- Email: [email protected]
Pegylated Interferon and Ribavirin for the Recurrence of Chronic Hepatitis C Genotype 1 in Transplant Patients
Pegylated Interferon and Ribavirin for the Recurrence of Chronic Hepatitis C Genotype 1 in Transplant Patients E. Oton, R. Barcena, S. Garcia-Garzon, A. Moreno-Zamora, A. Moreno, M. Garcia-Gonzalez, C. Blesa, J.R. Foruny, and P. Ruiz ABSTRACT The efficacy of pegylated interferon (p-IFN) and ribavirin (RB) in transplant patients is not well known. Chronic hepatitis C evolves in a more aggressive form after transplantation, causing a worse survival. Twenty-one naïve patients with recurrent chronic hepatitis C demonstrated by biopsy were treated for 48 weeks with p-IFN alpha2b (1.5 g/kg/wk) and RB (⬎10.6 mg/kg/d). Quantification of RNA was performed (Amplicor Cobas 2.0 Roche) at baseline, 4, 12, 24, 48, and 72 weeks. A qualitative technique was used when quantitative levels were undetectable. At more than 1 year since liver transplantation we did not detect coinfection with human immunodeficiency virus or use steroid treatment. Among the cohort there were 16 men (76.2%). The mean overall age was 52 ⫾ 12 years. Time from liver transplant to treatment was 1637 ⫾ 1030 days. They were all infected with genotype 1. Eight patients received cyclosporine and the others tacrolimus. One patient was coinfected with hepatitis B virus and was receiving lamivudine. The mean initial histological activity index was 6.9 ⫾ 1.5 and fibrosis, 2.52 ⫾ 1.8 (Ishak). Two patients needed spleen embolization before the treatment. Two patients had to stop the treatment: one due to clinical intolerance, and the other one due to a cholangitis. In 14%, p-IFN doses were adjusted. In 32% RB was adjusted. Five (23.8%) did not respond at 24 weeks. Fourteen (66.7%) showed end-treatment responses but four relapsed at 72 weeks. A sustained viral response was achieved in 9 (42.8%). One patient died due to arterial thrombosis just after completing the treatment.
F
ORTY-EIGHT WEEKS of pegylated interferon (p-IFN) and ribavirin (RB) is the most effective treatment for chronic hepatitis C (CHC), leading to a sustained viral response of 42% to 46% in genotype 1 patients.1,2 After liver transplantation, recurrence of CHC happens in almost 100%; frequently its evolution is more aggressive, leading to cirrhosis in few years. Liver transplant patient survival in the presence of CHC has shown to be lower than that after other etiologies.3 The effectiveness and adverse events of this treatment among transplant patients are not well known; there is no standard treatment. Another matter of debate is the moment to start the treatment as the immunosuppression varies during the posttransplant evolution. PATIENTS AND METHODS Twenty-one naïve patients with recurrent chronic hepatitis C, as demonstrated by liver biopsy, were treated for 48 weeks with p-IFN alpha2b (1.5 g/kg/wk) and RB (more than 10.6 mg/kg). Coinfection with human immunodeficiency virus was excluded. None of the
patients were receiving steroids at that time. All patients were genotype 1. There was at least 1 year since liver transplantation. Quantification of RNA was performed (Amplicor Cobas 2.0 Roche) at baseline, 4, 12, 24, 48, and 72 weeks. A qualitative technique was used when quantitative levels were undetectable. High or low viral loads were classified based upon a cutoff of 800,000 IU/mL. If there was no decrease in viral load at 24 weeks, we considered the patient to be a nonresponder and treatment was discontinued.
From the Liver Gastroenterology Service, (E.O., R.B., S.G.-G., M.G.-G., C.B., J.R.F.), Infectious Diseases Service (A.M.-Z.), Pathology Service (A.M.), and Microbiology Service (P.R.), Ramon y Cajal Hospital, Madrid, Spain. Address reprint requests to Elena Oton, Liver Gastroenterology Service, Ramon y Cajal Hospital, Carretera Colmenar Viejo km 9, 1, CP 28034 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.2005.10.060
Transplantation Proceedings, 37, 3963–3964 (2005)
3963
3964
RESULTS
Among 21 recruited patients were 16 men and five women. The mean age was 52 ⫾ 12 years. The time from liver transplant to the beginning of the treatment was 1637 ⫾ 1030 days (range: 420 to 4394). All patients were genotype 1. Eight patients received cyclosporine and the rest tacrolimus. Mycophenolate mofetil had been added to the immunosuppression of five patients due to renal failure. One patient was coinfected with hepatitis B virus and therefore was receiving lamivudine. The mean initial histological activity index was 6.9 ⫾ 1.5 and fibrosis, 2.52 ⫾ 1.8 (Ishak). Fifteen patients showed chronic hepatitis on liver biopsy; six patients had histological cirrhosis. Two patients needed spleen embolization before the treatment to correct cytopenias, particularly thrombocytopenia. The mean initial aspartate aminotransferase was 134 ⫾ 66 IU/L and alanine aminotransferase 197 ⫾ 111 IU/L. The initial viral load was high in eight patients and low in 13. Six (28.6%) patients showed viral responses at 4 weeks versus 13 (62%) at 12 and 24 weeks. An end-treatment response was achieved in 14 (66.7%). However, four patients relapsed at 72 weeks. One patient with an endtreatment response developed an arterial thrombosis 2 months after completing treatment, leading to death. Therefore nine patients (42.8%) showed sustained viral responses at 72 weeks. Two patients (9.5%) had to stop treatment in the second month of treatment, due to clinical intolerance in one and cholangitis in the other. We did not observe any acute rejection episode. The doses of p-IFN and RB were adjusted in 14% and 32%, respectively. DISCUSSION
The efficacy and safety of p-IFN and RB for transplanted patients are not well established. The possibility of acute or chronic rejection remains controversial.4 In a recent article
OTON, BARCENA, GARCIA-GARZON ET AL
Chalasani et al5 treated 54 patients with p-IFN alone at 3 weeks after liver transplantation, achieving only an 8% sustained viral response. Several authors have treated with p-IFN and RB at progressive doses, obtaining sustained viral responses in about 26% to 45%.6,7 From these results and those of our study, the best strategy in those patients seems to be treatment with p-IFN and RB at the doses usually employed in nontransplant patients, beginning more than 1 year after liver transplantation, when immunosuppression is reduced. The sustained viral response in these patients seems to be similar to that in nontransplanted patients. REFERENCES 1. Manns MP, McHutchison JG, Gordon SC, et al: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958, 2001 2. Fried MW, Shiffman ML, Reddy KR, et al: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347:975, 2002 3. Forman LM, Lewis JD, Berlin JA, et al: The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 122:889, 2002 4. Stravitz RT, Shiffman ML, Sanyal AJ, et al: Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation. Liver Transpl 10:850, 2004 5. Chalasani N, Manzarbeitia C, Ferenci P, et al: Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology 41:289, 2005 6. Rodriguez-Luna H, Khatib A, Sharma P, et al: Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon alpha2b and ribavirin: an open-label series. Transplantation 77:190, 2004 7. Dumortier J, Scoazec JY, Chevallier P, et al: Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination. J Hepatol 40:699, 2004
F
ORTY-EIGHT WEEKS of pegylated interferon (p-IFN) and ribavirin (RB) is the most effective treatment for chronic hepatitis C (CHC), leading to a sustained viral response of 42% to 46% in genotype 1 patients.1,2 After liver transplantation, recurrence of CHC happens in almost 100%; frequently its evolution is more aggressive, leading to cirrhosis in few years. Liver transplant patient survival in the presence of CHC has shown to be lower than that after other etiologies.3 The effectiveness and adverse events of this treatment among transplant patients are not well known; there is no standard treatment. Another matter of debate is the moment to start the treatment as the immunosuppression varies during the posttransplant evolution. PATIENTS AND METHODS Twenty-one naïve patients with recurrent chronic hepatitis C, as demonstrated by liver biopsy, were treated for 48 weeks with p-IFN alpha2b (1.5 g/kg/wk) and RB (more than 10.6 mg/kg). Coinfection with human immunodeficiency virus was excluded. None of the
patients were receiving steroids at that time. All patients were genotype 1. There was at least 1 year since liver transplantation. Quantification of RNA was performed (Amplicor Cobas 2.0 Roche) at baseline, 4, 12, 24, 48, and 72 weeks. A qualitative technique was used when quantitative levels were undetectable. High or low viral loads were classified based upon a cutoff of 800,000 IU/mL. If there was no decrease in viral load at 24 weeks, we considered the patient to be a nonresponder and treatment was discontinued.
From the Liver Gastroenterology Service, (E.O., R.B., S.G.-G., M.G.-G., C.B., J.R.F.), Infectious Diseases Service (A.M.-Z.), Pathology Service (A.M.), and Microbiology Service (P.R.), Ramon y Cajal Hospital, Madrid, Spain. Address reprint requests to Elena Oton, Liver Gastroenterology Service, Ramon y Cajal Hospital, Carretera Colmenar Viejo km 9, 1, CP 28034 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.2005.10.060
Transplantation Proceedings, 37, 3963–3964 (2005)
3963
3964
RESULTS
Among 21 recruited patients were 16 men and five women. The mean age was 52 ⫾ 12 years. The time from liver transplant to the beginning of the treatment was 1637 ⫾ 1030 days (range: 420 to 4394). All patients were genotype 1. Eight patients received cyclosporine and the rest tacrolimus. Mycophenolate mofetil had been added to the immunosuppression of five patients due to renal failure. One patient was coinfected with hepatitis B virus and therefore was receiving lamivudine. The mean initial histological activity index was 6.9 ⫾ 1.5 and fibrosis, 2.52 ⫾ 1.8 (Ishak). Fifteen patients showed chronic hepatitis on liver biopsy; six patients had histological cirrhosis. Two patients needed spleen embolization before the treatment to correct cytopenias, particularly thrombocytopenia. The mean initial aspartate aminotransferase was 134 ⫾ 66 IU/L and alanine aminotransferase 197 ⫾ 111 IU/L. The initial viral load was high in eight patients and low in 13. Six (28.6%) patients showed viral responses at 4 weeks versus 13 (62%) at 12 and 24 weeks. An end-treatment response was achieved in 14 (66.7%). However, four patients relapsed at 72 weeks. One patient with an endtreatment response developed an arterial thrombosis 2 months after completing treatment, leading to death. Therefore nine patients (42.8%) showed sustained viral responses at 72 weeks. Two patients (9.5%) had to stop treatment in the second month of treatment, due to clinical intolerance in one and cholangitis in the other. We did not observe any acute rejection episode. The doses of p-IFN and RB were adjusted in 14% and 32%, respectively. DISCUSSION
The efficacy and safety of p-IFN and RB for transplanted patients are not well established. The possibility of acute or chronic rejection remains controversial.4 In a recent article
OTON, BARCENA, GARCIA-GARZON ET AL
Chalasani et al5 treated 54 patients with p-IFN alone at 3 weeks after liver transplantation, achieving only an 8% sustained viral response. Several authors have treated with p-IFN and RB at progressive doses, obtaining sustained viral responses in about 26% to 45%.6,7 From these results and those of our study, the best strategy in those patients seems to be treatment with p-IFN and RB at the doses usually employed in nontransplant patients, beginning more than 1 year after liver transplantation, when immunosuppression is reduced. The sustained viral response in these patients seems to be similar to that in nontransplanted patients. REFERENCES 1. Manns MP, McHutchison JG, Gordon SC, et al: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958, 2001 2. Fried MW, Shiffman ML, Reddy KR, et al: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347:975, 2002 3. Forman LM, Lewis JD, Berlin JA, et al: The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 122:889, 2002 4. Stravitz RT, Shiffman ML, Sanyal AJ, et al: Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation. Liver Transpl 10:850, 2004 5. Chalasani N, Manzarbeitia C, Ferenci P, et al: Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology 41:289, 2005 6. Rodriguez-Luna H, Khatib A, Sharma P, et al: Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon alpha2b and ribavirin: an open-label series. Transplantation 77:190, 2004 7. Dumortier J, Scoazec JY, Chevallier P, et al: Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination. J Hepatol 40:699, 2004