- Email: [email protected]
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
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 R. Bárcena, S. Del Campo, G. Moraleda, T. Casanovas, M. Prieto, M. Buti, J.M. Moreno, V. Cuervas, E. Fraga, M. De la Mata, A. Otero, M. Delgado, C. Loinaz, C. Barrios, M.L.G. Dieguez, A. Mas, J.M. Sousa, J.I. Herrero, R. Muñoz, J.F. Avilés, A. Gonzalez, and M. Rueda ABSTRACT Hepatitis B virus (HBV) recurrence and de novo HBV infection are frequent events in liver transplantation recipients. Treatment with lamivudine is initially efficient in both infections but the incidence of lamivudine-resistant HBV emergence increases over time. Adefovir appears to be promising in post–liver transplantation patients with recurrent HBV infection and lamivudine-resistant HBV. This study analyzed adefovir treatment in 42 post–liver transplantation patients who developed recurrent HBV or de novo HBV infection with lamivudine-resistant HBV (54.8% HCV-coinfected). Patients received 10 mg of oral adefovir once daily for a mean period of time of 21.5 months (range from 12 to 31 months). In 62.9% of patients, ALT levels decreased significantly. Serum HBV-DNA was undetectable in 64% of the cases. Twenty percent of patients lost HBeAg marker and 13.3% of them developed anti-HBe. In 9.5% of recipients, HBsAg became negative. There was no significant change in serum creatinine levels. In only one patient was worsening of the renal function detected, making dose adjustment necessary. No other side effects were reported. Our results confirm the efficacy and safety of adefovir treatment in post–liver transplantation patients with lamivudine-resistant HBV, neither were adefovir-resistant mutations identified in patients after 21 months of therapy, nor were there adverse events, especially renal toxicity.
R
ECURRENT hepatitis B virus (HBV) has been a frequent event that still occurs in some patients.1– 4 Also, de novo HBV infection has been common after liver transplantation (OLT) because of the use of anti-HBc-positive livers.1,5 Both HBV infections have been successfully treated with lamivudine, but emergence of lamivudine-resistant HBV mutants occurs at a rate of 65% after 4 years of treatment.4,5 Adefovir, an analogue of adenosine monophosphate, has been shown to be effective in the treatment of HBV infection, whether hepatitis B e antigen-positive6 or hepatitis B e antigen-negative,7 so it was recently approved for treatment of chronic HBV. Moreover, adefovir has been shown to have activity against lamivudine-resistant strains of HBV.8,9 However, clinical experience in treatment of HBV infection after OLT is still not entirely clear. We report our experience in the adefovir treatment of 42 liver transplantation recipients who developed recurrent HBV or de novo HBV infection with lamivudine-resistant HBV.
PATIENTS AND METHODS This retrospective-prospective, observational, non placebocontrolled, multicenter study included 42 liver recipients treated
From the Hospital Ramón y Cajal (R.B., S.D.C., G.M.), Madrid; C.S.U. De Bellvitge (T.C.), L’Hospitalet De Llobregat; Hospital Universitario La Fe (M.P.), Valencia; Hospital Vall d’Hebron (M.B.), Barcelona; Hospital Puerta de Hierro (J.M.M., V.C., C.B.), Madrid; Hospita Reina Sofia (E.F., M.D.L.M.), Córdoba; Hospital Juan Canalejo (A.O.), La Coruña; Hospital Universitario de Santiago (M.D.), Santiago de Compostela; Hospital 12 de Octubre (C.L., R.M.), Madrid; Hospital Central de Asturias (M.L.G.D.), Oviedo; Hospital Clinic I Provincial (A.M.), Barcelona; Hospital Universitario Virgen del Rocı´o (J.M.S.), Sevilla; Cliníca de Navarra (J.I.H.), Pamplona; Hospital Virgen de la Candelaria (J.F.A., A.G.), Tenerife; and Gilead ciences, Inc. (M.R.), Spain. Address reprint requests to R. Bárcena, Hospital Ramón y Cajal, Department of Gastroenterology, Ctra. Colmenar Km 9.1, 28034 Madrid, Spain. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.10.061
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3960
Transplantation Proceedings, 37, 3960 –3962 (2005)
ADEFOVIR DIPIVOXIL TREATMENT
3961
Table 1. Basal and Final Clinical and Biochemical Features of the Patients Basal
Male sex, n (%) Age (y): mean ⫾ SD HBeAg⫹, n (%) HBeAg⫺, n (%) Anti-HBe⫹, n (%) HBsAg⫹, n (%) HBV-DNA⫹, n (%) ALT(IU/L; mean ⫾ SD) AST(IU/L; mean ⫾ SD) Bilirubin (mg/dL; mean ⫾ SD) Creatinine (mg/dL; mean ⫾ SD) Platelets (109/L; mean ⫾ SD)
36 (85.7%) 53 ⫾ 8.71 30 (71.4%) 12 (28.6%) 12 (28.6%) 42 (100%) 42 (100%) 116.2 ⫾ 109.55 93.9 ⫾ 69.06 1.31 ⫾ 0.79 1.21 ⫾ 0.37 133.95 ⫾ 65.34
Final
24 (57.1%) 18 (42.9%) 16 (38.1%) 38 (90.5%) 15 (35.7%) 45.74 ⫾ 38.49* 39.24 ⫾ 24.98* 0.89 ⫾ 0.36* 1.34 ⫾ 0.49 149.96 ⫾ 75.62*
*P ⬍ .05.
with adefovir before this drug was commercialized in Spain (May 11, 2000 to July 13, 2003). Eighteen patients had de novo HBV infection and 24 recurrent HBV infection (22 cases [54.8%] were coinfected with hepatitis C virus). Median time from OLT to beginning adefovir treatment was 5 years. The post-OLT immunosuppressive regimen during adefovir treatment consisted of cyclosporine (CsA) monotherapy (47.6%), tacrolimus monotherapy (45.2%), or combinations with mycophenolate. All patients were previously treated with lamivudine and all had developed lamivudine-resistant HBV. Patients were given a dose of 10 mg/d of adefovir by oral administration. They returned for study visits on a 3-month basis; blood counts, liver biochemical analyses, and serum HBV-DNA were assessed at each visit. Serum HBV-DNA was determined by polymerase chain reaction (PCR). Hepatitis B e antigen (HBeAg) and antibodies against HBeAg (anti-HBe) were analyzed in patients positive for HBeAg, and hepatitis B s antigen (HBsAg) in patients who became negative for HBV DNA by PCR.
RESULTS
All patients were HBV-DNA-positive with 88% of them having elevated alanine aminotransferase (ALT) levels. The mean adefovir treatment was 21.5 months (range from 12 to 31 months). Table 1 shows the baseline and final clinical and biochemical features of the patients. In 62.9% of the patients, ALT levels decreased significantly (116.2 ⫾ 109.55 vs 45.74 ⫾ 38.49 IU/L, P ⬍ .001). Serum HBV-DNA was undetectable in 64% of the cases (27/42). Six patients (20%) lost HBeAg marker and four of them (13.3%) developed anti-HBe. In four patients (9.5%), HBsAg became negative after a mean adefovir treatment of 24 months. There was no significant change in serum creatinine levels (1.21 ⫾ 0.37 vs 1.34 ⫾ 0.49 mg/dL, P ⬎ .05). Only one patient had worsening renal function (creatinine level: 1.4 vs 3 mg/dL), requiring dose adjustment. No other side effects were reported. DISCUSSION
The first international, multicenter, open-label, compassionate use study in pre- and post-OLT patients treated with adefovir in combination with lamivudine or HBIG, has
shown the efficacy of adefovir to suppress HBV replication.10 Other published studies in post-OLT patients treated with adefovir only include a few number of patients11 or isolated cases.12, 13 We treated 42 patients with adefovir, showing its activity in post-OLT patients with lamivudine-resistant HBV as well as in nontransplanted immunocompetent patients infected with wild-type HBV6 or precore HBV mutant.7 It seems that the immunosuppressive regimen in these patients did not influence the outcome. None of the patients developed adefovir-resistant mutations after a median of 21 months of treatment. Some patients are already in 60 months of treatment, a finding that agrees with the low resistance frequency of this drug. The first published study of resistance to adefovir dipivoxil therapy showed that mutants developed after 96 weeks of treatment14 at an incidence less than 2% after 2 years of therapy.15 Recently, the first case of adefovir resistance16 in an OLT patient treated with lamivudine has been reported. Adefovir was well tolerated. Only one patient with impaired renal function at the beginning of adefovir therapy (creatinine level: 1.4 mg/dL) had increased levels after 12 months of treatment, so dose reduction was necessary. Probably, the renal toxicity was due to CsA administration because reported adefovir renal toxicity is rare.17 In conclusion, our results confirmed the efficacy and safety of adefovir treatment in post-OLT patients with lamivudine-resistant HBV. Moreover, there was no evidence of emergence of adefovirresistant HBV over the first year of therapy as well as no appearance of adverse events in this population, especially renal toxicity.8 REFERENCES 1. Wang ZX, Ding GS, Fu H, et al: Prevention of hepatitis B virus reinfection after orthotopic liver transplantation. Hepatobiliary Pancreat Dis Int Aug 3:345, 2004 2. Neff GW, O’brien CB, Nery J, et al: Outcomes in liver transplant recipients with hepatitis B virus: resistance and recurrence patterns from a large transplant center over the last decade. Liver Transpl 10:1372, 2004 3. Perrillo RP, Wright T, Rakela J, et al: Lamivudine North American Transplant Group. A multicenter United StatesCanadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 33:424, 2001 4. Rayes N, Seehofer D, Hopf U, et al: Comparison of famciclovir and lamivudine in the long-term treatment of hepatitis B infection after liver transplantation. Transplantation 71:96, 2001 5. Ben-Ari Z, Mor E, Shapira Z, Tur-Kaspa R: Long-term experience with lamivudine therapy for hepatitis B virus infection after liver transplantation. Liver Transpl 7:113, 2001 6. Marcellin P, Chang TT, Lim SG, et al: Adefovir Dipivoxil 437 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 27:808, 2003 7. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al: Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. New Engl J Med 348:800, 2003 8. Perrillo R, Hann HW, Mutimer D, et al: Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMMD mutant hepatitis B virus. Gastroenterology 126:81, 2004 9. Peters MG, Hann HW, Martin P, et al: Adefovir dipivoxil alone or in combination with Lamivudine inpatients with
3962 Lamivudine-resistant chronic hepatitis B. Gastroenterology 126:91, 2004 10. Schiff ER, Lai CL, Hadziyannis S, et al: Behalf of the Adefovir Dipovoxil Study 435 International Investigators Group. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology 38:1419, 2003 11. Barcena R, Cid L, Lopez P: Use of adefovir in the treatment of the chronic hepatitis B virus infection with resistance to lamivudine. Transplant Proc 35:1841, 2003 12. Lo CM, Cheung ST, Ng IO, et al: Fibrosing cholestatic hepatitis secondary to precore/core promoter hepatitis B variant with lamivudine resistance: successful retransplantation with combination adefovir dipivoxil and hepatitis B immunoglobulin. Liver Transpl 10:557, 2004 13. Beckebaum S, Malago M, Dirsch O, et al: Efficacy of combined lamivudine and adefovir dipivoxil treatment for severe
BÁRCENA, DEL CAMPO, MORALEDA ET AL HBV graft reinfection after living donor liver transplantation. Clin Transplant 17:554, 2003 14. Angus P, Vaughan R, Xiong S, et al: Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 125:292, 2003 15. Westland CE, Yang H, Delaney WE, et al: 437 and 438 Study Teams. Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology 38:96, 2003 16. Villeneuve JP, Durantel D, Durantel S, et al: Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient. J Hepatol 39:1085, 2003 17. Izzedine H, Hulot JS, Launay-Vacher V, et al: Adefovir Dipivoxil International 437 Study Group; Adefovir Dipivoxil International 438 Study Group. Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies. Kidney Int 66:1153, 2004
R
ECURRENT hepatitis B virus (HBV) has been a frequent event that still occurs in some patients.1– 4 Also, de novo HBV infection has been common after liver transplantation (OLT) because of the use of anti-HBc-positive livers.1,5 Both HBV infections have been successfully treated with lamivudine, but emergence of lamivudine-resistant HBV mutants occurs at a rate of 65% after 4 years of treatment.4,5 Adefovir, an analogue of adenosine monophosphate, has been shown to be effective in the treatment of HBV infection, whether hepatitis B e antigen-positive6 or hepatitis B e antigen-negative,7 so it was recently approved for treatment of chronic HBV. Moreover, adefovir has been shown to have activity against lamivudine-resistant strains of HBV.8,9 However, clinical experience in treatment of HBV infection after OLT is still not entirely clear. We report our experience in the adefovir treatment of 42 liver transplantation recipients who developed recurrent HBV or de novo HBV infection with lamivudine-resistant HBV.
PATIENTS AND METHODS This retrospective-prospective, observational, non placebocontrolled, multicenter study included 42 liver recipients treated
From the Hospital Ramón y Cajal (R.B., S.D.C., G.M.), Madrid; C.S.U. De Bellvitge (T.C.), L’Hospitalet De Llobregat; Hospital Universitario La Fe (M.P.), Valencia; Hospital Vall d’Hebron (M.B.), Barcelona; Hospital Puerta de Hierro (J.M.M., V.C., C.B.), Madrid; Hospita Reina Sofia (E.F., M.D.L.M.), Córdoba; Hospital Juan Canalejo (A.O.), La Coruña; Hospital Universitario de Santiago (M.D.), Santiago de Compostela; Hospital 12 de Octubre (C.L., R.M.), Madrid; Hospital Central de Asturias (M.L.G.D.), Oviedo; Hospital Clinic I Provincial (A.M.), Barcelona; Hospital Universitario Virgen del Rocı´o (J.M.S.), Sevilla; Cliníca de Navarra (J.I.H.), Pamplona; Hospital Virgen de la Candelaria (J.F.A., A.G.), Tenerife; and Gilead ciences, Inc. (M.R.), Spain. Address reprint requests to R. Bárcena, Hospital Ramón y Cajal, Department of Gastroenterology, Ctra. Colmenar Km 9.1, 28034 Madrid, Spain. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.10.061
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3960
Transplantation Proceedings, 37, 3960 –3962 (2005)
ADEFOVIR DIPIVOXIL TREATMENT
3961
Table 1. Basal and Final Clinical and Biochemical Features of the Patients Basal
Male sex, n (%) Age (y): mean ⫾ SD HBeAg⫹, n (%) HBeAg⫺, n (%) Anti-HBe⫹, n (%) HBsAg⫹, n (%) HBV-DNA⫹, n (%) ALT(IU/L; mean ⫾ SD) AST(IU/L; mean ⫾ SD) Bilirubin (mg/dL; mean ⫾ SD) Creatinine (mg/dL; mean ⫾ SD) Platelets (109/L; mean ⫾ SD)
36 (85.7%) 53 ⫾ 8.71 30 (71.4%) 12 (28.6%) 12 (28.6%) 42 (100%) 42 (100%) 116.2 ⫾ 109.55 93.9 ⫾ 69.06 1.31 ⫾ 0.79 1.21 ⫾ 0.37 133.95 ⫾ 65.34
Final
24 (57.1%) 18 (42.9%) 16 (38.1%) 38 (90.5%) 15 (35.7%) 45.74 ⫾ 38.49* 39.24 ⫾ 24.98* 0.89 ⫾ 0.36* 1.34 ⫾ 0.49 149.96 ⫾ 75.62*
*P ⬍ .05.
with adefovir before this drug was commercialized in Spain (May 11, 2000 to July 13, 2003). Eighteen patients had de novo HBV infection and 24 recurrent HBV infection (22 cases [54.8%] were coinfected with hepatitis C virus). Median time from OLT to beginning adefovir treatment was 5 years. The post-OLT immunosuppressive regimen during adefovir treatment consisted of cyclosporine (CsA) monotherapy (47.6%), tacrolimus monotherapy (45.2%), or combinations with mycophenolate. All patients were previously treated with lamivudine and all had developed lamivudine-resistant HBV. Patients were given a dose of 10 mg/d of adefovir by oral administration. They returned for study visits on a 3-month basis; blood counts, liver biochemical analyses, and serum HBV-DNA were assessed at each visit. Serum HBV-DNA was determined by polymerase chain reaction (PCR). Hepatitis B e antigen (HBeAg) and antibodies against HBeAg (anti-HBe) were analyzed in patients positive for HBeAg, and hepatitis B s antigen (HBsAg) in patients who became negative for HBV DNA by PCR.
RESULTS
All patients were HBV-DNA-positive with 88% of them having elevated alanine aminotransferase (ALT) levels. The mean adefovir treatment was 21.5 months (range from 12 to 31 months). Table 1 shows the baseline and final clinical and biochemical features of the patients. In 62.9% of the patients, ALT levels decreased significantly (116.2 ⫾ 109.55 vs 45.74 ⫾ 38.49 IU/L, P ⬍ .001). Serum HBV-DNA was undetectable in 64% of the cases (27/42). Six patients (20%) lost HBeAg marker and four of them (13.3%) developed anti-HBe. In four patients (9.5%), HBsAg became negative after a mean adefovir treatment of 24 months. There was no significant change in serum creatinine levels (1.21 ⫾ 0.37 vs 1.34 ⫾ 0.49 mg/dL, P ⬎ .05). Only one patient had worsening renal function (creatinine level: 1.4 vs 3 mg/dL), requiring dose adjustment. No other side effects were reported. DISCUSSION
The first international, multicenter, open-label, compassionate use study in pre- and post-OLT patients treated with adefovir in combination with lamivudine or HBIG, has
shown the efficacy of adefovir to suppress HBV replication.10 Other published studies in post-OLT patients treated with adefovir only include a few number of patients11 or isolated cases.12, 13 We treated 42 patients with adefovir, showing its activity in post-OLT patients with lamivudine-resistant HBV as well as in nontransplanted immunocompetent patients infected with wild-type HBV6 or precore HBV mutant.7 It seems that the immunosuppressive regimen in these patients did not influence the outcome. None of the patients developed adefovir-resistant mutations after a median of 21 months of treatment. Some patients are already in 60 months of treatment, a finding that agrees with the low resistance frequency of this drug. The first published study of resistance to adefovir dipivoxil therapy showed that mutants developed after 96 weeks of treatment14 at an incidence less than 2% after 2 years of therapy.15 Recently, the first case of adefovir resistance16 in an OLT patient treated with lamivudine has been reported. Adefovir was well tolerated. Only one patient with impaired renal function at the beginning of adefovir therapy (creatinine level: 1.4 mg/dL) had increased levels after 12 months of treatment, so dose reduction was necessary. Probably, the renal toxicity was due to CsA administration because reported adefovir renal toxicity is rare.17 In conclusion, our results confirmed the efficacy and safety of adefovir treatment in post-OLT patients with lamivudine-resistant HBV. Moreover, there was no evidence of emergence of adefovirresistant HBV over the first year of therapy as well as no appearance of adverse events in this population, especially renal toxicity.8 REFERENCES 1. Wang ZX, Ding GS, Fu H, et al: Prevention of hepatitis B virus reinfection after orthotopic liver transplantation. Hepatobiliary Pancreat Dis Int Aug 3:345, 2004 2. Neff GW, O’brien CB, Nery J, et al: Outcomes in liver transplant recipients with hepatitis B virus: resistance and recurrence patterns from a large transplant center over the last decade. Liver Transpl 10:1372, 2004 3. Perrillo RP, Wright T, Rakela J, et al: Lamivudine North American Transplant Group. A multicenter United StatesCanadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 33:424, 2001 4. Rayes N, Seehofer D, Hopf U, et al: Comparison of famciclovir and lamivudine in the long-term treatment of hepatitis B infection after liver transplantation. Transplantation 71:96, 2001 5. Ben-Ari Z, Mor E, Shapira Z, Tur-Kaspa R: Long-term experience with lamivudine therapy for hepatitis B virus infection after liver transplantation. Liver Transpl 7:113, 2001 6. Marcellin P, Chang TT, Lim SG, et al: Adefovir Dipivoxil 437 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 27:808, 2003 7. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al: Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. New Engl J Med 348:800, 2003 8. Perrillo R, Hann HW, Mutimer D, et al: Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMMD mutant hepatitis B virus. Gastroenterology 126:81, 2004 9. Peters MG, Hann HW, Martin P, et al: Adefovir dipivoxil alone or in combination with Lamivudine inpatients with
3962 Lamivudine-resistant chronic hepatitis B. Gastroenterology 126:91, 2004 10. Schiff ER, Lai CL, Hadziyannis S, et al: Behalf of the Adefovir Dipovoxil Study 435 International Investigators Group. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology 38:1419, 2003 11. Barcena R, Cid L, Lopez P: Use of adefovir in the treatment of the chronic hepatitis B virus infection with resistance to lamivudine. Transplant Proc 35:1841, 2003 12. Lo CM, Cheung ST, Ng IO, et al: Fibrosing cholestatic hepatitis secondary to precore/core promoter hepatitis B variant with lamivudine resistance: successful retransplantation with combination adefovir dipivoxil and hepatitis B immunoglobulin. Liver Transpl 10:557, 2004 13. Beckebaum S, Malago M, Dirsch O, et al: Efficacy of combined lamivudine and adefovir dipivoxil treatment for severe
BÁRCENA, DEL CAMPO, MORALEDA ET AL HBV graft reinfection after living donor liver transplantation. Clin Transplant 17:554, 2003 14. Angus P, Vaughan R, Xiong S, et al: Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 125:292, 2003 15. Westland CE, Yang H, Delaney WE, et al: 437 and 438 Study Teams. Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology 38:96, 2003 16. Villeneuve JP, Durantel D, Durantel S, et al: Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient. J Hepatol 39:1085, 2003 17. Izzedine H, Hulot JS, Launay-Vacher V, et al: Adefovir Dipivoxil International 437 Study Group; Adefovir Dipivoxil International 438 Study Group. Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies. Kidney Int 66:1153, 2004