Hepatitis c virus and liver transplantation

J Hepatol ; 41 : —6. Donor age influences year liver graft histology independently of hepatitis C virus infection. J Hepatol ; 41 : — Differential effects of donor age in liver transplant recipients infected with hepatitis B, hepatitis C and without viral hepatitis. Am J Transplant ; 5 : — Impact of donor age and year of transplant on graft survival in liver transplant recipients with chronic hepatitis C.

Am J Transplant ; 4 : —8. Pilot study of the combination of interferon alfa and ribavirin as therapy of recurrent hepatitis C after liver transplantation. Hepatology ; 26 : —4. Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence. Gut ; 52 : —7.

Treatment of recurrent hepatitis C in liver transplant recipients: Is there any histologic benefit? Liver Transplantation ; 9 : —9.

Recurrent hepatitis C after liver transplantation: A nonrandomized trial of interferon alfa alone versus interferon alfa and ribavirin. Liver Transplantation ; 7 : —9. Combination of interferon alfa-2b and ribavirin in liver transplant recipients with histological recurrent hepatitis C. Liver Transplantation ; 8 : —6. Interferon-alpha and ribavirin for the treatment of recurrent hepatitis c after liver transplantation. Transplantation ; 71 : — Discordance between ALT values and fibrosis in liver transplant recipients treated with ribavirin for recurrent hepatitis C.

Am J Transplant ; 3 : — Treatment of posttransplantation recurrence of hepatitis C with interferon and ribavirin: lessons on tolerability and efficacy. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Liver transplantation with use of cyclosporin a and prednisone. N Engl J Med ; : —9. Randomised trial comparing tacrolimus FK and cyclosporin in prevention of liver allograft rejection.

Lancet ; : —8. A comparison of tacrolimus FK and cyclosporine for immunosuppression in liver transplantation. A pilot study of immunosuppressive monotherapy in liver transplantation: tacrolimus versus microemulsified cyclosporin. Transplantation ; 68 : —8. Impact of tacrolimus versus cyclosporine in hepatitis C virus-infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial.

Liver Transplantation ; 10 : — A prospective randomized trial of mycophenolate mofetil with neoral or tacrolimus after orthotopic liver transplantation. Transplantation ; 66 : — A prospective randomized trial of mycophenolate mofetil in liver transplant recipients with hepatitis C.

Liver Transplantation ; 8 : 40 —6. Transplant Proc ; 34 : A model to predict severe HCV-related disease following liver transplantation. Hepatology ; 38 : 34 — MMF and calcineurin taper in recurrent hepatitis C after liver transplantation: impact on histological course. American Journal of Transplantation ; 5 : — Immunosuppression and donor age with respect to severity of HCV recurrence after liver transplantation.

Liver Transplantation ; 11 : — Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation. Am J Gastroenterol ; 92 : —7. Slowly tapering off steroids protects the graft against hepatitis C recurrence after liver transplantation. Liver Transplantation ; 8 : —8. Tapering off steroids three months after liver transplantation is not detrimental for hepatitis C virus disease recurrence. Liver Transplantation ; 9 : —2. Berenguer M. Sirolimus: a potent new immunosuppressant for liver transplantation.

Transplantation ; 67 : —9. Sirolimus rapamycin -based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus european renal transplant study group. Transplantation ; 67 : — Sirolimus-associated eyelid edema in kidney transplant recipients.

Transplantation ; 72 : —4. The side effect profile of sirolimus: a phase i study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int ; 49 : — Blum CB.

Effects of sirolimus on lipids in renal allograft recipients: an analysis using the Framingham risk model. Am J Transplant ; 2 : —9. Guilbeau JM. Delayed wound healing with sirolimus after liver transplant. Ann Pharmacother ; 36 : —5. Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil.

Transplantation ; 75 : — Sirolimus allows renal recovery in lung and heart transplant recipients with chronic renal impairment. J Heart Lung Transplant ; 21 : —6. Sirolimus-based immunosuppresive protocol for calcineurin sparing in liver transplantation. Transplant Proc ; 34 : —3. Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients. Am J Transplant ; 2 : — In conclusion, it is possible that the continued improvements in antiviral therapy against HCV infection may ultimately decrease the number of patients needing liver transplantation.

Suitable candidates with chronic HCV infection thus warrant treatment with pegylated interferon plus ribavirin combination therapy in the hope of decreasing disease progression. Recent studies, which require confirmation, suggest that nonresponders to standard antiviral therapy may benefit from maintenance therapy. The safety and tolerability of these DAA agents have expanded the feasibility of HCV treatment even in the challenging pre— and post—liver transplant settings.

However, the unique properties of DAA agents and the host profiles in these settings can limit the generalizability of HCV regimens, and prolongation of treatment duration or addition of ribavirin may be required in certain scenarios to optimize treatment outcomes. HCV therapy in the liver transplant setting is not one-size-fits-all; thus, this review summarizes the published data and emphasizes the applicability of currently available DAA therapies in patients with decompensated cirrhosis and in liver transplant recipients.

Hepatitis C virus HCV remains the leading infectious cause of liver-related mortality in the developed world and accounts for approximately , deaths per year due to decompensated cirrhosis or hepatocellular carcinoma HCC.

This review summarizes the published literature to date regarding HCV therapies in the liver transplant setting Table. Cirrhosis is the final common pathway in the natural history of most chronic liver diseases leading to hepatic decompensation, HCC, or death in the absence of liver transplant.

Untreated HCV prior to liver transplantation results in universal recurrence of the infection in the allograft, accelerated liver fibrosis, and subsequent graft failure.

HCV is also associated with various extrahepatic risk factors and overall mortality, which add significantly to the economic and public health burden. With the availability of DAA agents in the United States, patients with advanced fibrosis as well as liver transplant recipients have been given priority for HCV treatment, as they experience the most benefit from HCV cure. The currently approved DAA agents have shown great efficacy and tolerability in HCV patients with advanced fibrosis and compensated cirrhosis.

In clinical trials, simeprevir has been known to cause modest elevation in bilirubin levels; however, there have been reports of markedly elevated bilirubin and hepatic decompensation in the postmarketing period even without the use of interferon.

There are currently no available data with the regimen in patients with CTP class C decompensated cirrhosis, and based upon data from the trial, the regimen is not endorsed in patients with decompensated cirrhosis. Inactivation or delisting from the liver transplant waitlist was feasible after successful HCV therapy and, therefore, HCV treatment is recommended in patients with a MELD score of less than 16 who are expected to derive the most benefit.

In patients with a MELD score greater than 16, only few cautiously selected patients may benefit from HCV treatment and, thus, the treatment can be deferred until after liver transplantation. In addition, treated patients may face a MELD purgatory effect and hampered access or delay in liver transplantation due to biochemical improvement MELD score but no meaningful clinical improvement.

A recent retrospective study reported higher rates of recurrent HCC in the immediate period following HCV eradication with DAA agents due to presumed immune alteration. Future prospective studies would help address the several unanswered questions in this difficult-to-treat pre—liver transplant cohort. Among waitlisted patients, achieving SVR12 prior to liver transplantation prevents HCV recurrence in the allograft and is associated with favorable outcomes.

Theoretically, a short course of DAA agents in the peritransplant period should be sufficient to prevent recurrent HCV in the allograft. The proof of concept was demonstrated in a study in which liver transplant candidates with HCC were treated with sofosbuvir and ribavirin for up to 48 weeks. Fluid shifts, renal function, and variable pharmacokinetic patterns in the immediate postoperative period would also impact HCV therapy strategies.

Patients with HCV viremia at the time of liver transplantation universally develop recurrent HCV in the allograft, which results in accelerated fibrosis and negatively impacts graft and patient outcomes.

Almost all DAA agents are approved for use in liver transplant recipients, and drug interactions need to be carefully monitored. It should be noted that the study participants had mild fibrosis F0-F2 , and the concerns for toxicity in patients with advanced fibrosis remain as in the pre—liver transplant setting. The longer duration 24 weeks and adverse events of ribavirin also need to be considered when treating liver transplant recipients with this regimen.

Sofosbuvir, daclatasvir, and ribavirin for 12 weeks were administered in liver transplant recipients with HCV genotypes 1, 3, and 6 in the open-label ALLY-I study.

SOLAR-1 was a phase 2, randomized, open-label study that enrolled liver transplant recipients from the United States. Several real-world case series have been published regarding the use of the regimen with or without ribavirin; however, the role of ribavirin could not be ascertained. In the absence of strong evidence, the addition of ribavirin in the post—liver transplant setting appears to enhance the SVR12 rate, at least in patients with advanced liver disease.

Velpatasvir has a similar profile to ledipasvir, and no significant drug interactions are expected when used in combination with tacrolimus or cyclosporine. All 10 recipients derived hepatitis C infection from their donor and achieved sustained virologic response at 12 weeks posttreatment with DAA-based regimens, with a median time from transplant to treatment initiation of 43 days IQR There have been no instances of graft loss or death, with median follow-up of days IQR posttransplant.

Transplantation of HCV-viremic livers into non-viremic recipients results in acceptable short-term outcomes.