Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2012)

Liver transplantation for HBV-related cirrhosis in Europe: An ELTR study on evolution and outcomesJournal of HepatologyVol. 58Issue 2PreviewHBV-related chronic liver disease is one of the most common indications for liver transplantation (LT) in Europe. The ELTR database was used to evaluate outcomes and evolution over 20 years (01/1988 and 12/2010). Full-Text PDF Liver transplantation for chronic hepatitis B: An ongoing learning curve over the past 20 yearsBillions of people residing mainly in Africa, Asia, and East European countries have been infected with the hepatitis B virus (HBV) during their lifetime. Migration of large populations from HBV endemic to non-endemic countries has contributed to the increase in the number of patients with chronic hepatitis B (CHB) in the Western hemisphere as well as in Australia. Although the majority have seroconverted and recovered at least serologically, persistent HBV infection still affects ∼400 million individuals worldwide [1World Health Organization Hepatitis B vaccines.Wkly Epidem Rec. 2009; 84: 405-420PubMed Google Scholar, 2Ott J.J. Stevens G.A. Groeger J. Wiersma S.T. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity.Vaccine. 2012; 30: 2212-2219Crossref PubMed Scopus (1317) Google Scholar]. The global epidemiology of HBV is changing rapidly for a number of reasons including improved safety of blood products and most importantly due to highly successful immunization programs which are leading to a massive drop in HBV carrier rates and incidence of hepatocellular carcinoma (HCC). By 2010, 179/193 WHO member countries incorporated HBV vaccination into their national immunization programs. In addition, new and potent anti-viral agents have been very effective in slowing down and controlling progression of chronic hepatitis B (CHB). The results of this worldwide effort are already quite encouraging, as reflected in a reduction of HBV infected candidates for LT [2Ott J.J. Stevens G.A. Groeger J. Wiersma S.T. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity.Vaccine. 2012; 30: 2212-2219Crossref PubMed Scopus (1317) Google Scholar, 3Camci C. Gurakar A. Rose J. et al.Liver transplantation for hepatitis B in the United States.Transplant Proc. 2005; 37: 4350-4353Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 4Kim W.R. Poterucha J.J. Kremers W.K. Ishitani M.B. Dickson E.R. Outcome of liver transplantation for hepatitis B in the United States.Liver transpl. 2004; 10: 968-974Crossref PubMed Scopus (173) Google Scholar]. Yet, it will take a few more decades until the full impact of such prevention programs will reach its peak. Meanwhile, large cohorts of already infected patients have or will develop end stage CHB without or with HCC for which liver transplantation (LT) remains the only life saving solution. Originally until the 1990s, overall HBV graft recurrence after LT in HBsAg+ patients with cirrhosis given no immunoprophylaxis was 67% rising to >80% in HBeAg+ patients [[5]Samuel D. Muller R. Alexander G. et al.Liver transplantation in European patients with the hepatitis B surface antigen.N Engl J Med. 1993; 329: 1842-1847Crossref PubMed Scopus (975) Google Scholar]. Since then and over the past two decades, the pre and post LT management of such patients has improved dramatically as reflected in several reviews and metanalyses [6Shouval D. Samuel D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review.Hepatology. 2000; 32: 1189-1195Crossref PubMed Scopus (232) Google Scholar, 7Chen J. Yi L. Jia J.D. Ma H. You H. Hepatitis B immunoglobulins and/or lamivudine for preventing hepatitis B recurrence after liver transplantation: a systematic review.J Gastroenterol Hepatol. 2010; 25: 872-879Crossref PubMed Scopus (24) Google Scholar, 8Cholongitas E. Goulis J. Akriviadis E. Papatheodoridis G.V. Hepatitis B immunoglobulin and/or nucleos(t)ide analogues for prophylaxis against hepatitis B virus recurrence after liver transplantation: a systematic review.Liver Transpl. 2011; 17: 1176-1190Crossref PubMed Scopus (97) Google Scholar, 9Levstik M. Wong P. Greanya E.D. Yoshida E.M. The role of hepatitis B immunoglobulin in hepatitis B related liver transplantation: Canadian Transplant Centre Position Paper.Ann Hepatol. 2011; 10: 441-444PubMed Google Scholar, 10Laryea M.A. Watt K.D. Immunoprophylaxis against and prevention of recurrent viral hepatitis after liver transplantation.Liver Transpl. 2012; 18: 514-523Crossref PubMed Scopus (25) Google Scholar, 11Fox A.N. Terrault N.A. The option of HBIG-free prophylaxis against recurrent HBV.J Hepatol. 2012; 56: 1189-1197Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar].The changing epidemiology of HBV, the introduction of potent anti-viral agents, the improvement in surgical techniques and medical practices, the rising age of donors as well as the changes in referral rules for LT in Europe and the United States (especially for HCC) justify an updated look back. In the present issue of the Journal, Burra and co-workers took advantage of the very large database of the European Liver Transplant Registry (ELTR) collected for 20 years between January 1988 and December 2010 to evaluate evolution and outcome in 5912 European patients with HBV who underwent LT [[12]Burra P. Germani G. Adam R. et al.Liver transplantation for HBV-related cirrhosis in Europe: a ELTR study on evolution and outcomes.J Hepatol. 2013; 58: 287-296Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. Data obtained in decompensated CHB patients or HBV and HCC registered at the ELTR were compared to data obtained in 3 groups of co-infected patients: HBV with HDV; HBV with HCV, HBV with HDV and HCV and a 4th group of HCV monoinfected patients. Data were stratified into 4 periods of 8, 5, 5, and 5 years apart, starting in 1988.The main results indicate that the majority of HBV patients were transplanted for decompensated CHB (78%) while 22% had HBV and HCC. The proportion of HBV patients with HCC in this large cohort rose from 15.8% in 1988–1995 to 29.6% between 2006 and 2010. Patient and graft survival rates were similar in decompensated CHB patients, ranging from 83% to 80% at one year post LT to 68% and 64% at 10 years post LT, respectively. Patients and graft survival in HBV/HCC patients was 84% and 81% at one year post LT and 61% and 58% at 10 years post LT, respectively. Patient and graft survival improved progressively in both the CHB and the HBV/HCC cohorts over the 20 years of observation. HBV-DNA was undetectable in 71.5% of recipients at time of transplantation but methodology and sensitivity of detection were variable. Patient and graft survival for decompensated CHB as well as for HBV/HCC was better in HBV-DNA negative patients as compared to patients with circulating virus, but an accurate analysis was not possible due to the crude and relatively insensitive technology used in early years to assess viremia. Nevertheless the proportion of HBV-DNA negative recipients at LT dropped from ∼81–82% to ∼51–57% in the past 20 years. Disease recurrence leading to graft failure or death fell significantly in recent years from 3–<1%, respectively. However HCC remains an independent risk factor in LT candidates with HBV. Additional important information includes among others a rising donor age for decompensated CHB and HBV/HCC patients between 2006 and 2010. Slight differences, statistically significant but clinically less important, were observed in the age of decompensated CHB patients and HBV/HCC recipients. As expected, in view of the rising number of HBV/HCC candidates for LT, the rates of LT patients with decompensated CHB in the entire cohort dropped from 84% to 70% while the rates of HBV/HCC patients rose from ∼16% to ∼30% during the last 5 years of the survey. Cox regression analysis identified age >60 years, HBV-DNA positivity at time of transplantation, presence of HCC, transplantation between 1988 and 1995 and use of reduced size grafts as risk factors for graft loss or death.This report summarizes the impressive experience in LT for HBV cirrhosis as well as for HBV and HCC of the European members of the EUROHEP ELTR. Being the last and the largest survey of its kind, it allows to identify and confirm trends and previous observations as reflected in a large number of reviews and reports from Europe and the US, published between the late 1990s and 2012. The present report strengthen and confirms previous data regarding the falling number of CHB and rising number of HBV/HCC candidates for liver transplantation in Europe and the US. It also provides reassurance that LT is after all a viable solution for viremic patients who were excluded from the waiting list until a few years ago. The significant progress in the ability to identify and suppress HBV replication through potent anti-viral agents and the improvement in surgical techniques have all contributed to this remarkable success story and the record drop in HBV graft re-infection post LT.As also stated by the authors, analysis of data was dependant on the pre-agreed upon variables collected in the ELTR database. Consequently (and regretfully), the investigators were unable to analyze important information including pre and post LT monitoring of viral load, ethnic background of patients as well as use of and response to the old and new anti-viral agents, including hepatitis B immune globulin (HBIG) and its route and frequency of administration. Regardless of these reservations, this very large database has again been extremely useful in the quality control of European liver transplant programs.Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Liver transplantation for chronic hepatitis B: An ongoing learning curve over the past 20 years Billions of people residing mainly in Africa, Asia, and East European countries have been infected with the hepatitis B virus (HBV) during their lifetime. Migration of large populations from HBV endemic to non-endemic countries has contributed to the increase in the number of patients with chronic hepatitis B (CHB) in the Western hemisphere as well as in Australia. Although the majority have seroconverted and recovered at least serologically, persistent HBV infection still affects ∼400 million individuals worldwide [1World Health Organization Hepatitis B vaccines.Wkly Epidem Rec. 2009; 84: 405-420PubMed Google Scholar, 2Ott J.J. Stevens G.A. Groeger J. Wiersma S.T. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity.Vaccine. 2012; 30: 2212-2219Crossref PubMed Scopus (1317) Google Scholar]. The global epidemiology of HBV is changing rapidly for a number of reasons including improved safety of blood products and most importantly due to highly successful immunization programs which are leading to a massive drop in HBV carrier rates and incidence of hepatocellular carcinoma (HCC). By 2010, 179/193 WHO member countries incorporated HBV vaccination into their national immunization programs. In addition, new and potent anti-viral agents have been very effective in slowing down and controlling progression of chronic hepatitis B (CHB). The results of this worldwide effort are already quite encouraging, as reflected in a reduction of HBV infected candidates for LT [2Ott J.J. Stevens G.A. Groeger J. Wiersma S.T. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity.Vaccine. 2012; 30: 2212-2219Crossref PubMed Scopus (1317) Google Scholar, 3Camci C. Gurakar A. Rose J. et al.Liver transplantation for hepatitis B in the United States.Transplant Proc. 2005; 37: 4350-4353Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 4Kim W.R. Poterucha J.J. Kremers W.K. Ishitani M.B. Dickson E.R. Outcome of liver transplantation for hepatitis B in the United States.Liver transpl. 2004; 10: 968-974Crossref PubMed Scopus (173) Google Scholar]. Yet, it will take a few more decades until the full impact of such prevention programs will reach its peak. Meanwhile, large cohorts of already infected patients have or will develop end stage CHB without or with HCC for which liver transplantation (LT) remains the only life saving solution. Originally until the 1990s, overall HBV graft recurrence after LT in HBsAg+ patients with cirrhosis given no immunoprophylaxis was 67% rising to >80% in HBeAg+ patients [[5]Samuel D. Muller R. Alexander G. et al.Liver transplantation in European patients with the hepatitis B surface antigen.N Engl J Med. 1993; 329: 1842-1847Crossref PubMed Scopus (975) Google Scholar]. Since then and over the past two decades, the pre and post LT management of such patients has improved dramatically as reflected in several reviews and metanalyses [6Shouval D. Samuel D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review.Hepatology. 2000; 32: 1189-1195Crossref PubMed Scopus (232) Google Scholar, 7Chen J. Yi L. Jia J.D. Ma H. You H. Hepatitis B immunoglobulins and/or lamivudine for preventing hepatitis B recurrence after liver transplantation: a systematic review.J Gastroenterol Hepatol. 2010; 25: 872-879Crossref PubMed Scopus (24) Google Scholar, 8Cholongitas E. Goulis J. Akriviadis E. Papatheodoridis G.V. Hepatitis B immunoglobulin and/or nucleos(t)ide analogues for prophylaxis against hepatitis B virus recurrence after liver transplantation: a systematic review.Liver Transpl. 2011; 17: 1176-1190Crossref PubMed Scopus (97) Google Scholar, 9Levstik M. Wong P. Greanya E.D. Yoshida E.M. The role of hepatitis B immunoglobulin in hepatitis B related liver transplantation: Canadian Transplant Centre Position Paper.Ann Hepatol. 2011; 10: 441-444PubMed Google Scholar, 10Laryea M.A. Watt K.D. Immunoprophylaxis against and prevention of recurrent viral hepatitis after liver transplantation.Liver Transpl. 2012; 18: 514-523Crossref PubMed Scopus (25) Google Scholar, 11Fox A.N. Terrault N.A. The option of HBIG-free prophylaxis against recurrent HBV.J Hepatol. 2012; 56: 1189-1197Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. The changing epidemiology of HBV, the introduction of potent anti-viral agents, the improvement in surgical techniques and medical practices, the rising age of donors as well as the changes in referral rules for LT in Europe and the United States (especially for HCC) justify an updated look back. In the present issue of the Journal, Burra and co-workers took advantage of the very large database of the European Liver Transplant Registry (ELTR) collected for 20 years between January 1988 and December 2010 to evaluate evolution and outcome in 5912 European patients with HBV who underwent LT [[12]Burra P. Germani G. Adam R. et al.Liver transplantation for HBV-related cirrhosis in Europe: a ELTR study on evolution and outcomes.J Hepatol. 2013; 58: 287-296Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. Data obtained in decompensated CHB patients or HBV and HCC registered at the ELTR were compared to data obtained in 3 groups of co-infected patients: HBV with HDV; HBV with HCV, HBV with HDV and HCV and a 4th group of HCV monoinfected patients. Data were stratified into 4 periods of 8, 5, 5, and 5 years apart, starting in 1988. The main results indicate that the majority of HBV patients were transplanted for decompensated CHB (78%) while 22% had HBV and HCC. The proportion of HBV patients with HCC in this large cohort rose from 15.8% in 1988–1995 to 29.6% between 2006 and 2010. Patient and graft survival rates were similar in decompensated CHB patients, ranging from 83% to 80% at one year post LT to 68% and 64% at 10 years post LT, respectively. Patients and graft survival in HBV/HCC patients was 84% and 81% at one year post LT and 61% and 58% at 10 years post LT, respectively. Patient and graft survival improved progressively in both the CHB and the HBV/HCC cohorts over the 20 years of observation. HBV-DNA was undetectable in 71.5% of recipients at time of transplantation but methodology and sensitivity of detection were variable. Patient and graft survival for decompensated CHB as well as for HBV/HCC was better in HBV-DNA negative patients as compared to patients with circulating virus, but an accurate analysis was not possible due to the crude and relatively insensitive technology used in early years to assess viremia. Nevertheless the proportion of HBV-DNA negative recipients at LT dropped from ∼81–82% to ∼51–57% in the past 20 years. Disease recurrence leading to graft failure or death fell significantly in recent years from 3–<1%, respectively. However HCC remains an independent risk factor in LT candidates with HBV. Additional important information includes among others a rising donor age for decompensated CHB and HBV/HCC patients between 2006 and 2010. Slight differences, statistically significant but clinically less important, were observed in the age of decompensated CHB patients and HBV/HCC recipients. As expected, in view of the rising number of HBV/HCC candidates for LT, the rates of LT patients with decompensated CHB in the entire cohort dropped from 84% to 70% while the rates of HBV/HCC patients rose from ∼16% to ∼30% during the last 5 years of the survey. Cox regression analysis identified age >60 years, HBV-DNA positivity at time of transplantation, presence of HCC, transplantation between 1988 and 1995 and use of reduced size grafts as risk factors for graft loss or death. This report summarizes the impressive experience in LT for HBV cirrhosis as well as for HBV and HCC of the European members of the EUROHEP ELTR. Being the last and the largest survey of its kind, it allows to identify and confirm trends and previous observations as reflected in a large number of reviews and reports from Europe and the US, published between the late 1990s and 2012. The present report strengthen and confirms previous data regarding the falling number of CHB and rising number of HBV/HCC candidates for liver transplantation in Europe and the US. It also provides reassurance that LT is after all a viable solution for viremic patients who were excluded from the waiting list until a few years ago. The significant progress in the ability to identify and suppress HBV replication through potent anti-viral agents and the improvement in surgical techniques have all contributed to this remarkable success story and the record drop in HBV graft re-infection post LT. As also stated by the authors, analysis of data was dependant on the pre-agreed upon variables collected in the ELTR database. Consequently (and regretfully), the investigators were unable to analyze important information including pre and post LT monitoring of viral load, ethnic background of patients as well as use of and response to the old and new anti-viral agents, including hepatitis B immune globulin (HBIG) and its route and frequency of administration. Regardless of these reservations, this very large database has again been extremely useful in the quality control of European liver transplant programs. Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.