Hepatitis C Virus Recurrence After Liver Transplantation: How to Treat and When V. Aguilera* Hospital Universitari i Politècnic la Fe, Valenza, Valencia, Spain Valencia, Spain
ABSTRACT Chronic hepatitis C (CHC) is an important cause of cirrhosis and hepatocellular carcinoma and a common indication of liver transplantation (LT). Recurrence of hepatitis C occurs universally after LT with an accelerated course of the natural history of CHC in the graft. Treatment of hepatitis C before transplantation is the most effective strategy because it prevents graft reinfection, but applicability is low with pegylated interferon regimens. Treatment after LT is the strategy more frequently used. A sustained viral response (SVR) is achieved by one-third of those treated with dual therapy and is associated with better outcomes after LT. Triple therapy with protease inhibitors after LT has efficacy to 60%e70% of SVR but is associated with higher rates of secondary effects and drug-drug interactions that require an intensified and frequent monitoring of calcineurin inhibitors during treatment. In the near future, interferon-free regimens with new oral antiviral drugs will likely prevent viral reinfection before or after LT, and shorter treatment regimens and less toxicity are expected.
C
HRONIC hepatitis C is an important cause of cirrhosis and hepatocellular carcinoma (HCC) in the Western world, and end-stage liver disease due to hepatitis C virus (HCV) cirrhosis is still a common indication of liver transplantation (LT) [1]. Moreover, HCC as a primary indication of LT in HCV cirrhosis is increasing, reflecting changes in the prioritization of HCC as well as a true increased prevalence of HCC in the HCV-infected population. Recurrence of HCV infection occurs universally in the graft and is the most frequent cause of death and graft loss in these patients, owing to the accelerated course of the natural history of chronic hepatitis C in the graft [2]. Some patients (2%e9%) develop fibrosing cholestatic hepatitis, a form associated with extremely poor prognosis and high mortality [3]. Factors that have been associated with a more severe recurrence and that could be potentially modifiable are older donor age, prolonged cold ischemia, acute rejection treatment, cytomegalovirus hepatitis, ILB28 donor genotype, and post-LT insulin resistance. Other factors not modifiable that have also been associated with a more severe progression are female sex, African-American recipient, recipient age, HIV coinfection, ILB28 genotype, genotype 1b, and high viral load [4e7]. In terms of immunosuppression, no single drug or combination has been associated with benefits in histologic disease progression. Owing to the impact that recurrent hepatitis C has on patient and graft survivals, treatment of patients with
recurrent hepatitis C is an important goal. In fact, sustained viral response (SVR) has been associated with prevention of liver-related complications due to HCV recurrence, graft loss, and patient survival [8,9]. THE TIME TO TREAT HCV RECURRENCE
Two strategies can be used in these patients: (i) pretransplantation antiviral therapy with the intention of preventing HCV infection after LT; and (ii) post-transplantation antiviral therapy given with the intent of eradicating the virus in those with established viral or histologic recurrence. The most effective treatment to prevent HCV recurrence is to treat HCV infection before LT. However, this strategy can be used in very few candidates, with compensated cirrhosis or mild decompensated cirrhosis and Model for End-Stage Liver Disease score 1 and there is moderate or severe necroinflammation. However, post hoc analysis of treated cohorts have shown better results in patients with mild disease, arguing for treatment at less advanced disease. SVR rates range 25%e40% in patients with genotype 1 and 45%e65% in patients with nonegenotype 1 [12,13]. The strongest variable associated with SVR is viral kinetics. Patients with absence of early viral response have very few possibilities of achieving an SVR after a 12-month course of Peg-IFN þ RBV therapy, and, in contrast, those achieving a rapid viral response after the 1st month of therapy are likely to achieve a good treatment response. In addition, higher response rates have been observed in those who tolerate the complete course of therapy with full doses of peg-IFN and RBV. Pretreatment conditions, such as high viral load, ILB28 polymorphism of both donor and recipient, male sex, mild disease before treatment, genotype non-1, low body weight, immunosuppression with cyclosporine, and donor age, have also been associated with higher viral response [14,15]. In
contrast, increased donor age and cirrhosis have been associated with poor results. Unfortunately, side effects occur very frequently, leading to a continued and constrained follow-up, high rate of discontinuation, use of granulocyte colonyestimulating factor and erythropoietin, hospital admissions, and blood transfusions. The most frequent side effects are hematologic, including anemia, neutropenia, thrombocytopenia, and psychiatric disorders, such as depression. In addition, rejection and “de novo” autoimmune hepatitis can be triggered by the use of peg-IFN. In a United States multicenter study the percentage of autoimmune complications during peg-IFN treatment was 7.2%, and the complications were associated with impaired graft survival (38.5% in those with autoimmune complications vs 85.6% in those without) [16]. TREATMENT OF HCV RECURRENCE WITH TRIPLE THERAPY
Triple therapy with protease inhibitors (PI), boceprevir (BOC), and telaprevir (TPV) in the LT setting is now being evaluated, and results regarding efficacy have been published in the past months, most of them in abstract form. First reports have shown early viral response rates of 60%e100% [17]. Werner et al reported the experience in 12 patients. Eight patients at week 12 of treatment were HCV-RNA negative [18]. Recently, 3 large international series have shown results of end of treatment (EOT) response and SVR of 4 and 12, respectively [19-25] (Table 1). The French multicenter study [19], which included 98 patients, showed an early viral response (EVR) of 83% with BOC and 61% with TPV. Only 17 and 16 patients in the BOC and TPV groups, respectively, had finished the antiviral treatment when the data were shown. Of these, 82% and 43%, respectively, achieved an EOT response. Among 9 patients treated with BOC, 6 achieved SVR 12, and among 5 patients treated with TPV, 1 achieved SVR 12 [19]. In the CRUSH (Consortium to Study Health Outcomes in HCV Liver Transplant Recipients) study [20], a multicenter study in the United States reported in abstract form, the results were SVR 4 in 101 patients, most of them treated with telaprevir, 43% with bridging fibrosis and cirrhosis, and 10% with fibrosing cholestatic hepatitis. Of note, immunosuppression with
Table 1. Results of Triple Therapy in Liver Transplant Recipients
Retrospective study Multicenter Randomized study No. of patients Protease inhibitor used (TVR/BOC) Median age (y)/male (%) Prior treatment (%) Fibrosis 3-4 RVR SVR
Coilly [21]
CRUSH [20]
Pungpapong [25]
Yes Yes (France, Belgium, Switzerland) No 98 57/41 56/87% 33% TVR 78%/BOC 47% TVR 47%/BOC 56% TVR-12 20%/BOC 71%
Yes USA No 101 90/11 57/84% 31% 43% 69% SVR-4 41%
Yes USA, the Netherlands No 60 35/25 50/68% 34% TPV/16% BOC TVR 57%/BOC 52% TVR 17%/BOC 24% No data
Abbreviations: TVR, telaprevir; BOC, boceprevir; RVR, rapid viral response; SVR, sustained viral response.
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cyclosporine was changed in most patients when possible before starting antiviral treatment. SVR at week 4 was 41%, but among those with an early rapid viral response, the SVR 4 was 70% [20]. In the USA multicenter experience, 67% of TVR-treated patients and 45% of BOC-treated patients were HCV-RNA negative at week 24 of treatment [25]. The French group has recently published the results of triple therapy with SVR 12 in 37 liver transplant recipients [21]: 18 patients treated with BOC and 19 with TPV. Only 28 patients (78%) had completed the treatment at the time of writing the paper. One-fourth had cirrhosis before starting treatment, and 12% and 21% in the BOC and TPV groups, respectively, had fibrosing cholestatic hepatitis. A complete EVR was achieved in 89% of BOC patients and 58% of TPV, and the SVR 12 was 20% in the TPV group (1/5) and 71% in the BOC group (5/7) [21]. Despite these better results in SVR, tolerability remains a major issue. It is known that drug-drug interactions (DDI) of immunosuppressive drugs (calcineurin inhibitors and sirolimus) and PI exists because TPV is a substrate and inhibitor of CYP34/5 and BOC is a strong inhibitor of CYP3A4/5. The use of BOC in healthy volunteers has been associated with an increase in the levels of tacrolimus and cyclosporine. Coadministration of BOC and cyclosporine increased the levels of cyclosporine by 3-fold and the levels of tacrolimus by 17-fold, and the coadministration of TPV with cyclosporine increased the bioability of cyclosporine by 4.5-fold and coadministration with tacrolimus increased the bioability of tacrolimus by 70-fold [22,23]. Coilly et al reported the use of BOC associated with pegIFN and RBV in combination with calcineurin inhibitors in liver transplant recipients. They showed that the combination of BOC with tacrolimus, cyclosporine, and everolimus is associated with a decrease in the clearence of calcineurin inhibitors. With cyclosporine this decrease was w50%, with tacrolimus w80%, and with everolimus w50%, requiring dose adjustment. The mean time to achieve stable levels and dose adjustments were 3e7 days [24]. Thus, recipients receiving TPV or BOC require calcineurin dose reductions when PI is started and, conversely, increased again when PI is stopped. To avoid risk of toxicity or, in contrast, risk of rejection due to low levels, an intensified and frequent monitoring of calcineurin inhibitor levels is needed when beginning and stopping the PI. As in the cirrhotic population, high rates of adverse events are being reported and tolerability is poor (Table 2). In particular, anemia occurs almost invariably (80%e100% of cases) and results in an extremely frequent use of erythropoietin and RBV dose reductions as well as frequent transfusions in 46%e64% of patients. Whether the RBV reduction would affect SVR in the transplant setting is still unknown. Other side effects are infections, reported in 25% of patients, some of them severe. Diabetes and renal failure during triple therapy have been reported in 10% and 20%, respectively. Rejection has been reported in some series in 5% of patients. Owing to the DDI, some groups have changed to cyclosporine when possible to minimize drug interactions with BOC and TPV.
AGUILERA Table 2. Side Effects in Patients Treated With Triple Therapy
Death Coilly [21] Pungpapong [25] CRUSH [20] Anemia Coilly [21] Pungpapong [25] CRUSH [20] Transfusion Coilly [21] Pungpapong [25] CRUSH [20] Renal Failure Coilly [21] Pungpapong [25] (Cr >0.5 mg/dL) CRUSH [20] Hospitalization Coilly [21] Pungpapong [25] CRUSH [20] Infection Coilly [21] Pungpapong [25] CRUSH [20] Rejection Coilly [21] Pungpapong [25] CRUSH [20] Rash Coilly [21] Pungpapong [25] CRUSH [20]
n
Boceprevir
Telaprevir
37 60 101
2 (11%) 1 (4%) d
1 (5%) 1 (3%) 2 (2%)
37 60 101
100% 75% d
84% 77% d
37 60 101
d 64% d
d 46% 46%
37 60
1 (5%) 40%
4 (21%) 36%
101
d
d
37 60 101
33% d d
31% d 21%
37 60 101
27% 4% d
26% 17% d
37 60 101
d 4% d
d 6% 4%
37 60 101
5% d d
5% d d
In summary, results of triple therapy in the liver transplant setting have shown an increase of SVR of w30% compared with dual therapy. However, there is still major concern regarding safety and toxicity issues. Some reports have been published regarding the use of new direct antiviral therapies. Two examples published by Fontana et al have shown good results: one with daclatasvir in combination with peg-IFN and RBV in a fibrosing cholestatic hepatitis case after retransplantation, and the other using sofosbuvir and daclatasvir without IFN for 24 weeks [26,27]. Clinical trials with combination of 2 or 3 drugs (protease inhibitors, NS5A and NS5B inhibitors with or without RBV and peg-IFN) in the LT setting are currently underway to evaluate the efficacy in these difficult-to-treat patients. Greater efficacy, less toxicity owing to less DDI, and shorter treatment durations are expected with these new regimes.
REFERENCES [1] Kim WR, Terrault NA, Pederesn RA, et al. Evolution of liver transplantion in Europe: report of the European Liver Transplant Registry. Liver Transpl 2003;9:1231e43.
HEPATITIS C VIRUS RECURRENCE [2] Berenguer M, Ferrel L, Watson J, et al. HCV-related fibrosis progression following liver transplantation:increase in recent years. J Hepatol 2000;32:673e84. [3] Taga SA, Washington MK, Terrault N, et al. Cholestatic hepatitis C in liver allografts. Liver Transpl Surg 1998;4:304e10. [4] Saxena V, Lai JC, O’Leary JG, et al. Recipient-donor race mismatch for African-American liver transplant patients with chronic hepatitis C. Liver Transpl 2012;18:524e31. [5] Miro JM, Montejo M, Castells L, et al. Outcome of HCV/ HIV-coinfected liver transplant recipients: a prospective and multicenter cohort study. Am J Transplant 2012;18:716e26. [6] Burak KW, Kremers WK, Batts KP, et al. Impact of cytomegalovirus infection, year of transplantation and donor age on outcomes after liver transplantation for hepatitis C. Liver Transpl 2002;8:362e9. [7] Lange CM, Moradpour D, Dooehring A, et al. Impact of donor and recipient ILB28 rs12979860 genotypes on hepatitis C virus liver graft reinfection. J Hepatol 2011;55:322e7. [8] Picciotto FP, Tritto G, Lanza AG, et al. Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after transplantation. J Hepatol 2007;46:459e65. [9] Berenguer M, Palau A, Aguilera V, et al. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant 2008;8:679e87. [10] Mazzafeerro V, Tagger A, Schiavo M, et al. Prevention of recurrent hepatitis C after liver transplantation with early interferon and ribavirin. Transplant Proc 2001;33:1355e7. [11] Castells L, Vargas V, Allende H, et al. Combined treatment (alpha 2-b) and ribavirin in the acute phase of hepatitis C virus recurrence after liver transplantation. J Hepatol 2005;43:53e9. [12] Berenguer M, Aguilera V, Prieto M, et al. Worse recent efficacy of antiviral therapy in liver transplant recipients with recurrent hepatitis C: impact of donor age and baseline cirrhosis. Liver Transpl 2009;15:738e46. [13] Roche B, Sebagh M, Canforra ML, et al. Hepatitis C virus therapy in liver transplant recipients: response, predictors, effect of fibrosis progression and importance of the initial stage of fibrosis. Liver Transpl 2008;14:1766e77. [14] Coto-Llerena M, Perez-Del-Pulgar S, Crespo G, et al. Donor and recipient IL28B polymorphisms in HCV-infected patients undergoing antiviral therapy before and after liver transplantation. Am J Transplant 2011;11:1051e7. [15] Berenguer M, Aguilera V, Rubin A, et al. Comparison of two noncontemporaneous HCV-liver transplant cohorts: strategies to improve the efficacy of antiviral therapy. J Hepatol 2012;56: 1310e6.
3103 [16] Levitsky J, Fiel MI, Norvell JP, et al. Risk for immunemediated graft dysfunction in liver transplant recipients with recurrent HCV infection treated with pegylated interferon. Gastroenterology 2012;142:1132e9. [17] Coilly A, Roche T, Antonini T, et al. Efficacy and safety of protease inhibitors for hepatitis C recurrence after liver transplantation; a first multicentric experience. Hepatology 2012; 56(Suppl):9. [18] Werner CR, Egetemeyr DP, Lauer UM, et al. Short report: telaprevir-based triple therapy in liver transplanted HCV patients: a 112 week pilot study providing safety and efficacy. Liver Transpl 2012;18:1464e70. [19] Coilly A, Dumortiere J, Botta-Fridlund D, et al. End of treatment response after protease inhibitor (PI)ebased therapy for hepatitis C recurrence after liver transplantation: a multicentric European experience. J Hepatol 2013;58:S572e3. [20] Verna EC, Burton JG, O’Leary JG, et al. A multicenter study of protease inhibitoretriple therapy in HCV-infected liver transplant recipients: reported from the CRUSH-C group. J Hepatol 2013;58:S10e1. [21] Coilly A, Roche B, Dumortier J, Leroy V, et al. Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation. A multicenter experience. J Hepatol 2014;60:78e86. [22] Garg V, van Heeswijk R, Lee JE, et al. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011;54:20e7. [23] Hulskotte E, Gupta S, Xuan F, et al. Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology 2012;56:1622e30. [24] Coilly A, Furlan V, Roche B, et al. Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence. Antimicrob Agents Chemother 2012;56:5727e34. [25] Pupapong S, Aqel B, Koning L, et al. Multicenter experience using telaprevir or boceprevir with peg-interferon and ribavirin treat hepatitis C genotype 1 after liver transplantation. Liver Transpl 2013;19:690e700. [26] Fontana RJ, Hughes EA, Appelman H, et al. Case report of successful peginterferon, ribavirin and daclatasvir therapy for recurrent cholestatic hepatitis C after liver retransplantation. Liver Transpl 2012;18:1053e9. [27] Fontana JC, Hughes EA, Bifano M, et al. Sofosbuvir and daclatasvir combination therapy in a liver transplant recipient with severe recurrent cholestatic hepatitis C. Am J Transplant 2013;13: 1601e5.
ABSTRACT Chronic hepatitis C (CHC) is an important cause of cirrhosis and hepatocellular carcinoma and a common indication of liver transplantation (LT). Recurrence of hepatitis C occurs universally after LT with an accelerated course of the natural history of CHC in the graft. Treatment of hepatitis C before transplantation is the most effective strategy because it prevents graft reinfection, but applicability is low with pegylated interferon regimens. Treatment after LT is the strategy more frequently used. A sustained viral response (SVR) is achieved by one-third of those treated with dual therapy and is associated with better outcomes after LT. Triple therapy with protease inhibitors after LT has efficacy to 60%e70% of SVR but is associated with higher rates of secondary effects and drug-drug interactions that require an intensified and frequent monitoring of calcineurin inhibitors during treatment. In the near future, interferon-free regimens with new oral antiviral drugs will likely prevent viral reinfection before or after LT, and shorter treatment regimens and less toxicity are expected.
C
HRONIC hepatitis C is an important cause of cirrhosis and hepatocellular carcinoma (HCC) in the Western world, and end-stage liver disease due to hepatitis C virus (HCV) cirrhosis is still a common indication of liver transplantation (LT) [1]. Moreover, HCC as a primary indication of LT in HCV cirrhosis is increasing, reflecting changes in the prioritization of HCC as well as a true increased prevalence of HCC in the HCV-infected population. Recurrence of HCV infection occurs universally in the graft and is the most frequent cause of death and graft loss in these patients, owing to the accelerated course of the natural history of chronic hepatitis C in the graft [2]. Some patients (2%e9%) develop fibrosing cholestatic hepatitis, a form associated with extremely poor prognosis and high mortality [3]. Factors that have been associated with a more severe recurrence and that could be potentially modifiable are older donor age, prolonged cold ischemia, acute rejection treatment, cytomegalovirus hepatitis, ILB28 donor genotype, and post-LT insulin resistance. Other factors not modifiable that have also been associated with a more severe progression are female sex, African-American recipient, recipient age, HIV coinfection, ILB28 genotype, genotype 1b, and high viral load [4e7]. In terms of immunosuppression, no single drug or combination has been associated with benefits in histologic disease progression. Owing to the impact that recurrent hepatitis C has on patient and graft survivals, treatment of patients with
recurrent hepatitis C is an important goal. In fact, sustained viral response (SVR) has been associated with prevention of liver-related complications due to HCV recurrence, graft loss, and patient survival [8,9]. THE TIME TO TREAT HCV RECURRENCE
Two strategies can be used in these patients: (i) pretransplantation antiviral therapy with the intention of preventing HCV infection after LT; and (ii) post-transplantation antiviral therapy given with the intent of eradicating the virus in those with established viral or histologic recurrence. The most effective treatment to prevent HCV recurrence is to treat HCV infection before LT. However, this strategy can be used in very few candidates, with compensated cirrhosis or mild decompensated cirrhosis and Model for End-Stage Liver Disease score 1 and there is moderate or severe necroinflammation. However, post hoc analysis of treated cohorts have shown better results in patients with mild disease, arguing for treatment at less advanced disease. SVR rates range 25%e40% in patients with genotype 1 and 45%e65% in patients with nonegenotype 1 [12,13]. The strongest variable associated with SVR is viral kinetics. Patients with absence of early viral response have very few possibilities of achieving an SVR after a 12-month course of Peg-IFN þ RBV therapy, and, in contrast, those achieving a rapid viral response after the 1st month of therapy are likely to achieve a good treatment response. In addition, higher response rates have been observed in those who tolerate the complete course of therapy with full doses of peg-IFN and RBV. Pretreatment conditions, such as high viral load, ILB28 polymorphism of both donor and recipient, male sex, mild disease before treatment, genotype non-1, low body weight, immunosuppression with cyclosporine, and donor age, have also been associated with higher viral response [14,15]. In
contrast, increased donor age and cirrhosis have been associated with poor results. Unfortunately, side effects occur very frequently, leading to a continued and constrained follow-up, high rate of discontinuation, use of granulocyte colonyestimulating factor and erythropoietin, hospital admissions, and blood transfusions. The most frequent side effects are hematologic, including anemia, neutropenia, thrombocytopenia, and psychiatric disorders, such as depression. In addition, rejection and “de novo” autoimmune hepatitis can be triggered by the use of peg-IFN. In a United States multicenter study the percentage of autoimmune complications during peg-IFN treatment was 7.2%, and the complications were associated with impaired graft survival (38.5% in those with autoimmune complications vs 85.6% in those without) [16]. TREATMENT OF HCV RECURRENCE WITH TRIPLE THERAPY
Triple therapy with protease inhibitors (PI), boceprevir (BOC), and telaprevir (TPV) in the LT setting is now being evaluated, and results regarding efficacy have been published in the past months, most of them in abstract form. First reports have shown early viral response rates of 60%e100% [17]. Werner et al reported the experience in 12 patients. Eight patients at week 12 of treatment were HCV-RNA negative [18]. Recently, 3 large international series have shown results of end of treatment (EOT) response and SVR of 4 and 12, respectively [19-25] (Table 1). The French multicenter study [19], which included 98 patients, showed an early viral response (EVR) of 83% with BOC and 61% with TPV. Only 17 and 16 patients in the BOC and TPV groups, respectively, had finished the antiviral treatment when the data were shown. Of these, 82% and 43%, respectively, achieved an EOT response. Among 9 patients treated with BOC, 6 achieved SVR 12, and among 5 patients treated with TPV, 1 achieved SVR 12 [19]. In the CRUSH (Consortium to Study Health Outcomes in HCV Liver Transplant Recipients) study [20], a multicenter study in the United States reported in abstract form, the results were SVR 4 in 101 patients, most of them treated with telaprevir, 43% with bridging fibrosis and cirrhosis, and 10% with fibrosing cholestatic hepatitis. Of note, immunosuppression with
Table 1. Results of Triple Therapy in Liver Transplant Recipients
Retrospective study Multicenter Randomized study No. of patients Protease inhibitor used (TVR/BOC) Median age (y)/male (%) Prior treatment (%) Fibrosis 3-4 RVR SVR
Coilly [21]
CRUSH [20]
Pungpapong [25]
Yes Yes (France, Belgium, Switzerland) No 98 57/41 56/87% 33% TVR 78%/BOC 47% TVR 47%/BOC 56% TVR-12 20%/BOC 71%
Yes USA No 101 90/11 57/84% 31% 43% 69% SVR-4 41%
Yes USA, the Netherlands No 60 35/25 50/68% 34% TPV/16% BOC TVR 57%/BOC 52% TVR 17%/BOC 24% No data
Abbreviations: TVR, telaprevir; BOC, boceprevir; RVR, rapid viral response; SVR, sustained viral response.
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cyclosporine was changed in most patients when possible before starting antiviral treatment. SVR at week 4 was 41%, but among those with an early rapid viral response, the SVR 4 was 70% [20]. In the USA multicenter experience, 67% of TVR-treated patients and 45% of BOC-treated patients were HCV-RNA negative at week 24 of treatment [25]. The French group has recently published the results of triple therapy with SVR 12 in 37 liver transplant recipients [21]: 18 patients treated with BOC and 19 with TPV. Only 28 patients (78%) had completed the treatment at the time of writing the paper. One-fourth had cirrhosis before starting treatment, and 12% and 21% in the BOC and TPV groups, respectively, had fibrosing cholestatic hepatitis. A complete EVR was achieved in 89% of BOC patients and 58% of TPV, and the SVR 12 was 20% in the TPV group (1/5) and 71% in the BOC group (5/7) [21]. Despite these better results in SVR, tolerability remains a major issue. It is known that drug-drug interactions (DDI) of immunosuppressive drugs (calcineurin inhibitors and sirolimus) and PI exists because TPV is a substrate and inhibitor of CYP34/5 and BOC is a strong inhibitor of CYP3A4/5. The use of BOC in healthy volunteers has been associated with an increase in the levels of tacrolimus and cyclosporine. Coadministration of BOC and cyclosporine increased the levels of cyclosporine by 3-fold and the levels of tacrolimus by 17-fold, and the coadministration of TPV with cyclosporine increased the bioability of cyclosporine by 4.5-fold and coadministration with tacrolimus increased the bioability of tacrolimus by 70-fold [22,23]. Coilly et al reported the use of BOC associated with pegIFN and RBV in combination with calcineurin inhibitors in liver transplant recipients. They showed that the combination of BOC with tacrolimus, cyclosporine, and everolimus is associated with a decrease in the clearence of calcineurin inhibitors. With cyclosporine this decrease was w50%, with tacrolimus w80%, and with everolimus w50%, requiring dose adjustment. The mean time to achieve stable levels and dose adjustments were 3e7 days [24]. Thus, recipients receiving TPV or BOC require calcineurin dose reductions when PI is started and, conversely, increased again when PI is stopped. To avoid risk of toxicity or, in contrast, risk of rejection due to low levels, an intensified and frequent monitoring of calcineurin inhibitor levels is needed when beginning and stopping the PI. As in the cirrhotic population, high rates of adverse events are being reported and tolerability is poor (Table 2). In particular, anemia occurs almost invariably (80%e100% of cases) and results in an extremely frequent use of erythropoietin and RBV dose reductions as well as frequent transfusions in 46%e64% of patients. Whether the RBV reduction would affect SVR in the transplant setting is still unknown. Other side effects are infections, reported in 25% of patients, some of them severe. Diabetes and renal failure during triple therapy have been reported in 10% and 20%, respectively. Rejection has been reported in some series in 5% of patients. Owing to the DDI, some groups have changed to cyclosporine when possible to minimize drug interactions with BOC and TPV.
AGUILERA Table 2. Side Effects in Patients Treated With Triple Therapy
Death Coilly [21] Pungpapong [25] CRUSH [20] Anemia Coilly [21] Pungpapong [25] CRUSH [20] Transfusion Coilly [21] Pungpapong [25] CRUSH [20] Renal Failure Coilly [21] Pungpapong [25] (Cr >0.5 mg/dL) CRUSH [20] Hospitalization Coilly [21] Pungpapong [25] CRUSH [20] Infection Coilly [21] Pungpapong [25] CRUSH [20] Rejection Coilly [21] Pungpapong [25] CRUSH [20] Rash Coilly [21] Pungpapong [25] CRUSH [20]
n
Boceprevir
Telaprevir
37 60 101
2 (11%) 1 (4%) d
1 (5%) 1 (3%) 2 (2%)
37 60 101
100% 75% d
84% 77% d
37 60 101
d 64% d
d 46% 46%
37 60
1 (5%) 40%
4 (21%) 36%
101
d
d
37 60 101
33% d d
31% d 21%
37 60 101
27% 4% d
26% 17% d
37 60 101
d 4% d
d 6% 4%
37 60 101
5% d d
5% d d
In summary, results of triple therapy in the liver transplant setting have shown an increase of SVR of w30% compared with dual therapy. However, there is still major concern regarding safety and toxicity issues. Some reports have been published regarding the use of new direct antiviral therapies. Two examples published by Fontana et al have shown good results: one with daclatasvir in combination with peg-IFN and RBV in a fibrosing cholestatic hepatitis case after retransplantation, and the other using sofosbuvir and daclatasvir without IFN for 24 weeks [26,27]. Clinical trials with combination of 2 or 3 drugs (protease inhibitors, NS5A and NS5B inhibitors with or without RBV and peg-IFN) in the LT setting are currently underway to evaluate the efficacy in these difficult-to-treat patients. Greater efficacy, less toxicity owing to less DDI, and shorter treatment durations are expected with these new regimes.
REFERENCES [1] Kim WR, Terrault NA, Pederesn RA, et al. Evolution of liver transplantion in Europe: report of the European Liver Transplant Registry. Liver Transpl 2003;9:1231e43.
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