Sofosbuvir, Ribavirin for Graft Failure Due to Recurrent HCV
Sofosbuvir, Ribavirin for Graft Failure Due to Recurrent HCV
A 54-year-old Caucasian male developed end-stage liver failure due to HCV genotype 1b infection and received LT for a first time in 2007. Recurrent hepatitis C was documented in 2008 (Metavir score A2F1) and treated with pegylated interferon-α (PEG-IFN-α) and RBV, with a null response. Advanced fibrosis (Metavir score A2F3) was documented in 2011. Incipient graft failure and right retinal detachment subsequently precluded IFN-based antiviral therapy. Progressive graft failure was noted toward the end of 2012. At no point there was any evidence of allograft rejection. In September 2013, the Child-Pugh score increased to C10 and model for end-stage liver disease (MELD) score to 26, with jaundice, ascites, edema and profound fatigue. Total bilirubin was 229 μmol/l, albumin 29 g/l, prothrombin time 41%, INR 1.6, and serum creatinine 140 μmol/l. Immunosuppressive treatment consisted of cyclosporine 50 mg bid (with trough levels around 80 μg/l) and prednisone 5 mg qd. Multidisciplinary team discussion concluded to listing of the patient for re-transplantation provided that he could benefit from effective antiviral therapy before his second LT.
SOF was provided by Gilead Sciences Inc. (Foster City, CA) on a compassionate use basis and was started at a dose of 400 mg qd at the beginning of November 2013. Given the impaired renal function, RBV was started 3 weeks prior to SOF to ensure tolerability and pursued thereafter at a daily dose of 400–600 mg. As shown in Figure 1, HCV RNA declined rapidly upon the introduction of SOF and became undetectable 3 weeks later. Treatment was well tolerated and there was no need for the administration of erythropoietin.
(Enlarge Image)
Figure 1.
Evolution of HCV RNA and MELD score in a 54-year-old patient with end-stage recurrent hepatitis C treated with sofosbuvir (SOF) and ribavirin (RBV) prior to liver re-transplantation. Despite the rapid virological response to SOF and RBV, the recipient remained severely decompensated and liver re-transplantation was performed in January 2014. HCV RNA was undetectable in serum for 46 days prior to liver re-transplantation and remained undetectable on follow-up throughout January 2015 (i.e. more than 1 year post-liver re-transplantation). Re-LT, liver re-transplantation.
The results of therapeutic drug monitoring (TDM) for SOF, RBV and cyclosporine are shown in Table 1. Details of the methodology developed to measure plasma concentrations of SOF, based on liquid chromatography coupled with tandem mass spectrometry, will be reported elsewhere (LAD, unpublished data). RBV plasma concentrations were determined using a previously described analytical method. Cyclosporine trough levels were determined by enzyme multiplied immunoassay on a Cobas Integra® 400 plus system using reagents from Roche Diagnostics (Rotkreuz, Switzerland).
As shown in Table 1, SOF was measurable in the ng/ml concentration range in some of the plasma samples obtained 24 hours after drug administration. RBV concentrations reached a steady state between 2000 and 2500 ng/ml after around 4 weeks. Doses of cyclosporine had to be reduced by 25% in the last weeks before re-transplantation likely due to progressive liver dysfunction.
As shown in Figure 1, liver function continued to deteriorate despite the virological response, with an increase of the MELD score to 29. Therefore, re-transplantation was performed in January 2014, after a total of 66 days on SOF and 46 days of undetectable serum HCV RNA. SOF and RBV were both discontinued at re-transplantation.
The postoperative course was uneventful and the patient returned home 4 weeks later. An episode of acute cellular rejection (Banff 7) was treated with high-dose corticosteroid boluses in March 2014. Liver function tests have remained normal in the following and, most importantly, HCV RNA has remained undetectable throughout the entire postoperative course until January 2015, i.e. more than 1 year after re-transplantation.
Case Presentation
A 54-year-old Caucasian male developed end-stage liver failure due to HCV genotype 1b infection and received LT for a first time in 2007. Recurrent hepatitis C was documented in 2008 (Metavir score A2F1) and treated with pegylated interferon-α (PEG-IFN-α) and RBV, with a null response. Advanced fibrosis (Metavir score A2F3) was documented in 2011. Incipient graft failure and right retinal detachment subsequently precluded IFN-based antiviral therapy. Progressive graft failure was noted toward the end of 2012. At no point there was any evidence of allograft rejection. In September 2013, the Child-Pugh score increased to C10 and model for end-stage liver disease (MELD) score to 26, with jaundice, ascites, edema and profound fatigue. Total bilirubin was 229 μmol/l, albumin 29 g/l, prothrombin time 41%, INR 1.6, and serum creatinine 140 μmol/l. Immunosuppressive treatment consisted of cyclosporine 50 mg bid (with trough levels around 80 μg/l) and prednisone 5 mg qd. Multidisciplinary team discussion concluded to listing of the patient for re-transplantation provided that he could benefit from effective antiviral therapy before his second LT.
SOF was provided by Gilead Sciences Inc. (Foster City, CA) on a compassionate use basis and was started at a dose of 400 mg qd at the beginning of November 2013. Given the impaired renal function, RBV was started 3 weeks prior to SOF to ensure tolerability and pursued thereafter at a daily dose of 400–600 mg. As shown in Figure 1, HCV RNA declined rapidly upon the introduction of SOF and became undetectable 3 weeks later. Treatment was well tolerated and there was no need for the administration of erythropoietin.
(Enlarge Image)
Figure 1.
Evolution of HCV RNA and MELD score in a 54-year-old patient with end-stage recurrent hepatitis C treated with sofosbuvir (SOF) and ribavirin (RBV) prior to liver re-transplantation. Despite the rapid virological response to SOF and RBV, the recipient remained severely decompensated and liver re-transplantation was performed in January 2014. HCV RNA was undetectable in serum for 46 days prior to liver re-transplantation and remained undetectable on follow-up throughout January 2015 (i.e. more than 1 year post-liver re-transplantation). Re-LT, liver re-transplantation.
The results of therapeutic drug monitoring (TDM) for SOF, RBV and cyclosporine are shown in Table 1. Details of the methodology developed to measure plasma concentrations of SOF, based on liquid chromatography coupled with tandem mass spectrometry, will be reported elsewhere (LAD, unpublished data). RBV plasma concentrations were determined using a previously described analytical method. Cyclosporine trough levels were determined by enzyme multiplied immunoassay on a Cobas Integra® 400 plus system using reagents from Roche Diagnostics (Rotkreuz, Switzerland).
As shown in Table 1, SOF was measurable in the ng/ml concentration range in some of the plasma samples obtained 24 hours after drug administration. RBV concentrations reached a steady state between 2000 and 2500 ng/ml after around 4 weeks. Doses of cyclosporine had to be reduced by 25% in the last weeks before re-transplantation likely due to progressive liver dysfunction.
As shown in Figure 1, liver function continued to deteriorate despite the virological response, with an increase of the MELD score to 29. Therefore, re-transplantation was performed in January 2014, after a total of 66 days on SOF and 46 days of undetectable serum HCV RNA. SOF and RBV were both discontinued at re-transplantation.
The postoperative course was uneventful and the patient returned home 4 weeks later. An episode of acute cellular rejection (Banff 7) was treated with high-dose corticosteroid boluses in March 2014. Liver function tests have remained normal in the following and, most importantly, HCV RNA has remained undetectable throughout the entire postoperative course until January 2015, i.e. more than 1 year after re-transplantation.