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Adefovir Dipivoxil Therapy in Liver Transplant Recipients With Lamivudine-Resistant Hepatitis B Virus
COMPLICATIONS
Adefovir Dipivoxil Therapy in Liver Transplant Recipients With Lamivudine-Resistant Hepatitis B Virus A. Herreros de Tejada Echanojáuregui, J.M. Moreno Planas, E. Rubio González, F. Portero Azorin, J. López Monclús, J. Revilla Negro, J.L. Lucena de la Poza, V. Sánchez Turrión, C. Barrios Peinado, and V. Cuervas-Mons Martı´nez ABSTRACT: Hepatitis B virus (HBV) infection is the leading cause of cirrhosis worldwide. One effective strategy to prevent recurrence or transmission of HBV infection after liver transplantation exists is prescription of Lamivudine, although it is associated with high resistance rates. Adefovir dipivoxil (AD) is a nucleotide analogue of adenosine that has achieved significant results in virologic, biochemical, and clinical parameters in lamivudine-resistant HBVinfected patients. Between 1990 and 2003 7 adult recipients of ortothopic liver transplants who experienced lamivudine-resistant HBV infection (pretransplantation or posttransplantation) were enrolled in a prospective study to administer AD for 48 weeks. At baseline they showed serum HBV DNA between 2.2 ⫻ 106 and 1.1 ⫻ 108 copies/mL. After 48 weeks of AD treatment, the median time-weighted average change in serum HBV DNA (log 10 copies/mL) was ⫺3.19 (SD, 1.65). In 3 patients with HBV, DNA was undetectable (⬍400 copies/mL) at the end of the follow-up. HBe antigen seroconversion was observed in 1 patient. No significant adverse effects were recorded, except for renal functional impairment in 1 patient who had previous renal insufficiency. In our study, adefovir was an effective drug to suppression HBV replication in liver transplant recipients with lamivudine-resistant HBV. Excluding renal function abnormalities, tolerance of the drug was excellent. None of the patients developed resistance to adefovir. Therapy with AD in liver transplant recipients is effective and safe, although renal function should be monitored closely.
H
EPATITIS B virus (HBV) infection is the leading cause of cirrhosis and hepatocellular carcinoma worldwide.1 Currently, strategies to prevent recurrence of HBV infection in the liver allograft2 are not completely successful; some orthotopic liver transplant (OLT) recipients display HBV infection in the graft. The most frequent therapy for posttransplantation HBV recurrence is lamivudine (LAM), but this drug is associated with high resistance rates.2 Adefovir dipivoxil (AD) is a nucleotide analogue of adenosine with activity against HBV. In preliminary re-
ports, adefovir has achieved significant improvements in
From the Liver Transplant Unit (A.H.d.T.E., J.M.M.P., E.R.G., J.L.M., J.R.N., J.L.d.l.P., V.S.T., C.B.P., V.C.-M.M.), and Microbiology Department (F.P.A.), Hospital Puerta de Hierro, Madrid, Spain. Address reprint requests to Dr José Marı´a Moreno Planas, Unidad de Trasplante Hepático, Hospital Puerta de Hierro, San Martı´n de Porres 4, 28035 Madrid, Spain. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.02.031
Transplantation Proceedings, 37, 1507–1508 (2005)
1507
1508
virologic, biochemical, and clinical parameters3–5 in patients with HBV. We designed this study to evaluate the efficacy of AD as therapy for LAM-resistant HBV in patients with posttransplantation HBV infection. PATIENTS AND METHODS Seven adult recipients of an OLT between 1990 and 2003 with LAM-resistant HBV infection were enrolled in a prospective study to evaluate the efficacy and safety of AD. The primary end point was the virologic response in terms of change in serum HBV DNA (log 10 copies/mL) from baseline up to weeks 24 and 48. Sèrum DNA was measured with the Roche Amplicor Monitor PCR; the lower limit of detection was ⬍400 copies/mL. Each patient was initially given 10 mg AD per day. Adverse events were recorded to assess safety.
RESULTS
The study population was composed of 6 men and 1 woman of mean age 46 years (range, 33– 66). The mean follow-up after OLT was 80 months (range, 9 –153). Immunosuppressive therapy was cyclosporine in 5 patients (57%) and tacrolimus in 2 patients (29%). Three patients (43%) had creatinine clearance value ⬍60 mL/min. All patients had LAM-resistant HBV infection with baseline serum HBV DNA between 2.2 ⫻ 106 and 1.1 ⫻ 108 copies/mL (median, 1.5 ⫻ 106). Four patients (57%) had recurrence of HBV infection in the liver graft, and 3 had “de novo” HBV infection. Five patients (71%) had positive HBe antigen and 2 (29%) had negative HBe antigen hepatitis. In 5 patients, LAM was changed to AD, in the other 2 AD was added to LAM. In 1 patient with previous renal dysfunction, AD was withdrawn after 45 days due to worsening renal function. A mild increase in serum creatinine level was observed in another patient. No other significant adverse effects were recorded. After 24 and 48 weeks, the median time-weighted average change in serum HBV DNA (log 10 copies/mL) was ⫺2.41 and ⫺3.19 (SD, 1.65), respectively. In 3 out of 6 patients who completed 1 year of therapy, HBV DNA was undetectable (⬍400 copies/mL). The decrease in DNA was similar among patients with AD or AD-LAM. HBe antigen seroconversion was achieved in 1 patient. DISCUSSION
In the absence of effective therapies, HBV infection of the liver allograft is associated with reduced graft and patient survival. The first-line therapy for these patients is LAM,
ECHANOJÁUREGUI, PLANAS, GONZÁLEZ ET AL
which is an effective drug, but shows high resistance rates in OLT recipients. In our study, AD was an effective drug to achieve suppression of HBV replication in OLT recipients with LAM-resistant HBV. This beneficial effect has been previously reported in patients with4,5 and without OLT.3,6 However, as in previous trials, HBe antigen seroconversion is uncommon after 1 year of follow-up.7 Renal dysfunction in OLT recipients is common, mainly due to the use of calcineurin inhibitors. A higher frequency of renal laboratory abnormalities has been associated with the use of adefovir.5,7 In our population, the only severe adverse event was an increased creatinine level in a patient with chronic renal dysfunction, which did not improve after discontinuation of adefovir, making its direct relationship with the drug questionable. Another patient showed a mild increase in the creatinine value. Excluding renal abnormalities, tolerance to the drug was excellent, as has been reported in many series.5,7 Although the number of patients was small, none of them developed resistance to adefovir. Previous reports have pointed out the uncommon development of resistance to this drug.8 In summary, therapy with AD in liver transplant recipients is effective and safe. However, these patients require close monitoring of renal function.
REFERENCES 1. Conjeevaram HS, Lok ASF: Management of chronic hepatitis B. J Hepatol 38:S90, 2003 2. Papatheodoridis GV, Sevastianos V, Burroughs AK: Prevention and treatment for hepatitis B virus infection after liver transplantation in the nucleoside analogues era. Am J Transplant 3:250, 2003 3. Perrillo R, Schiff E, Yoshida E, et al: Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 32:129, 2000 4. Ahmed J, Dodson SF, Balan V, et al: Adefovir dipivoxil suppresses lamivudine resistant hepatitis B virus in liver transplant recipients. Hepatology 32:292A, 2003 5. Schiff ER, Lai CL, Hadziyannis S, et al: Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre and post liver transplantation patients. Hepatology 38:1419, 2003 6. Peters MG, Hann HW, Martin P, et al: Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 126:91, 2004 7. Marcellin P, Chang TT, Lim SG, et al: Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 348:808, 2003 8. Westland CE, Yang H, Delaney IV WE, et al: Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology 38:96, 2003
Adefovir Dipivoxil Therapy in Liver Transplant Recipients With Lamivudine-Resistant Hepatitis B Virus A. Herreros de Tejada Echanojáuregui, J.M. Moreno Planas, E. Rubio González, F. Portero Azorin, J. López Monclús, J. Revilla Negro, J.L. Lucena de la Poza, V. Sánchez Turrión, C. Barrios Peinado, and V. Cuervas-Mons Martı´nez ABSTRACT: Hepatitis B virus (HBV) infection is the leading cause of cirrhosis worldwide. One effective strategy to prevent recurrence or transmission of HBV infection after liver transplantation exists is prescription of Lamivudine, although it is associated with high resistance rates. Adefovir dipivoxil (AD) is a nucleotide analogue of adenosine that has achieved significant results in virologic, biochemical, and clinical parameters in lamivudine-resistant HBVinfected patients. Between 1990 and 2003 7 adult recipients of ortothopic liver transplants who experienced lamivudine-resistant HBV infection (pretransplantation or posttransplantation) were enrolled in a prospective study to administer AD for 48 weeks. At baseline they showed serum HBV DNA between 2.2 ⫻ 106 and 1.1 ⫻ 108 copies/mL. After 48 weeks of AD treatment, the median time-weighted average change in serum HBV DNA (log 10 copies/mL) was ⫺3.19 (SD, 1.65). In 3 patients with HBV, DNA was undetectable (⬍400 copies/mL) at the end of the follow-up. HBe antigen seroconversion was observed in 1 patient. No significant adverse effects were recorded, except for renal functional impairment in 1 patient who had previous renal insufficiency. In our study, adefovir was an effective drug to suppression HBV replication in liver transplant recipients with lamivudine-resistant HBV. Excluding renal function abnormalities, tolerance of the drug was excellent. None of the patients developed resistance to adefovir. Therapy with AD in liver transplant recipients is effective and safe, although renal function should be monitored closely.
H
EPATITIS B virus (HBV) infection is the leading cause of cirrhosis and hepatocellular carcinoma worldwide.1 Currently, strategies to prevent recurrence of HBV infection in the liver allograft2 are not completely successful; some orthotopic liver transplant (OLT) recipients display HBV infection in the graft. The most frequent therapy for posttransplantation HBV recurrence is lamivudine (LAM), but this drug is associated with high resistance rates.2 Adefovir dipivoxil (AD) is a nucleotide analogue of adenosine with activity against HBV. In preliminary re-
ports, adefovir has achieved significant improvements in
From the Liver Transplant Unit (A.H.d.T.E., J.M.M.P., E.R.G., J.L.M., J.R.N., J.L.d.l.P., V.S.T., C.B.P., V.C.-M.M.), and Microbiology Department (F.P.A.), Hospital Puerta de Hierro, Madrid, Spain. Address reprint requests to Dr José Marı´a Moreno Planas, Unidad de Trasplante Hepático, Hospital Puerta de Hierro, San Martı´n de Porres 4, 28035 Madrid, Spain. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.02.031
Transplantation Proceedings, 37, 1507–1508 (2005)
1507
1508
virologic, biochemical, and clinical parameters3–5 in patients with HBV. We designed this study to evaluate the efficacy of AD as therapy for LAM-resistant HBV in patients with posttransplantation HBV infection. PATIENTS AND METHODS Seven adult recipients of an OLT between 1990 and 2003 with LAM-resistant HBV infection were enrolled in a prospective study to evaluate the efficacy and safety of AD. The primary end point was the virologic response in terms of change in serum HBV DNA (log 10 copies/mL) from baseline up to weeks 24 and 48. Sèrum DNA was measured with the Roche Amplicor Monitor PCR; the lower limit of detection was ⬍400 copies/mL. Each patient was initially given 10 mg AD per day. Adverse events were recorded to assess safety.
RESULTS
The study population was composed of 6 men and 1 woman of mean age 46 years (range, 33– 66). The mean follow-up after OLT was 80 months (range, 9 –153). Immunosuppressive therapy was cyclosporine in 5 patients (57%) and tacrolimus in 2 patients (29%). Three patients (43%) had creatinine clearance value ⬍60 mL/min. All patients had LAM-resistant HBV infection with baseline serum HBV DNA between 2.2 ⫻ 106 and 1.1 ⫻ 108 copies/mL (median, 1.5 ⫻ 106). Four patients (57%) had recurrence of HBV infection in the liver graft, and 3 had “de novo” HBV infection. Five patients (71%) had positive HBe antigen and 2 (29%) had negative HBe antigen hepatitis. In 5 patients, LAM was changed to AD, in the other 2 AD was added to LAM. In 1 patient with previous renal dysfunction, AD was withdrawn after 45 days due to worsening renal function. A mild increase in serum creatinine level was observed in another patient. No other significant adverse effects were recorded. After 24 and 48 weeks, the median time-weighted average change in serum HBV DNA (log 10 copies/mL) was ⫺2.41 and ⫺3.19 (SD, 1.65), respectively. In 3 out of 6 patients who completed 1 year of therapy, HBV DNA was undetectable (⬍400 copies/mL). The decrease in DNA was similar among patients with AD or AD-LAM. HBe antigen seroconversion was achieved in 1 patient. DISCUSSION
In the absence of effective therapies, HBV infection of the liver allograft is associated with reduced graft and patient survival. The first-line therapy for these patients is LAM,
ECHANOJÁUREGUI, PLANAS, GONZÁLEZ ET AL
which is an effective drug, but shows high resistance rates in OLT recipients. In our study, AD was an effective drug to achieve suppression of HBV replication in OLT recipients with LAM-resistant HBV. This beneficial effect has been previously reported in patients with4,5 and without OLT.3,6 However, as in previous trials, HBe antigen seroconversion is uncommon after 1 year of follow-up.7 Renal dysfunction in OLT recipients is common, mainly due to the use of calcineurin inhibitors. A higher frequency of renal laboratory abnormalities has been associated with the use of adefovir.5,7 In our population, the only severe adverse event was an increased creatinine level in a patient with chronic renal dysfunction, which did not improve after discontinuation of adefovir, making its direct relationship with the drug questionable. Another patient showed a mild increase in the creatinine value. Excluding renal abnormalities, tolerance to the drug was excellent, as has been reported in many series.5,7 Although the number of patients was small, none of them developed resistance to adefovir. Previous reports have pointed out the uncommon development of resistance to this drug.8 In summary, therapy with AD in liver transplant recipients is effective and safe. However, these patients require close monitoring of renal function.
REFERENCES 1. Conjeevaram HS, Lok ASF: Management of chronic hepatitis B. J Hepatol 38:S90, 2003 2. Papatheodoridis GV, Sevastianos V, Burroughs AK: Prevention and treatment for hepatitis B virus infection after liver transplantation in the nucleoside analogues era. Am J Transplant 3:250, 2003 3. Perrillo R, Schiff E, Yoshida E, et al: Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 32:129, 2000 4. Ahmed J, Dodson SF, Balan V, et al: Adefovir dipivoxil suppresses lamivudine resistant hepatitis B virus in liver transplant recipients. Hepatology 32:292A, 2003 5. Schiff ER, Lai CL, Hadziyannis S, et al: Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre and post liver transplantation patients. Hepatology 38:1419, 2003 6. Peters MG, Hann HW, Martin P, et al: Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 126:91, 2004 7. Marcellin P, Chang TT, Lim SG, et al: Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 348:808, 2003 8. Westland CE, Yang H, Delaney IV WE, et al: Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology 38:96, 2003