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or Tenofovir for Prophylaxis and Treatment of Hepatitis B Recurrence Post–Liver Transplant
Efficacy and Safety of Entecavir and/or Tenofovir for Prophylaxis and Treatment of Hepatitis B Recurrence Post–Liver Transplant M. Jiménez-Pérez, A.B. Sáez-Gómez, L. Mongil Poce, J.M. Lozano-Rey, J. de la Cruz-Lombardo, and J.M. Rodrigo-López ABSTRACT Aims. To establish the efficacy and safety of entecavir (ETV) and/or tenofovir (TDF) in the treatment and prevention of hepatitis B virus (HBV) recurrence after liver transplantation. Patients and methods. Eight patients (four men) received treatment with ETV and/or TDF after liver transplantation as prophylaxis for HBV recurrence or as posttransplant treatment of HBV. Four liver transplants were in patients with HBV-associated cirrhosis who had received prior nucleos(t)ide analogue treatment until HBV DNA became undetectable. After transplantation, two of these four were treated with ETV ⫹ TDF and the other two with just TDF. All received intramuscular hepatitis B immunoglobulins. The reasons for the other four liver transplants were primary biliary cirrhosis in two cases, alcoholic cirrhosis, and hepatitis C virus. Two of the patients were donor anti-HBcAbpositive/recipient anti-HBcAb-negative. They received no anti-HBV prophylaxis so they had a recurrence of HBV. These four patients required treatment with ETV ⫹ TDF for the HBV DNA to become negative. Results. The mean age was 60 (39 – 67) years. The mean follow-up was 9.5 (3–20) months. The mean follow-up of the patients who received prophylaxis was 8.2 (3–19) months. These had no HBV recurrence. The mean follow-up of the patients who received treatment for HBV recurrence was 12 (3–19) months. ETV combined with TDF was necessary for the HBV DNA to become undetectable because this was not possible using different nucleos(t)ide analogues. There were no significant adverse effects from these drugs and no alteration of renal function during the follow-up period. Conclusions. Therapy with ETV and/or TDF seems to be efficient and safe when used in the prophylaxis and treatment of HBV recurrence after liver transplantation. They are well tolerated and seem to have no interactions with immunosuppressive medication. ECURRENCE OF HEPATITIS B VIRUS (HBV) after liver transplantation may lead to graft loss as a result of the development of recurrent aggressive hepatitis. In the absence of preventive therapy, HBV recurrence occurs in around 70% of cases, with a 5-year survival of 40% to 60%. Prevention of reinfection or effective treatment of the recurrence is paramount in the prognosis of these patients.1,2 The appearance of new antiviral drugs for the treatment of chronic HBV, like entecavir (ETV) and tenofovir (TDF), which are more powerful and have lower rates of resistance, has resulted in a favorable change. However, these drugs
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have not yet been approved for use in liver transplant recipients. The aim of this study was to determine the efficacy and safety of the use of ETV and/or TDF in the treatment and prophylaxis of HBV recurrence after liver transplantation.
From the Unidad de Hepatología-Trasplante Hepático, Servicio de Aparato Digestivo, Hospital Universitario Carlos Haya, Málaga, Spain. Address reprint requests to Dr Miguel Jiménez-Pérez, Servicio de Aparato Digestivo Hospital Universitario Carlos Haya, Avda Carlos Haya s/n, 29010 Málaga, Spain. E-mail: mjimenezp@ commalaga.com
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2010.05.127
Transplantation Proceedings, 42, 3167–3168 (2010)
3167
3168
PATIENTS AND METHODS The study comprised eight patients, four men and four women, with a mean age of 60 (39 – 67) years. They all received treatment with ETV and/or TDF after liver transplantation, either as prophylaxis against HBV recurrence or as treatment for it. The reason for liver transplantation was HBV cirrhosis in four patients, primary biliary cirrhosis in two, alcoholic cirrhosis in one, and hepatitis C virus cirrhosis in one. The mean follow-up period with posttransplant treatment was 9.5 (3–20) months. The four patients transplanted due to HBV had previously received treatment with nucleos(t)ide analogues until their viral load was undetectable. Two of these four patients were treated after the transplant with ETV plus TDF and the other two with TDF. All received posttransplant intramuscular antihepatitis B gamma globulin together with the antivirals. The other patients developed HBV after transplantation, two related with a anti-HBcAb-positive donor/anti-HBcAb-negative recipient and no anti-HBV prophylaxis. These four patients required treatment with ETV plus TDF to achieve negativization of HBV DNA.
RESULTS
The mean follow-up of the patients who received prophylaxis with ETV and/or TDF was 8.2 (3–19) months, with no posttransplant recurrence. In those patients who received it as treatment of a recurrence, the mean follow-up was 12 (3–19) months, with the combination of ETV ⫹ TDF being required to achieve an undetectable viral load. All the patients received immunosuppressive therapy with tacrolimus, and no interactions were detected with the antiviral agents. No important side effects were noted that were attributable to these drugs, and renal function was maintained within normal limits throughout the whole follow-up period. DISCUSSION
Recurrence of HBV after liver transplantation is an important clinical problem that has resulted in the need for pretransplant therapy with powerful antiviral agents in HBsAg-positive patients, in order to achieve negativization or the lowest possible levels of HBV DNA prior to transplantation. To date, the combined use of lamivudine and/or adefovir with specific antihepatitis B gammaglobulin has managed to reduce the risk of reinfection of the graft to
JIMÉNEZ-PÉREZ, SÁEZ-GÓMEZ, MONGIL POCE ET AL
below 10%,3 though the resistance rates seen in clinical practice may limit its long-term use. The efficacy and safety of the new more potent antivirals (ETV and TDF) with a high genetic barrier for resistance in transplant patients still remains to be determined. The profile of these antivirals together with the need for prolonged treatment as prophylaxis against the recurrence of HBV after liver transplantation warrant consideration of these drugs for these patients.4,5 No studies have yet been published on the use of ETV and/or TDF in cirrhotic patients or in liver transplant patients, except for small series or single cases,6 –9 where, as they did in our series, they seem to be efficient and safe in this type of patient. Nevertheless, these data need to be confirmed with welldesigned studies involving larger series. REFERENCES 1. Mutimer D: Review article: hepatitis B and liver transplantation. Aliment Pharmacol Ther 23:1031, 2006 2. Terrault N, Roche B, Samuel D: Management of the hepatitis B virus in the liver transplantation setting: a European and an American perpective. Liver Transpl 11:716, 2005 3. Villamil FG: Prophylaxis with anti-HBs immune globulins and nuecleoside analogues after liver transplantation for HBV infection. J Hepatol 39:466, 2003 4. Lok ASF, McMahon BJ: AASLD Practice Guidelines. Chronic hepatitis B: Update 2009. Hepatology 50:1, 2009 5. European Association for the Study of the Liver: EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol 50:227, 2009 6. Petersen J, Lutgehetmann M, Zoulin F, et al: Entecavir and tenofvir combination therapy in chronic hepatitis B: rescue therapy in patients with advanced fibrosis and multiple previous treatment failures. Results from an international multicenter cohort study. Hepatology 50(suppl 4):496A, 2009 7. Liaw Y, Raptopoulou-Gigi M, Cheinquer, et al: Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with evidence of hepatic decompensation. Hepatology 50(suppl 4):505A, 2009 8. Liaw Y, Lee C, Akarca US, et al: Interim results of a double-blind, randomized phase 2 study of the safety of tenefovir disoproxil fumurate, emtricitabine plus tenofovir disoproxil fumarate and entecavir in the treatment of chronic hepatitis B subjects with decompensated liver disease.Hepatology 50(suppl 4):409A, 2009 9. Amarapurkar D: Efficacy of combination of entecavir and tenofovir treatment in hepatitis B related decompensated chronic liver disease: pilot study. J Hepatol 50(suppl 1):327, 2009
R
have not yet been approved for use in liver transplant recipients. The aim of this study was to determine the efficacy and safety of the use of ETV and/or TDF in the treatment and prophylaxis of HBV recurrence after liver transplantation.
From the Unidad de Hepatología-Trasplante Hepático, Servicio de Aparato Digestivo, Hospital Universitario Carlos Haya, Málaga, Spain. Address reprint requests to Dr Miguel Jiménez-Pérez, Servicio de Aparato Digestivo Hospital Universitario Carlos Haya, Avda Carlos Haya s/n, 29010 Málaga, Spain. E-mail: mjimenezp@ commalaga.com
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2010.05.127
Transplantation Proceedings, 42, 3167–3168 (2010)
3167
3168
PATIENTS AND METHODS The study comprised eight patients, four men and four women, with a mean age of 60 (39 – 67) years. They all received treatment with ETV and/or TDF after liver transplantation, either as prophylaxis against HBV recurrence or as treatment for it. The reason for liver transplantation was HBV cirrhosis in four patients, primary biliary cirrhosis in two, alcoholic cirrhosis in one, and hepatitis C virus cirrhosis in one. The mean follow-up period with posttransplant treatment was 9.5 (3–20) months. The four patients transplanted due to HBV had previously received treatment with nucleos(t)ide analogues until their viral load was undetectable. Two of these four patients were treated after the transplant with ETV plus TDF and the other two with TDF. All received posttransplant intramuscular antihepatitis B gamma globulin together with the antivirals. The other patients developed HBV after transplantation, two related with a anti-HBcAb-positive donor/anti-HBcAb-negative recipient and no anti-HBV prophylaxis. These four patients required treatment with ETV plus TDF to achieve negativization of HBV DNA.
RESULTS
The mean follow-up of the patients who received prophylaxis with ETV and/or TDF was 8.2 (3–19) months, with no posttransplant recurrence. In those patients who received it as treatment of a recurrence, the mean follow-up was 12 (3–19) months, with the combination of ETV ⫹ TDF being required to achieve an undetectable viral load. All the patients received immunosuppressive therapy with tacrolimus, and no interactions were detected with the antiviral agents. No important side effects were noted that were attributable to these drugs, and renal function was maintained within normal limits throughout the whole follow-up period. DISCUSSION
Recurrence of HBV after liver transplantation is an important clinical problem that has resulted in the need for pretransplant therapy with powerful antiviral agents in HBsAg-positive patients, in order to achieve negativization or the lowest possible levels of HBV DNA prior to transplantation. To date, the combined use of lamivudine and/or adefovir with specific antihepatitis B gammaglobulin has managed to reduce the risk of reinfection of the graft to
JIMÉNEZ-PÉREZ, SÁEZ-GÓMEZ, MONGIL POCE ET AL
below 10%,3 though the resistance rates seen in clinical practice may limit its long-term use. The efficacy and safety of the new more potent antivirals (ETV and TDF) with a high genetic barrier for resistance in transplant patients still remains to be determined. The profile of these antivirals together with the need for prolonged treatment as prophylaxis against the recurrence of HBV after liver transplantation warrant consideration of these drugs for these patients.4,5 No studies have yet been published on the use of ETV and/or TDF in cirrhotic patients or in liver transplant patients, except for small series or single cases,6 –9 where, as they did in our series, they seem to be efficient and safe in this type of patient. Nevertheless, these data need to be confirmed with welldesigned studies involving larger series. REFERENCES 1. Mutimer D: Review article: hepatitis B and liver transplantation. Aliment Pharmacol Ther 23:1031, 2006 2. Terrault N, Roche B, Samuel D: Management of the hepatitis B virus in the liver transplantation setting: a European and an American perpective. Liver Transpl 11:716, 2005 3. Villamil FG: Prophylaxis with anti-HBs immune globulins and nuecleoside analogues after liver transplantation for HBV infection. J Hepatol 39:466, 2003 4. Lok ASF, McMahon BJ: AASLD Practice Guidelines. Chronic hepatitis B: Update 2009. Hepatology 50:1, 2009 5. European Association for the Study of the Liver: EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol 50:227, 2009 6. Petersen J, Lutgehetmann M, Zoulin F, et al: Entecavir and tenofvir combination therapy in chronic hepatitis B: rescue therapy in patients with advanced fibrosis and multiple previous treatment failures. Results from an international multicenter cohort study. Hepatology 50(suppl 4):496A, 2009 7. Liaw Y, Raptopoulou-Gigi M, Cheinquer, et al: Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with evidence of hepatic decompensation. Hepatology 50(suppl 4):505A, 2009 8. Liaw Y, Lee C, Akarca US, et al: Interim results of a double-blind, randomized phase 2 study of the safety of tenefovir disoproxil fumurate, emtricitabine plus tenofovir disoproxil fumarate and entecavir in the treatment of chronic hepatitis B subjects with decompensated liver disease.Hepatology 50(suppl 4):409A, 2009 9. Amarapurkar D: Efficacy of combination of entecavir and tenofovir treatment in hepatitis B related decompensated chronic liver disease: pilot study. J Hepatol 50(suppl 1):327, 2009