- Email: [email protected]
Impact of cyclosporine on the development of immunosuppressive therapy in liver transplantation
Impact of Cyclosporine on the Development of Immunosuppressive Therapy in Liver Transplantation T. Casanovas Taltavull ABSTRACT Over the last 20 years, immunosuppression protocols in liver transplant patients have been based on calcineurin inhibitors, such as cyclosporine (CsA). Currently, there are three outstanding clinical issues related to the use of CsA in the liver transplant setting that merit further attention: (1) dose adjustment according to 2-hour postdose (instead of trough) concentrations to improve efficacy and safety, (2) possible synergistic effect between CsA and antiviral treatments for recurrent posttransplant hepatitis C infection, and (3) preliminary results showing favorable outcomes after liver transplantation in HIV-positive patients receiving antiviral therapy.
F
ROM THE mid-1980s to the present, orthotopic liver transplantation (OLT) has become the treatment of choice for selected patients with acute liver failure, advanced liver disease and hepatic tumors.1 The first OLT in Spain was performed in the Liver Transplant Unit of Hospital Universitario de Bellvitge in 1984. Since then, 780 such procedures have been carried out in this center and cyclosporine (CsA), a calcineurin inhibitor, has remained the basis of immunosuppressive protocols in these patients.2 Since the start of the liver transplant program, the goal of the medical-surgical team has centered on achieving clinical benefits, high survival rates, and an excellent quality of life for transplant recipients.3,4 Early immunosuppressive regimens used in OLT consisted of CsA administered in combination with corticoids and azathioprine. However, there was a notable incidence of acute rejection episodes that required high doses of corticoids and, sometimes, monoclonal antibodies. With the use of induction treatment based on lymphocyte depletion preparations, added to corticosteroids and azathioprine as well as sequentially administered, calcineurin inhibitors, rejection episodes have decreased and 1-year survival rates have reached 90%. Recently, anti–IL-2 humanized antibodies (basiliximab and daclizumab) have been substituted for antilymphocytic globulins during the induction period.5 In our experience, acute rejection has decreased without an apparent increase in short-term toxicity.6 Tacrolimus (TAC), another calcineurin inhibitor and potent immunosuppressant, has been applied in liver transplantation since the 1990s. When combined with corticoids, the occurrence of acute rejection episodes decreased to around 30%.7 Both CsA and TAC have a narrow therapeu© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 291S⫺294S (2004)
tic index; both inhibit T-cell–mediated responses by preventing formation of interleukin-2 (IL-2) through a common mechanism. They are, however, structurally dissimilar with different secondary effects. The principal clinical drawbacks of these drugs are nephrotoxicity as well as infectious and malignant complications. Cyclosporine-related adverse effects include gingival hyperplasia and hypertrichosis. TAC shows a diabetogenic effect and poorer outcomes of infection in patients with hepatitis C, although these results may be due to the more potent immunosuppression administered in some series.8 CsA and TAC may differ in their effects on TH1 and TH2 cytokine expression. These preliminary observations may have long-term implications for the choice of immunosuppressive therapy.9,10 A new CsA formulation, Sandimmun Neoral, became available in 1994. This drug shows improved dose linearity, with a more constant relationship between administered dose and the area under the concentration curve (AUC).11 With the more potent immunosuppressive regimens— anti-lymphocyte therapies, monoclonal antibodies, mycophenolate mofetil (MMF), and so on—preservation of initial renal function may be obtained until it is safe to deliver therapeutic levels of calcineurin inhibitor; however, a greater number of infections have been observed due to overimmunosuppression. Recent data raise concern as to From the Liver Transplant Unit, Hospital Universitario de Belvitge, L’Hospitalet de Llobregat, Barcelona, Spain. Address reprint requests to Dr. Teresa Casanovas Taltavull, Liver Transplant Unit Hospital Universitario de Bellvitge, L’Hospitalet de Llobregat 08907, Barcelona, Spain. E-mail: [email protected] 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2003.12.032 291S
292S
whether the prognosis of recurrent hepatitis C after OLT might have worsened during the last years because of the more potent initial immunosuppression and the increased donor age.12 NEW THERAPEUTIC GOALS
There are three outstanding clinical issues related to the use of CsA that merit further attention: (1) establishment of a rational basis for dose adjustment using circulating levels of CsA obtained 2 hours postadministration to improve safety and efficacy; (2) treatment of recurrent hepatitis C, based on reports showing better outcome in patients receiving CsA; and (3) the possibility to use OLT to treat end-stage liver disease in HIV-positive patients receiving antiretroviral treatment. Use of C2 Levels for Adjustment of CsA Dose
Determining the relationship between clinical outcome and CsA pharmacokinetics (absorption profile) and pharmacodynamics (effects and mechanisms of action) remains a challenge because of the drug’s narrow therapeutic window. Transplant recipients have been studied in recent years to determine the pharmacokinetic constants of CsA and interindividual differences. Maximum calcineurin and IL-2 inhibition occur at around 2 hours after administration of the drug. For this reason, the 2-hour postdose point (C2), which correlates with the AUC as the most constant maximum period of immunosuppression, has been chosen for monitoring purposes.13 Dose adjustment according to C2 (rather than trough) concentrations seems to improve the clinical outcome of de novo or long-term OLT.14 Better knowledge of the therapeutic window and the use of C2 to adjust CsA doses have led to the implementation of a new therapeutic protocol in our center. A randomized study was performed using basiliximab induction with CsA in two groups: one with and another without corticoids. The preliminary results in 64 patients (April 2001 to July 2002) showed no increase in rejection rates, fewer cases of de novo diabetes and fewer infectious complications in the steroid-free group 6 at a follow up of 9 months (range 3⫺15 months), as reported in an abstract at the 2003 meeting of the European Association for the Study of the Liver (Geneva, Switzerland). Adjustment of CsA dose by C2 levels is advantageous for HCV-positive patients, since the lower rejection risk implies fewer extra doses of corticoids, one of the known factors for an unfavorable prognosis. Treatment of Post-OLT Hepatitis C
As compared with HCV infection in immunocompetent individuals, recurrent post-OLT of HCV usually display an accelerated course.15,16 The anti-HCV immune response is essential not only to clear HCV-RNA, but also to form the hepatic lesions observed on histologic examination. Because immunosuppressants can influence both viral levels and host immune responses, immunosuppression would be expected to affect posttransplant HCV hepatitis; neverthe-
CASANOVAS TALTAVULL
less data supporting this hypothesis are scarce.7 Treatment of acute rejection episodes with bolus administration of methylprednisolone has been consistently associated with a worse outcome of recurrent hepatitis C.17 Standardized management of recurrent hepatitis C is currently not available. The indications as to who should receive anti-HCV treatment, when, and for how long are still issues to be resolved. Only one randomized controlled study on this issue has been published, but several questions remain; responders did not show histological improvement.18 In 1997, relatively good results were reported19 with the use of interferon alfa and ribavirin for recurrent HCV in liver transplant patients receiving CsA as monotherapy or in association with corticoids and/or azathioprine. Based on these findings, we initiated a pilot study in 1999 to investigate the effect of interferon alfa combined with ribavirin for treatment of recurrent post-liver transplant hepatitis C in selected patients receiving either CsA or TAC monotherapy. Although the primary goal was to eradicate HCV-RNA, the histologic lesion was also examined seeking possible improvement. All patients had undergone liver transplantation due to HCV-related cirrhosis, and had experienced recurrent hepatitis C diagnosed by liver biopsy, HCV-RNA by PCR, and elevated ALT levels. Basal characteristics were, however, restricted: age, 18 to 65 years; enrollment at least 3 months after transplant; leukocytes ⬎3 ⫻ 109/L; neutrophils ⬎1.5 ⫻ 109/L; platelets ⬎100 ⫻ 109/L, hemoglobin ⬎12 g/dL; and no renal dysfunction, rejection, or other transplant complications. Fourteen patients were treated for 12 months with standard doses of a combination of IFN-alpha 2a and ribavirin. Immunosuppression consisted of CsA or TAC monotherapy. Inflammatory activity and fibrosis stage were assessed in liver biopsy samples according to the method of Scheuer et al.20 A sustained viral response was defined as a biochemical and virologic response that persisted at least 6 months after cessation of therapy. After 12 months of the combination treatment, serum HCV-RNA was undetectable and ALT levels were normal in seven patients (50%). One patient relapsed, giving a sustained viral response in 6 of 14 (42.8%). The basal data of responders versus nonresponders showed no differences in age, HCV genotype, pretreatment ALT, HCV-RNA levels, or histologic scores. The most frequent genotype was 1b and corticosteroid treatment duration was similar in both groups. However, all the responders were receiving CsA immunosuppression, whereas most of the nonresponders were on TAC therapy (Table 1). We concluded that CsA treatment might be a favorable factor in this situation and that the influence of calcineurin inhibitors on hepatitis C recurrence and response to treatment warrants further investigation. These preliminary results, presented as posters in the 200121 and 200222 AASLD Congresses, suggest that a subset of patients with recurrent post-OLT hepatitis C may benefit from combination antiviral therapy. In our pilot study, histologic
IMPACT OF CYCLOSPORINE
293S
Table 1. Characteristics of Treated Patients Showing Differences Between Sustained Viral Responders and Nonresponders
Sex (M/F) Age (y) Genotype (1b/1a/4) ALT (kat/L) Months post-LT HCV-RNA (UI/mL) IFN-pre (Y/N) Inflammatory grade Fibrosis (1/2/3/4) Immun. (CsA/TAC) Corticosteroids (mo)
Sustained Viral Responders (n ⫽ 6)
Nonresponders (n ⫽ 8)
P
5/1 51 ⫾ 9 4/2/1 4.3 ⫾ 1.6 39 ⫾ 27 2.13 ⫾ 1.84 ⫻ 106 1/6 3.1 ⫾ 0.7 5/1/0/0 6/0 5.4 ⫾ 1.1
4/4 55 ⫾ 9 6/1/0 5.1 ⫾ 1.3 23 ⫾ 32 7.36 ⫾ 1.86 ⫻ 106 3/4 2.5 ⫾ 0.6 7/0/0/1 2/6 3.8 ⫾ 3.4
.030* .340 .420 .330 .330 .120 .560 .120 .260 .005* .440
Abbreviations: M/F, male/female; Y/N, yes/no; CsA, cyclosporine; TAC, tacrolimus. ALT (normal values ⬍ 0.6 kat/L). Liver biopsy assessed pretreatment. *Statistically significant variables.
follow-up after antiviral treatment showed a significant improvement, even in fibrosis stage in patients showing sustained viral responses. Recent reports have attributed the action of CsA to a probable antiviral activity or a synergism with some antiviral agents. In a study of OLT patients with HCV hepatitis, Ghobrial et al. failed to observe a difference in survival as a function of the calcineurin inhibitor (CsA vs TAC), but they did observe that the interval between the first and second procedure in patients requiring retransplantation was longer in those receiving CsA (787 ⫾ 805 vs 185 ⫾ 90 days).23 Kugelmas et al noted that clearance of HCV may predispose to acute rejection by lowering immunosuppression.” The risk of rejection was related to low levels of CsA or TAC. We highlight the authors’ observation that patients under treatment with CsA presented an earlier, more effective antiviral responses.24 Cyclosporine has been used as antiviral therapy in nontransplanted patients. Kakumu et al administered CsA for 3 months to 10 HCV-RNA positive patients with genotype 1b and elevated ALT levels, who had not responded to previous antiviral treatments. In five patients ALT levels were found to be normal at the end of treatment. Although this response was transitory, viremia levels did not increase and there were no changes in lymphocyte counts or subpopulations during the treatment.25 In 2003, Inoue et al26 reported the results of a controlled therapeutic study in which interferon alfa 2b plus CsA versus interferon alfa 2b monotherapy were administered to 120 patients with chronic hepatitis C. The authors found that the interferon plus CsA combination was more effective than interferon alone, particularly in patients with high viral loads and genotype 1b HCV. The precise mechanisms underlying the antiviral effect of CsA on HCV are unknown.26 From the clinical viewpoint, it is interesting that the beneficial effect of CsA observed in this study was more marked in patients with high viral loads and 1b genotypes, the most frequent type in the transplanted population and the most difficult to treat.
HIV-Positive Patients and OLT
The current use of highly active antiretroviral therapy (HAART) has improved HIV-related morbidity and mortality. However, a large proportion of HIV-infected persons present with HCV or HBV coinfection, which can progress to liver failure. Hence, there is a demand for liver transplants in HIV patients with life-threatening end-stage liver disease.27 This situation has prompted a reevaluation of transplantation for selected HIV patients in some centers. Preliminary data indicate that transplantation may be a viable treatment option for individuals with well-controlled HIV disease. However, as occurs after OLT in HIVnegative patients, recurrence of HCV is a serious problem.28 HIV-infected patients usually receive large quantities of drugs after transplantation, making them highly susceptible to toxic complications and drug interactions. Calcineurin inhibitors are metabolized through cytochrome P450 (CYP) 3A, the same enzyme complex responsible for the clearance of drugs in the HAART regimen. Overloading of the metabolic pathway may result in faster elimination of CsA or TAC, or an accumulation of antiretroviral agents. Adverse outcomes have mainly been due to interactions, for example, between interferon and ribavirin during HCV infection treatment in the early posttransplant period. The complex pharmacologic issues associated with organ transplantation in HIV-positive patients underscore the importance of clinical experience in their postoperative management.28,29 In our preliminary experience, four liver transplants have been performed in HIV/HCV coinfected patients with end-stage liver disease (one additionally with HCC). This cohort includes four men of mean age 38 years (range, 36 to 46 years), with a mean follow-up of 11 months (range, 2 to 21 months who show a survival at the time of writing 100%. The patients are receiving CsA monotherapy based on C2 target levels after basiliximab induction. In one of these patients, HCV-RNA became negative during the combined
294S
anti-HCV therapy. To date there has been no progression of HIV infection and no adverse effects on allograft function owing to HIV. ACKNOWLEDGMENT The author thanks Celine L. Cavallo for English language support.
REFERENCES 1. Prieto M, Clemente G, Casafont F, et al: Documento de consenso de indicaciones de trasplante hepa´tico. Gastroenterol Hepatol 26:355, 2003 2. Jaurrieta E, Casais L, Figueras J, et al: Ana´lisis de 500 transplantes hepa´ticos en el Hospital de Bellvitge. Med Clin (Barc) 115:521, 2000 3. Figueras J, Casanovas T, Rafecas A, et al: Quality of life after liver transplant. Med Clin (Barc) 93:207, 1989 4. Casanovas Taltavull T, Vallejo G, Herdman M, et al: Transcultural adaptation of the Liver Disease Quality of Life Instrument (LDQOL 1.0) for its use in the Spanish population. Gastroenterol Hepatol 26:234, 2003 5. Calmus Y, Soldevila-Pico I, Jaurrieta EJ, et al: Immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with azathioprine-containing triple therapy in liver transplant recipients. Liver Transpl 8:219, 2002 6. Xiol X, Castellote J, Va´zquez S, et al: Prospective randomized trial on the safety and efficacy of steroid free immunosuppression after liver transplantation. Preliminary results. J Hepatol 38(suppl 2):A 154, 2003 7. Adams DH, Liu QI: FK 506 inhibits lymphocyte migration and the production of lymphocyte chemotactic factors in liver allograft recipients. Hepatology 23:1476, 1996 8. Nelson DR, Soldevila-Pico C, Reed A, et al: Anti-interleukin-2 receptor therapy in combination with mycophenolate mofetil is associated with more severe hepatitis C recurrence after liver transplantation. Liver Transpl 7:1064, 2001 9. Zamanskaite A: FK 506 and CsA differ in their effect on intracellular cytokine expression following kidney transplantation. Transplant Proc 33:1046, 2001 10. Rosen HR: Hepatitis C virus in the human liver transplantation model. Clin Liver Dis 7:107, 2003 11. Winkler M: Cyclosporin as baseline immunosuppression in solid organ transplantation. BioDrugs 14:185, 2000 12. Berenguer M, Ferrell L, Watson J, et al: HCV-related fibrosis progression following liver transplantation: increase in recent years. J Hepatol 32:673, 2000 13. Levy G, Burra P, Cavallari A, et al: Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2 hours post-dose levels (C2). Transplantation 73:953, 2002
CASANOVAS TALTAVULL 14. Santoyo J, Suarez MA, Perez-Daga JA, et al: Efficacy of C2 monitoring of Cyclosporine Neoral in adult liver transplantation: a comparative study. Transplant Proc 33:3096, 2001 15. Rosen HR: Hepatitis B and C in the liver transplant recipient. current understanding and treatment. Liver Transplantation 7(Suppl 1):S87, 2001 16. Gane EJ, Portmann BC, Naoumov NV, et al: Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med 334:815, 1996 17. Prieto M, Berenguer M, Rayon M, et al: High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes. Hepatology 29:250, 1999 18. Samuel D, Bizollon T, Feray, et al: Interferon alfa 2b plus Ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study. Gastroenterology 124:642, 2003. 19. Bizollon T, Palazzo U, Ducerf C, et al: Pilot study of the combination of interferon alfa and ribavirin as therapy of recurrent hepatitis C after liver transplantation. Hepatology 26:500, 1997 20. Scheuer PJ: Classification of chronic viral hepatitis: a need for a reassessment. J Hepatol 13:372, 1991 21. Casanovas Taltavull T, Ramos E, Serrano T, et al: Pilot study with the combination of interferon alfa and ribavirin for recurrent post-liver transplantation hepatitis C. Causes of treatment failure in two different populations. Hepatology 34:A477, 2001 22. Casanovas Taltavull T, Ramos E, Serrano T, et al: Long term histological and virological follow-up of a selected group of liver transplanted patients with hepatitis C recidive who were treated with interferon alfa and ribavirin. Hepatology 36:A58, 2002 23. Ghobrial RM, Farmer DG, Baquerizo A, et al: Orthotopic liver transplantation for hepatitis C: outcome, effect of immunosuppression, and causes of retransplantation during an 8-year single-center experience. Ann Surg 229:824, 1999 24. Kugelmas M, Osgood MJ, Trotter JF, et al: Hepatitis C virus therapy, hepatocyte drug metabolism, and risk for acute cellularrejection. Liver Transpl 9:1159, 2003 25. Kakumu S, Takayanagi M, Iwata K, et al: Cyclosporine therapy affects aminotransferase activity but not hepatitis C virus RNA levels in chronic hepatitis C. J Gastroenterol Hepatol 12:62, 1997 26. Inoue K, Sekiyama K, Yamada M, et al: Combined interferon alfa 2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial. J Gastroenterol 38:567, 2003 27. Samuel D, Duclos Vallee J Ch, Teicher E, et al: Liver transplantation in patients with HIV infection. J Hepatol 39:3, 2003 28. Stock PC, Roland ME, Carlson L, et al: Kidney and liver transplantation in human immunodeficiency virus-infected patients: a pilot safety and efficacy study. Transplantation 76:370, 2003 29. Neff GW, Bonham A, Tzakis AG, et al: Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease. Liver Transpl 9:239, 2003
F
ROM THE mid-1980s to the present, orthotopic liver transplantation (OLT) has become the treatment of choice for selected patients with acute liver failure, advanced liver disease and hepatic tumors.1 The first OLT in Spain was performed in the Liver Transplant Unit of Hospital Universitario de Bellvitge in 1984. Since then, 780 such procedures have been carried out in this center and cyclosporine (CsA), a calcineurin inhibitor, has remained the basis of immunosuppressive protocols in these patients.2 Since the start of the liver transplant program, the goal of the medical-surgical team has centered on achieving clinical benefits, high survival rates, and an excellent quality of life for transplant recipients.3,4 Early immunosuppressive regimens used in OLT consisted of CsA administered in combination with corticoids and azathioprine. However, there was a notable incidence of acute rejection episodes that required high doses of corticoids and, sometimes, monoclonal antibodies. With the use of induction treatment based on lymphocyte depletion preparations, added to corticosteroids and azathioprine as well as sequentially administered, calcineurin inhibitors, rejection episodes have decreased and 1-year survival rates have reached 90%. Recently, anti–IL-2 humanized antibodies (basiliximab and daclizumab) have been substituted for antilymphocytic globulins during the induction period.5 In our experience, acute rejection has decreased without an apparent increase in short-term toxicity.6 Tacrolimus (TAC), another calcineurin inhibitor and potent immunosuppressant, has been applied in liver transplantation since the 1990s. When combined with corticoids, the occurrence of acute rejection episodes decreased to around 30%.7 Both CsA and TAC have a narrow therapeu© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 291S⫺294S (2004)
tic index; both inhibit T-cell–mediated responses by preventing formation of interleukin-2 (IL-2) through a common mechanism. They are, however, structurally dissimilar with different secondary effects. The principal clinical drawbacks of these drugs are nephrotoxicity as well as infectious and malignant complications. Cyclosporine-related adverse effects include gingival hyperplasia and hypertrichosis. TAC shows a diabetogenic effect and poorer outcomes of infection in patients with hepatitis C, although these results may be due to the more potent immunosuppression administered in some series.8 CsA and TAC may differ in their effects on TH1 and TH2 cytokine expression. These preliminary observations may have long-term implications for the choice of immunosuppressive therapy.9,10 A new CsA formulation, Sandimmun Neoral, became available in 1994. This drug shows improved dose linearity, with a more constant relationship between administered dose and the area under the concentration curve (AUC).11 With the more potent immunosuppressive regimens— anti-lymphocyte therapies, monoclonal antibodies, mycophenolate mofetil (MMF), and so on—preservation of initial renal function may be obtained until it is safe to deliver therapeutic levels of calcineurin inhibitor; however, a greater number of infections have been observed due to overimmunosuppression. Recent data raise concern as to From the Liver Transplant Unit, Hospital Universitario de Belvitge, L’Hospitalet de Llobregat, Barcelona, Spain. Address reprint requests to Dr. Teresa Casanovas Taltavull, Liver Transplant Unit Hospital Universitario de Bellvitge, L’Hospitalet de Llobregat 08907, Barcelona, Spain. E-mail: [email protected] 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2003.12.032 291S
292S
whether the prognosis of recurrent hepatitis C after OLT might have worsened during the last years because of the more potent initial immunosuppression and the increased donor age.12 NEW THERAPEUTIC GOALS
There are three outstanding clinical issues related to the use of CsA that merit further attention: (1) establishment of a rational basis for dose adjustment using circulating levels of CsA obtained 2 hours postadministration to improve safety and efficacy; (2) treatment of recurrent hepatitis C, based on reports showing better outcome in patients receiving CsA; and (3) the possibility to use OLT to treat end-stage liver disease in HIV-positive patients receiving antiretroviral treatment. Use of C2 Levels for Adjustment of CsA Dose
Determining the relationship between clinical outcome and CsA pharmacokinetics (absorption profile) and pharmacodynamics (effects and mechanisms of action) remains a challenge because of the drug’s narrow therapeutic window. Transplant recipients have been studied in recent years to determine the pharmacokinetic constants of CsA and interindividual differences. Maximum calcineurin and IL-2 inhibition occur at around 2 hours after administration of the drug. For this reason, the 2-hour postdose point (C2), which correlates with the AUC as the most constant maximum period of immunosuppression, has been chosen for monitoring purposes.13 Dose adjustment according to C2 (rather than trough) concentrations seems to improve the clinical outcome of de novo or long-term OLT.14 Better knowledge of the therapeutic window and the use of C2 to adjust CsA doses have led to the implementation of a new therapeutic protocol in our center. A randomized study was performed using basiliximab induction with CsA in two groups: one with and another without corticoids. The preliminary results in 64 patients (April 2001 to July 2002) showed no increase in rejection rates, fewer cases of de novo diabetes and fewer infectious complications in the steroid-free group 6 at a follow up of 9 months (range 3⫺15 months), as reported in an abstract at the 2003 meeting of the European Association for the Study of the Liver (Geneva, Switzerland). Adjustment of CsA dose by C2 levels is advantageous for HCV-positive patients, since the lower rejection risk implies fewer extra doses of corticoids, one of the known factors for an unfavorable prognosis. Treatment of Post-OLT Hepatitis C
As compared with HCV infection in immunocompetent individuals, recurrent post-OLT of HCV usually display an accelerated course.15,16 The anti-HCV immune response is essential not only to clear HCV-RNA, but also to form the hepatic lesions observed on histologic examination. Because immunosuppressants can influence both viral levels and host immune responses, immunosuppression would be expected to affect posttransplant HCV hepatitis; neverthe-
CASANOVAS TALTAVULL
less data supporting this hypothesis are scarce.7 Treatment of acute rejection episodes with bolus administration of methylprednisolone has been consistently associated with a worse outcome of recurrent hepatitis C.17 Standardized management of recurrent hepatitis C is currently not available. The indications as to who should receive anti-HCV treatment, when, and for how long are still issues to be resolved. Only one randomized controlled study on this issue has been published, but several questions remain; responders did not show histological improvement.18 In 1997, relatively good results were reported19 with the use of interferon alfa and ribavirin for recurrent HCV in liver transplant patients receiving CsA as monotherapy or in association with corticoids and/or azathioprine. Based on these findings, we initiated a pilot study in 1999 to investigate the effect of interferon alfa combined with ribavirin for treatment of recurrent post-liver transplant hepatitis C in selected patients receiving either CsA or TAC monotherapy. Although the primary goal was to eradicate HCV-RNA, the histologic lesion was also examined seeking possible improvement. All patients had undergone liver transplantation due to HCV-related cirrhosis, and had experienced recurrent hepatitis C diagnosed by liver biopsy, HCV-RNA by PCR, and elevated ALT levels. Basal characteristics were, however, restricted: age, 18 to 65 years; enrollment at least 3 months after transplant; leukocytes ⬎3 ⫻ 109/L; neutrophils ⬎1.5 ⫻ 109/L; platelets ⬎100 ⫻ 109/L, hemoglobin ⬎12 g/dL; and no renal dysfunction, rejection, or other transplant complications. Fourteen patients were treated for 12 months with standard doses of a combination of IFN-alpha 2a and ribavirin. Immunosuppression consisted of CsA or TAC monotherapy. Inflammatory activity and fibrosis stage were assessed in liver biopsy samples according to the method of Scheuer et al.20 A sustained viral response was defined as a biochemical and virologic response that persisted at least 6 months after cessation of therapy. After 12 months of the combination treatment, serum HCV-RNA was undetectable and ALT levels were normal in seven patients (50%). One patient relapsed, giving a sustained viral response in 6 of 14 (42.8%). The basal data of responders versus nonresponders showed no differences in age, HCV genotype, pretreatment ALT, HCV-RNA levels, or histologic scores. The most frequent genotype was 1b and corticosteroid treatment duration was similar in both groups. However, all the responders were receiving CsA immunosuppression, whereas most of the nonresponders were on TAC therapy (Table 1). We concluded that CsA treatment might be a favorable factor in this situation and that the influence of calcineurin inhibitors on hepatitis C recurrence and response to treatment warrants further investigation. These preliminary results, presented as posters in the 200121 and 200222 AASLD Congresses, suggest that a subset of patients with recurrent post-OLT hepatitis C may benefit from combination antiviral therapy. In our pilot study, histologic
IMPACT OF CYCLOSPORINE
293S
Table 1. Characteristics of Treated Patients Showing Differences Between Sustained Viral Responders and Nonresponders
Sex (M/F) Age (y) Genotype (1b/1a/4) ALT (kat/L) Months post-LT HCV-RNA (UI/mL) IFN-pre (Y/N) Inflammatory grade Fibrosis (1/2/3/4) Immun. (CsA/TAC) Corticosteroids (mo)
Sustained Viral Responders (n ⫽ 6)
Nonresponders (n ⫽ 8)
P
5/1 51 ⫾ 9 4/2/1 4.3 ⫾ 1.6 39 ⫾ 27 2.13 ⫾ 1.84 ⫻ 106 1/6 3.1 ⫾ 0.7 5/1/0/0 6/0 5.4 ⫾ 1.1
4/4 55 ⫾ 9 6/1/0 5.1 ⫾ 1.3 23 ⫾ 32 7.36 ⫾ 1.86 ⫻ 106 3/4 2.5 ⫾ 0.6 7/0/0/1 2/6 3.8 ⫾ 3.4
.030* .340 .420 .330 .330 .120 .560 .120 .260 .005* .440
Abbreviations: M/F, male/female; Y/N, yes/no; CsA, cyclosporine; TAC, tacrolimus. ALT (normal values ⬍ 0.6 kat/L). Liver biopsy assessed pretreatment. *Statistically significant variables.
follow-up after antiviral treatment showed a significant improvement, even in fibrosis stage in patients showing sustained viral responses. Recent reports have attributed the action of CsA to a probable antiviral activity or a synergism with some antiviral agents. In a study of OLT patients with HCV hepatitis, Ghobrial et al. failed to observe a difference in survival as a function of the calcineurin inhibitor (CsA vs TAC), but they did observe that the interval between the first and second procedure in patients requiring retransplantation was longer in those receiving CsA (787 ⫾ 805 vs 185 ⫾ 90 days).23 Kugelmas et al noted that clearance of HCV may predispose to acute rejection by lowering immunosuppression.” The risk of rejection was related to low levels of CsA or TAC. We highlight the authors’ observation that patients under treatment with CsA presented an earlier, more effective antiviral responses.24 Cyclosporine has been used as antiviral therapy in nontransplanted patients. Kakumu et al administered CsA for 3 months to 10 HCV-RNA positive patients with genotype 1b and elevated ALT levels, who had not responded to previous antiviral treatments. In five patients ALT levels were found to be normal at the end of treatment. Although this response was transitory, viremia levels did not increase and there were no changes in lymphocyte counts or subpopulations during the treatment.25 In 2003, Inoue et al26 reported the results of a controlled therapeutic study in which interferon alfa 2b plus CsA versus interferon alfa 2b monotherapy were administered to 120 patients with chronic hepatitis C. The authors found that the interferon plus CsA combination was more effective than interferon alone, particularly in patients with high viral loads and genotype 1b HCV. The precise mechanisms underlying the antiviral effect of CsA on HCV are unknown.26 From the clinical viewpoint, it is interesting that the beneficial effect of CsA observed in this study was more marked in patients with high viral loads and 1b genotypes, the most frequent type in the transplanted population and the most difficult to treat.
HIV-Positive Patients and OLT
The current use of highly active antiretroviral therapy (HAART) has improved HIV-related morbidity and mortality. However, a large proportion of HIV-infected persons present with HCV or HBV coinfection, which can progress to liver failure. Hence, there is a demand for liver transplants in HIV patients with life-threatening end-stage liver disease.27 This situation has prompted a reevaluation of transplantation for selected HIV patients in some centers. Preliminary data indicate that transplantation may be a viable treatment option for individuals with well-controlled HIV disease. However, as occurs after OLT in HIVnegative patients, recurrence of HCV is a serious problem.28 HIV-infected patients usually receive large quantities of drugs after transplantation, making them highly susceptible to toxic complications and drug interactions. Calcineurin inhibitors are metabolized through cytochrome P450 (CYP) 3A, the same enzyme complex responsible for the clearance of drugs in the HAART regimen. Overloading of the metabolic pathway may result in faster elimination of CsA or TAC, or an accumulation of antiretroviral agents. Adverse outcomes have mainly been due to interactions, for example, between interferon and ribavirin during HCV infection treatment in the early posttransplant period. The complex pharmacologic issues associated with organ transplantation in HIV-positive patients underscore the importance of clinical experience in their postoperative management.28,29 In our preliminary experience, four liver transplants have been performed in HIV/HCV coinfected patients with end-stage liver disease (one additionally with HCC). This cohort includes four men of mean age 38 years (range, 36 to 46 years), with a mean follow-up of 11 months (range, 2 to 21 months who show a survival at the time of writing 100%. The patients are receiving CsA monotherapy based on C2 target levels after basiliximab induction. In one of these patients, HCV-RNA became negative during the combined
294S
anti-HCV therapy. To date there has been no progression of HIV infection and no adverse effects on allograft function owing to HIV. ACKNOWLEDGMENT The author thanks Celine L. Cavallo for English language support.
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