Telbivudine Prophylaxis for Hepatitis B Virus Recurrence After Liver Transplantation Improves Renal Function A. Perrellaa,b, A.G. Lanzac, D. Pisanielloa, G. DiCostanzoc, F. Calised, and O. Cuomoa,* a Laparoscopic, Hepatic and Liver Transplant Unit, AORN A. Cardarelli, Naples, Italy; bVII Department of Infectious Disease and Immunology, AORN Monaldi-Cotugno-CTO, Naples, Italy; cHepatology Unit, AORN A. Cardarelli, Naples, Italy; and dHepatobiliary Surgery and Liver Transplant Center, AORN A. Cardarelli, Naples, Italy
ABSTRACT Introduction. Renal impairment after liver transplantation represents an important issue in the management of transplantation patients, particularly when those subjects may need prophylaxis for fungal or viral infection. Herein we report our experience with 12 transplantation patients receiving telbivudine 600 mg/d while on the waiting list, followed by treatment for 18 months after liver transplantation, showing an improvement on their renal function during the follow-up period. Methods. Our series consisted of men with hepatitis B virus (HBV)erelated end-stage liver disease. The viral load decreased rapidly while on the waiting list once the patient was started on antiviral treatment. Those subjects were compared with 12 patients on lamivudine prophylaxis. All patients were evaluated for liver and renal function, immunosuppression trough levels, and creatine phosphokinase (CPK) before liver transplantation (T0) and at 3, 6, 12, and 18 months (T3, T6, T12, T18). Results. All patients received a calcineurin inhibitor immunosuppression-based regimen. Creatinine clearance (Modification of Diet in Renal Disease) was 67 mL/min at T0, with a statistically significant improvement after month 6 compared with those on lamivudine and with the value at the beginning of the prophylaxis (Mann-Whitney U test P < .05). Neither CPK nor transaminase serum levels increased throughout the study period. Once HBV DNA was cleared while on the waiting list, it remained negative throughout the follow-up period. Conclusions. Telbivudine prophylaxis for HBV is safe and effective, without any significant deleterious effect on the liver; on the contrary, it seems to improve renal function after liver transplantation through 18 months. Further studies and larger series are warranted to confirm these findings.
H
EPATITIS B VIRUS (HBV) infection still remains to be associated with increased morbidity and mortality, representing one of the major indications for liver transplantation (LT). In fact, of the more than 350 million people currently infected worldwide, it is estimated that more than half a million patients will die every year of complications from HBV-related chronic liver disease [1]. One of the most important factors influencing outcomes during the first year after LT is renal impairment. In recent decades, the use of viral prophylaxis by means of hepatitis B immunoglobulin (HBIG) and/or antiviral drugs has significantly improved the survival for these patients by preventing recurrence, or in
fewer cases, their action has been through viral escape or mutation [2e4]. With one of the goals being the reduction in the need for HBIG preparations, which are expensive, oral antivirals, nucleotide analogues given both pretransplantation and posttransplantation, have been used extensively in recent times. In the particular setting of posttransplantation, alternative antiviral drugs have been used as tangible alternatives *Address correspondence to Oreste Cuomo, CLSE-CTF AORN Cardarelli, Via A. Cardarelli 9, 80131 Naples, Italy. E-mail: oreste. [email protected]
ª 2014 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.07.058
Transplantation Proceedings, 46, 2319e2321 (2014)
2319
2320
with the aim of reducing the need for HBIG preparations, hence significantly reducing cost with very promising results [5]. However, only 2 antivirals are currently used in HBV prophylaxis, lamivudine and adefovir dipivoxil. These drugs may have an important impact on renal function [6]. Very few series have been published on other drugs, such as telbivudine, which seems to have a reduced impact on renal function. The present study is composed of 12 patients on telbivudine treatment started at the time of listing, following up their renal function during an 18-month period. We present our results in this particular cohort of patients while comparing them with matched patients on lamivudine prophylaxis. PATIENTS AND METHODS The present study evaluated patients who underwent transplantation because of HBV end-stage liver disease and prophylaxis with telbivudine started at the time of listing throughout 18 months of follow-up, evaluating renal function by Modification of Diet in Renal Disease (MDRD) creatinine clearance and comparing them with those on lamivudine prophylaxis. All patients, after written informed consent, were randomized when entering the waiting list. After LT we evaluated renal and liver function, antiviral activity by assaying HBV DNA and hepatitis B surface antigen monthly for the first month and successively every 3 months, hepatitis B surface antibody titer, Immunosuppression trough levels, and creatine phosphokinase (CPK) serum levels. We also considered the key parameters associated with end-stage liver disease caused by HBV, such as age and disease severity, creating a matched set of patients on lamivudine treatment (group B) for comparison purposes. Group A consisted of 12 patients who were successfully followed up for 18 months after LT. All patients in the study received the same immunosuppressive schedule: steroid induction at anhepatic phase consisting of 500 mg intravenously and the downscaling through a prednisone taper up to the third month, when they were stopped, plus calcineurin inhibitor (CNI) drugs (tacrolimus or cyclosporine). Patients also received prophylactic drug therapies for infection diseases other than HBV, in accordance with our most current post-LT protocol [7].
PERRELLA, LANZA, PISANIELLO ET AL Table 1. Descriptive Analysis of Studied Subjects Patient Parameters
Age (y SD) Sex Male Female Model for End-Stage Liver Disease score at transplantation Antiviral treatment pretransplantation Telbivudine Tenofovir Entecavir Lamivudine þ adefovir Immunosuppression Tacrolimus Cyclosporine
Group A, N ¼ 12
Group B, N ¼ 10
45 3
42 4
9/12 3/12 22
8/12 4/12 21
12/12 0/12 0/12 0/12
0/12 5/12 4/12 3/12
8/12 4/12
8/12 4/12
T0 in group B. No statistically significant differences were found at intragroup analysis (Mann-Whitney U > .05) or at intergroup analysis (P > .05). However, when we evaluated the creatinine clearance by MDRD during the follow-up, we had a statistically significant improvement in patients in group A compared with those in group B (Fig 1). The CPK serum level was not observed to increase throughout the study period in group A as previously shown (ref Tranpls). HBV DNA, once cleared before transplantation, remained negative in both groups in all evaluated time points up to the 6-month posttransplantation scope of this study. No significant differences were found in FK trough levels in patients on this type of CNI treatment in either group. CONCLUSIONS
Renal impairment after LT is one of the most important clinical conditions possibly influencing the outcome of liver transplantation. In those patients who underwent transplantation for HBV infection, the combination of HBIG and lamivudine is mandatory and it is the only viable therapeutic
RESULTS
Patients in group A received the following CNI schedule: 8 patients with tacrolimus and 4 patients with cyclosporine, whereas 6 of the 7 patients in group B were on tacrolimus. Table 1 shows descriptive statistical data from both groups. Patients in group A were on telbivudine treatment at least 3 months before transplantation, all being HBV DNA negative at the time of transplantation. Of note, 7 of 12 patients who composed our group A were referred to our center after the first episode of ascites, and were unknown HBV-infected cirrhotic patients. All patients receiving telbivudine had a viral load not greater than a mean of 15,000 IU/mL, representing an ideal therapeutic scenario. Patients who composed group B received antiviral treatment at listing consisting of entecavir in 4 patients, tenofovir in 5 patients, and lamivudine plus adefovir in 3. The mean value of creatinine clearance (MDRD) was 67 mL/min at T0 in group A, whereas it was 66 mL/min at
Fig 1. Creatinine clearance, expressed in mg/mL in different time points (T0 ¼ before liver transplantation; T1, 3, 6, 12, 18 ¼ 1, 3, 6, 12, 18 months after liver transplantation).
TELBIVUDINE PROPHYLAXIS
alternative to avoid viral recurrence; however, the use of lamivudine may have some influence on renal function. Up to now, the most commonly used antiviral agent has been lamivudine, alone or with adefovir [1e3]. However, these drugs may have an impact on renal function. Previously we reported the safety of telbivudine prophylaxis in those patients who underwent transplantation because of chronic HBV infection. Nonetheless, during the follow-up of those patients, interestingly we found that those receiving telbivudine had an improvement in renal function throughout 18 months, even if on immunosuppressant treatment. Indeed, it has already been reported that telbivudine therapy was associated with improvement in renal function in other subsets of patients at high risk for renal impairment, including patients with acuteon-chronic liver failure, and those receiving chemotherapy [8,9]. More recently, an analysis from the GLOBE study has shown that telbivudine increases renal function in patients with chronic hepatitis B, comprising those on other antiviral treatment including tenofovir [10]. The present study, although using a narrow cohort, is the first to demonstrate an improvement in renal function in LT patients undergoing telbivudine prophylaxis compared with those on lamivudine. It is of note that during the first 3 months, after an initial worsening of renal function, probably caused by immunosuppressants, patients on telbivudine clearly have improved renal function for the next 6 months without any difference in immunosuppressant serum levels compared with patients on lamivudine prophylaxis. There are no reports in the literature regarding the use of telbivudine in a transplant setting such as the one presented here. Therefore, in our experience, telbivudine not only showed the same properties and efficacy of lamivudine in regard to viral suppression, but also seems to give some advantages to LT patients. A very significant finding was the almost-absent increase in CPK levels that is usually associated with the use of antiviral drugs and was not seen in our telbivudine study patients, as already shown in a previous study [7]. This becomes an even more relevant issue in patients undergoing LT, who usually experience significant muscular impairment after surgery. A concurrent increase in CPK levels with muscular pain might represent a significant obstacle to rehabilitation and hence a negative impact on the quality of life. In summary, this is the first report to show an improvement of renal function during the use of telbivudine as prophylaxis treatment after LT for HBV recurrence. Our report shows that this antiviral agent has the same properties and efficacy as
2321
lamivudine in terms of viral suppression. It can be safely administered to transplantation patients without any interference with immunosuppression and without any evident effects on renal function after a 6-month follow-up. The limited number of patients that formed our study groups warrants future studies on the safety and efficacy of telbivudine in regard to HBV recurrence in the LT setting. It is not clear what the possible effect of telbivudine on renal function is, nor whether it could be related to some kind of protective role of this antiviral drug. However, we speculate that the use of telbivudine could be of great interest, particularly because of recent evidence regarding the role of this drug on renal impairment in chronic hepatitis B.
REFERENCES [1] Maddrey WC. Hepatitis B: an important public health issue. J Med Virol 2000;61:362e6. [2] O’Grady JG, Smith HM, Davies SE, et al. Hepatitis B virus reinfection after orthotopic liver transplantation. Serological and clinical implications. J Hepatol 1992;14:104e11. [3] Bárcena R, del Campo S, Moraleda G, Casanovas T, Prieto M, Buti M, et al. Study on the efficacy and safety of adefovir dipivoxil treatment in post-liver transplant patients with hepatitis B virus infection and lamivudine-resistant hepatitis B virus. Transplant Proc 2005;37:3960e2. [4] Schiff E, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl 2007;13:349e60. [5] Buti M, Mas A, Prieto M, Casafont F, González A, Miras M, et al. A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation. J Hepatol 2003;38:811e7. [6] Tanaka M, Suzuki F, Seko Y. Renal dysfunction and hypophosphatemia during long-term lamivudine plus adefovir dipivoxil therapy in patients with chronic hepatitis B. J Gastroenterol 2013;49:470e80. [7] Perrella A, Lanza AG, Santaniello W, et al. Telbivudine as prophylaxis for hepatitis B virus recurrence after liver transplantation: a case series in single-center experience. Transplant Proc 2012;44:1986e8. [8] Gerasimova O, Granov DA, Zherebtsov FK, et al. Efficacy and safety of telbivudine in patients after orthotopic liver transplantation: a single-center clinical experience. Hepatol Int 2011;5:129e30. [9] Amarapurkar DN, Patel N. Increased eGFR with telbivudine in combination therapy of chronic hepatitis B infection. Indian J Gastroenterol 2013;33:89e91. [10] Kamar N, Milioto O, Alric L, et al. Entecavir therapy for adefovir-resistant hepatitis B virus infection in kidney and liver allograft recipients. Transplantation 2008;86:611e4.
ABSTRACT Introduction. Renal impairment after liver transplantation represents an important issue in the management of transplantation patients, particularly when those subjects may need prophylaxis for fungal or viral infection. Herein we report our experience with 12 transplantation patients receiving telbivudine 600 mg/d while on the waiting list, followed by treatment for 18 months after liver transplantation, showing an improvement on their renal function during the follow-up period. Methods. Our series consisted of men with hepatitis B virus (HBV)erelated end-stage liver disease. The viral load decreased rapidly while on the waiting list once the patient was started on antiviral treatment. Those subjects were compared with 12 patients on lamivudine prophylaxis. All patients were evaluated for liver and renal function, immunosuppression trough levels, and creatine phosphokinase (CPK) before liver transplantation (T0) and at 3, 6, 12, and 18 months (T3, T6, T12, T18). Results. All patients received a calcineurin inhibitor immunosuppression-based regimen. Creatinine clearance (Modification of Diet in Renal Disease) was 67 mL/min at T0, with a statistically significant improvement after month 6 compared with those on lamivudine and with the value at the beginning of the prophylaxis (Mann-Whitney U test P < .05). Neither CPK nor transaminase serum levels increased throughout the study period. Once HBV DNA was cleared while on the waiting list, it remained negative throughout the follow-up period. Conclusions. Telbivudine prophylaxis for HBV is safe and effective, without any significant deleterious effect on the liver; on the contrary, it seems to improve renal function after liver transplantation through 18 months. Further studies and larger series are warranted to confirm these findings.
H
EPATITIS B VIRUS (HBV) infection still remains to be associated with increased morbidity and mortality, representing one of the major indications for liver transplantation (LT). In fact, of the more than 350 million people currently infected worldwide, it is estimated that more than half a million patients will die every year of complications from HBV-related chronic liver disease [1]. One of the most important factors influencing outcomes during the first year after LT is renal impairment. In recent decades, the use of viral prophylaxis by means of hepatitis B immunoglobulin (HBIG) and/or antiviral drugs has significantly improved the survival for these patients by preventing recurrence, or in
fewer cases, their action has been through viral escape or mutation [2e4]. With one of the goals being the reduction in the need for HBIG preparations, which are expensive, oral antivirals, nucleotide analogues given both pretransplantation and posttransplantation, have been used extensively in recent times. In the particular setting of posttransplantation, alternative antiviral drugs have been used as tangible alternatives *Address correspondence to Oreste Cuomo, CLSE-CTF AORN Cardarelli, Via A. Cardarelli 9, 80131 Naples, Italy. E-mail: oreste. [email protected]
ª 2014 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.07.058
Transplantation Proceedings, 46, 2319e2321 (2014)
2319
2320
with the aim of reducing the need for HBIG preparations, hence significantly reducing cost with very promising results [5]. However, only 2 antivirals are currently used in HBV prophylaxis, lamivudine and adefovir dipivoxil. These drugs may have an important impact on renal function [6]. Very few series have been published on other drugs, such as telbivudine, which seems to have a reduced impact on renal function. The present study is composed of 12 patients on telbivudine treatment started at the time of listing, following up their renal function during an 18-month period. We present our results in this particular cohort of patients while comparing them with matched patients on lamivudine prophylaxis. PATIENTS AND METHODS The present study evaluated patients who underwent transplantation because of HBV end-stage liver disease and prophylaxis with telbivudine started at the time of listing throughout 18 months of follow-up, evaluating renal function by Modification of Diet in Renal Disease (MDRD) creatinine clearance and comparing them with those on lamivudine prophylaxis. All patients, after written informed consent, were randomized when entering the waiting list. After LT we evaluated renal and liver function, antiviral activity by assaying HBV DNA and hepatitis B surface antigen monthly for the first month and successively every 3 months, hepatitis B surface antibody titer, Immunosuppression trough levels, and creatine phosphokinase (CPK) serum levels. We also considered the key parameters associated with end-stage liver disease caused by HBV, such as age and disease severity, creating a matched set of patients on lamivudine treatment (group B) for comparison purposes. Group A consisted of 12 patients who were successfully followed up for 18 months after LT. All patients in the study received the same immunosuppressive schedule: steroid induction at anhepatic phase consisting of 500 mg intravenously and the downscaling through a prednisone taper up to the third month, when they were stopped, plus calcineurin inhibitor (CNI) drugs (tacrolimus or cyclosporine). Patients also received prophylactic drug therapies for infection diseases other than HBV, in accordance with our most current post-LT protocol [7].
PERRELLA, LANZA, PISANIELLO ET AL Table 1. Descriptive Analysis of Studied Subjects Patient Parameters
Age (y SD) Sex Male Female Model for End-Stage Liver Disease score at transplantation Antiviral treatment pretransplantation Telbivudine Tenofovir Entecavir Lamivudine þ adefovir Immunosuppression Tacrolimus Cyclosporine
Group A, N ¼ 12
Group B, N ¼ 10
45 3
42 4
9/12 3/12 22
8/12 4/12 21
12/12 0/12 0/12 0/12
0/12 5/12 4/12 3/12
8/12 4/12
8/12 4/12
T0 in group B. No statistically significant differences were found at intragroup analysis (Mann-Whitney U > .05) or at intergroup analysis (P > .05). However, when we evaluated the creatinine clearance by MDRD during the follow-up, we had a statistically significant improvement in patients in group A compared with those in group B (Fig 1). The CPK serum level was not observed to increase throughout the study period in group A as previously shown (ref Tranpls). HBV DNA, once cleared before transplantation, remained negative in both groups in all evaluated time points up to the 6-month posttransplantation scope of this study. No significant differences were found in FK trough levels in patients on this type of CNI treatment in either group. CONCLUSIONS
Renal impairment after LT is one of the most important clinical conditions possibly influencing the outcome of liver transplantation. In those patients who underwent transplantation for HBV infection, the combination of HBIG and lamivudine is mandatory and it is the only viable therapeutic
RESULTS
Patients in group A received the following CNI schedule: 8 patients with tacrolimus and 4 patients with cyclosporine, whereas 6 of the 7 patients in group B were on tacrolimus. Table 1 shows descriptive statistical data from both groups. Patients in group A were on telbivudine treatment at least 3 months before transplantation, all being HBV DNA negative at the time of transplantation. Of note, 7 of 12 patients who composed our group A were referred to our center after the first episode of ascites, and were unknown HBV-infected cirrhotic patients. All patients receiving telbivudine had a viral load not greater than a mean of 15,000 IU/mL, representing an ideal therapeutic scenario. Patients who composed group B received antiviral treatment at listing consisting of entecavir in 4 patients, tenofovir in 5 patients, and lamivudine plus adefovir in 3. The mean value of creatinine clearance (MDRD) was 67 mL/min at T0 in group A, whereas it was 66 mL/min at
Fig 1. Creatinine clearance, expressed in mg/mL in different time points (T0 ¼ before liver transplantation; T1, 3, 6, 12, 18 ¼ 1, 3, 6, 12, 18 months after liver transplantation).
TELBIVUDINE PROPHYLAXIS
alternative to avoid viral recurrence; however, the use of lamivudine may have some influence on renal function. Up to now, the most commonly used antiviral agent has been lamivudine, alone or with adefovir [1e3]. However, these drugs may have an impact on renal function. Previously we reported the safety of telbivudine prophylaxis in those patients who underwent transplantation because of chronic HBV infection. Nonetheless, during the follow-up of those patients, interestingly we found that those receiving telbivudine had an improvement in renal function throughout 18 months, even if on immunosuppressant treatment. Indeed, it has already been reported that telbivudine therapy was associated with improvement in renal function in other subsets of patients at high risk for renal impairment, including patients with acuteon-chronic liver failure, and those receiving chemotherapy [8,9]. More recently, an analysis from the GLOBE study has shown that telbivudine increases renal function in patients with chronic hepatitis B, comprising those on other antiviral treatment including tenofovir [10]. The present study, although using a narrow cohort, is the first to demonstrate an improvement in renal function in LT patients undergoing telbivudine prophylaxis compared with those on lamivudine. It is of note that during the first 3 months, after an initial worsening of renal function, probably caused by immunosuppressants, patients on telbivudine clearly have improved renal function for the next 6 months without any difference in immunosuppressant serum levels compared with patients on lamivudine prophylaxis. There are no reports in the literature regarding the use of telbivudine in a transplant setting such as the one presented here. Therefore, in our experience, telbivudine not only showed the same properties and efficacy of lamivudine in regard to viral suppression, but also seems to give some advantages to LT patients. A very significant finding was the almost-absent increase in CPK levels that is usually associated with the use of antiviral drugs and was not seen in our telbivudine study patients, as already shown in a previous study [7]. This becomes an even more relevant issue in patients undergoing LT, who usually experience significant muscular impairment after surgery. A concurrent increase in CPK levels with muscular pain might represent a significant obstacle to rehabilitation and hence a negative impact on the quality of life. In summary, this is the first report to show an improvement of renal function during the use of telbivudine as prophylaxis treatment after LT for HBV recurrence. Our report shows that this antiviral agent has the same properties and efficacy as
2321
lamivudine in terms of viral suppression. It can be safely administered to transplantation patients without any interference with immunosuppression and without any evident effects on renal function after a 6-month follow-up. The limited number of patients that formed our study groups warrants future studies on the safety and efficacy of telbivudine in regard to HBV recurrence in the LT setting. It is not clear what the possible effect of telbivudine on renal function is, nor whether it could be related to some kind of protective role of this antiviral drug. However, we speculate that the use of telbivudine could be of great interest, particularly because of recent evidence regarding the role of this drug on renal impairment in chronic hepatitis B.
REFERENCES [1] Maddrey WC. Hepatitis B: an important public health issue. J Med Virol 2000;61:362e6. [2] O’Grady JG, Smith HM, Davies SE, et al. Hepatitis B virus reinfection after orthotopic liver transplantation. Serological and clinical implications. J Hepatol 1992;14:104e11. [3] Bárcena R, del Campo S, Moraleda G, Casanovas T, Prieto M, Buti M, et al. Study on the efficacy and safety of adefovir dipivoxil treatment in post-liver transplant patients with hepatitis B virus infection and lamivudine-resistant hepatitis B virus. Transplant Proc 2005;37:3960e2. [4] Schiff E, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl 2007;13:349e60. [5] Buti M, Mas A, Prieto M, Casafont F, González A, Miras M, et al. A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation. J Hepatol 2003;38:811e7. [6] Tanaka M, Suzuki F, Seko Y. Renal dysfunction and hypophosphatemia during long-term lamivudine plus adefovir dipivoxil therapy in patients with chronic hepatitis B. J Gastroenterol 2013;49:470e80. [7] Perrella A, Lanza AG, Santaniello W, et al. Telbivudine as prophylaxis for hepatitis B virus recurrence after liver transplantation: a case series in single-center experience. Transplant Proc 2012;44:1986e8. [8] Gerasimova O, Granov DA, Zherebtsov FK, et al. Efficacy and safety of telbivudine in patients after orthotopic liver transplantation: a single-center clinical experience. Hepatol Int 2011;5:129e30. [9] Amarapurkar DN, Patel N. Increased eGFR with telbivudine in combination therapy of chronic hepatitis B infection. Indian J Gastroenterol 2013;33:89e91. [10] Kamar N, Milioto O, Alric L, et al. Entecavir therapy for adefovir-resistant hepatitis B virus infection in kidney and liver allograft recipients. Transplantation 2008;86:611e4.
