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Changes in the incidence and severity of recurrent hepatitis C after liver transplantation over 1990–1999
Viral Hepatitis
Changes in the Incidence and Severity of Recurrent Hepatitis C After Liver Transplantation Over 1990 –1999 O. Alonso, C. Loinaz, M. Abradelo, B. Pe´rez, A. Manrique, R. Go´mez, C. Jime´nez, J.C. Meneu, I. Garcı´a, and E. Moreno-Gonza´lez ABSTRACT Background/aim. Changes in immunosuppression and other factors may have changed the severity of recurrent hepatitis C during recent years. This study sought to establish the changes in incidence and severity of recurrent hepatitis C, and its association with the changes in acute rejection and induction immunosuppressive therapy between 1990 and 1999. Patients and methods. Among 213 liver transplants in HCV-infected recipients, 129 grafts were selected for this study: all grafts with severe recurrent hepatitis C (fibrosis 3– 4 in Scheuer’s score or fibrosing cholestatic hepatitis), and those grafts without severe recurrence with at least 2 years of follow up. Grafts were divided in 5 groups depending on the year of transplantation to compare recurrent hepatitis C-related variables, AR incidence and induction immunosuppression. Results. Hepatitis-free survival decreased in recent years (p ⫽ 0.015). The incidence of fibrosing cholestatic hepatitis was higher among 1996 –1997 and the 1998 –1999 periods (p ⫽ 0.019). Survival free of severe hepatitis at 1 year follow up was 95% in 1990 –1991 and 80% in 1998 –1999; however, in the long-term the survival was similar between groups (p ⫽ 0.933). HCV-related graft survival at 5 years was 93.5% in the 1990 –95 period and 82.5% in 1996 –99 (p ⫽ 0.068). Neither AR nor any regimen of induction immunosuppression was associated with changes in the occurrence of recurrent hepatitis C related survival. Conclusions. Severity of recurrent hepatitis C and HCV-related graft loss after liver transplantation were higher in the second half of the 1990s; however, there was no association with AR or induction immunosuppression.
S
INCE A DECREASED PATIENT SURVIVAL has been reported among liver transplantation (LT) recipients in recent years,1 this study sought to establish whether changes in the incidence and severity of recurrent hepatitis C, was associated with the changes in acute rejection (AR),
From the Department of Surgery, Hospital “12 de Octubre,” Madrid, Spain. Address reprint requests to O. Alonso, Department of Surgery, Hospital 12 de Octubre, Avda. Co´rdoba Km 5,5. Madrid 28041, Spain.
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00604-3
© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1836
Transplantation Proceedings, 35, 1836 –1837 (2003)
RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTS
induction immunosuppression or other factors between 1990 and 1999. PATIENTS AND METHODS Among 213 liver transplants performed on HCV-infected recipients between 1989 and 2000 in our institution, 129 patients engrafted between 1990 and 1999 were selected based upon the following criteria: grafts with severe recurrent hepatitis C (defined as fibrosis grade 3– 4 in Scheuer’s score or fibrosing cholestatic hepatitis on biopsy or at necropsy); and grafts without severe recurrence with at least 2 years of follow up. Exclusions included patients younger than 16 years or those with positive serum HBsAg or liver– kidney recipients. Mean follow up was 1848.5 ⫾ 1000.7 days. Biopsies following detection of alterations in liver function tests were performed. Induction immunosuppression consisted of cyclosporine (CsA), azathioprine and steroids (n ⫽ 89), or FK506 and steroids (n ⫽ 35), or CsA, azathioprine, steroids, and basiliximab (n ⫽ 5). Depending on the year of transplantation 5 groups were created: 1990 –1991 ⫽ 20; 1992–1993 ⫽ 18; 1994 –1995 ⫽ 25; 1996 –1997 ⫽ 41; 1998 –1999 ⫽ 25. The analysis of recurrent hepatitis C-related variables, AR incidence and induction immunosuppression compared the 5 groups. For HCV-related graft survival estimates we considered only HCV-related deaths or graft loss, considering patients with other causes of death or graft loss as “lost to follow up” at that event date. Hepatitis-free survival estimated only grafts with at least one biopsy after 100 days post-OLT. Statistical analysis was performed with chi square and ANOVA. Graft survival distributions were estimated by the Kaplan–Meier method with comparisons by the log-rank test.
RESULTS
The percentage of grafts without recurrent hepatitis at the end of follow up was similar (15% to 25%) between the 5 periods, but the hepatitis-free survival decreased in the recent years (6%, 18%, 6%, 0%, 0% at 5 years follow up from 1990 –1991 to 1998 –1999, respectively; P ⫽ .015). The incidence of fibrosing cholestatic hepatitis increased in recent years (0%, 5.6%, 0%, 12.2%, 24%, respectively; P ⫽ .019). The percentage of grafts with severe recurrence within the first two years post-OLT was similar between groups (16% to 25%), but freedom from severe hepatitis at one-year follow up decreased from 95% in 1990 –1991 to 80% in 1998 –1999. However, in the long-term the survival was similar between groups (P ⫽ .933). The mean time to severe hepatitis diagnosis among those grafts which developed it within the first two years post-OLT, decreased from 487.4 days in 1990 –1991 to 215.6 in 1998 –1999 (P ⫽ .169). HCV-related graft survival at one and four years follow up was 100%, 94.4%, 100%, 95.1%, 92%, and 100%, 94.4%, 88%, 83%, 82% in the 5 periods, respectively (P ⫽ .183). When the transplants were considered only in two time periods, HCV-related graft survival at 5 year follow up was 93.5% in the 1990 –1995 period and 82.5% in 1996 –1999 (P ⫽ .068). The incidence of AR has decreased significantly and
1837
progressively during the last decade (95% in 1990 –1991 group and 28% in 1998 –1999; P ⬍ .001) as well as the percentage of treated AR (95% to 71.4%; P ⫽ .045). Double therapy has been mainly used since 1996 with quadruple therapy in the 1998 –1999 period. Neither AR nor any induction immunosuppression regimen was associated with changes in recurrent hepatitis C-related survival distributions. Among grafts treated with basiliximab, two (40%) developed severe recurrent hepatitis within the first year post-OLT. DISCUSSION
The results show a trend toward a worsening severity of recurrent hepatitis C after OLT, with a short time to the diagnosis of hepatitis, a higher incidence of severe recurrence at one year follow up, a higher incidence of fibrosing cholestatic hepatitis, and a higher HCV-related mortality rate in recent years. These findings agree with the results of Berenguer et al. who showed a higher incidence of cirrhosis and lower graft survival among patients transplanted in recent years. The changes in immunosuppressive regimens introduced in recent years may have contributed to the changes in the severity of recurrence. However, as in our experience, most studies did not find differences in the severity of recurrent hepatitis C among CsA and FK506 treated patients.2– 4 Only the grafts treated with basiliximab showed a worse evolution of recurrent hepatitis C, but the small number of cases in that group did not allow us to draw any conclusion, particularly since other studies have demonstrated good results with anti-interleukin2 receptor antibodies in HCV-infected patients.5,6 AR, a factor associated with the severity of recurrent hepatitis C according to some authors,7,8 did not show that association in this study. Moreover, the results show an important decrease in AR incidence in recent years. If AR is a factor associated with the severity of the recurrence, it should have translated to a better evolution of recurrences, but this was not the case. Therefore other factors must be studied to ascertain which ones contribute to the recent worsening of the evolution of hepatitis C recurrences. REFERENCES 1. Berenguer M, Prieto M, San Juan F, et al: Hepatology 36:202, 2002 2. Ghobrial RM, Farmer DG, Baquerizo A, et al: Ann Surg 229:824, 1999 3. Charlton M, Seaberg E, Wiesner R, et al: Hepatology 28:823, 1998 4. Zervos XA, Weppler D, Fragulidis GP, et al: Transplantation 65:1044, 1998 5. Washburn K, Speeg KV, Esterl R, et al: Transplantation 72:1675, 2001 6. Nelson DR, Soldevila-Pico C, Reed A, et al: Liver Transpl 7:1064, 2001 7. Prieto M, Berenguer M, Rayo ´n JM, et al: Hepatology 29:250, 1999 8. Singh N, Gatowski T, Ndimbie OK, et al: Surgery 119:452, 1996
Changes in the Incidence and Severity of Recurrent Hepatitis C After Liver Transplantation Over 1990 –1999 O. Alonso, C. Loinaz, M. Abradelo, B. Pe´rez, A. Manrique, R. Go´mez, C. Jime´nez, J.C. Meneu, I. Garcı´a, and E. Moreno-Gonza´lez ABSTRACT Background/aim. Changes in immunosuppression and other factors may have changed the severity of recurrent hepatitis C during recent years. This study sought to establish the changes in incidence and severity of recurrent hepatitis C, and its association with the changes in acute rejection and induction immunosuppressive therapy between 1990 and 1999. Patients and methods. Among 213 liver transplants in HCV-infected recipients, 129 grafts were selected for this study: all grafts with severe recurrent hepatitis C (fibrosis 3– 4 in Scheuer’s score or fibrosing cholestatic hepatitis), and those grafts without severe recurrence with at least 2 years of follow up. Grafts were divided in 5 groups depending on the year of transplantation to compare recurrent hepatitis C-related variables, AR incidence and induction immunosuppression. Results. Hepatitis-free survival decreased in recent years (p ⫽ 0.015). The incidence of fibrosing cholestatic hepatitis was higher among 1996 –1997 and the 1998 –1999 periods (p ⫽ 0.019). Survival free of severe hepatitis at 1 year follow up was 95% in 1990 –1991 and 80% in 1998 –1999; however, in the long-term the survival was similar between groups (p ⫽ 0.933). HCV-related graft survival at 5 years was 93.5% in the 1990 –95 period and 82.5% in 1996 –99 (p ⫽ 0.068). Neither AR nor any regimen of induction immunosuppression was associated with changes in the occurrence of recurrent hepatitis C related survival. Conclusions. Severity of recurrent hepatitis C and HCV-related graft loss after liver transplantation were higher in the second half of the 1990s; however, there was no association with AR or induction immunosuppression.
S
INCE A DECREASED PATIENT SURVIVAL has been reported among liver transplantation (LT) recipients in recent years,1 this study sought to establish whether changes in the incidence and severity of recurrent hepatitis C, was associated with the changes in acute rejection (AR),
From the Department of Surgery, Hospital “12 de Octubre,” Madrid, Spain. Address reprint requests to O. Alonso, Department of Surgery, Hospital 12 de Octubre, Avda. Co´rdoba Km 5,5. Madrid 28041, Spain.
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00604-3
© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1836
Transplantation Proceedings, 35, 1836 –1837 (2003)
RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTS
induction immunosuppression or other factors between 1990 and 1999. PATIENTS AND METHODS Among 213 liver transplants performed on HCV-infected recipients between 1989 and 2000 in our institution, 129 patients engrafted between 1990 and 1999 were selected based upon the following criteria: grafts with severe recurrent hepatitis C (defined as fibrosis grade 3– 4 in Scheuer’s score or fibrosing cholestatic hepatitis on biopsy or at necropsy); and grafts without severe recurrence with at least 2 years of follow up. Exclusions included patients younger than 16 years or those with positive serum HBsAg or liver– kidney recipients. Mean follow up was 1848.5 ⫾ 1000.7 days. Biopsies following detection of alterations in liver function tests were performed. Induction immunosuppression consisted of cyclosporine (CsA), azathioprine and steroids (n ⫽ 89), or FK506 and steroids (n ⫽ 35), or CsA, azathioprine, steroids, and basiliximab (n ⫽ 5). Depending on the year of transplantation 5 groups were created: 1990 –1991 ⫽ 20; 1992–1993 ⫽ 18; 1994 –1995 ⫽ 25; 1996 –1997 ⫽ 41; 1998 –1999 ⫽ 25. The analysis of recurrent hepatitis C-related variables, AR incidence and induction immunosuppression compared the 5 groups. For HCV-related graft survival estimates we considered only HCV-related deaths or graft loss, considering patients with other causes of death or graft loss as “lost to follow up” at that event date. Hepatitis-free survival estimated only grafts with at least one biopsy after 100 days post-OLT. Statistical analysis was performed with chi square and ANOVA. Graft survival distributions were estimated by the Kaplan–Meier method with comparisons by the log-rank test.
RESULTS
The percentage of grafts without recurrent hepatitis at the end of follow up was similar (15% to 25%) between the 5 periods, but the hepatitis-free survival decreased in the recent years (6%, 18%, 6%, 0%, 0% at 5 years follow up from 1990 –1991 to 1998 –1999, respectively; P ⫽ .015). The incidence of fibrosing cholestatic hepatitis increased in recent years (0%, 5.6%, 0%, 12.2%, 24%, respectively; P ⫽ .019). The percentage of grafts with severe recurrence within the first two years post-OLT was similar between groups (16% to 25%), but freedom from severe hepatitis at one-year follow up decreased from 95% in 1990 –1991 to 80% in 1998 –1999. However, in the long-term the survival was similar between groups (P ⫽ .933). The mean time to severe hepatitis diagnosis among those grafts which developed it within the first two years post-OLT, decreased from 487.4 days in 1990 –1991 to 215.6 in 1998 –1999 (P ⫽ .169). HCV-related graft survival at one and four years follow up was 100%, 94.4%, 100%, 95.1%, 92%, and 100%, 94.4%, 88%, 83%, 82% in the 5 periods, respectively (P ⫽ .183). When the transplants were considered only in two time periods, HCV-related graft survival at 5 year follow up was 93.5% in the 1990 –1995 period and 82.5% in 1996 –1999 (P ⫽ .068). The incidence of AR has decreased significantly and
1837
progressively during the last decade (95% in 1990 –1991 group and 28% in 1998 –1999; P ⬍ .001) as well as the percentage of treated AR (95% to 71.4%; P ⫽ .045). Double therapy has been mainly used since 1996 with quadruple therapy in the 1998 –1999 period. Neither AR nor any induction immunosuppression regimen was associated with changes in recurrent hepatitis C-related survival distributions. Among grafts treated with basiliximab, two (40%) developed severe recurrent hepatitis within the first year post-OLT. DISCUSSION
The results show a trend toward a worsening severity of recurrent hepatitis C after OLT, with a short time to the diagnosis of hepatitis, a higher incidence of severe recurrence at one year follow up, a higher incidence of fibrosing cholestatic hepatitis, and a higher HCV-related mortality rate in recent years. These findings agree with the results of Berenguer et al. who showed a higher incidence of cirrhosis and lower graft survival among patients transplanted in recent years. The changes in immunosuppressive regimens introduced in recent years may have contributed to the changes in the severity of recurrence. However, as in our experience, most studies did not find differences in the severity of recurrent hepatitis C among CsA and FK506 treated patients.2– 4 Only the grafts treated with basiliximab showed a worse evolution of recurrent hepatitis C, but the small number of cases in that group did not allow us to draw any conclusion, particularly since other studies have demonstrated good results with anti-interleukin2 receptor antibodies in HCV-infected patients.5,6 AR, a factor associated with the severity of recurrent hepatitis C according to some authors,7,8 did not show that association in this study. Moreover, the results show an important decrease in AR incidence in recent years. If AR is a factor associated with the severity of the recurrence, it should have translated to a better evolution of recurrences, but this was not the case. Therefore other factors must be studied to ascertain which ones contribute to the recent worsening of the evolution of hepatitis C recurrences. REFERENCES 1. Berenguer M, Prieto M, San Juan F, et al: Hepatology 36:202, 2002 2. Ghobrial RM, Farmer DG, Baquerizo A, et al: Ann Surg 229:824, 1999 3. Charlton M, Seaberg E, Wiesner R, et al: Hepatology 28:823, 1998 4. Zervos XA, Weppler D, Fragulidis GP, et al: Transplantation 65:1044, 1998 5. Washburn K, Speeg KV, Esterl R, et al: Transplantation 72:1675, 2001 6. Nelson DR, Soldevila-Pico C, Reed A, et al: Liver Transpl 7:1064, 2001 7. Prieto M, Berenguer M, Rayo ´n JM, et al: Hepatology 29:250, 1999 8. Singh N, Gatowski T, Ndimbie OK, et al: Surgery 119:452, 1996