17 patients needed additional vaccinations to increase the serum HBsAb titer. Because many different responses to different vaccination protocols were observed, data from larger trials using different vaccination schedules over a longer observation period are needed to determine adequate vaccine doses and the timing of booster injections. In conclusion, vaccination could provide a new effective strategy for the prevention of de novo hepatitis B infection after liver transplantation in pediatric recipients who receive allografts from anti-hbc ( ) donors. 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