Pediatr Transplantation 2015: 19: 267–272
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12432
De novo hepatitis B virus infection after pediatric liver transplantations with hepatitis B core antibody-positive donors: A single-center 20-yr experience Lee YJ, Oh SH, Kim KM, Song SM, Namgoong J-M, Kim DY, Lee S-G. (2015) De novo hepatitis B virus infection after pediatric liver transplantations with hepatitis B core antibody-positive donors: A single-center 20-yr experience. Pediatr Transplant, 19: 267–272. DOI: 10.1111/petr.12432. Abstract: DNHB is common in countries with high prevalence of hepatitis B, and therefore, contracting hepatitis B after LT with HBcAb+ grafts is a major concern. We studied DNHB in 247 children (aged 200 mIU/mL) to HBsAg prior to LT can prevent DNHB development (20). However, our study did not confirm a significant protective effect of pretransplant recipient HBsAb >120 mIU/mL. In our institution, the HBsAb titer was reported at up to 120 mIU/mL until 270
2003; therefore, we could not fully evaluate the effect of the HBsAb titer in the present study. Some studies have suggested that active immunization can prevent DNHB in pediatric LT recipients (21–23). Currently, we regularly monitor the HBsAb titer in recipients and if it falls below 100 mIU/mL, a single booster vaccination is given. An active immunization strategy might be another option for preventing DNHB development from HBcAb liver grafts. However, more research is required, specifically, a well-designed multicenter, large cohort study. Long-term use of LAM effectively prevented development of DNHB in our study. However, development of resistance was one of the concerns. Four of 13 (30.8%) DNHB patients experienced drug resistance. In four LAM-resistant patients, the cumulative duration of drug usage for both prophylaxis and treatment was 62– 156 months. All four patients who experienced LAM resistance had the rtM204I mutation and three also had the rtM204V and rtL180M mutations. In both adults and children, a high rate of viral resistance over time has been reported: 23% in year 1 and 65% in year 5 (24). Mutations in the YMDD motif of the HBV polymerase gene frequently occur. One US LT center used adefovir in adult recipients as prophylaxis and reported that it effectively prevented HBV replication in the recipients (14). However, the study consisted of only 16 adult patients, and the follow-up duration was only 1.8 yr. Recently, another study reported that adefovir prophylaxis had a higher rate of DNHB than LAM prophylaxis (15% and 8%, respectively) (13). The number of patients in each group was only 33 and 62, and
HBV infection after pediatric LT
the differences did not reach statistical significance. Thus, the suitability of the prophylactic use of high-genetic barrier drugs such as adefovir, ETV, and tenofovir is still inconclusive and many concerns remain. There are also concerns about the risk of developing stronger viral resistant strains, high cost, and drug safety in children. Until now, the treatment of chronic hepatitis B in children has been limited to LAM and interferon-a. In March 2014, the US FDA approved ETV for children aged ≥2 yr. Adefovir and telbivudine have been approved for the treatment of chronic HBV infection only in patients aged over 12 and 16 yr. Tenofovir disoproxil fumarate has not yet been approved for the treatment of chronic HBV infection in children and adolescents. In our study, the use of short-term HBIG was ineffective at preventing long-term DNHB development. These data were similar to previous studies (7, 8); however, it remains unclear whether HBIG was totally ineffective against DNHB. There is still a lack of data surrounding the efficacy of HBIG, and therefore, further studies are required. There are a few reports in the pediatric field about HBcAb+ graft LT. The treatment strategy generally follows adult study guidelines (8, 9). However, children are distinct from adults, with a longer life expectancy and greater exposure to various infections, such as herpes simplex virus, enteroviruses, and cytomegalovirus. It is better to prevent the occurrence of DNHB using prophylaxis than to treat DNHB after infection. However, because of the longer life expectancy of children, the length of prophylactic treatment is a major concern. There were several limitations to our study. The small number of patients meant that the study did not have much statistical power. In the early period, the HBsAb titer was not fully quantified. Therefore, we could not fully and quantitatively analyze the effect of the host HBsAb titer on DNHB development. In Cox regression analysis, other variables such as the effect of HBV vaccination or immunosuppressants were not included. In conclusion, our long-term follow-up study revealed a 19.7% incidence of DNHB in recipients who received HBcAb+ grafts (13 of 66 recipients) compared with 0.6% in recipients who received HBcAb– grafts (one of 166 recipients). The overall incidence of DNHB in recipients who received HBcAb+ grafts with or without LAM prophylaxis was 10.8% (four of 37 recipients) and 31.0% (nine of 29 recipients), respectively. LAM prophylaxis in LT recipients of HBcAb+ grafts
was effective in preventing DNHB. However, the long-term effect of LAM prophylaxis resulted in a high incidence of drug resistance. Further research and discussion are needed to build a consensus on the optimal duration of LAM prophylaxis or optimal alternative treatment. Conflicts of interest None of the authors have any conflict of interest to declare and take full responsibility for the manuscript.
Authors’ contributions Lee YJ and Kim KM: Designed this study; Lee YJ, Oh SH, Song SM, and Namgung GM: Collected the data; Lee YJ and Kim KM: Analyzed the data; Kim KM and Kim DY: Revised the manuscript critically for important intellectual content.
References 1. WACHS ME, AMEND WJ, ASCHER NL, et al. The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors. Transplantation 1995: 59: 230–234. 2. ROCHE B, SAMUEL D, GIGOU M, et al. De novo and apparent de novo hepatitis B virus infection after liver transplantation. J Hepatol 1997: 26: 517–526. 3. DICKSON RC, EVERHART JE, LAKE JR, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Gastroenterology 1997: 113: 1668–1674. 4. JUNG CW, JANG JY, KIM KM, LEE SG. Detection of hepatitis B virus DNA in liver grafts obtained from HBsAb and HBcAb positive organ donors. Korean J Pediatr Gastroenterol Nutr 2007: 10: 166–172. 5. YU AS, VIERLING JM, COLQUHOUN SD, et al. Transmission of hepatitis B infection from hepatitis B core antibody–positive liver allografts is prevented by lamivudine therapy. Liver Transpl 2001: 7: 513–517. 6. ROQUE-AFONSO AM, FERAY C, SAMUEL D, et al. Antibodies to hepatitis B surface antigen prevent viral reactivation in recipients of liver grafts from anti-HBC positive donors. Gut 2002: 50: 95–99. 7. BROCK GN, MOSTAJABI F, FERGUSON N, et al. Prophylaxis against denovo hepatitis B for liver transplantation utilizing hep B core (+) donors: Does hepatitis B immunoglobulin provide a survival advantage? Transpl Int 2011: 24: 570–581. 8. SAAB S, WATERMAN B, CHI AC, TONG MJ. Comparison of different immunoprophylaxis regimens after liver transplantation with hepatitis B core antibody-positive donors: A systematic review. Liver Transpl 2010: 16: 300–307. 9. PERRILLO R. Hepatitis B virus prevention strategies for antibody to hepatitis B core antigen-positive liver donation: A survey of North American, European, and Asian-Pacific transplant programs. Liver Transpl 2009: 15: 223–232. 10. YU L, KOEPSELL T, MANHART L, IOANNOU G. Survival after orthotopic liver transplantation: The impact of antibody against hepatitis B core antigen in the donor. Liver Transpl 2009: 15: 1343–1350. 11. DE VILLA VH, CHEN YS, CHEN CL. Hepatitis B core antibodypositive grafts: Recipient’s risk. Transplantation 2003: 75: S49– S53.
271
Lee et al. 12. BOHORQUEZ HE, COHEN AJ, GIRGRAH N, et al. Liver transplantation in hepatitis B core-negative recipients using livers from hepatitis B core-positive donors: A 13-year experience. Liver Transpl 2013: 19: 611–618. 13. CHANG MS, OLSEN SK, PICHARDO EM, et al. Prevention of de novo hepatitis B in recipients of core antibody-positive livers with lamivudine and other nucleos(t)ides: A 12-year experience. Transplantation 2013: 95: 960–965. 14. CHANG MS, OLSEN SK, PICHARDO EM, et al. Prevention of denovo hepatitis B with adefovir dipivoxil in recipients of liver grafts from hepatitis B core antibody-positive donors. Liver Transpl 2012: 18: 834–838. 15. YEN RD, BONATTI H, MENDEZ J, ARANDA-MICHEL J, SATYANARAYANA R, DICKSON RC. Case report of lamivudine-resistant hepatitis B virus infection post liver transplantation from a hepatitis B core antibody donor. Am J Transplant 2006: 6: 1077–1083. 16. LEONG J, COTY P, FIEL MI, CHANG C, FLORMAN S, SCHIANO T. Lamivudine resistance leading to de novo hepatitis B infection in recipients of hepatitis B core antibody positive liver allografts. Hepatol Res 2014: 44: 1248–1252. 17. FENG S, GOODRICH NP, BRAGG-GRESHAM JL, et al. Characteristics associated with liver graft failure: The concept of a donor risk index. Am J Transplant 2006: 6: 783–790.
272
18. BRAAT AE, BLOK JJ, PUTTER H, et al. The Eurotransplant donor risk index in liver transplantation: ET-DRI. Am J Transplant 2012: 12: 2789–2796. 19. ANGELICO M, NARDI A, MARIANELLI T, et al. Hepatitis B-core antibody positive donors in liver transplantation and their impact on graft survival: Evidence from the Liver Match cohort study. J Hepatol 2013: 58: 715–723. 20. SU WJ, HO MC, NI YH, et al. High-titer antibody to hepatitis B surface antigen before liver transplantation can prevent denovo hepatitis B infection. J Pediatr Gastroenterol Nutr 2009: 48: 203–208. 21. LIN CC, CHEN CL, CONCEJERO A, et al. Active immunization to prevent de novo hepatitis B virus infection in pediatric live donor liver recipients. Am J Transplant 2007: 7: 195–200. 22. KWON CH, SUH KS, YI NJ, et al. Long-term protection against hepatitis B in pediatric liver recipients can be achieved effectively with vaccination after transplantation. Pediatr Transplant 2006: 10: 479–486. 23. PARK JB, KWON CH, LEE KW, et al. Hepatitis B virus vaccine switch program for prevention of de novo hepatitis B virus infection in pediatric patients. Transplant Int 2008: 21: 346–352. 24. LOK AS, LAI CL, LEUNG N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003: 125: 1714–1722.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12432
De novo hepatitis B virus infection after pediatric liver transplantations with hepatitis B core antibody-positive donors: A single-center 20-yr experience Lee YJ, Oh SH, Kim KM, Song SM, Namgoong J-M, Kim DY, Lee S-G. (2015) De novo hepatitis B virus infection after pediatric liver transplantations with hepatitis B core antibody-positive donors: A single-center 20-yr experience. Pediatr Transplant, 19: 267–272. DOI: 10.1111/petr.12432. Abstract: DNHB is common in countries with high prevalence of hepatitis B, and therefore, contracting hepatitis B after LT with HBcAb+ grafts is a major concern. We studied DNHB in 247 children (aged 200 mIU/mL) to HBsAg prior to LT can prevent DNHB development (20). However, our study did not confirm a significant protective effect of pretransplant recipient HBsAb >120 mIU/mL. In our institution, the HBsAb titer was reported at up to 120 mIU/mL until 270
2003; therefore, we could not fully evaluate the effect of the HBsAb titer in the present study. Some studies have suggested that active immunization can prevent DNHB in pediatric LT recipients (21–23). Currently, we regularly monitor the HBsAb titer in recipients and if it falls below 100 mIU/mL, a single booster vaccination is given. An active immunization strategy might be another option for preventing DNHB development from HBcAb liver grafts. However, more research is required, specifically, a well-designed multicenter, large cohort study. Long-term use of LAM effectively prevented development of DNHB in our study. However, development of resistance was one of the concerns. Four of 13 (30.8%) DNHB patients experienced drug resistance. In four LAM-resistant patients, the cumulative duration of drug usage for both prophylaxis and treatment was 62– 156 months. All four patients who experienced LAM resistance had the rtM204I mutation and three also had the rtM204V and rtL180M mutations. In both adults and children, a high rate of viral resistance over time has been reported: 23% in year 1 and 65% in year 5 (24). Mutations in the YMDD motif of the HBV polymerase gene frequently occur. One US LT center used adefovir in adult recipients as prophylaxis and reported that it effectively prevented HBV replication in the recipients (14). However, the study consisted of only 16 adult patients, and the follow-up duration was only 1.8 yr. Recently, another study reported that adefovir prophylaxis had a higher rate of DNHB than LAM prophylaxis (15% and 8%, respectively) (13). The number of patients in each group was only 33 and 62, and
HBV infection after pediatric LT
the differences did not reach statistical significance. Thus, the suitability of the prophylactic use of high-genetic barrier drugs such as adefovir, ETV, and tenofovir is still inconclusive and many concerns remain. There are also concerns about the risk of developing stronger viral resistant strains, high cost, and drug safety in children. Until now, the treatment of chronic hepatitis B in children has been limited to LAM and interferon-a. In March 2014, the US FDA approved ETV for children aged ≥2 yr. Adefovir and telbivudine have been approved for the treatment of chronic HBV infection only in patients aged over 12 and 16 yr. Tenofovir disoproxil fumarate has not yet been approved for the treatment of chronic HBV infection in children and adolescents. In our study, the use of short-term HBIG was ineffective at preventing long-term DNHB development. These data were similar to previous studies (7, 8); however, it remains unclear whether HBIG was totally ineffective against DNHB. There is still a lack of data surrounding the efficacy of HBIG, and therefore, further studies are required. There are a few reports in the pediatric field about HBcAb+ graft LT. The treatment strategy generally follows adult study guidelines (8, 9). However, children are distinct from adults, with a longer life expectancy and greater exposure to various infections, such as herpes simplex virus, enteroviruses, and cytomegalovirus. It is better to prevent the occurrence of DNHB using prophylaxis than to treat DNHB after infection. However, because of the longer life expectancy of children, the length of prophylactic treatment is a major concern. There were several limitations to our study. The small number of patients meant that the study did not have much statistical power. In the early period, the HBsAb titer was not fully quantified. Therefore, we could not fully and quantitatively analyze the effect of the host HBsAb titer on DNHB development. In Cox regression analysis, other variables such as the effect of HBV vaccination or immunosuppressants were not included. In conclusion, our long-term follow-up study revealed a 19.7% incidence of DNHB in recipients who received HBcAb+ grafts (13 of 66 recipients) compared with 0.6% in recipients who received HBcAb– grafts (one of 166 recipients). The overall incidence of DNHB in recipients who received HBcAb+ grafts with or without LAM prophylaxis was 10.8% (four of 37 recipients) and 31.0% (nine of 29 recipients), respectively. LAM prophylaxis in LT recipients of HBcAb+ grafts
was effective in preventing DNHB. However, the long-term effect of LAM prophylaxis resulted in a high incidence of drug resistance. Further research and discussion are needed to build a consensus on the optimal duration of LAM prophylaxis or optimal alternative treatment. Conflicts of interest None of the authors have any conflict of interest to declare and take full responsibility for the manuscript.
Authors’ contributions Lee YJ and Kim KM: Designed this study; Lee YJ, Oh SH, Song SM, and Namgung GM: Collected the data; Lee YJ and Kim KM: Analyzed the data; Kim KM and Kim DY: Revised the manuscript critically for important intellectual content.
References 1. WACHS ME, AMEND WJ, ASCHER NL, et al. The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors. Transplantation 1995: 59: 230–234. 2. ROCHE B, SAMUEL D, GIGOU M, et al. De novo and apparent de novo hepatitis B virus infection after liver transplantation. J Hepatol 1997: 26: 517–526. 3. DICKSON RC, EVERHART JE, LAKE JR, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Gastroenterology 1997: 113: 1668–1674. 4. JUNG CW, JANG JY, KIM KM, LEE SG. Detection of hepatitis B virus DNA in liver grafts obtained from HBsAb and HBcAb positive organ donors. Korean J Pediatr Gastroenterol Nutr 2007: 10: 166–172. 5. YU AS, VIERLING JM, COLQUHOUN SD, et al. Transmission of hepatitis B infection from hepatitis B core antibody–positive liver allografts is prevented by lamivudine therapy. Liver Transpl 2001: 7: 513–517. 6. ROQUE-AFONSO AM, FERAY C, SAMUEL D, et al. Antibodies to hepatitis B surface antigen prevent viral reactivation in recipients of liver grafts from anti-HBC positive donors. Gut 2002: 50: 95–99. 7. BROCK GN, MOSTAJABI F, FERGUSON N, et al. Prophylaxis against denovo hepatitis B for liver transplantation utilizing hep B core (+) donors: Does hepatitis B immunoglobulin provide a survival advantage? Transpl Int 2011: 24: 570–581. 8. SAAB S, WATERMAN B, CHI AC, TONG MJ. Comparison of different immunoprophylaxis regimens after liver transplantation with hepatitis B core antibody-positive donors: A systematic review. Liver Transpl 2010: 16: 300–307. 9. PERRILLO R. Hepatitis B virus prevention strategies for antibody to hepatitis B core antigen-positive liver donation: A survey of North American, European, and Asian-Pacific transplant programs. Liver Transpl 2009: 15: 223–232. 10. YU L, KOEPSELL T, MANHART L, IOANNOU G. Survival after orthotopic liver transplantation: The impact of antibody against hepatitis B core antigen in the donor. Liver Transpl 2009: 15: 1343–1350. 11. DE VILLA VH, CHEN YS, CHEN CL. Hepatitis B core antibodypositive grafts: Recipient’s risk. Transplantation 2003: 75: S49– S53.
271
Lee et al. 12. BOHORQUEZ HE, COHEN AJ, GIRGRAH N, et al. Liver transplantation in hepatitis B core-negative recipients using livers from hepatitis B core-positive donors: A 13-year experience. Liver Transpl 2013: 19: 611–618. 13. CHANG MS, OLSEN SK, PICHARDO EM, et al. Prevention of de novo hepatitis B in recipients of core antibody-positive livers with lamivudine and other nucleos(t)ides: A 12-year experience. Transplantation 2013: 95: 960–965. 14. CHANG MS, OLSEN SK, PICHARDO EM, et al. Prevention of denovo hepatitis B with adefovir dipivoxil in recipients of liver grafts from hepatitis B core antibody-positive donors. Liver Transpl 2012: 18: 834–838. 15. YEN RD, BONATTI H, MENDEZ J, ARANDA-MICHEL J, SATYANARAYANA R, DICKSON RC. Case report of lamivudine-resistant hepatitis B virus infection post liver transplantation from a hepatitis B core antibody donor. Am J Transplant 2006: 6: 1077–1083. 16. LEONG J, COTY P, FIEL MI, CHANG C, FLORMAN S, SCHIANO T. Lamivudine resistance leading to de novo hepatitis B infection in recipients of hepatitis B core antibody positive liver allografts. Hepatol Res 2014: 44: 1248–1252. 17. FENG S, GOODRICH NP, BRAGG-GRESHAM JL, et al. Characteristics associated with liver graft failure: The concept of a donor risk index. Am J Transplant 2006: 6: 783–790.
272
18. BRAAT AE, BLOK JJ, PUTTER H, et al. The Eurotransplant donor risk index in liver transplantation: ET-DRI. Am J Transplant 2012: 12: 2789–2796. 19. ANGELICO M, NARDI A, MARIANELLI T, et al. Hepatitis B-core antibody positive donors in liver transplantation and their impact on graft survival: Evidence from the Liver Match cohort study. J Hepatol 2013: 58: 715–723. 20. SU WJ, HO MC, NI YH, et al. High-titer antibody to hepatitis B surface antigen before liver transplantation can prevent denovo hepatitis B infection. J Pediatr Gastroenterol Nutr 2009: 48: 203–208. 21. LIN CC, CHEN CL, CONCEJERO A, et al. Active immunization to prevent de novo hepatitis B virus infection in pediatric live donor liver recipients. Am J Transplant 2007: 7: 195–200. 22. KWON CH, SUH KS, YI NJ, et al. Long-term protection against hepatitis B in pediatric liver recipients can be achieved effectively with vaccination after transplantation. Pediatr Transplant 2006: 10: 479–486. 23. PARK JB, KWON CH, LEE KW, et al. Hepatitis B virus vaccine switch program for prevention of de novo hepatitis B virus infection in pediatric patients. Transplant Int 2008: 21: 346–352. 24. LOK AS, LAI CL, LEUNG N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003: 125: 1714–1722.
