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Antiviral therapy in liver transplant recipients: Is SVR the only endpoint that matters?
Journal of Hepatology 46 (2007) 359–361 www.elsevier.com/locate/jhep
Editorial
Antiviral therapy in liver transplant recipients: Is SVR the only endpoint that matters? Alexander Kuo, Norah A. Terrault* Division of Gastroenterology, University of California San Francisco, San Francisco, CA 94143-0538, USA
See Article, pages 459–465
Recurrent hepatitis C virus (HCV) infection remains the scourge of liver transplantation. Optimum strategies to maximize patient and graft survival remain unclear. Patients transplanted for HCV-associated cirrhosis have a 23% increased rate of death and a 30% increased rate of graft loss at five years compared to those transplanted for other indications [1]. Several predictors of accelerated disease progression post-transplantation have been identified, including advanced donor age, cytomegalovirus infection, and prior treated acute rejection [2,3]. Unfortunately, most of the factors linked with accelerated disease progression are not easily modifiable. To date, management of recurrent HCV following liver transplantation has focused on the treatment of recurrent HCV disease. The decision to initiate treatment is usually prompted by abnormal serum aminotransferase levels combined with evidence of histologic disease. Aggressive subtypes of recurrent HCV, such as severe cholestatic hepatitis, are associated with rapid progression to cirrhosis and need early treatment. The goals of antiviral therapy are twofold: viral eradication is highly desirable, but attenuation of fibrosis progression is also important. Combination therapy with peginterferon and ribavirin currently offers the greatest efficacy, but rates of sustained virologic response (SVR), reported to be between 23% and 45% (median 36%), are inferior to those seen in non-transplant patients [4–8]. Moreover, tolerability of therapy is limited, with cytopenias being a common dose-limiting side
*
Corresponding author. Tel.: +1 415 476 2227; fax: +1 415 502 6714. E-mail address: [email protected] (N.A. Terrault).
effect, and premature treatment discontinuations are more frequent than in non-transplant patients. It is assumed that achievement of SVR will halt fibrosis progression. Data to support this assumption are not abundant. Most studies focus on virologic rather than histologic outcomes, and those studies including histologic outcomes compare fibrosis scores at the beginning and end of therapy and not beyond. In studies comparing histology in treated and untreated patients within 6 months of completing treatment, treated patients have improved necroinflammatory indices compared to untreated patients but fibrosis scores are not significantly different [9,10]. There are two studies that stand out in their efforts to address the long-term impact of achieving SVR on fibrosis progression. In the study by Abdelmalek et al., 29 patients who had achieved SVR (28 with combination therapy, 1 with IFN monotherapy) were followed for a mean of 24.7 months after the end of therapy [11]. Two years after the end of therapy, 27% showed improvement, 38% showed no change, and 35% showed worsening of fibrosis stage. At 3–5 years post-treatment, 67% showed improvement, 13% showed no change, and 20% showed worsening fibrosis stage. This study, though uncontrolled, suggests that viral eradication leads to stabilization or improvement in fibrosis stage in the majority of patients achieving SVR and that the beneficial effects of SVR may be a delayed phenomenon. Bizollon et al. conducted a casecontrol study in which 34 patients who achieved SVR were compared with 46 non-responders [12]. Patients achieving SVR were followed for a mean of 52 months and non-responders for a mean of 57 months with yearly liver biopsies performed. At the end of follow-up in patients achieving SVR, 38% showed improvement,
0168-8278/$32.00 Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2006.12.009
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A. Kuo, N.A. Terrault / Journal of Hepatology 46 (2007) 359–361
44% showed no change, and 18% showed worsening of fibrosis stage. In non-responders, 0% showed improvement, 26% showed no change, and 74% showed worsening of fibrosis stage. These two studies provide support for the conclusion that viral eradication offers beneficial effects on fibrosis progression. Unfortunately, the majority of transplant recipients treated with combination therapy do not achieve SVR. Therefore, an equally important issue is whether antiviral therapy slows fibrosis progression in virologic nonresponders. Very few studies inform us on this question. Of the studies reporting histologic outcomes within 6 months of treatment discontinuation, fibrosis scores are not significantly different in patients achieving SVR compared to virologic non-responders, which may be indicative of a histologic benefit in non-responders [5–7,9,13,14]. In a study using standard interferon and ribavirin, 3 (38%) patients achieving SVR showed unchanged or improved fibrosis scores 6 months after treatment completion compared with 12 (75%) non-responders [15]. However, most of the published studies are of limited sample size and underpowered to compare outcomes in responders and non-responders, and the duration of follow-up after treatment discontinuation is short. Moreover, no study has compared histological outcomes in virologic non-responders compared to untreated patients. Therefore, the jury is still out as to whether antiviral therapy provides a beneficial effect on fibrosis progression, graft survival or mortality in virologic non-responders. The current study by Picciotto and colleagues describes the use of peginterferon-alfa-2b and ribavirin in the treatment of recurrent HCV in a single-center cohort and is the first study to focus on patient survival as an endpoint [16]. Sixty-one transplant recipients were enrolled over a three year period and started on antiviral treatment 25 (3–131) weeks, on average, post-transplantation. Using an intention-to-treat analysis, SVR was achieved in 17 (28%) patients. Histological endpoints were not evaluated, but the authors assessed survival stratified by achievement of SVR and showed that patients achieving SVR have a lower rate of mortality compared to those who were virologic treatment failures. Indeed, none of the patients with SVR died in follow-up, whereas nearly a third of the treated cohort without SVR died within a median follow-up of 19 months post-treatment and nearly all deaths were secondary to end-stage liver disease. This difference in survival persisted even when patients with cirrhosis at the onset of treatment were excluded. There results suggest that achievement of SVR is of critical importance in obtaining clinical benefits and prolonged survival. These data are encouraging and consistent with expectations regarding the achievement of viral clearance. The question of whether ‘‘treatment failures’’ derived any benefit from antiviral therapy is unanswered
by the Picciotto study. The death rate among non-responders in this cohort is striking. This may be related to the high proportion of patients with advanced fibrosis at the start of treatment; all 10 patients with cirrhosis were in the treatment failure group. The limited number of patients with SVR did not allow the authors to perform multivariate analysis to adjust for all factors potentially linked with survival, such as baseline histology, recipient age, and time from transplantation to treatment. Additionally, the lack of an untreated comparison group does not allow us to determine whether antiviral therapy in non-responders may have been beneficial in slowing histologic progression and reducing the risk of graft loss. Indeed, the high rate of liver-related deaths in the treatment failure group raises the possibility that treatment or its withdrawal was detrimental for these patients. Given the significant proportion of non-responders to interferon-based regimens, an improved understanding of the benefits and risks associated with antiviral therapy is needed. While the results of the Picciotto study and others allow us to conclude that achieving SVR confers histologic and survival benefits, the same cannot yet be said for non-responders or relapsers. New therapeutic options to increase the number of patients able to achieve SVR, and the histologic and clinical benefits associated with SVR, are clearly needed, but equally important are studies to clarify the effects (positive and negative) of antiviral therapy on fibrosis progression and survival in patients who do not achieve SVR. References [1] Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122:889–896. [2] Berenguer M, Prieto M, San Juan F, Rayon JM, Martinez F, Carrasco D, Moya A, Orbis F, Mir J, Berenguer J. Contribution of donor age to the recent decrease in patient survival among HCVinfected liver transplant recipients. Hepatology 2002;36:202–210. [3] Wiesner RH, Sorrell M, Villamil F. Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C. Liver Transpl 2003;9:S1–S9. [4] Fernandez I, Meneu JC, Colina F, Garcia I, Munoz R, Castellano G, Fuertes A, Abradelo M, Lumbreras C, Moreno E, SolisHerruzo JA. Clinical and histological efficacy of pegylated interferon and ribavirin therapy of recurrent hepatitis C after liver transplantation. Liver Transpl 2006;12:1805–1812. [5] Neumann U, Puhl G, Bahra M, Berg T, Langrehr JM, Neuhaus R, Neuhaus P. Treatment of patients with recurrent hepatitis C after liver transplantation with peginterferon alfa-2B plus ribavirin. Transplantation 2006;82:43–47. [6] Stravitz RT, Shiffman ML, Sanyal AJ, Luketic VA, Sterling RK, Heuman DM, Ashworth A, Mills AS, Contos M, Cotterell AH, Maluf D, Posner MP, Fisher RA. Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation. Liver Transpl 2004;10:850–858.
A. Kuo, N.A. Terrault / Journal of Hepatology 46 (2007) 359–361 [7] Oton E, Barcena R, Moreno-Planas JM, Cuervas-Mons V, Moreno-Zamora A, Barrios C, Garcia-Garzon S, Moreno A, Boullosa-Grana E, Rubio-Gonzalez EE, Garcia-Gonzalez M, Blesa C, Mateos ML. Hepatitis C recurrence after liver transplantation: viral and histological response to full-dose peg-interferon and ribavirin. Am J Transplant 2006;6:2348–2355. [8] Dumortier J, Scoazec JY, Chevallier P, Boillot O. Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination. J Hepatol 2004;40:669–674. [9] Samuel D, Bizollon T, Feray C, Roche B, Ahmed SN, Lemonnier C, Cohard M, Reynes M, Chevallier M, Ducerf C, Baulieux J, Geffner M, Albrecht JK, Bismuth H, Trepo C. Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study. Gastroenterology 2003;124:642–650. [10] Chalasani N, Manzarbeitia C, Ferenci P, Vogel W, Fontana RJ, Voigt M, Riely C, Martin P, Teperman L, Jiao J, Lopez-Talavera JC. Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology 2005;41:289–298. [11] Abdelmalek MF, Firpi RJ, Soldevila-Pico C, Reed AI, Hemming AW, Liu C, Crawford JM, Davis GL, Nelson DR. Sustained viral
[12]
[13]
[14]
[15]
[16]
361
response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2004;10:199–207. Bizollon T, Pradat P, Mabrut JY, Chevallier M, Adham M, Radenne S, Souquet JC, Ducerf C, Baulieux J, Zoulim F, Trepo C. Benefit of sustained virological response to combination therapy on graft survival of liver transplanted patients with recurrent chronic hepatitis C. Am J Transplant 2005;5:1909–1913. Berenguer M, Prieto M, Palau A, Carrasco D, Rayon JM, Calvo F, Berenguer J. Recurrent hepatitis C genotype 1b following liver transplantation: treatment with combination interferon-ribavirin therapy. Eur J Gastroenterol Hepatol 2004;16:1207–1212. Giostra E, Kullak-Ublick GA, Keller W, Fried R, Vanlemmens C, Kraehenbuhl S, Locher S, Egger HP, Clavien PA, Hadengue A, Mentha G, Morel P, Negro F. Ribavirin/interferon-alpha sequential treatment of recurrent hepatitis C after liver transplantation. Transpl Int 2004;17:169–176. Mukherjee S, Lyden E, McCashland TM, Schafer DF. Interferon alpha 2b and ribavirin for the treatment of recurrent hepatitis C after liver transplantation: cohort study of 38 patients. J Gastroenterol Hepatol 2005;20:198–203. Picciotto FP, Tritto G, Lanza AG, Addario L, De Luca M, Di Costanzo GG, et al. Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation. J Hepatol 2007;46:459–465.
Editorial
Antiviral therapy in liver transplant recipients: Is SVR the only endpoint that matters? Alexander Kuo, Norah A. Terrault* Division of Gastroenterology, University of California San Francisco, San Francisco, CA 94143-0538, USA
See Article, pages 459–465
Recurrent hepatitis C virus (HCV) infection remains the scourge of liver transplantation. Optimum strategies to maximize patient and graft survival remain unclear. Patients transplanted for HCV-associated cirrhosis have a 23% increased rate of death and a 30% increased rate of graft loss at five years compared to those transplanted for other indications [1]. Several predictors of accelerated disease progression post-transplantation have been identified, including advanced donor age, cytomegalovirus infection, and prior treated acute rejection [2,3]. Unfortunately, most of the factors linked with accelerated disease progression are not easily modifiable. To date, management of recurrent HCV following liver transplantation has focused on the treatment of recurrent HCV disease. The decision to initiate treatment is usually prompted by abnormal serum aminotransferase levels combined with evidence of histologic disease. Aggressive subtypes of recurrent HCV, such as severe cholestatic hepatitis, are associated with rapid progression to cirrhosis and need early treatment. The goals of antiviral therapy are twofold: viral eradication is highly desirable, but attenuation of fibrosis progression is also important. Combination therapy with peginterferon and ribavirin currently offers the greatest efficacy, but rates of sustained virologic response (SVR), reported to be between 23% and 45% (median 36%), are inferior to those seen in non-transplant patients [4–8]. Moreover, tolerability of therapy is limited, with cytopenias being a common dose-limiting side
*
Corresponding author. Tel.: +1 415 476 2227; fax: +1 415 502 6714. E-mail address: [email protected] (N.A. Terrault).
effect, and premature treatment discontinuations are more frequent than in non-transplant patients. It is assumed that achievement of SVR will halt fibrosis progression. Data to support this assumption are not abundant. Most studies focus on virologic rather than histologic outcomes, and those studies including histologic outcomes compare fibrosis scores at the beginning and end of therapy and not beyond. In studies comparing histology in treated and untreated patients within 6 months of completing treatment, treated patients have improved necroinflammatory indices compared to untreated patients but fibrosis scores are not significantly different [9,10]. There are two studies that stand out in their efforts to address the long-term impact of achieving SVR on fibrosis progression. In the study by Abdelmalek et al., 29 patients who had achieved SVR (28 with combination therapy, 1 with IFN monotherapy) were followed for a mean of 24.7 months after the end of therapy [11]. Two years after the end of therapy, 27% showed improvement, 38% showed no change, and 35% showed worsening of fibrosis stage. At 3–5 years post-treatment, 67% showed improvement, 13% showed no change, and 20% showed worsening fibrosis stage. This study, though uncontrolled, suggests that viral eradication leads to stabilization or improvement in fibrosis stage in the majority of patients achieving SVR and that the beneficial effects of SVR may be a delayed phenomenon. Bizollon et al. conducted a casecontrol study in which 34 patients who achieved SVR were compared with 46 non-responders [12]. Patients achieving SVR were followed for a mean of 52 months and non-responders for a mean of 57 months with yearly liver biopsies performed. At the end of follow-up in patients achieving SVR, 38% showed improvement,
0168-8278/$32.00 Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2006.12.009
360
A. Kuo, N.A. Terrault / Journal of Hepatology 46 (2007) 359–361
44% showed no change, and 18% showed worsening of fibrosis stage. In non-responders, 0% showed improvement, 26% showed no change, and 74% showed worsening of fibrosis stage. These two studies provide support for the conclusion that viral eradication offers beneficial effects on fibrosis progression. Unfortunately, the majority of transplant recipients treated with combination therapy do not achieve SVR. Therefore, an equally important issue is whether antiviral therapy slows fibrosis progression in virologic nonresponders. Very few studies inform us on this question. Of the studies reporting histologic outcomes within 6 months of treatment discontinuation, fibrosis scores are not significantly different in patients achieving SVR compared to virologic non-responders, which may be indicative of a histologic benefit in non-responders [5–7,9,13,14]. In a study using standard interferon and ribavirin, 3 (38%) patients achieving SVR showed unchanged or improved fibrosis scores 6 months after treatment completion compared with 12 (75%) non-responders [15]. However, most of the published studies are of limited sample size and underpowered to compare outcomes in responders and non-responders, and the duration of follow-up after treatment discontinuation is short. Moreover, no study has compared histological outcomes in virologic non-responders compared to untreated patients. Therefore, the jury is still out as to whether antiviral therapy provides a beneficial effect on fibrosis progression, graft survival or mortality in virologic non-responders. The current study by Picciotto and colleagues describes the use of peginterferon-alfa-2b and ribavirin in the treatment of recurrent HCV in a single-center cohort and is the first study to focus on patient survival as an endpoint [16]. Sixty-one transplant recipients were enrolled over a three year period and started on antiviral treatment 25 (3–131) weeks, on average, post-transplantation. Using an intention-to-treat analysis, SVR was achieved in 17 (28%) patients. Histological endpoints were not evaluated, but the authors assessed survival stratified by achievement of SVR and showed that patients achieving SVR have a lower rate of mortality compared to those who were virologic treatment failures. Indeed, none of the patients with SVR died in follow-up, whereas nearly a third of the treated cohort without SVR died within a median follow-up of 19 months post-treatment and nearly all deaths were secondary to end-stage liver disease. This difference in survival persisted even when patients with cirrhosis at the onset of treatment were excluded. There results suggest that achievement of SVR is of critical importance in obtaining clinical benefits and prolonged survival. These data are encouraging and consistent with expectations regarding the achievement of viral clearance. The question of whether ‘‘treatment failures’’ derived any benefit from antiviral therapy is unanswered
by the Picciotto study. The death rate among non-responders in this cohort is striking. This may be related to the high proportion of patients with advanced fibrosis at the start of treatment; all 10 patients with cirrhosis were in the treatment failure group. The limited number of patients with SVR did not allow the authors to perform multivariate analysis to adjust for all factors potentially linked with survival, such as baseline histology, recipient age, and time from transplantation to treatment. Additionally, the lack of an untreated comparison group does not allow us to determine whether antiviral therapy in non-responders may have been beneficial in slowing histologic progression and reducing the risk of graft loss. Indeed, the high rate of liver-related deaths in the treatment failure group raises the possibility that treatment or its withdrawal was detrimental for these patients. Given the significant proportion of non-responders to interferon-based regimens, an improved understanding of the benefits and risks associated with antiviral therapy is needed. While the results of the Picciotto study and others allow us to conclude that achieving SVR confers histologic and survival benefits, the same cannot yet be said for non-responders or relapsers. New therapeutic options to increase the number of patients able to achieve SVR, and the histologic and clinical benefits associated with SVR, are clearly needed, but equally important are studies to clarify the effects (positive and negative) of antiviral therapy on fibrosis progression and survival in patients who do not achieve SVR. References [1] Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122:889–896. [2] Berenguer M, Prieto M, San Juan F, Rayon JM, Martinez F, Carrasco D, Moya A, Orbis F, Mir J, Berenguer J. Contribution of donor age to the recent decrease in patient survival among HCVinfected liver transplant recipients. Hepatology 2002;36:202–210. [3] Wiesner RH, Sorrell M, Villamil F. Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C. Liver Transpl 2003;9:S1–S9. [4] Fernandez I, Meneu JC, Colina F, Garcia I, Munoz R, Castellano G, Fuertes A, Abradelo M, Lumbreras C, Moreno E, SolisHerruzo JA. Clinical and histological efficacy of pegylated interferon and ribavirin therapy of recurrent hepatitis C after liver transplantation. Liver Transpl 2006;12:1805–1812. [5] Neumann U, Puhl G, Bahra M, Berg T, Langrehr JM, Neuhaus R, Neuhaus P. Treatment of patients with recurrent hepatitis C after liver transplantation with peginterferon alfa-2B plus ribavirin. Transplantation 2006;82:43–47. [6] Stravitz RT, Shiffman ML, Sanyal AJ, Luketic VA, Sterling RK, Heuman DM, Ashworth A, Mills AS, Contos M, Cotterell AH, Maluf D, Posner MP, Fisher RA. Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation. Liver Transpl 2004;10:850–858.
A. Kuo, N.A. Terrault / Journal of Hepatology 46 (2007) 359–361 [7] Oton E, Barcena R, Moreno-Planas JM, Cuervas-Mons V, Moreno-Zamora A, Barrios C, Garcia-Garzon S, Moreno A, Boullosa-Grana E, Rubio-Gonzalez EE, Garcia-Gonzalez M, Blesa C, Mateos ML. Hepatitis C recurrence after liver transplantation: viral and histological response to full-dose peg-interferon and ribavirin. Am J Transplant 2006;6:2348–2355. [8] Dumortier J, Scoazec JY, Chevallier P, Boillot O. Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination. J Hepatol 2004;40:669–674. [9] Samuel D, Bizollon T, Feray C, Roche B, Ahmed SN, Lemonnier C, Cohard M, Reynes M, Chevallier M, Ducerf C, Baulieux J, Geffner M, Albrecht JK, Bismuth H, Trepo C. Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study. Gastroenterology 2003;124:642–650. [10] Chalasani N, Manzarbeitia C, Ferenci P, Vogel W, Fontana RJ, Voigt M, Riely C, Martin P, Teperman L, Jiao J, Lopez-Talavera JC. Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology 2005;41:289–298. [11] Abdelmalek MF, Firpi RJ, Soldevila-Pico C, Reed AI, Hemming AW, Liu C, Crawford JM, Davis GL, Nelson DR. Sustained viral
[12]
[13]
[14]
[15]
[16]
361
response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2004;10:199–207. Bizollon T, Pradat P, Mabrut JY, Chevallier M, Adham M, Radenne S, Souquet JC, Ducerf C, Baulieux J, Zoulim F, Trepo C. Benefit of sustained virological response to combination therapy on graft survival of liver transplanted patients with recurrent chronic hepatitis C. Am J Transplant 2005;5:1909–1913. Berenguer M, Prieto M, Palau A, Carrasco D, Rayon JM, Calvo F, Berenguer J. Recurrent hepatitis C genotype 1b following liver transplantation: treatment with combination interferon-ribavirin therapy. Eur J Gastroenterol Hepatol 2004;16:1207–1212. Giostra E, Kullak-Ublick GA, Keller W, Fried R, Vanlemmens C, Kraehenbuhl S, Locher S, Egger HP, Clavien PA, Hadengue A, Mentha G, Morel P, Negro F. Ribavirin/interferon-alpha sequential treatment of recurrent hepatitis C after liver transplantation. Transpl Int 2004;17:169–176. Mukherjee S, Lyden E, McCashland TM, Schafer DF. Interferon alpha 2b and ribavirin for the treatment of recurrent hepatitis C after liver transplantation: cohort study of 38 patients. J Gastroenterol Hepatol 2005;20:198–203. Picciotto FP, Tritto G, Lanza AG, Addario L, De Luca M, Di Costanzo GG, et al. Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation. J Hepatol 2007;46:459–465.